Selected Abstracts from Pharmacology 2024

139

Optimal safer antihypertensive drug dosing

Simon Dimmitt¹, Michael Kennedy², Hans Stampfer³ and Jennifer Martin⁴

¹University of Western Australia; ²University of New South, Wales; ³Joondalup Health Campus; ⁴University of Newcastle

Introduction

High blood pressure (BP) affects over 30% of the population, increases with age and contributes to arterial and heart disease. Only diuretics, beta-blockers and angiotensin-converting enzyme inhibitors (ACEIs) have been shown to improve survival in large long term randomized controlled trials (RCTs). Excess BP reduction may compromise vital organ perfusion. No long-term antihypertensive drug combination has lowered BP by greater than a mean of 20/8 mmHg.

This pilot study aimed to ascertain sufficient doses, when best therapy is combined, to lower diastolic BP (less subject to ‘white coat effect’) in more severe hypertension (identified by ECG evidence of left ventricular hypertrophy, LVH), within the range 60–90 mmHg (which was associated with the lowest incidence of cardiovascular events in large RCTs).

Method

From a clinic pool of over 400 patients on antihypertensive drug therapy (eGFR > 40 mL/min/1.73 m²), 43 patients were identified with ECG LVH by voltage criteria. At 2–3 monthly visits, drugs had been added, and doses reduced as side effects became apparent. Effective dose 50 (ED50) of antihypertensive drugs was estimated as the median oral dose sufficient to lower BP by 50% of the maximum possible (Emax, ED100) and enabled dose equivalence to be determined in each drug class.

Results

26 patients were excluded because of active comorbidities. 17 patients remained in the analysis (median age 72 years, 5 women). All had ECG left axis deviation and their mean clinic BP over the last 3 visits was 148/78 (heart rate 65). Systolic BP was a median of 41 mm lower than each patient's highest ever recorded. Five patients were on 2 antihypertensive drugs, nine were on 3, and three were on 4. The median observed daily doses of the 13 patients on thiazides was the equivalent of 6 mg of hydrochlorothiazide (ED50 around 20 mg), of the 13 patients on ACEIs was the equivalent of 1 mg of ramipril (ED50 3 mg), of the 12 patients on a beta-blocker was the equivalent of 7 mg metoprolol (ED50 60 mg), and of the 9 patients on a calcium channel blocker was the equivalent of 0.5 mg amlodipine (ED50 2 mg).

Conclusions

Moderate to severe hypertension may be controlled with 2–4 antihypertensive drugs in combination at low doses, with the potential advantages of greater tolerability and safety.

141

Efficacy of nitric oxide in stroke: Prospective randomised single blinded masked-endpoint phase IIb trial

Philip Bath^1,2, Lisa Woodhouse¹, Iris Mhlanga¹, Amanda Buck¹, Kennedy Cadman¹, Tiffany Hamilton¹, Diane Havard¹, Lee Haywood¹, Amanda Hedstrom², Tim England¹, Kailash Krishnan² and Nikola Sprigg^1,2

¹Stroke Trials Unit, University Of Nottingham; ²Stroke, Nottingham University Hospitals NHS Trust

Introduction

High blood pressure (BP), common in stroke, is associated independently with increased recurrence and dependency. Nitric-oxide donors, including glyceryl trinitrate (GTN), lower BP and are candidate treatments for acute stroke. We assessed feasibility of recruitment, safety and proof of concept of transdermal GTN vs. sham with treatment between 3 and 5 h of stroke.

Methods

120 adult patients with hyperacute stroke, with compatible CT/MR scans (if available), systolic BP > 120 mmHg, presenting with ≥1 of the following symptoms at the time of enrolment: dysphagia, neglect (NIHSS 1–2), hemianopia (NIHSS 1–3), or limb weakness (NIHSS on affected arm and/or leg 1–4) were to be recruited.

Patients were randomised (1:1) to receive 5 mg transdermal GTN/sham patch for 2 days and followed-up at 90 days. Patients, researchers and outcome assessors were masked to treatment allocation.

Outcomes include: Feasibility—recruitment of 100 IS and 20 ICH patients; safety—serious adverse event and death rates; proof of concept rate—dependency (modified Rankin Scale). Secondary outcomes include BP and heart rate over the first 2 days, and disability, cognition, mood and quality of life at day 90.

Results

Characteristics at baseline: average age 72.3 (13.2) years, systolic BP 161.8 (18.4) mmHg, NIHSS 9.1 (6.3), median onset-time-to-randomisation 215.6 [185.9, 251.0] minutes. 56.4% of participants had reperfusion therapy.

Conclusions

The database will be locked in quarter 3 and results available to present in quarter 4 2024.

159

Twenty-five years of lipid-lowering agents consumption in Croatia: Patterns and trends

Marta Kučan Štiglić¹, Andrej Belančić^1,2 and Dinko Vitezić^1,2

¹Department of Basic and Clinical Pharmacology with Toxicology, Faculty of Medicine, University of Rijeka; ²Department of Clinical Pharmacology, Clinical Hospital Centre Rijeka

Introduction

The objective was to evaluate the patterns and trends in lipid-lowering agent consumption in Croatia over a 25-year period and identify factors influencing prescription practices and drug usage.

Method

Data on lipid-lowering agent consumption from 2000 to 2023 were obtained from the International Medical Statistics (IMS) database for Croatia. Drug volumes were expressed in defined daily doses per 1000 inhabitants per day (DDD/1000), following the World Health Organization Collaborating Centre for Drug Statistics Methodology, providing a rough estimate of the proportion of the population treated daily. Population data were sourced from the Croatian Bureau of Statistics, using census data for 2001, 2011 and 2021, with estimates for other years.

Results

Over the 25-year period, lipid-lowering agent consumption in Croatia increased significantly, from 4.91 DDD/1000 in 2000 to 152.56 DDD/1000 in 2023. Statins were the most prescribed drug class, increasing from 4.42 DDD/1000 in 2000 to 135.13 DDD/1000 in 2023. PCSK9 inhibitors (PCSK9i) and inclisiran showed growth after their introduction in 2019 and 2022, respectively, with consumptions of 0.16 DDD/1000 and 0.09 DDD/1000 in 2023. More detailed data on the prescription trends of lipid-lowering agents is presented in Figure 1.

Conclusion

This study demonstrates significant shifts in lipid-lowering agent utilization in Croatia over 25 years, influenced by clinical guidelines, healthcare policies and external factors such as pricing policies and pharmaceutical marketing. Although the analysis is country-specific, the extensive dataset provides insights that may be valuable to the international community. Future research should examine the impact of these trends on clinical outcomes and healthcare costs.

Author contributions

Marta Kučan Štiglić and Andrej Belančić contributed equally to this paper and share the first-authorship.

23

Metabolites matter: Midazolam and 1-OH midazolam pharmacokinetics in intensive care

David Jackson

Cardiff Medical School

Introduction

Midazolam is a benzodiazepine used for sedation within intensive care and its relatively short half-life usually allows for rapid reversibility of sedation. Measurement of serum midazolam concentration is undertaken prior to testing brain-stem function to ensure any residual sedative effect does not mask normal physiological reflexes. This study investigated the pharmacokinetics of midazolam and 1-hydroxy midazolam (1-OH midazolam), an active metabolite, in intensive care patients to determine the necessity to develop an assay for 1-OH midazolam in addition to the parent compound.

Methods

Samples were obtained as part of routine clinical care for drug monitoring prior to brainstem function testing. The concentrations of midazolam and 1-OH midazolam were assayed by the City Toxicology Laboratory, Birmingham City Hospital, using an accredited method. Patients were included if they had at least three drug concentrations measured during a single intensive care unit admission, within the last 12 months. A single-compartment, first-order model, consistent with existing literature,¹ was constructed using Microsoft Excel and GraphPad Prism. It was assumed that the initial concentration was at time zero and no further exposure to midazolam occurred following the first sample. Ethical approval was not required since no additional clinical investigations were involved. Data were anonymised and processed in accordance with Cardiff and Vale University Health Board policies.

Results

Two patients met the inclusion criteria: a 64-day-old child (Patient 1) and a 67-year-old adult (Patient 2) were analysed, n = 2. The half-life of midazolam was estimated at 17.3 and 19.3 h in Patient 1 and 2, respectively. The half-life of 1-OH midazolam was estimated at 9.4 and 49.2 h in Patient 1 and 2, respectively (Figure 1a and 1b). The data correlated closely with the line of best fit in both cases, r > 0.99.

Conclusions

The elimination half-lives for both midazolam and 1-OH were considerably prolonged in both patients, the half-lives reported in literature being 2.5 and 1.5 h, respectively.² This may reflect a significant impact of the underlying illness on midazolam pharmacokinetics, confirming the necessity for assaying both midazolam and its metabolite for informed clinical decision-making within the intensive care setting. Although limited by a small sample size, these findings highlight the importance of individual pharmacokinetic variability, particularly in the intensive care setting.

Keywords

midazolam, 1-hydroxy midazolam, pharmacokinetics, half-life

References

1. Jeong W, Sunwoo J, You Y et al. Distribution and elimination kinetics of midazolam and metabolites after post-resuscitation care: a prospective observational study. Sci Rep 2024;14(1):4574.

2. Schwagmeier R, Alincic S, Striebel HW. Midazolam pharmacokinetics following intravenous and buccal administration. Br J Clin Pharm. 1998;46(3):203-206.

40

A single centre study of a biosimilar switching programme for adalimumab in inflammatory bowel disease

Louise Rabbitt¹, Áine Keogh², John Ferguson³, Anna Hobbins^4,5, Brian McGuire⁶, Paddy Gillespie⁵ and Laurence Egan^1,2

¹University of Galway; ²Department of Gastroenterology, Galway University Hospitals; ³School of Mathematical and Statistical Sciences, University of Galway; ⁴Centre for Research in Medical Devices (CÚRAM, SFI 13/RC/2073_P2); ⁵Health Economics & Policy Analysis Centre (HEPAC), Institute for Lifecourse & Society (ILAS), University of Galway; ⁶School of Psychology, University of Galway

Introduction

Amgevita is a licensed biosimilar to adalimumab, having demonstrated a high degree of similarity to the reference product (Humira) in pharmacokinetic and clinical trials. Patients switching to a medicine they perceive as lower cost may experience a nocebo effect, whereby an expectation of poorer efficacy may lead to worse clinical outcomes despite pharmacologically identical properties.¹ We hypothesized that in patients who self-administer biosimilar medicines, there would be a nocebo effect in some patients which may be predicted by certain variables, which would result in an unmeasured health and economic burden.

Methods

In this observational cohort study, patients with inflammatory bowel disease were followed before and after switching from Humira to Amgevita. Subjective scores of IBD-related symptoms using the IBD Control Questionnaire (IBDCQ), objective disease scores using the Harvey-Bradshaw Index (HBI) for Crohn's disease and the partial Mayo score for ulcerative colitis, the EQ-5D-5L for health-related quality of life, and biochemical measures of inflammation including faecal calprotectin (FC) and C-reactive protein (CRP) were measured pre- and post-switch. A cost analysis considered the staff time and resources required to plan and execute a dedicated switching clinic, the cost of the drug doses used, and unscheduled care costs for patients as a result of the switch.

Results

64 patients aged from 18 to 67 were enrolled. Patient-reported symptom measure (IBDCQ) scores were marginally better after the switch (13.33 vs. 12.49, p = .043). There were no significant changes in objective disease activity scores, FC or CRP. There was no significant different in health-related quality of life as measured 8 weeks pre-switch and 8 weeks post-switch. Mean EQ-5D-5L utility score was 0.88 pre-switch and 0.85 post-switch (t = −1.1306, df = 36, p = .27 [95% CI for difference: −0.11, 0.03]). No adverse effects were reported before switching and 17 new adverse effects were reported 4 weeks after switching (6 injection-site reactions and 11 non-injection site reactions including headache, malaise and joint pain; p = 9.8 × 10-4).

Individual marginal logistic regressions with a single explanatory variable showed a significant relationship between the Health Anxiety Index (HAI) and the occurrence of new adverse drug events (p = .0079). Each one unit increase in the HAI score increased the odds of having an adverse event by 21%. No evidence of other relationships between variables and reported side effects or reported symptoms was found. The average cost per patient of the switching clinic was €133. Two patients had unscheduled care needs as a result of the switch with a total cost of unscheduled care of €1622. In the 8-week time horizon for this analysis, the total drug cost saving for these 64 patients was €143,958; taking into account the switching clinic cost and the cost of unscheduled care, the cost saving per patient was €2091.

Conclusions

There was no objective evidence of a worsening of disease control or quality of life after switching to biosimilar adalimumab in this cohort. 25% of patients developed new side effects, particularly those with high levels of health anxiety. There were significant cost savings associated with the switch.

Reference

1. Colloca L, Panaccione R, Murphy TK. The clinical implications of nocebo effects for biosimilar therapy. Front Pharmacol. 2019;10:1–11.

41

Chemical adherence testing in the clinical management of hypertension: A scoping review

Louise Rabbitt^1,2, James Curneen^1,2, Michael Conall Dennedy^1,2 and Gerry Molloy³

¹University of Galway; ²Galway University Hospital, Saolta Healthcare Group; ³School of Psychology, University of Galway

Introduction

Despite growing use, questions remain surrounding the utility, acceptability and feasibility of chemical adherence testing (CAT) as part of hypertension management in clinical practice. This scoping review aimed to (i) identify and summarise studies using CAT in hypertension management and (ii) describe and critically evaluate how CAT is currently being used in the clinical management of hypertension.

Methods

Peer-reviewed and published studies in English, reporting original research in any setting, with any study design, were included. Search concepts included hypertension, medication adherence, CAT and their synonyms. Searches were carried out using Ovid Medline, EMBASE and PsycInfo (EBSCO), alongside manual searching of reference lists. Using Covidence software, we screened titles and abstracts, followed by full-text articles. Data from the included articles were tabulated and summarised.

Results

Of the 618 studies identified, 48 were included (Figure 1). Studies were mostly published in high-income countries, focussed on treatment-resistant hypertension in secondary or specialist healthcare settings, and usually observational in design (Figure 2). 7 studies reported adherence analyses within clinical trials for hypertension therapies. Few studies measured the impact that performing CAT has on clinical outcomes for patients, such as BP control. The use of theoretical frameworks to guide reporting was rare, and there was considerable variation in key terminology and definitions, most notably in the definition of adherence. Some studies consider a participant adherent only if there is 100% concordance between their prescribed and detected AHDs, and consider all other results to represent nonadherence, while others differentiate between categories such as ‘partial’ and ‘complete’ nonadherence, though the thresholds for these categories vary. Such discrepancies are a significant barrier to the development of a cumulative evidence base.

Conclusions

The current body of evidence demonstrates considerable variability in the approach to implementing CAT for hypertension management in clinical practice, and a paucity of randomised controlled trials to evaluate its impact. Future research could (i) adopt a cohesive theoretical framework including clear operational definitions to standardise the approach to this important topic and (ii) further explore the impact of CAT on clinical outcomes using RCTs.

43

Akram's lifestyle, a novel remedy for gastroesophageal reflux disease—Mini review

Mohammad Randhawa¹, Sadia Khan² and Tayyab Akhter²

¹Rawalpindi Medical University, Rawalpindi; ²Rawalpindi Medical University

Introduction

Prevalence of gastro-esophageal reflux disease (GERD) is increasing. Proton pump inhibitors are commonly prescribed but can cause achlorhydria, leading to infections and anaemia. Major causative factor is irregular dietary habit. A meal over a meal causes further release of acidic gastric juice and dilates upper stomach, which generate transient lower esophageal sphincter relaxations (TLESRs) and trigger reflux. Repeated refluxes produce inflammation and ulcerations in lower esophagus, dysphagia and other complications. It is proposed that sufficient interval between meals, two meals a day, morning and evening, with only fluids in intervening period (Akram's life-style) would prevent GERD.

Methods

Present review includes summary of few studies, conducted by our team relevant to practice of Akram's life-style for treatment of GERD. Initially, benefit of short-term (2–3 weeks) practice of our dietary regimen was demonstrated in cases report (n = 4).¹ In one case endoscopy before intervention showed inflammation, erosions and small Barrett at gastroesophageal junction. Patient continued our dietary regimen for long time. Endoscopy was done again (after 7 years) to see prognosis.² Pilot study was conducted on endoscopically diagnosed GERD patients (n = 20) who practiced our dietary schedule for two weeks.³ Finally, clinical study (n = 60) was conducted at Gastroenterology Unit, RMU, to evaluate effect of Akram's life-style on typical GERD symptoms, using questionnaire with Yes/No response and VAS.

Results

Studies relevant to practice of Akram's Life-style for GERD and their results are given in Table 1.

Conclusions

Intervention prevents TLESRs and reduces episodes of gastric acid reflux linked to irregular feasts. Longer interval between meals promotes generation of fasting Migrating Motor Complexes (MMCs). MMCs clear stomach, prevent delay in gastric emptying, thus reduce reflux. Therefore, Akram's life-style is proposed as a useful alternate to risky drug treatment for GERD.

Keywords

Akram's lifestyle, alternate remedy for GERD, gastroesophageal reflux disease, only fluids in between, two meals daily

References

1. Randhawa MA, Yar T, Gillessen A. An effective and physiological lifestyle change for management of gastroesophageal reflux disease-cases report. J Ayub Med Coll Abbottabad. 2013;25(1-2):206-7.

2. Randhawa MA, Khan SA, Naseer A, Baqai MT. Non-pharmacological approach for management of gastroesophageal reflux disease J Med Sci. 2024 40(3 Part-II):549-5.

3. Randhawa MA, Mahfouz SM, Selim NA, Yar T, Gillessen A. An old dietary regimen as a new lifestyle change for Gastro esophageal reflux disease: a pilot study. Pak J Pharm Sci. 2015; 28(5): 1583-86.

93

Development and validation of prediction models for outcomes in sepsis patients

Fengmei Guo¹, Yigao Liu¹, Shanshan Meng¹, Congshan Yang^1,2 and Jie Jiang¹

¹Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Southeast University; ²The Fifth Affiliated Hospital of Xinjiang Medical University

Introduction

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to various infections. A recent epidemiological analysis of sepsis in Chinese ICUs revealed that sepsis poses a substantial medical challenge, contributing to an ICU patient mortality rate of approximately 35.5%.¹ Timely diagnosis plays a crucial role in facilitating early intervention, treatment optimization, and decreasing mortality rates. Therefore, we developed a prediction model utilizing plasma metabolites as biomarkers to offer insights for clinical management.

Method

Plasma metabolomics data were collected and sequencing analysed from sepsis patients in ICU of Zhongda Hospital, School of Medicine, Southeast University, encompassing data from 2022. This study adhered rigorously to the diagnostic criteria for sepsis 3.0,² systematically collecting blood samples and comprehensive clinical data, including hospitalization duration, vital sign monitoring data, and an array of laboratory test results. The model construction process involved meticulous selection of predictive factors, including blood metabolites, fundamental physiological indicators, infection source, as well as key biochemical indicators. Utilizing a fivefold cross-validation strategy, the dataset was scientifically partitioned into train and test data sets to uphold model robustness and generalizability. Ultimately, a COX proportional hazards regression model for sepsis patient outcomes was constructed to aid clinical decision-making.

Results

A total of 69 septic patients from the ICU were included in the study. Following a meticulous analysis of annotated metabolites, 171 metabolites were rigorously identified (Figure 1b). Lasso regression analysis was then employed to accurately pinpoint two metabolites, trans-3-indoleacrylic acid (C₁₁H₉NO₂) and 4-hydroxyvoriconazole(C₁₆H₁₄F₃N₅O₂), serving as pivotal biomarkers in predictive models (Figure 1c). The machine learning experimental results showcased the model's exceptional accuracy in predicting patients' clinical outcomes (AUC = 0.83, Brier = 0.16. Figure 1d), strongly affirming the predictive efficacy of the selected biomarkers and the model's effectiveness (Figure 1e, f ).

Conclusions

The study successfully constructed a predictive model using blood metabolites to forecast clinical outcomes for septic patients, providing crucial aid for treatment strategies. However, validation and improvement through multi-centre data are essential for enhancing its generalizability and applicability in clinical decision-making. Supported by funds of National Natural Science Foundation of China (82372173, 82460383) and China Postdoctoral Science Foundation (2022M710685, 2024T170133).

References

1. Xie J, Wang H, Kang Y, et al. The epidemiology of sepsis in Chinese ICUs: a national cross-sectional survey. Crit Care Med. 2020;48(3):e209-e218. 10.1097/CCM.0000000000004155

2. Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801. 10.1001/jama.2016.0287

107

Comparative effectiveness, safety and economic evaluation of disease-modifying treatments in spinal muscular atrophy: Insights from croatian real-world data and systematic reviews

Andrej Belančić^1,2 and Dinko Vitezić^1,2

¹Department of Clinical Pharmacology, Clinical Hospital Centre Rijeka; ²Department of Basic and Clinical Pharmacology with Toxicology, Faculty of Medicine, University of Rijeka

Introduction

This abstract synthesizes findings from our four studies assessing the clinical effectiveness, safety and economic impact of disease-modifying therapies (DMTs) for spinal muscular atrophy (SMA). These studies focus on the real-world effectiveness of nusinersen in Croatia, the outcomes of switching from nusinersen to risdiplam, economic evaluations of DMTs, and a cost-minimization analysis comparing nusinersen and risdiplam.

Method

The studies included a retrospective analysis of Croatian SMA patients treated with nusinersen and risdiplam, incorporating demographic and clinical data from the Croatian Health Insurance Fund (CHIF).^1,2 A systematic literature review was conducted to evaluate pharmacoeconomic studies on DMTs for SMA, with data extracted from databases PubMed/Medline, Global Health and Embase.³ Lastly, a European budget impact analysis was developed to compare costs between risdiplam and nusinersen under the hypothesis of clinical equivalence in SMA type 1.⁴

Results

Nusinersen showed significant motor function improvement in paediatric SMA types 1 and 2 patients and was safe across a heterogeneous population. However, no significant improvement was seen in adult SMA type 3 patients who started treatment after 18 years.¹ The switch from nusinersen to risdiplam demonstrated non-inferiority in effectiveness for SMA types 1 and 3 over a one-year follow-up, with no new major safety concerns apart from weight gain in two patients.² The systematic review highlighted the need for specific willingness-to-pay thresholds for orphan drugs, given the high costs and incremental cost-effectiveness ratios of these therapies.³ The budget impact analysis, taking into account the highest permitted wholesale prices in 2023 according to Agency for Medicinal Products and Medical Devices of Croatia, suggested that prescribing risdiplam instead of nusinersen for newly diagnosed SMA type 1 patients could result in potential cost savings of up to €905.5 million over five years in Europe.^4,5

Conclusions

Such (re)evaluations might result in modification of the national health insurance fund's DMT administration criteria and reimbursement guidelines and a shift of the accompanied financial resources to other indications where more substantial clinical benefit was proven.

References

1. Belančić A, Strbad T, Kučan Štiglić M, Vitezić D. Effectiveness of nusinersen in type 1, 2 and 3 spinal muscular atrophy: Croatian real-world data. J Clin Med. 2023;12(8):2839. https://doi.org/10.3390/jcm12082839

2. Belančić A, Strbad T, Kučan Štiglić M, Vitezić D. Switching from nusinersen to risdiplam: a Croatian real-world experience on effectiveness and safety. J Pers Med. 2024;14(3):244. https://doi.org/10.3390/jpm14030244

3. Belančić A, Faour AK, Gkrinia EMM, Vitezić D. A systematic review of economic evaluations of orphan medicines for the management of spinal muscular atrophy. Manuscript under peer-review; Forthcoming.

4. Belančić A, Faour AK, Gkrinia EMM, Vitezić D. Could choosing risdiplam instead of nusinersen in the treatment of type 1 spinal muscular atrophy be a huge cost-minimization opportunity? Manuscript under peer-review; Forthcoming.

5. Agency for Medicinal Products and Medical Devices of Croatia (HALMED). Summary list of published medicinal product prices for 2023. Dec 30, 2023. https://www.halmed.hr/fdsak3jnFsk1Kfa/ostale_stranice/Zbirni-popis-objavljenih-cijena-lijekova_2023.pdf (accessed February 13, 2024).

111

Enoxaparin vs. dabigatran and rivaroxaban for prevention of venous thromboembolism in patients with cancer

Bahador Bagheri¹, Pouya Yousefli¹, Farahnaz Ghahremanfard¹, Masoumeh Masoudian¹ and Bahar Taherkhanchi²

¹Semnan University of Medical Sciences; ²Erfan Niayesh Hospital

Introduction

Venous thromboembolism (VTE) is a leading cause of death in patients with malignancies. The present study was designed to compare the efficacy of enoxaparin, dabigatran and rivaroxaban for prophylaxis against VTE in patients with cancer.^1,2

Method

This was a randomized clinical trial conducted from 2022 to 2023 and was registered (IRCT20200407046984N1). Included patients who had various metastatic malignancies were divided into 3 groups; group one received enoxaparin 40 mg daily (35 patients), group two received dabigatran 150 mg daily (11 patients), and group three received rivaroxaban 10 mg daily (11 patients) for 3 months. Primary endpoint was episodes of VTE.

Results

The mean age was 58 years with an excess of males (56% vs. 44%). The rate of response for dabigatran, enoxaparin and rivaroxaban against VTE occurrence were 90.9%, 94.3% and 100%, respectively. The bleeding rate for enoxaparin was 2.9%, and it was 0 for dabigatran and rivaroxaban. The differences were not statistically significant.

Conclusion

We showed no significant differences in dabigatran etexilate, enoxaparin and rivaroxaban for prophylaxis against VTE in patients with cancer. We also showed no significant differences in the bleeding rate following administration of these drugs.

References

1. Willems RA, Winckers K, Biesmans C, deVos-Geelen J, Ten Cate H. Evolving data on cardiovascular 268 complications in cancer. Thromb Res. 2022;213:S87-S94.

2. Grilz E, Posch F, Nopp S et al. Relative risk of arterial and venous thromboembolism in persons with cancer vs. persons without cancer—a nationwide analysis. Eur Heart J. 2021;42(23):2299-307.

113

A randomized, controlled study evaluating effects of Saccharomyces boulardii in adult patients with asthma

Bahador Bagheri¹, Kavosh Ansari³, Mahboubeh Darban¹, Anna Abdolshahi¹ and Bahar Taherkhanchi²

¹Semnan University of Medical Sciences; ²Erfan Niayesh Hospital; ³Qazvin University of Medical Sciences

Introduction

Asthma is the most common chronic respiratory disease affecting approximately 260 million people globally.¹ Probiotics as live microorganisms are associated with some beneficial effects in conditions like allergies, diabetes and gastrointestinal disorders.^2,3 Current data about probiotics in adulthood asthma are scarce and not conclusive. The present study was designed to determine whether daily use of Saccharomyces boulardii (S. boulardii) can improve asthma.

Method

In this randomized, double-blinded and placebo-controlled study, 50 patients with asthma were enrolled. The eligible subjects received either S. boulardii (N = 25) added to conventional medications or placebo added to conventional therapeutics (N = 25) for 3 months. Spirometry and measurement of IgE, IL-5, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were done at baseline and after termination of therapies. The clinical trial registry number was IRCT20151228025732N54. Changes in FEV1/FVC from baseline to 3 months of the treatment were the primary end-points.

Results

The mean age was 39.22 ± 12.55 years with an excess of females (56% vs. 44%). A significant improvement in FEV1 and FVC was observed in the probiotic group following the treatment, compared to the baseline (p = .002 and p = .037, respectively). In contrast, there was no significant change in the FEV1/FVC ratio and FEF 25%–75% in the probiotic group compared to the baseline (p ˃ .05).The percent of changes of FEV1/FVC ratio was statistically comparable between the two groups (p = .004); however, FEV1, FVC and FEF 25%–75% showed no significant difference between two groups (p ˃ .05). Furthermore, no significant differences were observed in serum levels of IL-5 and IgE following administration of probiotics.

Conclusion

Our findings showed that administration of S. boulardii in combination with conventional treatments may improve the pulmonary function in adult patients with asthma.

References

1. GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258):1204–1222. Erratum in: Lancet. 2020 Nov 14;396(10262):1562. doi: 10.1016/S0140-6736(20)32226-1.

2. Li J, Gao P-F, Xu Y-X, Gu H, Wang Q-X. Probiotic Saccharomyces boulardii attenuates cardiopulmonary bypass-induced acute lung injury by inhibiting ferroptosis. Am J Transl Res. 2022;14(7):5003.

3. Kaźmierczak-Siedlecka K, Ruszkowski J, Fic M, Folwarski M, Makarewicz W. Saccharomyces boulardii CNCM I-745: a non-bacterial microorganism used as probiotic agent in supporting treatment of selected diseases. Current Microbiol. 2020;77:1987-96

117

Leveraging routinely collected electronic health record data to understand real-world treatment effects: Trial emulation of the EMPA-REG outcome trial

David Ryan^1,2,3, Patrick Bidulka⁴, Anoop Shah^1,2, Elizabeth Williamson³ and Ruth Keogh^3,5

¹University College London Hospital; ²Institute of Health Informatics; ³Medical Statistics Department; ⁴Department of Non-Communicable Disease Epidemiology; ⁵Centre for Data and Statistical Science for Health

Introduction

Anti-diabetes medications, such as sodium-glucose co-transporter 2 inhibitors, are increasingly prescribed for populations that were not represented in large randomised controlled trials (RCTs). This can create a gap between the evidence base and clinical utilisation of key therapeutics.¹ To address this gap, there is a growing interest in using observational data, within a trial emulation framework,² to study real-world drug effects. Using this framework, we began by emulating an important trial, EMPA-REG RCT, which was pivotal in establishing the cardioprotective benefits of empagliflozin in patients with cardiovascular disease (CVD) and type 2 diabetes.³ We then extend the trial emulation to investigate drug effects in patients under-represented in the original trial.

Methods

We conducted a trial emulation of the EMPA-REG RCT using UK primary care data from the Health Improvement Network. Eligibility criteria were initially aligned with the original RCT. An active comparator design was employed, comparing initiators of empagliflozin to initiators of DPP-4 inhibitors from 01/01/2014 to 31/12/2022. The analysis followed an intention-to-treat approach, with all-cause mortality as the primary outcome. Confounding factors were adjusted for in the analysis, which used adjusted and inverse-probability of treatment weighted (IPTW) Cox proportional hazard models, with missing data handled using multiple imputation. Treatment effects (hazard ratios) estimated from the emulated trial were compared to those from EMPA-REG RCT using pre-defined agreement metrics. We then extended the trial emulation to include a wider patient population, by removing all inclusion/exclusion criteria and analysing all real-world recipients of empagliflozin to determine treatment effects.

Results

The emulated trial included 12,097 individuals. Among real-world users of empagliflozin, only 16.3% (n = 2130) met the eligibility criteria for the EMPA-REG RCT. The estimated all-cause mortality hazard ratios from the emulated trial, using both adjusted and IPTW Cox proportional hazards models, were very similar to that from the original RCT (Table 1). All pre-defined agreement metrics were met. When the trial emulation was extended to a wider patient population, the study population increased to 61,731 individuals, yet the treatment effects remained consistent.

Conclusions

To our knowledge, this is the first population-based primary care emulation of the EMPA-REG RCT. Real-world populations who received empagliflozin were substantially different to those included in the RCT but showed consistent treatment effect. Real-world use of empagliflozin is substantially different to the EMPA-REG RCT, but reassuringly, beneficial treatment effects were retained when it is prescribed in real-world practice for a wider population.

References

1. NICE. Final TYPE 2 diabetes pharmacological therapies with cardiovascular and other benefits in people with type 2 diabetes NICE guideline NG28. Published February 2022. https://www.nice.org.uk/guidance/ng28/evidence/b-pharmacological-therapies-with-cardiovascular-and-other-benefits-in-people-with-type-2-diabetes-pdf-10956473392

2. Methods for real-world studies of comparative effects. NICE real-world evidence framework. www.nice.org.uk. Published June 23, 2022. https://www.nice.org.uk/corporate/ecd9/chapter/methods-for-real-world-studies-of-comparative-effects

3. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. NEJM. 2015;373(22):2117-2128. https://doi.org/10.1056/nejmoa1504720

124

Methotrexate safety monitoring in patients with rheumatoid arthritis attending clinics in South Africa's Western Cape province

Onyinye Akunne¹, Yasmina Johnson², Yasmine Van Heerden¹, Nicole Keuler¹, Alex Wehmeyer¹ and Renier Coetzee¹

¹University of The Western Cape; ²Western Cape Government Health and Wellness

Introduction

Methotrexate (MTX) is the preferred disease-modifying antirheumatic medicine for Rheumatoid Arthritis (RA).¹ MTX use can cause hepatotoxicity, nephrotoxicity and bone marrow suppression.² To mitigate the adverse effects of MTX, the South African Standard Treatment Guidelines (STG) recommend monitoring aminotransferase (ALT) and Full blood count (FBC) levels before initiation of MTX and every 12 weeks during treatment.³ However, the Western Cape Department of Health recommends monitoring FBC and ALT levels at least every six months in stable patients (on MTX for at least 6 months). Additionally, patients should use 5 mg of folic acid while taking MTX. Monitoring adherence to MTX safety criteria is critical to reduce the adverse effects of MTX. This study assessed adherence to the STG safety monitoring recommendations for RA patients on MTX.

Method

This was a retrospective medical records review of RA patients receiving MTX from January to December 2022. Patients included (1) were ≥18 years old; (2) received oral MTX for ≥ six months; (3) had arthritis documented as a diagnosis. Data were extracted from the Western Cape Government Health and Wellness Central database. Data collected included the patient's age, sex, disease condition, MTX start dates, methotrexate treatment duration, FBC, platelets and ALT on initiation and during MTX treatment and folic acid prescription. Results were presented as counts, frequencies and means.

Results

Eight hundred and twenty patient records were reviewed. The mean (SD) age was 55 ± 13 years (82% females), and the mean (SD) duration of MTX treatment was 77 ± 46 months. At MTX initiation, 72% of the patients' FBC and ALT levels were recorded. About 91% and 89% of the patients had FBC and ALT tests done within six months of their latest MTX issue. Folic acid was prescribed in 96% of the patients at their latest MTX issue. White blood cell (WBC) count, platelet count and ALT concentration at the last test were within the normal range in 86%, 74% and 90% of the patients.

Conclusions

Most patients had FBC and ALT tests done at MTX initiation and within six months of their latest MTX prescription. Most patients also had WBC count and ALT concentrations within the normal ranges. A limitation of this study was that the prescribers' adherence to recommended guidelines was evaluated at the last patient's visit. A larger follow-up study is underway to evaluate adherence to the recommended guidelines and the impact on patients' outcomes to inform policy and resource allocations.

References

1. Hazlewood GS, Barnabe C, Tomlinson G, Marshall D, Devoe DJA, Bombardier C. Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease-modifying anti-rheumatic drugs for rheumatoid arthritis: a network meta-analysis. Cochrane Database Syst Rev 2016(8):CD010227. https://doi.org/10.1002/14651858.CD010227.pub2

2. El Masri AER, Tobler C, Willemijn B, Von Bueren AO, Ansari M and Samer CF (2023) Case report: hepatotoxicity and nephrotoxicity induced by methotrexate in a paediatric patient, what is the role of precision medicine in 2023? Front. Pharmacol. 14:1130548. https://doi.org/10.3389/fphar.2023.1130548

3. South African National Department of Health. Standard treatment guidelines and essential medicines list for South Africa: hospital-level adults. 2019.

131

Intravaginal delivery of oxybutynin via the MedRing OAB: a double blind three-way crossover study comparing intravaginal and oral oxybutynin administration

Anouk Meijs^1,2, Sophie Peltenburg^1,2, Naomi Klarenbeek^1,2 and Maaike Addicks³

¹Centre For Human Drug Research; ²Leiden University Medical Centre; ³LiGalli B.V

Introduction

The MedRing overactive bladder (OAB) is a device for preprogrammed and on-demand intravaginal oxybutynin delivery.¹ Oral oxybutynin is often prescribed as treatment for OAB, but often discontinued due to anticholinergic side-effects, such as a dry mouth. The side-effects have been linked to the hepatic metabolite N-desethyloxybutynin (DEOB). By administering oxybutynin intravaginally, the first pass metabolism is circumvented, resulting in a lower metabolite/parent ratio and potentially less side-effects. The aim of this study was to quantify the side-effects and to explore the pharmacokinetics (PK), safety and tolerability of intravaginal and oral administration of oxybutynin.

Methods

A double blind, placebo-controlled, three-way cross-over study was performed to compare multiple doses of 2.5 mg intravaginal and 5 mg oral oxybutynin in 24 healthy females aged 18–45. The Neurocart Test Battery (NTB) was used to quantify the anticholinergic side-effects containing eight different computerized tasks, of which the adaptive tracking test was the primary endpoint. Additionally, quantitative electro-encephalogram (qEEG), salivary flow, a dry-mouth questionnaire, pulse rate, visual acuity, PK, safety and tolerability were assessed.

Results

The average reaction time for N-Back test (NTB test for working memory) was significantly shorter after intravaginal compared to oral administration (estimated difference (ED) −24.5 ms (95% CI −48.8, −0.3), p = .047). The other NTB tests, including the primary endpoint, showed no significant differences between intravaginal-, oral administration and placebo. qEEG amplitudes decreased significantly on various frequency bands during both oxybutynin administration-routes compared to placebo. Participants reported a dry mouth more frequently after oral administration and the saliva weight was significantly lower compared to intravaginal administration (ED 0.51 grams (95% CI 0.16, 0.87), p = .0058). There was no significant difference in pulse rate and visual acuity between the three treatment arms.

The oxybutynin plasma concentration was comparable after intravaginal and oral administration, despite an absolute lower intravaginal dose. Intravaginal oxybutynin led to a 9.78-fold lower metabolite/parent ratio than oral administration (intravaginal 0.90 ± 0.42 and oral 8.80 ± 4.18). Finally, intravaginal administration was generally safe and well tolerated.

Conclusions

Certain AEs of oxybutynin, like dry mouth, are less pronounced after intravaginal compared to oral administration, which may be related to a substantial lower metabolite/parent ratio after intravaginal oxybutynin. The intravaginal administration of oxybutynin via the MedRing OAB can be considered as a favourable alternative to oral oxybutynin.

Reference

1. deLaat W, Pagan L, Malcolm RK, et al. First-in-human study to assess the pharmacokinetics, tolerability, and safety of single-dose oxybutynin hydrochloride administered via a microprocessor controlled intravaginal ring. Drug Delivery. 2023;30(1):2180113.

162

Endothelium-derived 6-nitrodopamine is an endogenous mediator of the human corpus cavernosum relaxation

Flaviano Lorenzon¹, Felipe Caliani Mathias-Netto¹, Gilberto Quirino dos Santos Junior¹, Felipe Placco Araujo Glina², Sidney Glina², Odair Paiva², Adriano Fregonesi¹, Alister de Miranda Cará³, Wilson Cintra Junior⁴, Rodrigo Itocazo Rocha⁴ and Gilberto De Nucci¹

¹University of Campinas; ²University Center FMABC; ³Humanitas Faculdade de Ciências Médicas de São José dos Campos; ⁴University of São Paulo

Introduction

Endothelium-derived 6-nitrodopamine (6-ND) has been identified as the most potent endogenous relaxant agent in the rabbit corpus cavernosum,¹ revealing a novel mechanism by which endothelium-derived and nitrergic nitric oxide (NO) cause relaxation of smooth muscle.² Here, it was investigated whether human isolated corpus cavernosum releases 6-ND and its action on this tissue.

Methods

Human corpora cavernosa (HCC) were obtained from 13 patients (mean age: 45 years) undergoing male-to-female gender reassignment surgery at Mário Covas State Hospital, Brazil. All patients had received antiandrogen and oestrogen treatments for at least two years. The study was approved by the ICB-USP institutional review board, and informed consent was obtained. A 3 cm portion of the HCC was suspended in a 3-mL chamber with Krebs-Henseleit solution (KHS) at 37 °C, oxygenated with 95% O₂ and 5% CO₂, and supplemented with ascorbic acid (3 mM) to prevent catecholamine oxidation. The tissues were incubated for 30 min with N(ω)-nitro-l-arginine methyl ester (L-NAME, 100 μM) and tetrodotoxin (TTX, 1 μM). KHS samples were analysed using LC-MS/MS. For functional analysis, HCC strips (1.5 cm) were mounted in an organ bath with 10 mL of KHS at 37 °C. One end was attached to a metal hook and the other to an isometric force transducer. After 45 min of equilibration under 10 mN tension, isometric tension was recorded with a PowerLab system. Strips were precontracted with U-46619 (30 nM), and relaxation responses to 6-ND (1 nM–100 μM) were assessed.

Results

Basal release of 6-nitrodopamine was detected in all HCC samples. Incubation with L-NAME significantly reduced 6-ND levels (Figure 1A), whereas incubation with TTX did not alter 6-ND release (Figure 1B). In pre-contracted HCC strips, exposure to 6-ND induced relaxation in a concentration-dependent manner, with a pEC50 value of 7.3 ± 0.4 and Emax of 35.1 ± 14.5% (n = 5; Figure 2).

Conclusion

These findings identify 6-ND as a novel endogenous, non-neurogenic mediator of HCC relaxation.

References

1. Lima AT, Britto-Júnior J, Moraes MO, et al. 6-Nitrodopamine is an endogenous mediator of the rabbit corpus cavernosum relaxation. Andrology. 2024;12(6):1419-1428. https://doi.org/10.1111/andr.13585

2. Britto-Júnior J, Coelho-Silva WC, Murari GF, et al. 6-Nitrodopamine is released by human umbilical cord vessels and modulates vascular reactivity. Life Sci 2021;276:119425. https://doi.org/10.1016/j.lfs.2021.119425

3. Júnior GQ, Britto-Júnior J, Magalhaes TB, et al. Measurement of 6-cyanodopamine, 6-nitrodopa, 6-nitrodopamine and 6-nitroadrenaline by LC-MS/MS in Krebs-Henseleit solution. Assessment of basal release from rabbit isolated right atrium and ventricles. Biomed Chromatogr 2023;37(9):e5691. https://doi.org/10.1002/bmc.5691

176

Adverse effects and discontinuation rates of oral darifenacin for overactive bladder: A systematic review and meta-analysis

Vineesha Veer¹, Felicity Smith¹, Anna Scott² and Christian Moro¹

¹Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University; ²Nuffield Department of Population Health, University of Oxford

Introduction

Overactive bladder (OAB) affects 11%–20% of the population, imposing a substantial burden on healthcare systems.¹ To manage OAB symptoms, muscarinic antagonist agents are typically recommended as first-line medications.² Among these, darifenacin, one of the newer generation medications, is commonly prescribed, with a higher selectivity for M3 receptors. This selectivity should reduce side effects, while helping to alleviate OAB symptoms. The aim of this study is to report discontinuation rates and adverse events among patients prescribed oral darifenacin for the treatment of OAB.

Methods

PubMed, Embase and Cochrane CENTRAL were searched for randomised control trials. The primary outcome was the discontinuation and adverse events (AE) of OAB patients from darifenacin and placebo treatment groups. The Cochrane risk of bias tool was used for a risk of bias assessment.

Results

From the searches and data extraction conducted, seven studies of 2387 participants were included. As this study is ongoing, preliminary results were obtained. There were no differences between the darifenacin group and the placebo groups in total patient discontinuations (RR 0.94, p = .64) and unaccounted patient discontinuations (RR 0.87, p = .55). The most commonly reported AE were dry mouth and constipation. There were significantly more people with dry mouth in the darifenacin group overall, RR 3.34 (95% CI 1.91 to 5.84, I² = 78%, p < .0001), and there is evidence of dose-response pattern. There were significantly more people with constipation in the darifenacin group than the placebo group overall, RR 2.44 (95% CI: 1.54 to 3.85, I² = 55%, p = .0001), with evidence of a dose-response pattern. Six of the seven studies were rated at high risk of bias due to the receipt of funding from interested companies, with one study unable to provide a conflict-of-interest statement.

Conclusion

The preliminary results suggest that participants in the darifenacin and placebo groups had similar discontinuation rates, yet higher AE for the darifenacin group compared to the placebo group. There is concern that most included studies were funded by interested companies, and this will be taken into consideration, as the study is ongoing.

References

1. Kim MK, Shin YS, Lee JH, Cho WJ, Kim DK. The prevalence of lower urinary tract symptoms and overactive bladder in South Korea: a cross-sectional, population-based study. Int Neurourol J 2022;26(1):31-36. https://doi.org/10.5213/inj.2142112.056

2. Veer V, Chess-William R, Moro C. Antimuscarinic actions on bladder urothelium and lamina propria contractions are similar to those observed in detrusor smooth muscle preparations. Neurourol Urodyn. 2023. https://doi.org/10.1002/nau.25176

179

Comparison of adverse drug reactions in clinical trials to national pharmacovigilance signals for sodium-glucose co-transporter-2 inhibitors

Ahmed Hassan, David Ryan and Andrew Scourfield

London North West University Healthcare NHS Trust

Background

Approximately 1 million sodium-glucose cotransporter-2 inhibitors (SGLT2-i) are dispensed each month in England. Whilst these drugs were originally developed to treat type 2 diabetes, they are now licensed for other indications including heart failure and chronic kidney disease.¹ The wider indications and populations now eligible for SGLT2-i raise questions regarding the generalisability of randomised controlled trials (RCTs) safety data to real-world populations. This study aims to qualitatively compare UK pharmacovigilance data for SGLT2-i with signals from RCTs.

Method

Safety data from important RCTs used by National Institute for Health and Care Excellence single technology appraisal papers were extracted to estimate risk ratio for adverse drug reactions (ADRs). To obtain real-world data relating to SGLT2-i safety, a pharmacovigilance analysis of the UK yellow card scheme was conducted,² analysing serious or fatal ADRs associated with SGLT2-i from January 2014 to November 2022. Disproportionality analysis using proportional reporting ratios (PRR) and 95% confidence intervals was employed to identify SGLT2-i ADRs. Statistically significant PRRs were compared to RCT ADRs to identify novel safety signals.

Results

Data from 14 RCTs were extracted showing ADRs related to euglycaemic diabetic ketoacidosis, infections, amputations and others (Table 1). There were 17,782 serious or fatal ADRs associated with SGLT2-i reported for 3991 people. The mean age of people with an ADR was 55 years ±12.8 years and approximately half were female (1782/3991; 44.7%). The greatest number of reports related to dapagliflozin (9344 reports; 53%), followed by empagliflozin (5512; 31%) and canagliflozin (2926; 16%). Reported ADRs were consistent with findings from RCTs with all SGLT2-i being associated with increased signals for diabetic complications, urinary and reproductive tract infections and amputations (Table 2). There were novel signals identified for polycythaemia (Table 2).

Conclusions

Real-world ADRs for SGLT2-i were largely congruent with data from RCTs. The association with polycythaemia, not readily evident in RCTs, is supported by some post-hoc analyses, showing a potential impact of SGLT-i on erythropoiesis.³ Real-world pharmacovigilance data may supplement safety data from RCTs, but caution must be applied due to reporting or misclassification bias in spontaneous ADR databases.

References

1. NICE. National Institute for Health and Care Excellence: SGLT2-i guidelines. https://cks.nice.org.uk/topics/diabetes-type-2/prescribing-information/sglt-2-inhibitors/

2. UK Yellow Card Scheme. https://yellowcard.mhra.gov.uk/

3. Oshima M, Neuen BL, Jardine MJ, et al. Effects of canagliflozin on anaemia in patients with type 2 diabetes and chronic kidney disease: a post-hoc analysis from the CREDENCE trial. Lancet Diabetes Endocrinol. 2020;8(11):903-914. https://doi.org/10.1016/s2213-8587(20)30300-4

182

Evaluation of oral black seed (Nigella sativa) and topical black seed oil for management of female sex disorders—Pilot study

Mohammad Randhawa, Farah Ayyaz, Lubna Meraj and Khola Noreen

Rawalpindi Medical University, Rawalpindi

Introduction

Human sexual function is important for propagation of race and quality of life. Incidence of female sexual disorders (FSD) is generally higher than male sex dysfunctions. Prevalence is greater in middle-aged and post-menopausal women because of decrease in oestrogen levels, which cause vaginal smooth muscle atrophy, thinning of mucosa and decrease in secretions, leading to dyspareunia, discomfort and stress. Topical oestrogen improves symptoms but there is a risk of systemic absorption and adverse effects. Oral administration of black seed (BS) in elderly women showed therapeutic and protective effects in menopause.¹ Present work aimed to conduct a pilot study to evaluate efficacy of BS oil (topical) and seed powder (oral) in elderly women having symptoms of FSD.

Methods

Middle-aged ladies reporting to Medicine and Gynecology units of Holy Family Hospital, RMU, who agreed to discuss their sex problem and had FSD symptoms, were included in study. Patients were randomly divided into four groups (10 each), A, B, C & D, receiving BS oil and BS-powder, BS oil, BS-powder and olive oil and Olive oil, respectively. BS-powder was given as BS-powder and honey mixture (equal by weight), one teaspoon orally twice daily and BS/Olive oil was given for application every night on external genitalia and outer-1/3 of vagina for one month and allowed to mate with spouses twice a week during this period. Female sex function index (FSFI)² was determined, pre-and post-treatment and results compared statistically.

Results

Forty women, aged 45 to 65 years, participated. Results of FSFI, pre and post treatment of all groups for effect on desire, arousal, lubrication, orgasm, satisfaction and pain are given in Table 1, demonstrating highly significant improvement in all parameters in group A.

Conclusion

Present study revealed that a combination of freshly prepared BS powder mixed with honey (oral) and BS oil (topical) effectively improved symptoms of FSD because of their local and systemic oestrogen like effects. Further studies with larger sample are needed to confirm these observations.

References

1. Hamidpour R, Rashan L. A natural remedy that reduces symptoms of menopause. Transl Biomed 2017;8(4):133.

2. Rosen R, Brown C, Heiman J, et al. The female sexual function index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther. 2000;26:191-208.

187

A pharmacodynamic interaction model for combined intravenous acetaminophen and ibuprofen in adults with acute postoperative pain

James Morse¹, Ioana Stanescu², Hartley Atkinson² and Brian Anderson¹

¹University of Auckland; ²AFT Pharmaceuticals

Introduction

Maxigesic® IV (combined acetaminophen 1000 mg + ibuprofen 300 mg/100 mL) has been developed for intravenous use to treat acute pain. Opioid analgesics are often used in addition to acetaminophen and ibuprofen for breakthrough pain. The interaction between Maxigesic® and other analgesics has not been fully examined. This study aimed to describe the pharmacodynamic interaction between Maxigesic®, oxycodone and morphine in adults with acute postoperative pain after bunionectomy.

Methods

Data were obtained from a phase 3, randomised, placebo-controlled study (ClinicalTrials.gov Identifier: NCT 02689063). Participants received either IV Maxigesic® (acetaminophen 1000 mg + ibuprofen 300 mg, N = 75), intravenous acetaminophen (1000 mg, N = 75,) intravenous ibuprofen (300 mg, N = 76) or placebo (N = 50) every 6 h for a total of 8 doses. Pain was assessed using a 100 mm visual analogue scale (VAS). Published models were used to describe the pharmacokinetics of acetaminophen, ibuprofen, oxycodone and morphine.^1–3 VAS was described using a sigmoidal maximal effect (EMAX) model. An effect-site compartment related analgesic concentration to pain score. Combined analgesic effects of acetaminophen, ibuprofen, oxycodone and morphine were described using the Greco response-surface model. The time-course of VAS in the inactive treatment group was explored using an exponential model.

Results

Data comprised 8469 VAS observations. Rescue analgesia was required by 96% of participants in the inactive group. The maximal placebo effect on VAS was small (<1 mm). Pharmacodynamic parameter estimates are shown in Table 1. Figure 1 shows the visual predictive check for VAS.

Conclusions

Treatment with Maxigesic® IV resulted in a 72% reduction in pain score from the predicted baseline. This pharmacodynamic model could be used to implement a target-concentration strategy to determine the analgesic dose associated with the desired reduction in pain score using Maxigesic® IV alone or in combination with either oxycodone or morphine. Placebo effect was difficult to determine given the small proportion of participants receiving no analgesia (either Maxigesic® IV or rescue).

References

1. Morse JD, Stanescu I, Atkinson HC, Anderson BJ. Population pharmacokinetic modelling of acetaminophen and ibuprofen: the influence of body composition, formulation and feeding in healthy adult volunteers. Eur J Drug Metab Pharmacokinet. 2022;47(4):497–507.

2. Morse JD, Sundermann M, Hannam JA, Kokki H, Kokki M, Anderson BJ. Population pharmacokinetics of oxycodone: premature neonates to adults. Pediatr Anesth. 2021;00:1-11.

3.Holford NH, Ma SC, Anderson BJ. Prediction of morphine dose in humans. Paediatr Anaesth. 2012;22(3):209-22.

222

Digital remote blood pressure monitoring after acute stroke: A pilot implementation study

Ali Hosin, Naveen Kumar, Selina Edwards, Ashley Laurie, Ceylan Safak, Harry Knights, Hashem Abu-Arafeh, Robert Simister, Arvind Chandratheva and Marc George

University College London Hospitals NHS Foundation Trust

Introduction

Blood pressure (BP) control following stroke is suboptimal, and the best means of monitoring it is unknown. Digital technology is becoming widespread across the NHS. At our comprehensive stroke service we conducted a pilot implementation study of remote BP monitoring following discharge.

Methods

In a single centre, eligible cases as assessed by the stroke nurse practitioner with either acute stroke or transient ischaemic attack (TIA) and a history of hypertension were selected for inclusion. Remote BP monitoring was conducted using a digital tool (app/web-based, linked to the electronic health record) or paper diaries. Patients were asked to perform a 7-day home BP diary prior to telephone review (<1 month from discharge) and a second diary prior to clinic followup. Patients were subsequently surveyed regarding their experience using the service. Quantitative outcomes included BP during admission and follow-ups, number of medication changes and level of engagement with BP monitoring. Qualitative outcomes explored included ease of use of the service and reasons for choosing BP monitoring modality.

Results

30 patients were enrolled (12 [40%] female, 18 [60%] male), mean age was 65 (30–92). Diagnosis was ischaemic in 21 (70%); haemorrhagic in 4 (13%) and TIA in 5 (17%). Mean BP on admission was 175/92 mmHg, and on discharge was 144/82 mmHg. 8 (27%) patients were treated with IV agents. 8 (27%) patients selected the digital tool and 22 (73%) a paper diary. Mean BP at 1st follow-up was 138/81 mmHg (n = 29) and at 2nd 137/80 mmHg (n = 18). Proportion of patients at target on discharge was 27% (8/30), at 1st follow up 45% (13/29), and at 2nd 56% (10/18). 15/29 (52%) of patients had their BP medications changed after the first review, and 9/18 (50%) at the second. From survey feedback, 100% of patients found it easy to use the BP monitor, record their measurements, and found information and advice given about their BP results useful. Reasons given for selecting a paper diary over the digital solution included ease of use and technical challenges with computers/phones.

Conclusions

There was a high level of patient engagement with home BP monitoring which translated to frequent intensification of BP therapy by the clinical team. Under a third of patients were at target on discharge, improving to over half with remote monitoring. A paper diary was more popular than app/web monitoring and future work should explore methods to improve onboarding and uptake of novel digital solutions.

235

Population pharmacokinetics of busulfan in paediatrics undergoing haematological stem cell transplantation

Chenyao Liu¹, Alessandro Di Deo¹, Bianca Goffredo², Raffaele Simeoli² and Oscar Della Pasqua¹

¹University College London; ²Bambino Gesù Children's Hospital

Introduction

Busulfan is a DNA-alkylating agent widely used in chemotherapy and conditioning regimen prior to haematological stem cell transplantation (HSCT), which is necessary to achieve immunosuppression and avoid graft rejection. Busulfan recommended doses range from 0.8 to 1.2 mg/kg, based on weight bands, and target exposure is based on a therapeutic window [900–1500 μM*min/L for AUC1¹ or 600–900 ng/mL for (Css)²]. However, busulfan shows large inter-individual variability in pharmacokinetics, which is attributable to a variety of factors such as hepatic metabolism, age, disease status and drug interactions.³ This study aimed to characterize the population pharmacokinetics of busulfan in paediatric and young adults undergoing haematological stem cell transplantation.

Methods

Pharmacokinetic and clinical data of 206 subjects receiving 2 h iv infusion QID for 4 consecutive days collected in a TDM-setting were available for this study (Table 1). Exposure derived by non-compartmental methods used as basis for dose adjustments. Drug concentrations (N = 1318) were collected at pre-dose, 2 h, 3 h, 4 h and 6 h after start of first daily infusion. A previously developed one-compartment model with first order elimination¹ was used as prior, including informative prior parameter distributions for the characterisation of the full pharmacokinetic profile in individual subjects. Demographic and clinical factors were tested as covariates in a stepwise manner. Model performance was assessed according to standard diagnostic criteria. Predicted individual busulfan concentration vs time profiles were used to derive AUC0–6 h and Css. All modelling and simulation procedures were implemented in NONMEM v.7.5. Data handling, statistical and graphical summaries were performed in R.

Results

The final pharmacokinetic model parameter estimates are shown in Table 2. Body weight was the only covariate factor to influence clearance and volume of distribution. No other demographic or clinical factors were found to have a significant effect on the disposition parameters of busulfan. An overview of the exposure range observed in this population over the pre-conditioning period is shown in Figure 1. Apparently, over 75% of subjects were below the target range on day1, followed by improvement on Day2 and Day3. Empirical dose adjustment has often resulted in exposure below the therapeutic target on Day4.

Conclusions

Inter-individual variability is greatly explained by body weight; however, the use of weight-based dosing regimen does not guarantee the achievement of the target exposure range on the first and last day of treatment. The use of a model-guided dosing is required to optimize initial dosing and sampling strategy for TDM in this patient population.

References

1. Paci A, Vassal G, Moshous D, et al. Pharmacokinetic behavior and appraisal of intravenous busulfan dosing in infants and older children: the results of a population pharmacokinetic study from a large pediatric cohort undergoing hematopoietic stem-cell transplantation. Ther Drug Monit. 2012;34(2):198-208.

2. McCune JS, Gooley T, Gibbs JP, et al. Busulfan concentration and graft rejection in pediatric patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant. 2002;30(3):167-173.

247

Intravenous lipopolysaccharide challenge induced expression of potentially druggable oncological targets in peripheral blood and bone marrow of healthy volunteers: An innovative approach for early pharmacology trials

Igor Radanovic^1,2, Ingrid Tomljanovic³, Manon A. A. Jansen¹, Matthijs Moerland^1,2 and Jacobus J. Bosch^1,2

¹Centre For Human Drug Research; ²Leiden University Medical Centre; ³Erasmus University Medical Centre

Introduction

Human challenge models accelerate clinical drug development by providing critical insights during early-phase trials. The intravenous (i.v.) lipopolysaccharide (LPS) challenge, commonly used in autoimmune and inflammatory research, offers a novel model in oncology due to the pro-inflammatory nature of tumour and their micro-environment (TME). We hypothesize that, by mimicking pro-inflammatory conditions in healthy volunteers, i.v. LPS induces the expression of druggable targets in various immune cells and tissues typically involved in TME. Furthermore, assessing bone marrow could reveal a unique set of targets otherwise inaccessible in peripheral blood. This study aimed to deeply characterize LPS-induced responses in peripheral blood and bone marrow to demonstrate the potential of the LPS challenge model in identifying and assessing druggable targets for early oncology trials.

Methods

An open-label study was conducted in healthy male subjects (aged 18–35 years). Ten participants were administered either 1 ng/kg (n = 5) or 2 ng/kg (n = 5) of i.v. LPS. Bone marrow samples were taken at baseline and 4 h post-administration, while blood samples were collected at multiple time points. Immunophenotyping, cytokine profiling, and bulk RNA sequencing were used to evaluate LPS responses in both blood and bone marrow. Differential gene expression analysis, gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA) were performed on the transcriptomic data. The Open Targets database helped identify druggable targets.

Results

LPS triggered a dose-dependent inflammatory response. Transcriptome analysis revealed activation of TNF, IL-1, RANKL, IFN-alpha/gamma, IL-6-JAK-STAT3, and complement pathways in blood, alongside upregulated druggable targets including DHRS13, PIM3, ITGAM, HCAR3, S100A12, PFKFB3, and GRN. These targets influence tumour metabolism, immune evasion, and survival, offering promising candidates for antagonists or agonists depending on their role in tumour progression. In bone marrow, LPS additionally activated E2F transcription factors, critical for cell cycle regulation, and the G2/M checkpoint pathway. Bone marrow-specific differentially expressed druggable targets included CD163, CXCR4, HSPA8, and CD36. This compartmentalization suggests that certain oncological targets can only be exclusively studied within the bone marrow micro-environment.

Conclusions

This study identifies LPS-induced druggable oncological targets in bone marrow and blood, supporting the use of the LPS challenge model in early oncology trials. This model could serve as a valuable tool to assess target engagement for novel cancer therapies by replicating tumour-like inflammatory responses in healthy volunteers.

254

Intranasal dexmedetomidine: A pilot pharmacokinetics/pharmacodynamics study in a preterm population undergoing percutaneous central venous catheter placement

Alessandro Di Deo¹, Francesca Cossovel², Gabriele Stocco², Jenny Bua² and Oscar Della Pasqua¹

¹University College London; ²Insitute for Maternal and Child Health IRCCS Burlo Garofolo

Introduction

Over 90% of hospitalized newborns undergo multiple painful procedures. Pain management is mainly based on the use of opioids in association with benzodiazepines. However, these drugs can lead to respiratory depression, hypotension, delayed gastric motility, and adverse neurologic events. Dexmedetomidine (DEX) is a highly selective α2-adrenergic agonist that has both sedative and mild analgesic properties. Despite these properties, data on newborns are limited and intranasal administration is used off-label in this population. The aim of this open-label phase II pilot study was to characterise the pharmacokinetics and pharmacodynamics of intranasal DEX (dose of 3 μg/kg), in preterm newborns of ≤36 weeks of gestational age, who had, for nutritional and/or therapeutic needs, an umbilical venous or arterial catheter which needed to be replaced by an epicutaneo-caval catheter.

Methods

In total 11 newborns were enrolled in this study (Table 1). Forty-four blood samples have been collected for the assessment of the pharmacokinetics using a micro-sampling method. The Premature Infant Pain Profile-Revised score (PIPP-R) was used as efficacy endpoint (sedation/pain reduction). A non-linear mixed effects modelling approach has been implemented using a Bayesian approach based on a previously published pharmacokinetic model for dexmedetomidine in paediatric patients. The model consisted of two-compartments with first-order absorption and elimination, and an absorption lag time. Allometric scaling factors based on body weight were added to describe the effect of body size on clearance and volume of distribution. Moreover, a maturation function was used to describe the effect of ontogeny on clearance.

Results

The apparent clearance and volume of distribution of DEX in newborns was 52.5 L/h and 130.8 L. Model-predicted median DEX exposure, expressed as AUC and Cmax was 1.75 ng/mL·h and 0.34 ng/mL, respectively. Moreover, in our study 8 patients (64%) maintained a PIPP-R score below 6 at the time of sampling, indicating an absence of pain. 3 patients (36%) exhibited values greater than 6, with two of them showing PIPP-R scores below 6 within 30 min of administration.

Conclusion

The pharmacokinetics of intranasal dexmedetomidine in a population of preterm infants was successfully described using nonlinear mixed effects modelling (Figure 1). The results also provide evidence the suitability of the tested dose (3 μg/kg) and safety profile in this population. We expect to use this model to define the dose rationale for DEX across a wide age range of paediatric patients undergoing similar interventions. Further studies in larger populations are warranted to confirm our observations.

263

Effect of omega-3 and 6 polyunsaturated fatty acids on diabetes mellitus type 2

Ahsan Aslam

Indus Medical College, Pakistan

Objectives

To evaluate the effects of optimized proportions of Omega-3 and Omega-6 polyunsaturated fatty acids on diabetes mellitus type.

Methodology

The experimental analytical study was carried out in the research lab of Isra University Hospital Hyderabad from March to August 2022. A total 50 male healthy albino Wistar rats weighing about 200 ~ 250 grams were procured from the animal house of Sindh Agricultural University Tandojam. After completion of the acclimatization period, rats were initially divided into group A and B Control n = 10 and Experimental groups n = 40, respectively. The control group received a standard chow diet and water ad libitum for one month. The experimental group rats were injected with Alloxan 150 mg/kg body weight mixed with 2 mL normal saline intraperitoneally to induce diabetes in the experimental groups. After induction experimental rats were further divided into 4 groups n = 10. Group B1 Diabetic control group after inducing diabetes fed with a normal chow diet ad labitum for 30 days. Group B2 Experimental Omega-3 Treated Group was fed a diet mixed with 0.3 g/kg body weight of Omega-3 fatty acid for 30 days. Group B3 Experimental Omega-6 Treated Group fed diet mixed with 0.3 g/kg body weight of Omega-6 fatty acid for 30 days. Group B4 Experimental combination Treated Groups was fed a diet mixed with equal amounts of Omega-3 and Omega-6 fatty acids in a dose of 0.3 g/kg body weight for 30 days.

Results

A significant difference between the mean body weight of rats of groups A, B1, B2, B3, B4 p < .05. The mean level of FBS before and Mean level of FBS after induction showed statistically significant at p-values <0.05 and <0.001 respectively. The mean level of C-reactive protein mg/L in Control was 0.11 ± 0.03 while in group B1 rats was 0.61 ± 0.12 in B2 rats was 0.24 ± 0.04, in B3 rats was 0.31 ± 0.08 and in B4 rats was 0.17 ± 0.03. The C reactive levels were found to be significantly elevated in group B1 compared with A, B2, B3, and B4 rats.

Conclusion

It is concluded from the present study that the administration of equal proportions of Omega-3 and Omega-6 polyunsaturated fatty acids plays a significant role in regulating body homeostasis and also impacts glycaemic control by improving markers of insulin resistance.

269

A translational pharmacology framework for the systematic prediction of treatment success of antimicrobial combinations in Buruli ulcer

Umberto Villani¹, Salvatore D’Agate¹, Emma Sáez López², Santiago Ramon Garcia³ and Oscar Della Pasqua¹

¹Clinical Pharmacology and Therapeutics Group, School of Pharmacy, University College London; ²Department of Microbiology, Faculty of Medicine, University of Zaragoza; ³Research and Development Agency of Aragón (ARAID) Foundation

Introduction

The standard-of-care (SoC) for Buruli ulcer (BU) is an 8-week oral antimicrobial regimen of rifampicin (RIF, 10 mg/kg o.d.) and clarithromycin (CLA, 7.5 mg/kg, b.d.). A novel combination therapy including amoxicillin-clavulanate (AMX-CLV) is currently being investigated in the clinic with the aim of shortening the treatment from 8 to 4 weeks.¹ However, the drug and dose selection strategies for investigational antimicrobial regimens have historically remained empirical. Hence, the aim of this work was to assess the probability of success of different drugs and dosing regimens in a clinical setting, leveraging translational pharmacokinetic-pharmacodynamic (PKPD) principles and antibacterial activity data from in vitro experimental settings.

Methods

In vitro time-kill assays with clinical isolates of Mycobacterium ulcerans were available for this analysis. A nonlinear mixed effects modelling framework was employed to quantify the effect of each drug on the overall antibacterial activity of the combination.² Clinical trial simulations were then implemented using the estimated PKPD relationships from in vitro protocols in conjunction with population PK models describing drug disposition and penetration into the skin in humans. Simulation scenarios including different regimens in a virtual cohort of patients with BU were evaluated: RIF (q.d., 10 mg/kg); RIF (q.d., 10 mg/kg) + CLA (b.i.d., 7.5 mg/kg); RIF (q.d., 10 mg/kg) + AMX-CLV (b.i.d., 22.5 mg/kg); RIF (q.d., 10 mg/kg) + CLA (b.i.d., 7.5 mg/kg) + AMX-CLV (b.i.d., 22.5 mg/kg); HIGHRIF (q.d., 20 mg/kg). The impact of initial bacterial burden and varying susceptibility in clinical isolates was assessed by differences in survival curves computed from the predicted times to microbiological eradication.

Results

Median predicted time (days) to bacterial eradication were similar across tested regimens (Figure 1), with marked differences in the 10th–90th range: RIF = 24 (14–42), RIF + CLA = 23 (14–39), RIF + AMX CLV = 22 (14–45), RIF + CLA + AMX-CLV = 22 (14–42), RIF20 = 22 (14–33). Notably, for the simulation scenario with clinically relevant bacterial load at the time of diagnosis (RNA copies/μg ~100), the 28-day RIF + CLA + AMX-CLV treatment was predicted to achieve similar microbiological eradication rates compared to the 56-days SoC (respectively, 97.8% and 98.1%)

Conclusions

Our analysis supports current ongoing trials¹ in the effort to shorten the treatment for BU. The framework we propose can be generalized to other drugs, offering the opportunity for the identification of novel drug combinations and regimens for the treatment of BU.

References

1. Johnson RC, Sáez-López E, Anagonou ES, et al. Comparison of 8 weeks standard treatment (rifampicin plus clarithromycin) vs. 4 weeks standard plus amoxicillin/clavulanate treatment [RC8 vs. RCA4] to shorten Buruli ulcer disease therapy (the BLMs4BU trial): study protocol for a randomized controlled multi-centre trial in Benin. Trials. 2022;23(1):559.

2. Muliaditan M, Della Pasqua O. Evaluation of pharmacokinetic-pharmacodynamic relationships and selection of drug combinations for tuberculosis. Br J Clin Pharmacol. 2021;87(1):140-151.

288

The effects of telmisartan and febuxostat on the pharmacokinetics of apixaban

Mikael O. W. Piha^1,2, Marica T. Engström¹, Päivi Hirvensalo¹, Kristiina Cajanus^1,2, Anna Linko-Parvinen^3,4, Eriika Savontaus^1,2, Anne M. Filppula⁵ and Aleksi Tornio^1,2

¹Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku; ²Unit of Clinical Pharmacology, Turku University Hospital; ³Department of Clinical Chemistry, Department of Clinical Medicine, University of Turku; ⁴Clinical Chemistry, Tyks Laboratories, Turku University Hospital; ⁵Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University

Introduction

The concomitant use of telmisartan, an antihypertensive agent, was recently linked with an increased bleeding risk in users of apixaban, an oral anticoagulant, in a case-control study.¹ Telmisartan inhibits the drug transporters P-glycoprotein and breast cancer resistance protein (BCRP) which participate in the disposition of apixaban. We investigated the effects of telmisartan and febuxostat, a potential clinical index inhibitor of BCRP,² on the pharmacokinetics of apixaban in healthy volunteers.

Method

We randomised ten healthy volunteers to ingest placebo or telmisartan 80 mg once daily for six days, or febuxostat 120 mg once daily for four days per an open-label, cross-over design. The participants then ingested a single 2.5 mg dose of apixaban one hour after the premedication on the penultimate day of each premedication course. We determined the plasma concentrations of apixaban and O-desmethyl apixaban sulfate in blood samples collected for up to 47 h, and the excreted amounts of apixaban in urine collected for up to 12 h, using liquid chromatographic-mass spectrometric methods. We compared the study phases by applying repeated-measures analysis of variance, with pairwise comparisons using the Bonferroni method, on logarithmically transformed pharmacokinetic data. Differences with Bonferroni-corrected P values below 0.05 were considered statistically significant.

Results

The pharmacokinetics of apixaban remained unchanged between the telmisartan and placebo phases (Table 1). Febuxostat, however, increased the Cmax of apixaban by 32% (90% CI 6–64%, p = .035), and its AUC0-∞ by 35% (90% CI 22–49%, p < .001), compared to placebo. Febuxostat also decreased the renal clearance of apixaban by 22% (90% CI 14–29%, p < .001), and the AUC0-∞ ratio between O-desmethyl apixaban sulfate and apixaban by 11% (90% CI 4–18%, p = .018), but had no effect on the t½ of apixaban.

Conclusions

In conclusion, telmisartan lacked a clinically meaningful effect on the pharmacokinetics of apixaban. However, BCRP inhibition by febuxostat increases the plasma concentrations of apixaban, a drug with a narrow therapeutic index, which might point to a clinically significant role of BCRP in pharmacokinetic drug-drug interactions of apixaban.

References

1. Kawano Y, Nagata M, Nakamura S, et al. Comprehensive exploration of medications that affect the bleeding risk of oral anticoagulant users. Biol Pharm Bull. 2021;44(5):611-619. https://doi.org/10.1248/bpb.b20-00791

2. Lehtisalo M, Keskitalo JE, Tornio A, et al. Febuxostat, but not allopurinol, markedly raises the plasma concentrations of the breast cancer resistance protein substrate rosuvastatin. Clin Transl Sci. 2020;13(6):1236-1243. https://doi.org/10.1111/cts.12809

294

The effect of beta1-adrenergic receptor antagonists on the vas deferens contractions induced by 6-cyanodopamine

Caroline Fernanda Sanches Dal Pozzo, Gilberto De Nucci, José Britto-Júnior, Leonel Custódio Ribeiro, Isabella Adriana Ramos dos Santos and Maria Clara Carvalho Ramos

State University of Campinas

6-Cyanodopamine (6-CYDA) is released from isolated rat vas deferens and represents a novel epithelium-derived catecholamine, similar to 6-nitrodopamine (Pozzo et al., 2024). 6-Nitrodopamine (6-ND) acts as a major endogenous modulator in the human vas deferens, with its effects being blocked by β1- and β1β2-adrenoceptor antagonists such as atenolol, betaxolol, metoprolol, propranolol, and pindolol.¹ 6-Cyanodopamine also plays a significant role in the modulation of vas deferens contractility, as it enhances contractions mediated by noradrenaline, adrenaline, and dopamine.² However, it remains unknown whether β1-adrenoceptor antagonists have any effect on the contractile activity induced by 6-cyanodopamine. Thus, it was investigated whether β1-adrenoceptor antagonists exert an inhibitory effect on the contractions induced by 6-cyanodopamine in rat vas deferens. Rat isolated vas deferens were incubated with 1 μM of the β1-adrenoceptor antagonists atenolol, betaxolol, and metoprolol, in the presence or absence of 100 nM of 6-cyanodopamine. Additionally, antagonists were co-incubated with 10 pM of 6-nitroadrenaline and 100 pM of 6-cyanodopamine. Concentration-response curves were generated using adrenaline, noradrenaline, and dopamine. The beta1-antagonists had no effect on the potentiation induced by 6-cyanodopamine in response to traditional catecholamines (Figure 1). However, all β1-adrenoceptor antagonists reduced the maximal response triggered by the co-incubation of 6-nitroadrenaline and 6-cyanodopamine (Figure 2). These results indicate that 6-cyanodopamine and 6-nitrodopamine do not act via adrenergic receptors and likely interact with their own distinct receptors. This is the first endogenous cyanide-based modulator described to be released by the epithelium of the vas deferens, exhibiting physiological activity.

References

1. Lima AT, Amorim AC, Britto-Júnior J, et al. β1- and β1/β2-adrenergic receptor antagonists block 6-nitrodopamine-induced contractions of the rat isolated epididymal vas deferens. Naunyn Schmiedebergs Arch Pharmacol. 2022;395(10):1257-1268. https://doi.org/10.1007/s00210-022-02268-6

2. Pozzo CFSD, Junior JEM, Britto-Júnior J, et al. Basal release of 6-cyanodopamine from rat isolated vas deferens and its role on the tissue contractility. Pflugers Arch. 2024;476(8):1263-1277. https://doi.org/10.1007/s00424-024-02985-2

303

The impact of aspirin on hemorheological parameters in pregnant women: A prospective cohort study

Merve Kabasakal Ilter¹, Muhammed Edib Mokresh², Muhammed Kahya², Emir Muvaffak², Lutfiye Uygur³ and Oya Demirci³

¹Department of Medical Pharmacology, Hamidiye Faculty of Medicine, University of Health Sciences; ²Hamidiye International School of Medicine, University of Health Sciences; ³Department of Obstetrics and Gynecology, Division of Perinatology, Zeynep Kamil Women and Children Health Research Hospital, University of Health Sciences

Introduction

Pregnancy induces significant physiological changes, including alterations in blood rheology.Impaired erythrocyte deformability and aggregation are also associated with preeclampsia. Low-dose aspirin is recommended for women at risk of preeclampsia, While the beneficial role of aspirin in improving blood viscosity and reducing cardiovascular disease risk is well established, there is a lack of studies addressing its rheological effects in pregnancy. Therefore, this study aims to investigate the hemorheological changes from the first to the second trimester in high-risk pregnant women using aspirin.

Method

This prospective observational cohort study included 100 pregnant women aged 18–40, divided into an aspirin group (n = 34) and a control group (n = 66) based on preeclampsia risk factors. Participants were monitored from 11 to 14 weeks until delivery. A method outlined by Hardeman and Baskurt^1,2 was used to test hemorheological characteristics, such as blood viscosity, erythrocyte aggregation, and deformability, at 11–14 and 24–28 weeks. Blood samples were analysed using an Ektacytometry LORRCA and a Brookfield Viscometer. Statistical evaluation of the data of this study was carried out using R statistical language.

Results

The change in whole blood viscosity (WBV) from the 1st to the 2nd trimester showed significant differences between Aspirin users and controls. While the control group showed a significant reduction only in WBV at shear rates of 75 and 112.5 s⁻¹, Aspirin users experienced a significant and consistently greater reduction across all WBV shear rates (p < .001) by the 2nd trimester follow-up (Figure 1). In the control group, the aggregation index AI % 69.85 to 73.71 (p < .001), and plasma viscosity in 60 rpm (1.31 to 1.38 cP, p < .001)significantly increased while no significant change was observed in the aspirin group (72.43 to 74.61, p = .189), (1.34 to 1.36 cP, p = .596).

Conclusion

In conclusion, the significant reduction in total blood viscosity observed in the high-risk pregnancy group receiving aspirin, along with the suppression of erythrocyte aggregation unlike in the control group where aggregation increased suggests that aspirin provides rheological benefits in high-risk pregnancies.

References

1. Baskurt OK, Meiselman HJ. Erythrocyte aggregation: basic aspects and clinical importance. Clin Hemorheol Microcirc. 2013;53(1-2):23-37. https://doi.org/10.3233/CH-2012-1573

2. Hardeman MR, Dobbe JG, Ince C. The laser-assisted optical rotational cell analyzer (LORCA) as red blood cell aggregometer. Clin Hemorheol Microcirc. 2001;25(1):1-11.

305

Medical record based active pharmacovigilance in a tertiary hospital: One year analysis

Antonio Gil Azevedo^1,2, Francisco Jorge Melo^1,2, Miguel Torre Souto¹, Diogo José M. Lopes¹, Filipa Borges-Carneiro¹, Andreia Dias¹, Isabel Silva¹, Paula Moreira¹, André Valois^1,2, Paula Ferraz¹, João Martins Mendes¹, Francisco Portal¹, Luís Figueira^1,3,4, Marta Reina-Couto^1,5 and Fernando Magro^1,2,6

¹Clinical Pharmacology Unit, University Hospital Center of São João; ²Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto; ³Department of Ophthalmology, University Hospital Center of São João; ⁴Center for Drug Discovery and Innovative Medicines (MedinUP), Faculty of Medicine, University of Porto; ⁵Emergency and Intensive Care Department, University Hospital Center of São João; ⁶Department of Gastroenterology, University Hospital Center of São João

Introduction

Adverse drug reactions (ADRs) are responsible for significant morbimortality.¹ Pharmacovigilance and post-marketing drug surveillance (PMDS) are vital for public health.^1,2 PMDS is required to be especially rigorous and intensive for drugs designated by the European Medicines Agency (EMA) as being under additional monitoring.³ However, PMDS typically relies on spontaneous reporting which can lead to incomplete information and under-reporting.² Proactive approaches have been developed to help mitigate these shortcomings.² The Clinical Pharmacology Unit (CPU) of University Hospital Center of São João (UHCSJ) developed a project of active pharmacovigilance based on medical records to address ADR detection for drugs under additional monitoring.

Method

A total of 7 drugs with on-label indication for treatment of solid tumours under additional monitoring by EMA as of June/2023 were selected. After daily identification of patients receiving these medications in the hospital´s adult oncological day clinic, their recorded medical data were reviewed by an element of the CPU in order to assess the presence of any suspected ADRs since the last drug administration. Detected ADRs were reported in the hospital´s internal notification programme.

Results

From July 2023 to June 2024, a total of 54 ADR were reported in 29 patients (demographics in Table 1). A first report of ADR was identified in 21 patients, with 6 (29%) of them having a second ADR notification with the same drug within this period (Table 2). All assessed drugs had reported ADRs (Tables 2 and 3). Regarding causality, 4 ADRs were classified as definite, 18 as probable and 32 as possible. Regarding severity, 35 were considered as non-serious and 19 as serious (18 clinically relevant and 1 hospitalization due to suspected avelumab neurotoxicity).

Conclusions

All selected drugs had ADRs within a 1 year period, several patients had more than 1 ADR for the same drug. An active medical record based pharmacovigilance programme performed by clinical pharmacologists was able to detect these ADRs, improving reporting.

References

1. Williams D. Monitoring medicines use: the role of the clinical pharmacologist. Br J Clin Pharmacol. 2012;74(4):685-690. https://doi.org/10.1111/j.1365-2125.2012.04316.x

2. Huang YL, Moon J, Segal JB. A comparison of active adverse event surveillance systems worldwide. Drug Saf. 2014;37(8):581-596. https://doi.org/10.1007/s40264-014-0194-3

3. Manso G, Neira F, Ortega S, Martín Arias LH, Sainz M, Salgueiro E. Medicines under additional monitoring in the European Union. Medicamentos sujetos a seguimiento adicional en la Unión Europea. Farm Hosp. 2019;43(1):19-23. https://doi.org/10.7399/fh.11041

313

Physiologically based pharmacokinetic (PBPK) modelling of tolterodine in different CYP2D6 genotypes

Pureum Kang, Chang-Keun Cho and Seok-Yong Lee

School of Pharmacy, Sungkyunkwan University

Introduction

Tolterodine is used as an antimuscarinic drug to treat overactive bladder symptoms such as urgency, frequency, or urge incontinence by relaxing the smooth muscle of the bladder. Cytochrome P450 2D6 (CYP2D6) serves as the primary enzyme responsible for metabolizing tolterodine into its major pharmacologically active metabolite, 5-hydroxymethyl derivative (5-HMT). CYP2D6 exhibits genetic polymorphism, which significantly influences the pharmacokinetics of tolterodine. This study aimed to establish the PBPK model for predicting tolterodine pharmacokinetics based on CYP2D6 genetic polymorphism.

Methods

PBPK model of tolterodine was developed using the software PK-Sim® v11.2. Healthy Korean subjects were divided into four different CYP2D6 diplotypes: CYP2D6*wt/*wt (*wt = *1 or *2, n = 14), CYP2D6*wt/*10 (n = 14), CYP2D6*10/*10 (n = 15), and CYP2D6*5/*10 (n = 3). Physicochemical properties and disposition characteristics of tolterodine were obtained from prior studies or adjusted to reflect plasma concentration-time profiles across various CYP2D6 genotypes. The discrepancy between observed and predicted values was adjusted through sensitivity analysis. The adjustment was performed using the Levenberg-Marquardt algorithm implemented in PK-Sim®.

Results

Subjects carrying the *5 allele showed notably elevated mean plasma concentrations of tolterodine compared to those with other alleles. Specifically, in observed values derived from clinical studies, Cmax in the CYP2D6*wt/*10, CYP2D6*10/*10, and CYP2D6*5/*10 groups were approximately 2.3-fold, 3.5-fold, and 6.8-fold higher, respectively, compared to the CYP2D6*wt/*wt group. For subjects with CYP2D6*10/*10 genotype, the observed value for AUCinf was 13.4, while the simulated value was 14.4. Additionally, the observed Cmax value was 1.1, whereas the simulated value was 1.08. Simulation results showed that the AUCinf of CYP2D6*10/*10 and CYP2D6*5/*10 were 1.47- and 3.52-fold higher, respectively, compared to CYP2D6*wt/10.

Conclusion

121

A lack of diversity of patient representation in medicine development

Graham McClelland, Arjin Koc and Fatima Auwal

King's College London

Introduction

In recent years, regulatory authorities, pharmaceutical companies and other clinical trial Sponsors have shifted to a more patient-centric approach, incorporating their input into medicine development decisions.¹ Patient advocates (PAs) play an essential role in representing that patient voice and their wishes. However, there remains a significant gap in research concerning the diversity of PAs and the extent to which they can truly represent the patient populations they are meant to represent. This study has examined the representativeness of self-identified PAs in medicine development against the known demographics.

Method

This research employed descriptive observational methods to assess the demographic representativeness of self-identified PAs based in the United Kingdom. Data were collected from LinkedIn profiles using specific inclusion criteria between May and August 2024. The collected data were classified according to age, sex, ethnicity and educational background. A comparative analysis was conducted between the demographics of PAs and the known demographics of the patient populations they represent. The methodology relied on visual assessments of publicly available information, acknowledging limitations in data accessibility and potential observer bias, particularly in the classification of demographic characteristics.

Results

This research revealed substantial disparities in the demographic representation of the 204 self-identified PAs registered with LinkedIn and based in the United Kingdom. Noted disparities were identified in gender, age, ethnic and educational characteristics. The study found that, of those who could reliably be classified, most PAs were adults aged under 65 years (95%), female (72%), White (87%), and 41% were health or life science graduates, suggesting an over-representation in all of these demographic characteristics.

Conclusions

The findings identified inequalities and a lack of a diversity among self-identified PAs in the United Kingdom. Whilst this research was limited to just the LinkedIn database, the results do indicate that there needs to be actions to ensure that there is a wider patient representation in the provision of input into medicine development decision-making.

Reference

1. Auwal F, Copeland C, Clark EJ, Naraynassamy C, McClelland GR. A review of models of patient engagement in the development and lifecycle management of medicines. Drug Discov Today. 2023; 89(9):103702-1037210. https://doi.org/10.1016/j.drudis.2023.103702

123

The contribution from patient organisations to patient engagement dialogues in medicine development

Graham McClelland, Arjin Koc and Fatima Auwal

King's College London

Introduction

The added value of bringing the patient perspectives, especially through patient organisations (POs) in medicine development is increasingly accepted and adopted.¹ Many POs actively create and maintain relationships with regulators, the pharmaceutical industry and other clinical trial Sponsors. However, the extent to which these views from POs can fully represent the needs of patients in the wider population is not well understood. The aim of this research was to investigate how POs represent the patients view when interacting with pharmaceutical companies and regulators.

Method

After obtaining ethical approval, a descriptive cross-sectional study was conducted to survey POs using a questionnaire adapted from a previous study and validated. The questionnaire had three parts, assessing the knowledge, attitude and practices of POs when participating in patient engagement initiatives with the pharmaceutical industry and regulators. All the 120 POs registered members of the UK Association of Medical Research Charities² were contacted through email and the questionnaire shared through Microsoft Forms during July to August 2023. Two follow-up emails were sent as a reminder to increase the response rate. The responses were analysed descriptively using Microsoft Excel.

Results

29 POs responded to the survey giving a response rate of 24.2%. While 86% of the responding POs had experience in patient engagement, only 23% had received any formal training, which in most cases were offered by the POs themselves. 76% reported that their patients were satisfied with the representation and 62% reported having impact on pharma. Patient groups (60%) and expert patients (25%) were their main sources of patient opinion. A lack of resources (40%) and pharma/regulators' hesitation (33%) were the major challenges experienced by POs. 86% expressed a willingness to contribute to medicine development.

Conclusions

POs are an important link between the patients and other stakeholders in clinical trials and medicine development and should be respected as valuable members in the patient engagement space. More research on individual patients is needed to understand how they feel their opinions are represented by POs and appropriate strategies identified to ensure a broad representative of the patient voice in medicine development decision-making.

References

1. Auwal F, Copeland C, Clark EJ, Naraynassamy C, McClelland GR. A review of models of patient engagement in the development and lifecycle management of medicines. Drug Discovery Today. 2023; 89(9):103702-1037210. doi.10.1016/j.drudis.2023.103702

2. https://www.amrc.org.uk/Pages/Category/member-directory

170

Does innovation translate into clinical or economic value?

Anushruti Yadav

Cardiff Univeristy

Introduction

In recent years, the market has witnessed a steady rise in novel pharmaceutical drugs, but does this growth also reflect an increase in beneficial products? Every product has the potential to improve clinical outcomes for patients and boost economic gains for both patients and the healthcare system. The magnitude of these advantages, however, is complicated to predict and varies depending on a wide range of factors, such as the disease being treated or the degree of market competition. The British Pharmacological Society's (BPS) award for the Drug Discovery of the Year served as the starting point for this project.¹ This award raised the issue of whether the degree of innovation affects the success or failure of these drugs when considering their clinical and economic value. The hypothesis is that the BPS innovation award winners are more innovative and perform better from a clinical and economic standpoint than the drugs which were deemed innovative by the EMA and FDA but did not win the award. The main aim of this project was to thoroughly assess each drug by taking its innovative, clinical and economic value into account.

Method

The European Public Assessment Reports, the NICE final appraisal documents and guidelines, the Summary of Product Characteristics, and lastly, the PharmGKB were reviewed to extract information about the innovative and economical levels of the drugs. A clinical benefit score from France's National Authority for Health (HAS) was applied to determine each drug's clinical value. The dataset was analysed by descriptive statistics and logistic regression.

Results

The BPS award winners, which were the more innovative group of drugs, had a higher clinical and economic value than the control group. On descriptive analysis, the BPS winners had a mean incremental cost-effectiveness ratio (ICER) of £161,685.50 whereas the control group had a considerably higher mean ICER of £205,084.62, p = .97. The findings of the logistic regression analysis showed that being a BPS award winner was associated with having a higher clinical benefit score, an odds ratio of 2.864 and p = .021.

Conclusions

The findings of the descriptive and logistic regression analysis supported the hypothesis that the BPS winners, who are more innovative, will produce a product that is more clinically advantageous. Innovative drugs benefit patients and the healthcare system significantly by increasing QALY gains by an average of 2 over the control group while saving £43,399.12 per QALY. Although it was determined that the findings for ICER and QALY were not statistically significant, this does not imply that the results are not clinically important.

Reference

1. BPS. Drug discovery of the year British Pharmacological Society 2023 [accessed 15 Jan]. Available from: https://www.bps.ac.uk/membership-awards/prizes,-awards-and-grants/our-prizes/drug-discovery-of-the-year

17

Transforming pharmacology education: Implementing team-based learning to engage medical students

Maryam Malekigorji

Queen Mary University of London

Background and Aims (K1, A1)

Team-Based Learning (TBL) has revolutionised pharmacology education at Barts and The London School of Medicine and Dentistry. Our initiative aims to foster medical student engagement, deepen comprehension of complex pharmacological concepts, and promote real-world application of knowledge1.

Summary of Work and Outcomes (A2, A3, K2-K4)

The introduction of TBL presents a unique challenge for early years medical students, who are unfamiliar with this approach. To address this, we collaborated with students to develop a TBL orientation session preceding pharmacology TBL sessions. Formal evaluations, including surveys and focus groups with students, faculty and professional services staff, were conducted to assess the effectiveness and impact of this teaching method. Preliminary results indicate that TBL has significantly improved students' comprehension and retention of pharmacological principles, fostered critical thinking skills and enhanced teamwork and communication abilities.

Discussion (A4, A5, K5, V1-V5)

Building on previous evaluations, students advocated for active learning methods such as TBL and Problem-Based Learning (PBL) to study pharmacology. Responding to this feedback, we implemented TBL into year 1 and 2 modules of our medical degree. We expanded traditional TBL application exercises to include debates, gallery walks, role-playing and poster presentations, providing diverse learning experiences. Additionally, we recruited simulated patient and clinician to reveal complex clinical pharmacology scenarios within the application exercises, which allowed students to apply their knowledge in clinical contexts. The TBL session on hormonal contraceptives emerged as the students' favourite session. This topic resonated well with their future roles as physicians, equipping them to offer informed clinical guidance to patients across various conditions. We anticipate that this TBL approach will enhance our medical students' readiness for success in their Prescribing Safety Assessment (PSA) exam, empowering them to effectively apply their clinical pharmacology knowledge and skills in their future practice.

Conclusion (A5, K5, V4-V5)

This abstract delineates our implementation process, key findings and positive feedback, offering valuable insights for institutions considering similar educational innovations in pharmacology instruction.

References

1. Zgheib NK, Simaan JA, Sabra R. Using team-based learning to teach pharmacology to second year medical students improves student performance. Med Teach. 2010;32(2):130-135.

2. Malekigorji M. The effect of continued team randomization on student’s perception and performance in a blended team-based teaching approach. Educ Sci. 2019;9(2):102.

3. Dollinger M, Lodge J, Coates H. Co-creation in higher education: towards a conceptual model. J Mark High Educ. 2018;28(2):210-231.

27

Contextualizing learning about race and ethnicity for pharmacology and pharmacy undergraduates

Sarah Bailey, Christine Edmead, Lyn Hanning and Sabin John

University of Bath

Background and Aims

Decolonizing biomedical science curricula is essential to equip drug discovery researchers and healthcare practitioners with the cultural competence to deliver improved patient outcomes. In the study of medicines, inter-individual differences exist in the response of human populations to drugs, adverse drug reactions and drug metabolism.¹ Genetic and environmental factors contribute to this inter-individual variation in drug response. While race is a socio-political construct and acknowledged to be a poor descriptor of the distribution of genetic variation, it continues to be used to categorize human populations in biological studies. This project aimed to identify what our pharmacology and pharmacy undergraduate students know and understand about race and ethnicity that enables them to contextualize their learning.

Summary of Work

Focus groups were conducted with student cohorts to identify whether students could distinguish between concepts of ‘race’ and ‘ethnicity’ and the extent to which these can be biologically distinguished. These focus groups highlighted confusion but also interest in this area. Two 2 h workshops were developed for delivery in the second year of both pharmacology and pharmacy programs. Workshop 1, ‘Understanding inter-individual variation’, was common to both programs. Using interactive reflective learning, students engaged in exercises to consider what old age is, to consider biases about age, their own social identity and experience. Students' knowledge and understanding of race, ethnicity and basic cell biology/genetics was surveyed using MS Forms. Then various definitions of race and ethnicity were presented, alongside the challenges inherent in biomedical literature using human population data categorized in this way. For pharmacology students, a second workshop used examples of pharmacological studies, treatment regimens and critique of a journal article to understand how categorising subjects according to race may not be ethical or accurate. For pharmacy students, the context was a discussion of the controversial inclusion of race in British hypertension guidance.²

Results and Discussion

In both student cohorts, the majority defined ‘race’ in biological terms whereas ‘ethnicity’ was overwhelmingly defined in social terms.³ However, at the end of the workshop, when asked ‘to what extent is there a biological or genetic basis for race?’ 80% of students responded, ‘very little/ not at all’. When asked ‘what was the best thing about these workshops?’ students responded ‘learning about the differences in identity’, ‘conversations meant we learned more about the people around us’ and ‘encouraged me to think critically about papers mentioning race and ethnicity’. We are looking at how this approach can be extended in our programmes.

Conclusion

This study shows the value of providing space for students to discuss these issues in their programs and to address misunderstandings about race and racial differences as being biological. Importantly, this contextual approach to decolonizing and diversifying curricula, has real-world impact in preparing our graduates to be culturally competent and equip them to communicate effectively with patients or make sense of complex biomedical literature in an era of personalized medicine.

Acknowledgements

We are grateful to Prof Jenny Koenig, University of Nottingham for helpful discussions and sharing resources. This project was funded by the University of Bath Access Participation Plan Seed Fund and Aryaa Choudhary performed background scoping work.

References

1. Cacabelos R, Naidoo V, Corzo L, Cacabelos N, Carril JC. Genophenotypic factors and pharmacogenomics in adverse drug reactions. Int J Mol Sci. 2021;22(24):13302. https://doi.org/10.3390/ijms222413302

2. Gopal DP, Okoli GN, Rao M. Re-thinking the inclusion of race in British hypertension guidance. J Hum Hypertens. 2021;36(3):333-335. https://doi.org/10.1038/s41371-021-00601-9

3. Ibrahim Z, Brown C, Crow B, Roumimper H, Kureshi S. The propagation of race and racial differences as biological in preclinical education. Med Sci Educ. 2022;32(1):209-219. https://doi.org/10.1007/s40670-021-01457-x

36

But you can't teach … to first years. An introductory human biosciences course suitable for both degree majors and non-science students

Mark D. Berry, Jaeok Park and Scott V. Harding

Memorial University of Newfoundland

Background and Aims

Typically, North American first-year University science courses are one of two formats: a discipline specific course mandatory for one or more degree programmes, usually taught from the perspective of majors of the Department delivering the course(s); or a general elective for non-majors, often outside of science, that cannot count towards science major requirements. Introductory Biochemistry typically requires Chemistry/Biology courses as mandatory pre-requisites. Following a comprehensive curriculum review, our department merged its two undergraduate programmes in Biochemistry and Nutrition into a single Human Biosciences degree. As part of this integration, we developed ‘Food, Drugs, and Your Body’ (FDYB), a first-year course designed to serve two purposes - an alternate entry point to the Human Biosciences major and a general elective accessible to anyone.

Summary of Work

328 students have completed FDYB across four offerings since 2020/21, comprising majors from multiple science and non-science disciplines, at all levels of degree progress (1st–4th+ year). Content was selected to be amenable to both Biochemistry and Nutrition perspectives, and designed to be modular, allowing rotation each year according to topicality and general media coverage (Table 1). Content is presented as a blend of cellular science and wider societal contexts, each lecture involving both a ‘Nutrition’ and a ‘Biochemistry’ instructor. Assessment items (Table 1) are an equal mix of traditional exams and individual/group assignments emphasizing wider societal/ethical questions, scientific literacy and knowledge translation.

Results and Discussion

Student grades were obtained from transcripts, along with their year at University when taking FDYB, and declared major. No significant effects of year at university, major or interaction (2-way ANOVA), on FDYB grade were observed (Figure 1). For each year at University, FDYB grade was significantly (p < .0001) correlated to semester grade average, cumulative university average, and departmental grade average, with no difference between the three lines of best fit. Over 90% of Course Experience Questionnaire responses (55% response rate) at the end of semester indicated material was accessible and increased understanding of both the science and its societal implications. Future monitoring will compare FDYB to traditional first-year courses with respect to student preparation for 2nd year Human Biosciences courses.

Conclusion

We have successfully developed an entry-level Human Biosciences course focused on health and disease that combines cellular science with wider societal implications, including indigenous and EDI (equity, diversity and inclusion) content, that is equally accessible to majors in Human Biosciences, other sciences and non-science degrees.

42

First implementation of the prescribing skills assessment for pharmacy students in Egypt: A pioneering initiative at Misr International University

Rania Salama

Misr International University

Introduction

In response to Egypt's goal of enhancing the competencies of clinical pharmacists and meeting international accreditation standards, the Faculty of Pharmacy at Misr International University (MIU) has pioneered the implementation of the Global Prescribing Skills Assessment (PSA) for pharmacy students, an online tool designed to measure and improve prescribing skills. This assessment is derived from the UK Prescribing Safety Assessment (PSA).¹ Supported by the British Pharmacological Society (BPS), this initiative represents a significant step forward in pharmacy education in Egypt.²

Summary of Work

The PSA course was introduced during the 2023/2024 academic year, with an initial cohort of 269 students, all of whom were entering their final year (5th year) of pharmacy school. A comprehensive weekly tutorial series was developed, integrating e-learning modules that covered the eight sections of the PSA and selected key topics. Two mock exams were administered: the first at the end of the Fall semester, which involved all 269 students, and the second at the end of the Spring semester, which included 242 students.

Discussion

The mean scores of the two mock exams were comparable, but improved performance was observed across multiple sections in the second exam (Figure 1). Student feedback highlighted a growing confidence in the relevance of this assessment as an effective tool for evaluating their competencies. However, a common concern was the insufficient time allocated for the exam (Figure 2). Additionally, students' self-assessments indicated increased confidence in prescribing and other related skills following the second mock exam compared to the first (Figure 3).

Conclusion

The PSA has proven to be a valuable tool for assessing pharmacy students' competencies prior to their experiential year. The final assessment for this cohort is scheduled for September 2024. Efforts are currently underway to refine the course further and integrate drug information resources aligned with the PSA, in preparation for the next cohort of senior students starting in Fall 2024.

This study adheres to the ethical standards of research involving human participants and was approved by the Ethical Committee of Faculty of Pharmacy, Misr International University. Participation in this survey was entirely voluntary. All responses were kept anonymous and confidential, and data collected were used solely for academic and research purposes. No personal identifying information will be collected or stored. The survey poses minimal risk to participants, as it does not involve sensitive or invasive questions. By completing the survey, participants provided their informed consent for their responses to be used in this research. All data will be securely stored and only accessible to the research team.

References

1. Mucklow J, Bollington L, Maxwell S. Assessing prescribing competence. Br J Clin Pharmacol. 2012;74(4):632-9. https://doi.org/10.1111/j.1365-2125.2011.04151.x

2. BPS Assessment Welcomes Misr International University as a Valued Customer Posted on September 7, 2023. https://www.bpsassessment.com/bps-assessment-welcomes-misr-international-university-as-a-valued-customer

49

Patient and public involvement in the cancer theme of the clinical pharmacology BSc degree

Efthymia Papaevangelou and Fu Liang Ng

City St George's University of London

Background and Aims

Patients should be the focus of all health-related courses. Embedding patient and public involvement (PPI) in health education leads to several educational benefits, including development of communication skills, demonstrating the relevance of student learning, cultivating student empathy and inspiring them in their future careers.¹ Additionally, by being part of the educational process, patients feel more valued and empowered.² To provide patient-centred learning we need to adopt a sustainable PPI pedagogy in all aspects of student education including curriculum development. We aimed to embed PPI in the Clinical Pharmacology BSc degree starting with patient involvement in the cancer curriculum.

Summary and Outcomes

The cancer theme spans across three core modules (fundamentals of science, pharmacodynamics and drugs in healthcare) and small group teaching (drug-based learning) lasting three weeks in semester three (Year 2). The Breast Cancer Now charity identified two breast cancer survivors willing to participate in the project. Patients were provided with information containing details on the project, the lectures, and their learning objectives and were invited to review in-person the module content on the final day of the cancer theme. Prior the event, there was a short briefing explaining the schedule of the visit, the expectations of patients, faculty and students. Patients attended a full day of teaching, engaged with students and provided written feedback. A detailed action plan was then prepared and shared with the charity and patients.

Discussion

Patient participation was positively received by our students. We received valuable feedback from the patients, highlighting areas of good practice but also areas for improvement, for which we made changes to be implemented this academic year (Table 1). For example, we learnt that we need to review certain terms used in lectures and be more aware of the psychosocial impact of (cancer) diagnoses. In addition, continued communication with the patient network regarding progress is important to encourage further collaborations. Breast Cancer Now are preparing an article on this project to be shared via different networks including a healthcare professionals bulletin and the Voices network.

Conclusion

PPI can have a transformative impact on pharmacology teaching by improving the curriculum and help prepare students for their future careers. Our next steps are to carry out similar projects for other themes of the curriculum (i.e., neuroscience and psychiatry) and share our project with the wider education community.

References

1. Stewart M. Patient-Centred Medicine. Transforming the Clinical Method. Oxford: Radcliffe Med Press; 2003.

2. Ocloo J, Matthews R. From tokenism to empowerment: progressing patient and public involvement in healthcare improvement. BMJ Qual Saf. 2016;25:626-632.

86

Collaborative learning and debate in PGx education

Vikki Moye and Mark Carew

Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter

Background and Aims

Pharmacogenomics (PGx) explores how an individual's genetics influence drug responses. Recognising the growing importance of PGx in research and clinical practice¹ and the need for education in this area,² we formalised and expanded PGx teaching at both undergraduate (UG) and postgraduate (PG) levels in 2017. Two 15-credit modules were developed (Table 1) for two diverse groups of students. Designed to accommodate varying prior knowledge and interests, these modules address and adapt to student differences.

Summary of Work and Outcomes

Modules are designed to have weekly topics that include foundational concepts, clinical applications and future directions of PGx. There are lectures covering the fundamental principles required for each topic with a flipped classroom approach used bridge knowledge gaps or deepen understanding as a needed. Collaborative learning is encouraged, enabling students to share their areas of expertise and perspectives, this is achieved with interactive teaching sessions and group work (Table 2). Students are expected to engage with all module content, but assessments are tailored to reflect diverse interests while still aligning with the intended learning outcomes of the modules. UG students write a letter to the editor and PG students produce an information leaflet. Topic choices for both modules include oncology, cardiovascular medicine, gastroenterology, psychiatry, transplant medicine and infectious diseases.

Discussion

Mid and end of module student feedback has consistently been positive, always scoring >4.2/5. Free text comments positively acknowledge the clinical focus of the modules and the teaching approach and assessment (Table 3). The group debate is highlighted as a positive learning experience. Other areas that are highlighted as positive include clinical relevance, the choice of course work and the understanding demonstrated by the course leaders regarding the mixed backgrounds of the students.

Conclusion

Both modules have provided an engaging and inclusive PGx learning experience for students from diverse academic backgrounds. By using interactive teaching methods and mixed-group activities, our students have developed a detailed understanding of PGx, equipping them for the future. Debate, known to enhance deep learning, critical thinking and communication,³ has been especially effective, serving as an authentic test of knowledge while developing students' communication skills.

References

1. Relling MV, Evans WE. Pharmacogenomics in the clinic. Nature. 2015;526(7573):343-350.

2. Daly AK. Is there a need to teach pharmacogenetics? Clin Pharmacol Ther. 2014;95(3):245-247.

3. Rodger D, Stewart-Lord A. Students’ perceptions of debating as a learning strategy: a qualitative study. Nurse Educ Pract. 2020;42:102681.

103

NHS Greater Glasgow and Clyde (NHS GGC), supporting junior doctors pragmatic prescribing—Clinical pharmacology and medicines safety session for junior doctors

Rhona Shannon¹, Stefanie Lip¹, Waiken Chan¹, Colette Byrne¹, Colin Perry¹, Pamela McCamley², Michael McCrossan² and Linsay McCallum¹

¹NHS Greater Glasgow and Clyde, Queen Elizabeth University Hospital; ²Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde

Background and Aims

Recent studies have shown that focused prescribing teaching can lead to improvements in prescribing ability and confidence.¹ A key recommendation of the Royal College of Physicians is that junior doctors should be supported to safely prescribe and that the prescribing induction should be practically focused covering key safety principles.² In NHS GGC there were limited educational prescribing sessions for newly qualified Foundation Year 1 (FY1) doctors. To address this, an innovative prescribing session for new FY1 doctors joining NHSGGC was curated. This session utilised a multidisciplinary approach consisting of the NHS GGC Medical Education Team, Medicines Governance Pharmacists, Clinical Pharmacologists and Safer Use of Medicine Committees. Key high risk prescribing areas were identified from current prescribing incidents. Our aim was to improve prescribing confidence of newly qualified FY1s joining NHS GGC by delivering a targeted prescribing safety education session during their induction.

Summary of Session and Outcomes

The session outline is shown in Figure 1. The pre- and post-session survey feedback is demonstrated in Figure 2. Pre-session, low prescribing confidence was reported in multiple key areas. In the post-session survey, there was an improvement in confidence, especially in prescribing of gentamicin and vancomycin, palliative care, opioids and insulin. Pre-session, 64% of FY1s did not have exposure to NHS GGC prescribing charts. Following the session 35% of FY1s still requested further support with prescribing.

Discussion

Positive feedback was received following this session as it provided a hands-on approach to prescribing and increased familiarity with prescribing charts. An increase in confidence was observed from the pre- and post-surveys. However, evaluation of prescribing confidence needs to be continuous over the FY1 year. In order to support this, we have organised drop-in prescribing workshops in local hospital sites.

Conclusions

A targeted prescribing safety education session can increase confidence in newly qualified FY1s before they start; however, continuous support and evaluation of confidence is required. This session will be provided for subsequent FY1 inductions in NHS GGC to foster good prescribing practice early on, to try to reduce the incidence of medicine prescribing incidents which directly impact upon patient care.

Reference

1. Ross S, Ryan C, Duncan EM et al Perceived causes of prescribing errors by junior doctors in hospital inpatients: a study from the PROTECT programme; BMJ Quality & Safety 2013;22:97-102.

2. The Royal College of Physicians (RCP). Supporting Junior Doctors in Safe Prescribing Guide 2017. https://www.rcp.ac.uk/media/2ujnwmba/supporting-safe-prescribing_0_0.pdf Accessed on 3.9.24.

110

Evaluation of the knowledge, perception and attitude of non-healthcare students on antibiotics and antibiotic resistance: A study in the Central University, Ghana

Peace Doe¹, Cynthia Amaning Danquah, Kwasi Adomako Ohemeng, Geeta Hitch, Michael Annan Kasukose, Melvina Amma Dukely, Kwabena Oteng-Boahen and Michael Ofori

¹Central University, Ghana; ²Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences (FPPS), College of Health Sciences (CHS), Kwame Nkrumah University of Science and Technology (KNUST); ³Department of Medicinal Chemistry, School of Pharmacy. Central University; ⁴Faculty of Health Sciences and Wellbeing, University of Sunderland in London (Formerly of University of Sussex), 197 Marsh Wall, Docklands, London, E14 9SG, UK

Background and Aims

Antibiotics have played an essential role in the management of infectious diseases since penicillin was discovered over 100 years ago and their use in healthcare has improved the health and wellbeing of patients over the years¹. Along with these benefits, the misuse of antibiotics has emerged contributing to the development of multidrug-resistant microorganisms.² It is imperative to consistently evaluate the use of antibiotics among the public. This study was designed to evaluate the knowledge, attitude and perception of non-healthcare students on antibiotic use and antibiotic resistance in Central University, Ghana.

Summary of Work

A cross-sectional study was carried out at Central University, Ghana. The questionnaire (both online and paper forms) was administered to undergraduates studying non-health care programs. The questionnaire included questions on respondents' knowledge, attitude and perception on the use of antibiotics and antibiotic resistance. Data were analysed using STATA analysis software version 12.0.

Discussion

The sample size comprised 1000 students with 550 being females and 450 males. Of these, 60.96% stated that they had used antibiotics within the last 12 months. A small number of respondents (31%) indicated that they always consulted with a physician before starting an antibiotic and students (68.75%) across all levels agreed that most colds get better on their own without antibiotics. This study also showed a significant association between students' knowledge of antibiotics and their level of study (p < .01). Over half of them (60.96 %) had taken antibiotics orally in the last 12 months with just 16% prescribed by a doctor. This study also found that respondents whose household or family member worked in the healthcare sector were unlikely to obtain their antibiotic medication from an approved healthcare provider compared to others (Figure 1).

Conclusion

Our study suggests that most of the respondents were aware of the severity of antibiotic resistance but almost all of them had inadequate knowledge on the use of antibiotics because non-healthcare students are often overlooked when it comes to antibiotic education programs. There is therefore a need to include information programs on the judicious use of antibiotics and antibiotic resistance as part of all degree programs.

References

1. Piddock LJV. The crisis of no new antibiotics--what is the way forward? Lancet Infect Dis. 2012;12(3):249-253. https://doi.org/10.1016/S1473-3099(11)70316-4

2. Magill SS, Edwards JR, Beldavs ZG, et al. Prevalence of antimicrobial use in us acute care hospitals, May-September 2011. JAMA - J Am Med Assoc. 2014;312(14):1438-1446. https://doi.org/10.1001/jama.2014.12923

135

How med students and educators vibe with pharmacology teaching at Barts and The London Medical School

Raji Lalli and Maryam Malekigorji

Barts and The London School of Medicine and Dentistry

Background and Aims

Pharmacology knowledge and prescribing skills are crucial competencies for medical students, directly contributing to their readiness for clinical practice¹ (A1, A4). Despite this, past research indicates dissatisfaction among students with the current pharmacology education, raising concerns about their preparedness.² This study aims to evaluate the perceptions of medical students and educators at Barts and The London School of Medicine and Dentistry concerning the teaching methods in the MBBS programme, with a focus on informing curriculum development and enhancing teaching practices¹ (K2, K6).

Methods and Summary of Work

To capture a comprehensive view, two online questionnaires were distributed: one targeting medical students and another for educators in the Institute of Health Sciences Education. Responses from 82 students and 6 educators were collected and analysed. Quantitative data were processed using Microsoft Excel, and thematic analysis was applied to qualitative responses.³ This approach aligns with the UKPSF dimensions of assessing and evaluating student learning¹ (A3) and critically reflecting on professional practices¹ (A5).

Results and Discussion

The results revealed concerns regarding the organisation of pharmacology teaching, the effectiveness of e-learning tools such as SCRIPT and the lack of practical prescribing experiences, as perceived by students (Table 1). Educators, while recognising these challenges, emphasised the need for more clinical context and streamlined content delivery (Table 2). The feedback underscores the necessity of a more integrated and student-cantered curriculum, promoting active engagement and effective learning experiences¹ (K3, V1).

Conclusions

The findings suggest that restructuring the pharmacology curriculum is essential to better align with student needs and the UKPSF's emphasis on promoting effective learning environments¹ (K4, V2). Recommendations include enhancing the integration of pharmacology throughout the curriculum, increasing practical training opportunities and improving e-learning resources to support diverse learning needs. These changes are expected to foster a more inclusive and effective learning experience, in line with the principles of the UKPSF¹ (V3).

References

1. Advance HE. The UK Professional Standards Framework for Teaching and Supporting Learning in Higher Education 2011. 2011. https://www.advance-he.ac.uk/knowledge-hub/uk-professional-standards-framework-ukpsf

2. Kennedy MB, Williams SE, Haq I, Okorie M. UK medical students' perspectives on practical prescribing teaching and learning provisions: a cross-sectional survey. Eur J Clin Pharmacol. 2019;75(10):1451-1458. https://doi.org/10.1007/s00228-019-02718-w

3. Braun V, Clarke V. Using thematic analysis in psychology. Qual Res Psychol. 2006;3(2):77-101. https://doi.org/10.1191/1478088706qp063oa

161

Comparison of post-graduate clinical pharmacology and therapeutics curricula and trainees' experience in the United Kingdom and Sri Lanka

Patkiri Mudishya Abeywickrama^1,2, Reya V. Shah^1,3 and Daniel Burrage^1,3

¹St. George's University Hospitals NHS Foundation Trust; ²Post-Graduate Institute of Medicine, University of Colombo; ³City St. George's University of London

Background and Aims

Clinical Pharmacology and Therapeutics (CPT) is an essential medical specialty that focuses on the safe, effective and economic use of medications. It is a well-established field in the United Kingdom but an emerging one in Sri Lanka. A comparison was conducted to identify similarities and differences in the postgraduate CPT curricula and a trainee's experience in each country.

Summary of Work and Outcomes

The JRCPTB 2022 curriculum for CPT training in the United Kingdom¹ was compared with the MD-CPT curriculum from the Post Graduate Institute of Medicine, University of Colombo in Sri Lanka.² A desk review was conducted on the curricula objectives, duration and assessment criteria. One trainee from each country was interviewed using a semi-structured questionnaire to identify the learning activities. These activities were classified according to Bloom's Taxonomy of learning and the data was analysed. Both curricula have broadly similar objectives with a portfolio-based assessment. The UK curriculum learning outcomes are generally broader with more flexibility in delivery of training compared to the more detailed outcomes and structure of the Sri Lankan programme.

Discussion

The Sri Lankan CPT programme is a recent innovation modelled on the 2010 UK CPT curriculum whereas UK CPT training is well established and has evolved since 1969.³ The JRCPTB CPT 2022 curriculum has been developed with trainee and stakeholder input and enables diversity in training delivery and opportunities to engage in high-order cognitive activities in both general CPT and within special interest subjects. From a practical perspective, the UK training programme also allows for a fixed salary scale and flexible training. The Sri Lankan curriculum offers a shorter and less flexible training period with a meticulous programme. Trainees experience brief exposure to a broad range of specialties, but limited time to develop longer-term projects, thus providing less exposure to higher-order cognitive skills development. There is also a financial burden for Sri Lankan trainees due to significant salary reduction during training.

Conclusion

Curricula evolution can impact significantly on skills acquisition and trainee experience. This comparison highlights potential development of the new Sri Lankan CPT training programme to enhance training.

References

1. JRCPTB. Curriculum for clinical pharmacology and therapeutics training August 2022. RCP. 2022.

2. PGIM. University of Colombo, Prospectus for board certification in clinical pharmacology & Therapeutics 2020:2020.

3. Aronson, J. K. A manifesto for clinical pharmacology from principles to practice. Br J Clin Pharmacol. 2010, 70 (1), 3-13. DOI: 10.1111/j.1365-2125.2010.03699.x.

183

Analytics of pharmacology course scores against overall academic performance among bachelor of nursing science students at national open University of Nigeria

Helen Kwanashie and Olugbenga Ojo

National Open University of Nigeria

Background and Aims

Established in 1983 as a springboard for open and distance learning (ODL) in Nigeria, the National Open University of Nigeria (NOUN) became operational in 2002. Until 2023 when three other single-mode open universities were licensed by the National Universities Commission, NOUN was the only ODL university in the country, offering flexible, accessible and affordable degree programmes including Bachelor of Nursing Science (BNSc). To be admitted into the BNSc programme, the candidate must be a registered nurse (RN) with Nursing and Midwifery Council of Nigeria (NMCN), have a valid practice license and be working in a clinical setting for the 4-year duration of the study programme. For graduation, one Pharmacology course, namely, NSC307-Clinical Pharmacology and Chemotherapy being one (1) of fifty-nine (59) compulsory courses in addition to one (1) of three (3) elective courses must be passed by the student at ≥50% equivalent to Grade C or higher. Our earlier study had demonstrated close association of biochemistry grades with subsequent performance in pharmacology and overall performance in a Nigerian pharmacy school.¹ Similar reports from elsewhere have been made for pharmacology among medical students.^{2, 3} An understanding of how pharmacology score is associated with academic performance will be useful in diverse ways including curriculum adjustments, counselling, early intervention and other learner support services. Thus, the aim of this study was to undertake analytics of the sole pharmacology course scores including impact (if any), on overall students' performance as determined by graduating CGPA, among BNSc students at NOUN, from the inception of the programme to date. To achieve this aim, the theories and principles translated in the study were educational data mining, correlation and causation analysis as well as predictive analytics.

Summary of Work and Outcomes

The data collected were a composite pharmacology course score, cumulative grade point average (CGPA) at graduation and gender (as a demographic information) for each of all 9958 graduated BNSc students from inception of the programme to date. A pharmacology course score (maximum being 100 marks) was made up of three (3) continuous assessment CBT scores (also known as Tutor-Marked-Assignments or TMAs totalling 3 × 10 = 30 marks maximum), plus a final Pen-on-Paper (PoP) essay-type examination in which students were required to answer one compulsory question (30 marks) and two out of three other questions (20 marks each), totalling 70 marks maximum. The CGPA (an average of all accumulated grade points earned by a student at any point in time, and generally considered to be a fair and acceptable index of academic performance) was recorded as such on a scale of 5.00 maximum (CGPA_CGPA) up to the first semester of the 2022 academic session (2022_1) and as a percentage (CGPA_Percentage) from 2022_2 to 2024_1; change being at the dictates of the NMCN. These methodologies are not specific to pharmacology and would apply to generic similar studies. Sixty-three percent (63%) of the cohort size of 9958 (amounting to 6274 students) were captured within the older CGPA_CGPA format whereas the balance thirty-seven percent (37%) made up of 3684 students were captured under the newer CGPA_Percentage format. Statistical analysis carried out were correlation, regression and comparative analyses using SPSS version 25, with outcomes summarised in the below. Other than gender differences in parts of Table 2 (new CGPA_Percentage format), the outcomes of the correlation and regression analyses were similar for both the old and new formats of measuring overall academic performance (Table 1, Figures 1 and 2).

Discussion

The Pearson correlation coefficient, r, of 0.261 and 0.266 indicated positive but weak relationship between pharmacology course score and CGPA as shown in Table 1 and depicted in the scatter plots in Figures 1 and 2. The broad spread of points across the charts indicated that factors other than pharmacology course score also influenced the CGPA. The correlations were statistically significant being p = .000 (≤.01) for both old and new CGPA formats. The corresponding student sizes of 6274 and 3684 representing 63.00% and 37.00% of the total 9958 students were large enough for statistical validity of the aforementioned correlations. Qualitatively and quantitatively, the regression analysis, outcome and their importance are similar to those of the correlation analysis. However, Table 2 shows that the statistically significant difference between female and male students with male students having a higher mean CGPA of 0.332 in the older CGPA_CGPA format, was absent in the newer CGPA_Percentage format. Whereas the associations between pharmacology course score and CGPA were positive and significant, their weakness indicates that other factors were also influencing the students' overall academic performance. Such factors which may include student age, admission scores, number of semesters spent on the programme, location of study centres within Nigeria's predetermined six (6) geo-political zones, study strategy, among others, would constitute further research. Similar assessments of the impacts of some other courses, for example, anatomy, physiology and biochemistry (especially using a mixed-methods approach), need to also be carried out as the outcomes may have implications such as curriculum adjustments, support for targeted learners and academic advising. The aim of the project was met and the study will continue to further define relationships within and between the three TMAs and PoP examination using mixed-methods approaches including surveys, focus group discussions and interviews because it is expected that the outcomes may lead to changes that will improve the teaching-learning of pharmacology by nursing students.

Conclusion

There is a weak but statistically significant positive correlation between pharmacology course score and overall academic performance although understandably, other factors are also likely influencing the students' overall performance. The study outcome has contributed to scholarship, pharmacology and nursing education and may be adapted for more extensive benefits within the wider education community.

References

1. Kwanashie, H. and Abdu-Aguye, I. (1990). Association of biochemistry grades with subsequent performance in pharmacology and overall performance in a Nigerian pharmacy school. Biochem Educ. 18 (1), 16-7. https://doi.org/10.1016/0307-4412%2890%2990009-D

2. Nicolaou, S.A., Televantou, I., Papageorgiou, A. et al. (2024). Factors affecting pharmacology learning in integrated PBL in diverse medical students: a mixed methods study. BMC Med Educ. 24, 324. https://doi.org/10.1186/s12909-024-05289-2

3. Charan, J. and Vegada, B. (2019). Prediction of scores in pharmacology in the second MBBS university examination based on previous academic performance and gender of the students: a pilot study. Nat. J. Physiol Pharm Pharmacol. https://doi.org/10.5455/njppp.2019.9.0100526122018

213

Promoting student engagement in through digital game-based learning and non-linear storytelling

Harrison Crask, Brandon Linck-Hernandez, Harley Stevenson-Cocks and Christina Elliott

School of Biomedical, Nutritional & Sport Sciences, Faculty of Medical Sciences, Newcastle University

Background and Aims

Game-based learning is a powerful educational tool that promotes student engagement, motivation and deep learning.¹ It encourages critical thinking, problem-solving and creativity in a low-risk space and provides immediate feedback to reinforce understanding and adaptation. Game-based learning also fosters collaboration and teamwork. As part of our widening participation summer school, we have co-created with student partners a digital game-based learning resource to teach antimicrobial resistance. The aim of this project was to demonstrate proof of concept for these approaches to create an engaging learning experience and to build learning community.

Summary of Work and Outcomes

We created the game ‘Astrobiotics: Resistance Rising’, a choose-your-own adventure style game built in Twine (https://twinery.org/) and open-source tool for interactive nonlinear storytelling. The student players must navigate a series of interactive scenarios and branching storylines that present choices about antibiotic use, highlighting the consequences of misuse or overuse (Figure 1). Importantly, students must balance three key metrics [health, antibiotic resistance, money] to complete the game. After the game-based learning session on campus student experiences were captured by a short survey using a 5-point Likert Scale.

Results and Discussion

Student feedback indicates that they felt motivated to play the game and they felt it helped their understanding of the subject matter. Importantly, we found that the game-based learning session provided students the opportunity to connect with peers which overall enhanced their learning experience (Table 1). This project provided important proof-of-concept and technical knowhow and has formed the basis for collaborations for further game-development to support our laboratory practical skills provision.

Conclusion

Reference

1. Lester D, Skulmoski GJ, Fisher DP, et al. Drivers and barriers to the utilisation of gamification and game-based learning in universities: a systematic review of educators' perspectives. British Journal of Educational Technology. 2023;54:1748–1770. https://doi.org/10.1111/bjet.13311

238

The pharmacological effect of drugs of abuse—Can this be communicated to prevent students taking drugs?

Vaibhavi Sargade, Laura Sadofsky and Daniel Preece

Hull York Medical School, University of Hull

Background and Aims

Drug abuse among students is a serious issue with significant implications on academic performance, mental health and long-term wellbeing. Particularly, young adults are more vulnerable to drug use, which can lead to adversely affecting their psychological development. Traditional drug prevention programmes often focus on general awareness and social factors, but lack in-depth pharmacological education. Therefore, providing education on specific pharmacological and psychological effects of drugs could significantly enhance the effectiveness of prevention programs. This study, which was a dissertation project for a taught master's programme, aimed to assess if an educational intervention emphasizing the pharmacological and psychological effects of drugs can reduce drug use amongst students during their university years.

Method

Using a mixed-method approach, the study utilized a cross-sectional design involving 48 undergraduate university students selected via convenience sampling. All participants completed pre- and post-intervention surveys to measure their knowledge, attitudes and intentions towards drug use. The intervention included a recorded presentation on how these drugs of abuse affect brain function, behaviour and mental health. Quantitative data was analysed using descriptive statistics and paired t-tests to analyse the changes in knowledge and attitudes. Qualitative data was analysed through thematic analysis to identify recurring themes and insights from open-ended questions.

Results

The intervention showed a significant improvement in drug knowledge with a mean score of 2.83 (± 1.117) to 4.23 (± 0.778) (p ≤ .001) after intervention. Additionally, a positive shift in attitude was also observed with scores increasing from 3.35 (± 1.061) to 4.06 (± 0.755) (p ≤ .0.001). Despite these gain in knowledge, the intervention's effect on the participants intentions to use drugs were mixed. The proportion of students who felt unlikely to use drugs decreased marginally from a mean score of 2.645 (± 1.522) to 1.93 (± 1.099) (p = .19). This suggested that, while students pharmacological understanding improved, it did not deter drug use. While some participants were reinforced in their decision to avoid drugs, others remained uncertain about changing their behaviour.

Conclusion

The study highlights the importance of educational interventions in drug prevention, highlighting their role in improving knowledge and attitudes. However, to more effectively prevent drug use, such programmes should be implemented with continuous support, counselling and community involvement. The study suggests that, a comprehensive approach merging educational content with practical prevention techniques is essential. Overall, this study offers insights into effective drug abuse prevention strategies and underscores the need for ongoing refinement.

290

Enhancing research skills in pharmacy education: Outcomes of the PEAN's online research internship programme

Elijah Sunom Umaru and Kenneth Bitrus David

Pharmafluence Education Advancement Network, Nigeria

Background and Aims

The development of research skills among pharmacy students is crucial for advancing pharmacological sciences. The Pharmafluence Education Advancement Network (PEAN) launched a 9-week online Research Internship Programme to address the research skills gap among Nigerian undergraduate and recent graduate pharmacy students. Drawing on experiential learning theory¹ and the Communities of Practice model,² the programme aimed to foster a collaborative learning environment. This work adds to the pedagogical literature by evaluating the impact of mentorship-based research training in enhancing both theoretical knowledge and practical application within a pharmacology context.

Summary of Work and Outcomes

Twenty-six pharmacy students were selected for the programme, with 23 completing it successfully. The programme was structured around research modules facilitated by renowned scientists. Data collection included participant surveys and feedback sessions to measure the effectiveness of the training. The intern cohort was predominantly male (65.2%) and undergraduate (69.6%). Seventy-six per cent (76%) of participants reported significant gains in their understanding of research methodologies and their confidence in conducting independent research. The benefits extended beyond technical research skills, with improvements also noted in communication, collaboration and critical thinking—all of which are key generic competencies within pharmacology education. Recommendations from participants highlighted the need for more individualized assignments and session recordings to enhance learning flexibility.

Discussion

The programme's objectives were largely met, evidenced by the participants' improved research proficiency. Continued iterations of the programme will integrate individualized tasks to ensure equitable participation and session recordings to accommodate scheduling challenges. This research-led teaching initiative provides a scalable model for pharmacy education, contributing to both the teaching literature and the development of new mentoring frameworks. It suggests that pairing research training with mentorship can enhance learning outcomes in pharmacology education, with the potential to inform similar programs across the field.

Conclusion

References

1. Kolb DA. Experiential learning: experience as the source of learning and development. Prentice Hall; 1984.

2. Wenger E. Communities of practice: learning, meaning, and identity. Cambridge University Press; 1998.

291

Improving prescribing in acute maternity setting

Jemima Weir, Ursula Pendower and Lila Mayahi

St George's Hospital

Background and Aims

Maternity patients have medical co-morbidities,¹ requiring prescribed medication.² Reliable and accurate prescription of regular medications is an important aspect of inpatient maternity care and safety. Accuracy of prescriptions in inpatient maternity settings at St George's Hospital was assessed in aid of teaching safe practice to all doctors as prescribing in pregnancy is challenging area of practice for all clinicians.

Summary of Work and Outcomes

We sought to establish current practise by surveying all maternity inpatients (antenatal, labour and post-natal wards) over a period of four week in March 2024. For each patient the drugs prescribed as an inpatient were documented, along with regular medications in their drug history. For each patient length of stay was recorded (critically if remained an inpatient for >48 h when medicine reconciliation is due as per local medicines management policy) as was the presence or absence of a pharmacy medicines reconciliation. A total of 151 patients were surveyed, 51 (33%) took regular medications and were inpatients >48 h, only 1 of these patients (0.02%) received a medicines reconciliation. In total, 13 (19.6%) had their regular medicines correctly prescribed. A total of 118 medications were due and 40 were prescribed correctly (33.8%).

Discussion

Our results suggest current systems in place at our hospital are not working to ensure accurate prescription of patients' regular medications. A very small percentage of patients had their regular medications prescribed correctly and with almost no medicines reconciliation. There are areas of education, implementation of policies and training that could impact safer and more appropriate practice of prescribing and medicine reconciliation.

Conclusions

This work shows the important goal of safe prescribing practice for all doctors and understanding barriers in timely medicines reconciliation in maternity setting. Training and education would be the cornerstone for achieving this goal.

References

1. Lee SI, Ascomata-Lorenzo A, Agrawal U, et al. Epidemiology of pre-existing multimorbidity in pregnant women in the UK in 2018: a population-based cross-sectional study. BMC Pregnancy Childbirth 2022;22(1):120. https://doi.org/10.1186/s12884-022-04442-3

2. Daw JR, Hanley GE, Greyson DL, Morgan SG. Prescription drug use during pregnancy in developed countries: a systematic review. Pharmacoepidemiol Drug Saf. 2011;20(9):895-902. https://doi.org/10.1002/pds.2184

138

The clinical potential of targeting the FFA4 receptor in COPD and asthma

Bethany Strellis, Jeffrey Y. Lee, Ilan Davis, Graeme Milligan and Andrew B. Tobin

University of Glasgow

Lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) lead to abnormal structural changes and lung growth with chronic inflammation. The free fatty acid receptor 4 (FFA4) has been implicated in the regulation of inflammation (reviewed in Duncan et al.¹), and FFA4 agonists have shown promise as therapeutic agents in reducing inflammation in preclinical studies.^2,3 However, the precise physiological role of FFA4 in the lung remains underexplored. Our aim is to profile the expression of the FFA4 receptor within the airway and to explore the functional role of this receptor in a model of lung disease.

To profile the transcriptional landscape of the FFA4 receptor in the lung, hybridization chain reaction followed by single molecule fluorescence in situ hybridization was performed on 10 μm formalin-fixed paraffin embedded lung sections from wildtype and FFA4-KO mice. To analyse FFA4 protein expression, lung was dissected from FFA4-HA and FFA4-KO mice and Western blot analysis performed utilizing the anti-HA antibody against the HA-epitope tag present on the C-terminal tail of the receptor. To examine the functional role of FFA4 in the lung, 100 μM Carbachol was administered onto precision cut lung slices (PCLS) from wildtype, FFA4-HA and FFA4-KO mice to cause bronchoconstriction. To test whether FFA4 can relax the constricted airways, 100 μM of the FFA4 agonist TUG-891 was added to the lung slices. The resulting changes in airway diameter were imaged using the eVOS microscope.

Our findings demonstrate that FFA4 is expressed in the lung and plays a role in airway relaxation. Spatial transcriptomic analysis revealed that FFA4 is transcribed throughout the airway. Moreover, we also detected FFA4 at a protein level in the lung. The PCLS model demonstrated significant contraction of the airway lumen following carbachol treatment in all three mouse lines (P < .0001, two-way ANOVA; n = 6); however, only the wildtype and FFA4-HA mouse lines gave significant airway relaxation following treatment with TUG-891 (P < .05, two-way ANOVA; n = 6). No significant changes were observed in the FFA4-KO lungs (P > .05, two-way ANOVA; n = 6).

These data reveal the presence of the FFA4 receptor in the airway and provide evidence of its function in airway relaxation. This indicates its potential as a therapeutic target for lung diseases involving bronchoconstriction such as asthma and COPD.

References

1. Duncan EM, Nicol LM, O’Hare R, et al. Development of an acute ovine model of polycystic ovaries to assess the effect of ovarian denervation. Frontiers in Endocrinology, 2023;14.

2. Oh DY, Talukdar S, Bae EJ, et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell. 2010;142(5):687–698.

3. Walenta E, Walenta E, Akiyama TE, et al. A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice Nat Med. 2014;20(8): 942–7.

178

Somatostatin receptors in the human pregnant uterus: New insights for labour management

Kylie Hornaday, Stephen Wood and Donna Slater

University of Calgary

Introduction

The somatostatin receptors (SSTR) include five subtypes which primarily link via Gαi to elicit cellular effects via inhibition of adenylyl cyclase,¹ and some modulate L-type Ca²+ channel activity,² the primary route for Ca²+ entry into smooth muscle cells. However, the contribution of somatostatin receptors to uterine smooth muscle contractility during pregnancy and labour has yet to be explored.

Methods

Human uterine tissues (amnion, chorion, decidua, upper and lower myometrium) were biopsied from caesarean section deliveries at Foothills Hospital, Calgary, Canada. Subjects were split into four groups based on gestational age at delivery and presence of labour symptoms (term non-labour TNL, term labour TL, preterm non-labour PTNL, preterm labour PTL, n = 4–6/group). Additional lower segment myometrial biopsies (n = 6) were processed for primary myometrial smooth muscle (MSM) cell culture and then treated with DMSO solvent control, 1 μM prostaglandin E2 (PGE₂) and/or 1 ng/mL IL-1β and harvested 6 h post treatment. Isolated RNA from tissues and cells were analysed via RNA sequencing. Statistical significance was determined using DESeq2 in R v4.2.2.

Results

SSTR1, SSTR2 and SSTR3 were expressed in all uterine tissues, SSTR4 was amnion specific and SSTR5 was not identified in any tissue. Spatial analysis demonstrated that SSTR2 levels were higher in lower myometrium (LFC = 1.55, p-adj = .0008), and SSTR1 levels were higher in upper myometrium (LFC = −1.89, p-adj = .0019). Temporal changes with labour were found in the lower myometrium only, with SSTR1 levels higher at TL compared to TNL (LFC = 1.51, p-adj = .0427). In MSM cells, IL-1β treatment downregulated SSTR1 (LFC = −2.35, p-adj = .0002) and SSTR3 (LFC = −3.19, p-adj << .0001). However, co-treatment with PGE₂ attenuated the IL-1β-mediated downregulation of SSTR1 (LFC = −0.64, p-adj = .4502) and augmented the downregulation of SSTR3 (LFC = −4.77, p-adj << .0001). In contrast, SSTR2 expression was upregulated by IL-1β (LFC = 7.06, p-adj << .0001), and this was attenuated by co-treatment with PGE₂ (LFC = 5.01, p-adj << .0001) (summarized in Figure 1).

Conclusions

Spatial and temporal changes in Gαi-linked somatostatin receptor expression may mediate uterine contractility during labour, with more dynamic changes occurring in the lower myometrium. Subtype-specific response to treatment suggests a possible mechanism for regulating cAMP levels and smooth muscle contraction via inflammatory and prostaglandin signalling.

References

1. Siehler S, Hoyer D. Characterisation of human recombinant somatostatin receptors. 3. Modulation of adenylate cyclase activity. Naunyn Schmiedebergs Arch Pharmacol. 1999;360(5):510-21. https://doi.org/10.1007/s002109900143

2. Tallent M, Liapakis G, O'Carroll AM, Lolait SJ, Dichter M, Reisine T. Somatostatin receptor subtypes SSTR2 and SSTR5 couple negatively to an L-type Ca2+ current in the pituitary cell line AtT-20. Neuroscience. 1996;71(4):1073–81. https://doi.org/10.1016/0306-4522(95)00510-2

278

Dysfunction of COX2/PGE2 pathway and the muscular reactivity of bronchi and pulmonary arteries in COPD patients

Zhipeng Li¹, Salma Mani¹, Badji Hichem¹, Gaelle Merheb¹, Dan Longrois^1,2 and Xavier Norel¹

¹Inserm; ²Hôpital Bichat-Claude Bernard

Introduction

Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation, airflow obstruction and emphysema. The COX2/PGE2 pathway is a critical inflammatory pathway in the human lung and PGE2 concentrations are elevated in plasma of COPD patients.¹ PGE2 mediates a variety of physiologic effects including bronchodilatation and vasoconstriction through interaction with four prostanoid receptors called EP1-EP4. Our previous study showed that EP4 receptor activation is responsible for relaxation in human bronchi.² However, there is no study concerning the levels of PGE2, COX2, mPGES-1 and EP1-4 receptors expressions in COPD bronchi and human pulmonary arteries (HPA). Therefore, that was the aim of this study and muscular reactivity of human bronchi and HPA were evaluated.

Method

Pulmonary preparations were obtained after surgery for cancer or lung transplantation, with ethic committee agreement and informed consent obtained from each patient. We analysed the PGE2 levels, COX2, mPGES1, and EP1-4 receptors expressions in human bronchi and arteries homogenates using western blot, RT-PCR, ELISA and immunohistochemistry (IHC). The effects of PGE2 or carbachol on the muscular reactivity of COPD bronchi and HPA were measured by organ-bath system. Statistical analyses were performed using t-test or one-way ANOVA.

Results

In bronchi, PGE2 (n = 5) level, COX2 (n = 5) and mPGES1 (n = 4) enzymes were significantly increased in COPD patients compared with control. In contrast, EP4 (n = 6) receptor (protein and mRNA) expressions were significantly reduced by 33% in the COPD group versus controls and confirmed by IHC. No difference was found with EP1–3 (n = 3–6) receptors expressions. However, there was no difference in broncho-dilatations between COPD (n = 4) and control (n = 8) preparations. In arteries, no significant difference was found with all receptor expressions (n = 4–6). HPA contractions induced by carbachol, were not different between COPD and control preparations.

Conclusion

Our major results show that EP4 receptor presence is reduced in COPD bronchial preparations; however, that is without consequence on the bronchodilation. Considering the relationship between EP4 and inflammatory cells like macrophages, it may be involved in the inflammatory process of COPD which requires further studies.

References

1. Mani S, Norel X, Varret M, et al. Polymorphisms rs2745557 in PTGS2 and rs2075797 in PTGER2 are associated with the risk of chronic obstructive pulmonary disease development in a Tunisian cohort. Prostaglandins Leukot Essent Fatty Acids. 2021;166:102252. https://doi.org/10.1016/j.plefa.2021.102252

2. Benyahia C, Gomez I, Kanyinda L, et al. PGE(2) receptor (EP(4)) agonists: potent dilators of human bronchi and future asthma therapy? Pulm Pharmacol Ther. 2012;25(1):115–118. https://doi.org/10.1016/j.pupt.2011.12.012

45

Sevuparin effects on local and systemic LPS-induced inflammation in healthy volunteers

Digna de Bruin¹, Matthijs Moerland¹, Annelieke Kruithof¹, Jacobus Bosch¹, Göran Westerberg², Maria Klockare² and John Öhd²

¹Centre For Human Drug Research; ²Modus Therapeutics AB

Introduction

In search of novel treatments for acute systemic inflammatory disorders such as sepsis and endotoxemia, heparin and its derivatives have been suggested as potential candidates. Heparin, aside from its anticoagulant properties, is also known to possess properties that modify inflammation.¹ Sevuparin, a low-anticoagulant heparinoid, is a treatment candidate for acute systemic inflammatory disorders such as sepsis and endotoxemia. This proof-of-mechanism study evaluated the effect of sevuparin on LPS-induced inflammation.

Method

This was a randomized, double-blind, placebo-controlled phase 1 study in healthy participants. Participants received sevuparin (intravenous loading bolus dose of 0.3, 1 or 3 mg/kg followed by an infusion during 6 h at 0.08, 0.25 or 0.75 mg/kg/h, respectively) or placebo and were challenged with intradermal lipopolysaccharide (LPS) (4 injections of 5 ng) in part 1 and with intravenous LPS (1 ng/kg as a bolus injection) in part 2. The local LPS response was evaluated using imaging techniques for skin perfusion and erythema and by performing flow cytometry and cytokine analysis on blister fluid. The systemic LPS response was evaluated by measuring vital signs, circulating cytokine levels, leukocyte subsets and C-reactive protein and by performing flow cytometry.

Results

Seventy-one participants were randomized to study treatment in part 1 and part 2. Sevuparin was well-tolerated. A dose-dependent increase in activated partial thromboplastin time was observed in the active treatment groups, without clinical relevance in the study population. Sevuparin did not significantly modulate the local LPS response. In the systemic LPS challenge, sevuparin significantly increased the circulating basophil, neutrophil and lymphocyte counts at the highest dose level (n = 12) (estimated differences vs. placebo (n = 12): 0.009, p = .0010, 1.077, p = .0100, and 0.401, p < .0001, for basophils, neutrophils, and lymphocytes, respectively). The sevuparin effects on lymphocyte counts were confirmed by immunophenotyping of circulating immune cells. Furthermore, the LPS-induced relative tachypnoea was suppressed to a near-significant elevation in respiratory rate at the highest dose level (estimated difference vs. placebo: −1.3, p = .0598). For other systemic measures, sevuparin did not significantly differ from placebo.

Conclusions

Sevuparin primarily modulated LPS responses of select leukocyte populations and the LPS-driven relative tachypnoea in healthy volunteers. Based on observed pharmacodynamic effects along with the advantageous safety profile, further exploration of sevuparin as a treatment for acute systemic inflammatory disorders such as sepsis and endotoxemia is envisaged.

Reference

1. Mulloy B, Hogwood J, Gray E, Lever R, Page CP. Pharmacology of Heparin and Related Drugs. Pharmacol Rev. 2016;68(1):76–141. https://doi.org/10.1124/pr.115.011247

277

Differential expression of miR-451a between mild or moderate and severe or critical Coronavirus Disease 2019 (COVID-19) patients

Eder Pincinato¹, Julia Siguemoto¹, Marilia Visacri², Aline Nicoletti¹, Carolini Neri¹, Carla Ronda¹, Deise Ventura¹, Lilian Silva¹, Adriana Eguti¹, Mauricio Perroud Junior¹, Leonardo Reis¹, Jose Costa¹ and Patricia Moriel¹

¹Universidade Estadual de Campinas; ²Universidade de São Paulo

Introduction

It is known that patients with coronavirus disease 2019 (COVID-19) can exhibit different symptoms, ranging from mild and moderate symptoms of the upper respiratory tract to severe acute respiratory syndrome, which can lead to multiple organ failure, culminating in death. Many efforts have been made to discover molecular biomarkers for the severity of COVID-19, such as microRNAs (miRNAs).¹ Our preliminary results suggested that miR-451a could be a potential biomarker for the severity of COVID-19.² Therefore, this study aimed to investigate the expression levels of miR-451a in patients with different severities of COVID-19.

Method

This was an observational and multicentre study. The study was conducted in accordance with the declaration of Helsinki and approved by the ethics committee of the Universidade Estadual de Campinas (UNICAMP) (numbers 36041420.0.000.5404 and 31049320.7.1001.5404). All participants or their guardians signed a consent form authorizing the use of their samples and data. Patients with COVID-19 from the Hospital Estadual Sumaré Dr. Leandro Francheschini (HES) (Sumaré-SP, Brazil), the community health centre of the UNICAMP, and Paulínia Municipal Hospital (Paulínia-SP, Brazil) were allocated in mild/moderate or severe/critical groups, accordingly the National Institutes of Health severity criteria. MiRNAs were extracted from plasma of these patients and complementary DNA (cDNA) were synthesized. After that miR-451a and cel-miR-39 (exogenous control) were quantified by quantitative PCR (q-PCR). The expression level of miR-451a was calculated using the 2-∆CT method and subsequently correlated with disease severity. For comparisons between groups, chi-squared or Fisher's exact tests were used for categorical variables and the Mann–Whitney test was used for numeric variables. The significance level was set at 5%.

Results

Eighty-five subjects were enrolled in this study: 42 with severe/critical COVID-19 (59.5% male; 54.6 ± 14.3 years; 23.8% without comorbidities, 52.4% with hypertension, and 57.1% with obesity) and 43 with mild/moderate COVID-19 (44.2% male; 42.6 ± 11.3 years; 55.8% without comorbidities, 25.6% with hypertension and 11.6% with obesity). Expression levels of miR-451a (p < .0001) were significantly lower in the plasma samples of subjects with severe/critical COVID-19 (2-∆CT = 0.002 ± 0.004) compared to subjects with mild/moderate COVID-19 (2-∆CT = 0.085 ± 0.093) (Figure 1).

Conclusion

miR-451a might be used as possible biomarkers for the severity of COVID-19. Moreover, these miRNAs may be potential targets for developing therapeutics to treat severe COVID-19.

References

1. Visacri MB, Nicoletti A, Pincinato EC, et al. Role of miRNAs as biomarkers of COVID-19: a scoping review of the status and future directions for research in this field. Biomark Med. 1, 2021. https://doi.org/10.2217/bmm-2021-0348

2. Nicoletti A, Visacri MB, Ronda C, et al. Differentially expressed plasmatic microRNAs in Brazilian patients with Coronavirus disease 2019 (COVID-19): preliminary results. Mol Biol Rep. 2022;49:6931–6943. https://doi.org/10.1007/s11033-022-07338-9

39

Mitochondrial DNA analysis for acute respiratory distress syndrome patients

Shanshan Meng, Yixuan Chen and Fengmei Guo

Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University

Introduction

Acute respiratory distress syndrome (ARDS) is characterized with high morbidity and mortality in intensive care medicine. Mitochondria and mitochondria DNA (mtDNA) are easily affected with increasing ROS and free radicals, leading to lung dysfunction. The aim of this study was to identify mtDNA variants in ARDS patients applied with mitochondrial genes sequencing.

Method

We enrolled 20 patients diagnosed with ARDS according to Berlin definition. Patients venous blood samples were collected and mtDNA were extracted, amplified and enriched by PCR and tested with Illumina Hiseq platform sequencing. The final sequencing results and clinical characteristics were acquired and analysed in ARDS. We describe mtDNA variants distribution and analysed these in 28-day survivors and 28-day non-survivors.

Results

Totally, 220 mtDNA variants were found in ARDS with highest variant level of Complex I gene and lowest variant level of ATP synthase gene. The average mtDNA variants per patient was 39. For variant locations, 130 variants were in exonic, 63 variants were in intergenic and 27 variants were in ncRNA_exonic. For variant functions, 70% variants in exonic were nonsynonymous. The 28-day survivors had more variants in the whole coding gene and less ND5 variants numbers in (Complex I gene) compared with non-survivors. However, there was no statistical difference between these two groups.

Conclusions

This study profile the variants of mitochondrial genome in ARDS patients. Variants in mtDNA gene had no significant differences between 28-day survivors and 28-day non-survivors. Further studies were needed to explore ARDS mtDNA variants. Supported by funds of China Postdoctoral Science Foundation (2022M710685, 2024T170133).

132

Investigating the relationship between antipsychotic dose, inflammation and cognitive function in schizophrenia—A moderation analysis

Saahithh Patlola¹, Laurena Holleran¹, Maria Dauvermann¹, Karolina Rotika¹, Brian Hallihan¹, Ross McManus², Marcus Kenyon², Colm McDonald¹, Derek Morris¹, John Kelly¹, Gary Donohoe¹ and Declan Mckernan¹

¹University of Galway; ²Trinity College Dublin

Introduction

Schizophrenia is a complex, debilitating psychiatric disorder in which patients experience cognitive decline. Antipsychotic drugs (APDs) alleviate positive symptoms but do not improve cognitive performance. Previous studies indicate that APDs may have an immunomodulatory effect and an effect on cognition.¹ We have previously demonstrated that Toll-like receptors (TLRs) can predict cognitive deficits in schizophrenia patients. In this study, we aim to investigate the moderating effect of APDs on cytokines, TLRs and cognition.

Methods

311 participants (207 healthy controls [HC] and 104 cases schizophrenia [SZ]) were recruited from Galway and Dublin. Venous blood from the participants was treated with the TLR ligands: TLR2–heat-killed Listeria monocytogenes (108-cells); TLR3–polyriboinosinic:polyribocytidylic acid (10 μg/mL) and TLR4–lipopolysaccharide (LPS) (1 μg/mL). Levels of cytokines (Interleukin [IL]-6, IL-8, IL-10, IL-12, tumour necrosis factor-alpha [TNF-α]) and interferon-γ were measured from plasma and post-stimulation. The participants were administered a battery of cognitive tasks using Cambridge-neuropsychological-test-automated-battery and Wechsler-Adult-Intelligence-Scale-IIIR (Table 1). Olanzapine (OLZ) equivalents were calculated using the defined daily dose method.² Data was analysed using principal-component-analysis (PCA), multiple-linear-regression (MLR) and moderation-analysis (MA) using SPSS. TLR4-activity is a composite-score from PCA of LPS-stimulated cytokine levels.

Results

First, we explored whether APDs predicted the cytokine levels, TLR-activity and cognitive measures of the whole population using MLR. The results (Table 2) indicate that APD dose could predict TLR4-activity (B = 0.01; p = .024) and three cognitive domains: FSIQ (B = −0.14; p = .045), APS (B = −0.19; p = .003) and SC (B = −0.06; p = .003), further indicating that increasing APD dose decreases cognitive performance. We then investigated whether the APD dose moderated the relationship between TLR4-activity and the cognitive domains using MA. We found that TLR4-activity does not directly affect FSIQ and SC (Figure1). Moreover, the effect of TLR4-activity on these cognitive domains is not dependent on the APD dose. Although TLR4-activity alone does not directly impact APS, together with APD dose, it significantly (XW; B = 0.14; p < .05) improves APS scores (Figure 1a).

Conclusions

References

1. Patlola SR, Donohoe G, McKernan DP. Counting the toll of inflammation on schizophrenia—a potential role for toll-like receptors. Biomolecules. 2023;13(8):1188.

2. Leucht S, Samara M, Heres S, Davis JM. Dose equivalents for antipsychotic drugs: the DDD method. Schizophr Bull. 2016;42(Suppl 1):S90-4. https://doi.org/10.1093/schbul/sbv167

12

Vitamin misuse during the pandemics. How much is too much?—Single-centre experience

Marija Petrusevska, Dragica Zendelovska and Emilija Atanasovska

Faculty of Medicine, Institute of Preclinical and Clinical Pharmacology and Toxicology

Background and Aims

The global pandemic crisis affected almost every society and economy, challenged almost every health system worldwide. Above all, governments and non-governmental organizations had to fight with the misinformation and conspiracy theories placed by the social and mass media. All of this had a profound impact on the public in terms of vaccines safety and the advantages of vitamin use in fighting the virus. This fear has opened doors to alternative medicines such as supplements (vitamins, minerals, herbal products, oils) that may have profound effect on the immune system.

Our aim was to determine the pattern of use of supplements during the pandemics in healthy individuals tested negative for SARS-CoV-2.

Methods

33 healthy individuals tested negative for SARS-CoV-2 in the pandemic period were included (Group 1). Total antioxidant power, iron reducing (PAT) and plasma peroxides (d-ROMs) were measured using FRAS5 analytical photometric system and are reported in equivalents of ascorbic acid and H₂O₂, respectively. The oxidative stress index (OSI) was automatically calculated by the software. The obtained values were compared with 30 healthy individuals analysed prior pandemics (Group 2).

Results

The mean values for oxidative stress parameters in Group 1 versus Group 2 were as follows: d-ROMs 418 versus 266 U. Carr, PAT 3862 versus 2554 U. Carr and OSI 111 versus 36. In all comparisons, a statistically significant difference was obtained (p < .05, t-test). Individuals belonging to Group 1 had reported that they have consumed daily doses of Zinc (30 mg), Vitamin C (at least 1000 mg) and Vitamin D (at least 2000 IU) in a period of >1 month. Several of them have also used isoprinosine, magnesium and selenium.

Conclusions

Uncontrolled intake of supplements can have a profound effect on the pro- and antioxidant balance resulting in interruption of the physiological balance and leading to increased oxidative stress index in otherwise healthy individuals.

References

1. Meulmeester FL, Luo J, Martens LG, Mills K, vanHeemst D, Noordam R. Antioxidant supplementation in oxidative stress-related diseases: what have we Learned from studies on alpha-tocopherol? Antioxidants (Basel) 2022;11(12):2322.

2. Rafieian-Kopaei M, Baradaran A, Rafieian M. Oxidative stress and the paradoxical effects of antioxidants. J Res Med Sci. 2013;18(7):629.

3. Halliwell B. The antioxidant paradox: less paradoxical now? Br J Clin Pharmacol. 2013;75(3):637-44.

91

Denosumab versus zoledronic acid in the treatment of osteoporosis: A systematic overview of economic evaluations

Andrej Belančić^1,2, Marijana Vučković³, Josipa Radić³, Mislav Radić⁴ and Dinko Vitezić^1,2

¹Department of Clinical Pharmacology, Clinical Hospital Centre Rijeka; ²Department of Basic and Clinical Pharmacology with Toxicology, Faculty of Medicine, University of Rijeka; ³Department of Nephrology and Dialysis, University Hospital Centre Split; ⁴Department of Clinical Immunology and Rheumatology, University Hospital Centre Split

Introduction

This systematic review aimed to overview the body of evidence on cost-effectiveness of denosumab versus zoledronic acid for managing osteoporosis in adults at increased risk of fractures, in order to obtain both direct and indirect pharmacoeconomic comparisons between the latter agents.

Method

We have conducted a systematic literature review (as per PRISMA guidelines). Studies written in English, cost-effectiveness analyses (CEAs) and cost-utility analyses (CUAs) on denosumab (a single subcutaneous injection of 60 mg administered once every 6 months) and zoledronic acid (a single intravenous infusion of 5 mg administered once a year) for the treatment of osteoporosis and comparisons of those regimens against each other. A comprehensive search [(osteoporosis) AND (denosumab) AND (zoledronic acid) AND (econom* OR economic evaluation)] was conducted across PubMed/Medline database on 19th June 2024. Studies published between 2017 and June 2024, and using data after 2017, were deemed appropriate. Including studies that had been published before 2017 may have led to inclusion of out-of-date data, as the reimbursement and health economics environment changes regularly. Finally, data from the eligible studies was manually extracted.

Results

The literature search yielded 22 records in total. Following screening, 4 CEAs (1 United States, 1 Japan, 2 China, respectively) were included for further analysis.^1–4 Markov model was identified as the predominant modelling approach, whilst healthcare sector was the most commonly applied perspective. Economic outcomes of the included studies were conflicting and varied widely. Thus, we have also screened a systematic review by Li N et al.⁵ and identified several indirect comparisons between the two agents, which are potentially pointing out zolendronic acid as the more cost-effective option compared to denosumab.

Conclusions

Although the body of literature on the present topic is still quite scarce and conflicting, bearing in mind the aforementioned indirect economic findings as well as the wider availability of generics on the market, zoledronic acid seems to be a more cost-effective option. However, further head-to-head comparisons between the two agents, on national and regional levels, are highly needed to set the final conclusions. Due to high burden of the disease, those findings may result in the notable improvement of overall osteoporosis care, quality of life and allocation of financial resources.

References

1. Luo C, Qin SX, Wang QY, et al. Cost-effectiveness analysis of five drugs for treating postmenopausal women in the United States with osteoporosis and a very high fracture risk. J Endocrinol Invest. 2023 46(2):367-379. https://doi.org/10.1007/s40618-022-01910-7

2. Mori T, Crandall CJ, Fujii T, Ganz DA. Cost-effectiveness of zoledronic acid compared with sequential denosumab/alendronate for older osteoporotic women in Japan. Arch Osteoporos. 2021;16(1):113. https://doi.org/10.1007/s11657-021-00956-z

3. Tian L, Luo C, Li YF, Wang QY, Qu XL, Yue C, Xu LL, Yang YY, Sheng ZF. Economic evaluation of four treatment strategies for postmenopausal patients with osteoporosis and a recent fracture in mainland China: a cost-effectiveness analysis. Arch Osteoporos. 2023;18(1):100. https://doi.org/10.1007/s11657-023-01309-8

4. You R, Mori T, Ke L, Wan Y, Zhang Y, Luo F, Feng D, Yu G, Liu J. Which injected antiosteoporotic medication is worth paying for? A cost-effectiveness analysis of teriparatide, zoledronate, ibandronate, and denosumab for postmenopausal osteoporotic women in China. Menopause. 2021;29(2):210-218. https://doi.org/10.1097/GME.0000000000001911

5. Li N, Cornelissen D, Silverman S et al. An updated systematic review of cost-effectiveness analyses of drugs for osteoporosis. Pharmacoeconomics. 2021;39(2):181-209. https://doi.org/10.1007/s40273-020-00965-9

98

Is there a difference in the rate of resistance in Escherichia coli between bloodstream samples versus urine samples in the data shared with the World Health Organization (WHO) Global Antimicrobial Resistance and Use Surveillance System (GLASS)?

Saffiya Pirbhai

St Georges University of London

Introduction

This project aims to investigate whether there is a difference in the rate of resistance in Escherichia coli (E. coli) in bloodstream infections (BSI) versus urine samples, where E. coli was chosen as an indicator organism to help us determine if urine samples could be a proxy for the prevalence of resistance in sterile infections such as BSI improving patient care and combatting antimicrobial resistance (AMR). Resistance changes over time in different countries and is often monitored using sterile samples, it would be advantageous to use non-sterile samples. BSI in low-income countries are challenging to diagnose due to limited laboratory facilities. E. coli is often an indicator organism used to detect faecal organisms and water contamination. There is insufficient research done to compare resistance in sterile versus non-sterile sites for surveillance purposes.

Method

The World Health Organisation Global Antimicrobial Resistance and Use Surveillance System (GLASS) collates data from 109 participating countries through passive surveillance. This data was used to analyse the resistant proportions of E. coli bacteria in BSI versus urine samples. There was an abundance of data from Europe, and differences in resistance profiles from the United Kingdom (UK) and (Northern Ireland) NI, and Switzerland. Linear regression analysis was used to investigate correlations between two continuous variables such as antibiotic resistance and the years 2017–2020 in Europe. Switzerland contained the most data to compare resistance between blood and urine samples, representing the primary aim of the research. A t-test was conducted to determine whether there was a difference in resistance rates between the two sample types.

Results

In the UK and NI, the resistance in E. coli was highest to beta-lactam antibiotics, reaching a peak of 51.57% in 2017 with a non-significant fluctuation in antimicrobial resistance between 2017 and 2020 (p = .015). Comparison of resistance between blood and urine samples indicated no difference in prevalence of resistance of E. coli from blood versus urine samples (p = .615) in 2018.

Conclusions

From the GLASS report (2022), E. coli was the most frequently isolated pathogen with resistance variable over time (23 European countries) and the rates of resistance in BSI versus urine infections suggest urine would be a good proxy for detecting resistance in sterile samples particularly where laboratories are scarce.

We found no difference in the rate of resistance of E. coli in blood versus urine samples in Switzerland, but the prevalence of resistance increased over four years (UK and NI). An expanded data set with more data from low- and middle-income countries show a big difference, although this is complicated by limited healthcare facilities and poor sanitation.

112

Exam-induced hormonal fluctuations: The impact of academic stress on male university students' oxytocin and cortisol levels

Marwa Hamza¹, Mohamed Selim¹, Amira Taha¹, Asmaa Amr¹, Eman Younes¹, Gannat Gamal¹, Heba Khamis¹, Rana Ahmed¹, Rawan Mahmoud¹, Waleed Fathy¹, Yomna Ragab¹ and Mervat M. Omran²

¹Clinical Pharmacy Practice Department, Faculty of Pharmacy, The British University in Egypt; ²Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University

Introduction

Stress and social anxiety became prevalent among university students. Stress typically increases cortisol (COR), yet oxytocin (OXT) is thought to lower stress. OXT was shown to be anxiogenic in some investigations yet anxiolytic in others. This study aimed to investigate the influence of acute stress (exams) on salivary OXT and salivary COR levels among anxious university students.

Methods

A pre-post one-arm study was conducted with 46 male pharmacy students from the British University in Egypt. Saliva samples were collected before and after exams to measure OXT and COR levels. The study used passive drooling for sample collection, and the samples were taken around noon to account for diurnal rhythms. The Westside Test Anxiety Scale and the Leibowitz Social Anxiety Scale (LSAS) assessed anxiety levels.

Results

Academic exams significantly increased salivary COR levels and decreased OXT levels in students, particularly those with high test anxiety. The median baseline COR level significantly increased from 30.4 to 68.6 ng/mL post-exam (p = .001), while OXT levels dropped from a mean of 7.5 pg/mL to 6 pg/mL (p = .001). These findings suggest that exam stress may influence hormonal responses associated with stress and anxiety.

Conclusions

The study provides evidence that academic stress due to exams can alter salivary OXT and COR levels in male university students, with potential implications for managing stress-related conditions in this population. However, the study's limitations, including the exclusion of female participants and a small sample size, suggest that further research is needed to generalize these findings. Future studies should include both sexes and consider chronic stress effects over longer periods.

References

1. Sabihi S, Dong SM, Maurer SD, Post C, Leuner B. Oxytocin in the medial prefrontal cortex attenuates anxiety: anatomical and receptor specificity and mechanism of action. Neuropharmacology. 2017;125:1-12. https://doi.org/10.1016/j.neuropharm.2017.06.024

2. Carmassi C, Marazziti D, Mucci F, et al. Decreased plasma oxytocin levels in patients with PTSD. Front Psychol. 2021;12:612338. https://doi.org/10.3389/fpsyg.2021.612338

3. Llendick TH, Hirshfeld-Becker DR. The developmental psychopathology of social anxiety disorder. Biol Psychiatry. 2002;51(1):44-58. https://doi.org/10.1016/s0006-3223(01)01305-1

204

Development of a physiologically-based pharmacokinetic model to predict empagliflozin-metoclopramide interaction in gastroparesis

Rana Abutaima and Abdallah M. Alnabelsi

Faculty of Pharmacy, Zarqa University

Background and Objectives

Gastroparesis, a common condition in diabetic patients, is characterized by delayed gastric emptying due to enteric nervous system impairment. This delay can be managed with prokinetic agents like metoclopramide. Given the frequent co-prescription of empagliflozin and metoclopramide in diabetic patients with gastroparesis, this study aims to predict potential drug-drug interactions between empagliflozin (10 and 25 mg) and metoclopramide (10 mg, four times daily).

Methodology

GastroPlus® (Version 9.8; Simulations Plus, Inc., Lancaster, California, USA) was used to modify the ACAT model, simulating gastroparesis in a virtual Caucasian male population (n = 100) by extending transit time from 0.5 to 4 h or longer under fed state. The metabolic profiles of both drugs were obtained from existing literature.^1–3 The pharmacokinetics of empagliflozin and metoclopramide under normal conditions were simulated in both fasted and fed states, followed by similar simulations in gastroparesis while adjusting for the transit time and pH. The DDI was simulated over 24 h and 168 h, with empagliflozin considered the victim drug.

Results

The pharmacokinetics of empagliflozin did not alter after adding metoclopramide at all simulation conditions. However, empagliflozin mean Cmax and AUC0-∞ were different between fast and fed state and in normal compared to gastroparesis. Specifically, empagliflozin Cmax and AUC0-∞ for the 10 mg dose after single dose administration over 24 h in gastroparesis under fasting conditions were 0.86 ng/mL and 3.53 ng·h/mL, respectively, compared to 2.63 ng/mL and 13.87 ng·h/mL in normal transit time. For the fed state under gastroparesis, Cmax and AUC0-∞ were 0.68 ng/mL and 4.03 ng·h/mL, compared to 1.28 ng/mL and 5.43 ng·h/mL in normal conditions. Detailed pharmacokinetics of empagliflozin for the 10 and 25 mg doses in all simulation conditions are presented in Table 1.

Conclusion

The findings of this study indicate no significant interaction between metoclopramide and empagliflozin, with no substantial alterations in empagliflozin concentration. Additionally, gastroparesis appears to significantly impact the pharmacokinetics of empagliflozin, even though empagliflozin itself may induce gastroparesis. Further clinical studies are recommended to confirm these findings.

References

1. Rascher J, Cotton D, Haertter S, Brueckmann M. Clinical pharmacokinetics and pharmacodynamics of empagliflozin in patients with heart failure. Br J Clin Pharmacol. 2024.

2. Bateman DN. Clinical pharmacokinetics of metoclopramide. Clini Pharmacokinet 1983;8(6):523-529.

3. Lee YY, Erdogan A, Rao SS. How to assess regional and whole gut transit time with wireless motility capsule. J Neurogastroenterol Motil. 2014;20(2):265.

206

N-of-1 trials of pharmacological interventions versus standard care for chronic pain management: A rapid review and meta-analysis

Maria Malhotra, Ikran Salah, Andrew Lambarth and Emma H. Baker

City St George's University of London

Background

Chronic pain affects approximately 30% of adults and is a leading cause of disability worldwide.¹ Standard clinical practice (SCP) for pain management often relies on trial and error, which can be time-consuming, costly, and prone to prescription of ineffective medicines. N-of-1 trials, which use multiple crossover comparisons, offer a personalized alternative to assess treatment efficacy in individuals.² This review explores the landscape of N-of-1 trials for chronic pain management and compares their efficacy to SCP.

Method

Following Cochrane rapid review methodology, we systematically searched MEDLINE, EMBASE and CENTRAL from inception to February 2024. Indexed and free-text terms were used. We included multiple reversal (e.g., ABAB) N-of-1 trials involving pharmacological analgesics for adults with chronic non-cancer pain (CNCP). Two reviewers handled screening, data extraction and risk of bias assessment. Primary outcomes included pain intensity, patient satisfaction, treatment preferences and identification of effective or ineffective medications. Randomized controlled trials (RCTs) comparing N-of-1 trials with SCP were included in a meta-analysis.

Results

Of 1489 records, 16 satisfied inclusion criteria, with 14 individual or aggregated N-of-1 trials and 2 RCTs comparing N-of-1 trials with SCP (Figure 1a). These trials involved 535 participants, 405 in blinded studies, with osteoarthritis and neuropathic pain most commonly studied. Interventions included NSAIDs, paracetamol, opioids and cannabinoids. Statistically significant differences in pain scores were achieved with at least one intervention in 21.4% of N-of-1 participants.

Patients reported higher satisfaction with N-of-1 trials, identifying preferred treatments, reducing side effects and discontinuing ineffective medications. However, N-of-1 trials were time-consuming, and some patients experienced confusion in identifying drug preferences.

Meta-analysis of two RCTs with 266 participants revealed no significant difference in pain intensity between N-of-1 trials and SCP at the first follow-up, though later follow-up data suggested a benefit for N-of-1 trials. Confounding factors included attrition bias and lack of blinding.

Conclusion

References

1. Cohen SP, Vase L, Hooten WM, et al. Chronic pain: an update on burden, best practices, and new advances. Lancet. 2021;397(10289):2082–2097. DOI: 10.1016/S0140-6736(21)00393-7

2. Lillie EO, Patay B, Diamant J et al. The n-of-1 clinical trial: the ultimate strategy for individualizing medicine? Pers Med. 20118(2):161–173. DOI: 10.2217/pme.11.7

220

Addressing the underrepresentation of African and Caribbean populations in UK clinical trials and solutions

Marie-Therese Bultmann and Duncan Browne

University College London

Introduction

The underrepresentation of African and Caribbean populations in clinical trials is a persistent issue in the United Kingdom, raising concerns about the generalisability of research findings and the equity of healthcare outcomes. Herein I explore the causes of this underrepresentation and its implications for both clinical practice and public health. Addressing these barriers is essential to improving both the inclusion in clinical research and the resulting health outcomes for these populations.

Methods

An extensive literature review was conducted using Google Scholar, Google and PubMed, focusing on studies from 2000 to 2023 that examined ethnic representation in clinical trials. Search terms included ‘ethnic minorities in clinical trials’ and ‘African and Caribbean populations’. Relevant articles were selected based on their focus on Black participant enrolment and barriers to participation. Additionally, a semi-structured interview was conducted with Dr. Lia Hunter, an advocate for racial diversity in research, to gather qualitative insights into recruitment challenges and strategies. The interview data were analysed for key themes, which were integrated into the overall findings.

Results

The analysis revealed that Black participants were significantly underrepresented in clinical trials in the UK. In 30 UK COVID-19 trials, 1.5% of the 118,912 participants were Black, compared to 87.5% White participants.¹ The sample size of Black people would need to grow by 266% to be representative of the UK's Black population (4%). For conditions like hypertension and diabetes, participation rates were 10%–15% lower than expected, despite Black populations being 2–4 times more likely to suffer from these diseases. Additionally, mistrust in the healthcare system was reported by 65% of Black survey respondents, primarily due to historical and ongoing discrimination.² The analysis also highlighted the underrepresentation of these populations in healthcare staff and the lack of culturally tailored recruitment strategies exacerbated this issue. 29.2% of Black NHS staff reported harassment, contributing to the lack of trust. Pharmaceutical companies were also found to bear liability due to insufficient efforts to address these gaps. These factors collectively contributed to over 40% underrepresentation in the trials analysed, emphasizing the need for more inclusive approaches.

Conclusions

References

1. Murali M, Gumber L, Jethwa H, et al. Ethnic minority representation in UK COVID-19 trials: systematic review and meta-analysis. BMC Med. 2023;21(1). doi:10.1186/s12916-023-02809-7

2. Lacobucci G. Most black people in UK face discrimination from healthcare staff, survey finds. BMJ. 2022;378(378):o2337.

298

Assessment of medication adherence and reasons for non-adherence in patients with chronic diseases: A cross-sectional study

Nouran Omar El Said, Dina Khaled Aboelfadl and Eman Abdellatif Elmokadem

Pharmacy Practice & Clinical Pharmacy, Faculty of Pharmacy, Future University In Egypt

Introduction

Medication non-adherence is a significant problem in chronic disease management, leading to poor health outcomes and increased healthcare costs. This study aimed to assess medication adherence in patients with chronic diseases and identify reasons for non-adherence using the Morisky Medication Adherence Scale (MMAS-8).

Method

A cross-sectional survey was conducted from March to May 2023 at Future University in Egypt. Patients aged ≥18 years with chronic diseases and taking at least one medication were included. A questionnaire comprising demographic data, disease characteristics, and the MMAS-8 was administered. Adherence was categorized as high (score = 8), medium (score 6–7) or low (score <6). Descriptive statistics were used to analyse the data.

Results

A total of 476 patients participated in the study. The majority (40.9%) were taking more than three medications daily, with oral administration being the most common route (90.4%). Based on the MMAS-8 scores, 430 patients (90.3%) had low adherence, 37 (7.8%) had medium adherence, and only 9 (1.9%) had high adherence. The most common reason for non-adherence was forgetfulness (77.7%), followed by polypharmacy (40.9%) and medication side effects. Most patients (83.6%) preferred oral dosage forms. When forgetting a dose, 44% reported taking it upon remembering, while 31.9% waited for the next scheduled dose.

Conclusions

This study revealed a high prevalence of medication non-adherence among chronic disease patients. Forgetfulness was the primary reason for non-adherence, suggesting the need for reminder tools such as mobile applications and pill boxes to improve adherence. Further research with larger sample sizes is needed to assess adherence patterns across different chronic diseases and develop targeted interventions.

References

1. Jimmy B, Jose J. Patient medication adherence: measures in daily practice. Oman Med J. 2011;26(3):155-159.

2. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353(5):487-497.

3. Morisky DE, Ang A, Krousel-Wood M, Ward HJ. Predictive validity of a medication adherence measure in an outpatient setting. J Clin Hypertens. 2008;10(5):348-354.

25

Pharmacogene associated drug reports from over 1 million Yellow Card adverse drug reports in the United Kingdom from 1963 to 2024

Emma Forton Magavern¹, Maia Megase¹, Jack Thompson², Gabriel Marengo¹, Julius Jacobsen¹, Damian Smedley¹ and Mark Caulfield¹

¹William Harvey Research Institute, Queen Mary University of London; ²Department of Clinical Toxicology and General Medicine, St Thomas’ Hospital, Guy’s and St Thomas' NHS Foundation Trust

Introduction

Adverse drug reactions (ADRs) harm patients and are costly for health care systems. Genetic variation is one reason for variability in medication response and prospective knowledge of these variants can 6decrease risk of ADRs. However, reduction in ADRs would affect only those reactions to drugs contained in well-validated pharmacogene-drug pairs. The scope of ADRs represented by these drugs on a population scale is unclear. The objective of this study was to characterize the pharmacogene-drug associated ADR reporting landscape from a national regulatory pharmacovigilance dataset to elucidate the scale of potential ADR mitigation by pharmacogenomics (PGx) implementation in the United Kingdom.

Methods

All publicly available Yellow Card ADR reports to the United Kingdom (UK) Medicines and Healthcare Products Regulatory Agency (MHRA) from 1963 to 2024 were compiled. We chose 39 gene-drug pairs which impact on adverse drug reaction rather than purely efficacy, with stringent evidence criteria, and prospective clinical trial data demonstrating reduction in ADRs with PGx implementation. The ADRs were analysed with descriptive statistics, stratified by PGx status and by associated genes. Reporting trends were normalised by decade. Prescribing prevalence from the literature was compared with ADR reports for PGx associated drugs.

Results

There were 1,345,712 ADR reports, attributed to 2499 different substances. 115,789 adverse drug reports were associated with drugs for which ADR risk can be modified based on pharmacogenomic prescribing guidance. 75% of these were due to medicines which interact with only three pharmacokinetic pharmacogenes (CYP2C19, CYP2D6, SLCO1B1) (Figure 1). Over 47% of all the PGx mitigatable ADRs identified are attributed to psychiatric medications, followed by cardiovascular medications (24%) (Figure 1). Though Yellow Card reports are more likely to be associated with female patients, the PGx mitigatable ADRs were slightly more likely to be from male patients, slightly older patients, and were associated with more severe non-fatal reactions. They were more likely to be reported by patient or carers and more likely to be reported directly to the MHRA rather than reported from industry (Table 1). PGx associated psychiatric drug ADRs are overrepresented as compared with prescribing prevalence, but fatal cardiac arrhythmias were uncommon, comprising 0.4% of these reports (Figure 2).

Conclusion

9% of all reported ADRs are associated with pharmacogenomic drugs. A panel of only 3 pharmacogenes could mitigate 3 in every 4 PGx modifiable ADRs. Psychiatry would be the single highest impact specialty to pilot pharmacogenomics in the United Kingdom to reduce ADRs.

Ethics Statement

The data used in this abstract is openly sourced from the Medicines and Healthcare products Regulatory Agency (MHRA) and does not present any ethical implications

61

Simultaneous profiling of SNP genotyping, copy number variation and fragment length determination using nanofluidic qPCR for pharmacogenomics studies

Geoff Dance, Jian Qin, Hui Ren, Amit Khanna, Win Hwang, Joel Brockman, Arnaldo Barico, Greg Harris, Tom Goralski, Julie Alipaz, Charles Park, David King and Naveen Ramalingam

Standard Biotools

Background and Objectives

Pharmacogenomics (PGx) testing evaluates a person's genetic variation to determine how the individual may metabolize or respond to medications. It is vital in identifying responders vs. nonresponders to medications, optimizing drug doses, and mitigating the risk of adverse events. These genetic tests interrogate single-nucleotide polymorphisms (SNPs), copy number variation (CNV), and microsatellite repeat numbers within specific genes associated with differential drug metabolism. However, the traditional qPCR-based and capillary electrophoresis-based methods use separate, cumbersome workflows for SNP genotyping, CNV determination, and fragment size analysis for microsatellite markers (for example, UGT1A1 and NUDT15).

Methods

In this work, we report a single automated workflow using an qPCR-based nanofluidic system to simultaneously profile SNPs, CNVs, and microsatellite repeat numbers of genomic

DNA samples using buccal swabs without extraction.

Results

We have assessed this panel with 173 Coriell DNA samples with known genotypes or known copy numbers. The average call accuracy for SNP and CNV was 99.9% and 98.0%, respectively, for extracted genomic DNA.

Conclusions

This workflow can play a major role in PGx testing when implemented in clinical routines.

171

Associations between polymorphism in the GSTs genes and gastrointestinal adverse reactions in patients with gynecological tumours treated with paclitaxel and carboplatin

Nadine de Godoy Torso¹, Karine Tiemi Nakamura¹, Giovana Fernanda Santos Fidelis¹, Yasmim Gabriele Matos¹, Clarissa Lourenço de Castro², Luiz Carlos da Costa Junior², Julia Camargo Lepore¹, Estela Dias de Oliveira Lemes Ares¹, Paulo Caleb Júnior Lima Santos³, Eder C. Pincinato¹ and Patricia Moriel¹

¹UNICAMP; ²Hospital of Cancer II (HCII), National Cancer Institute (INCA); ³Pharmacology Department, Federal University of São Paulo

Introduction

Gynecological tumours, which include neoplasms affecting the female reproductive system, are among the most prevalent forms of cancer on a global scale1. Treatment modalities include chemotherapy with paclitaxel and carboplatin. Nevertheless, both agents are associated with drug-related adverse reactions (ADRs), including the gastrointestinal ones; furthermore, interindividual differences in the frequency of such ADRs are closely related with polymorphisms in key pharmacogenes. Therefore, this study aimed to evaluate potential associations between polymorphisms in the GSTM1, GSTP1, and GSTT1 genes and ADRs induced by paclitaxel-carboplatin chemotherapy in patients with gynecological malignancies.

Method

This retrospective study included participants diagnosed with gynecological tumours and treated with paclitaxel and carboplatin. It was conducted according to the Declaration of Helsinki and was approved by the research ethics committee of the University of Campinas (number: 20406413.6.3001.5404). DNA samples were isolated from peripheral blood leukocytes; the rs1695 (GSTP1) polymorphism was assessed by qPCR, and the GSTM1 and GSTT1 genes were accessed by high-resolution melting (HRM) analysis. The ADRs severity was classified according to the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0.)2.

Results

458 participants were included, 174 participants with ovarian cancer, 159 with cervical cancer and 125 with endometrial cancer. In all these subgroups, most patients were in advanced stages of the disease (stages III or IV, 82.8%). Among those participants who had any of the assessed ADRs, it was seen a grade 1 predominance (mild) (Table 1). Among the three GST family genes evaluated (Table 2), the rs1695 (GSTP1) variant was the only one to demonstrate a possible relationship between the genotype and the occurrence of gastrointestinal ADRs (Table 3).

Conclusion

Patients with the GG genotype (rs1695) were 2.5 times less likely to experience nausea (OR: 2.5; p < .05) but were 2.2 times more likely to experience diarrhoea (OR: 2.2; p < .05) when compared with other genotypes. Meanwhile, those with the AA genotype were 1.6 times more likely to experience nausea (OR: 1.6; p < .05). These results suggest a possible relationship between the AA genotype and nausea, while the G allele seems to reduce this ADR but increases the risk of diarrhoea during treatment.

References

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74(3):229–263. https://doi.org/10.3322/caac.21834

2. U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE)v.5.0. (National Institutes of Health, ed.). National Cancer Institute; 2017.

185

Influence of DPYD variants on hand-foot syndrome and neutropenia induced by capecitabine in patients with gastric and colorectal cancer

Eder Pincinato, Luciana Zollmann, Beatriz Possamai, Natalia Zimmermann, Carmen Lima, Jose Carvalheira and Patricia Moriel

Universidade Estadual de Campinas

Introduction

Capecitabine is an oral pro-drug of fluoropyrimidines widely used in the treatment of patients with advanced colorectal, breast, and gastric cancer.¹ Hand-foot Syndrome (HFS) and neutropenia are common adverse drug reactions (ADRs) associated with capecitabine treatment.² It may be related to reduced activity of the DPD enzyme, mostly caused by genetic variants in the DPYD gene.³ Therefore, this work aims to evaluate the influence of six DPYD variants (c.1129-5923 C > G (rs75017182); c.1905+1 G > A (rs3918290); c.1679 T > G (rs55886062); c.2846 A > T (rs67376798)); rs1801160 (c.2194G > A) and rs115232898 (c.557 A > G) and their association with the HFS and neutropenia induced by capecitabine in Brazilian patients with gastric and colorectal cancer.

Methods

We conducted a retrospective cohort study at the Hospital das Clínicas of the Universidade Estadual de Campinas, Brazil. This study was conducted according to the Declaration of Helsinki and was approved by the Ethics Committee (CAAE: 65683517.5.0000.5404). DNA samples were isolated from peripheral blood leukocytes; the DPYD variants were genotyped by q-PCR using TaqMan probes and capecitabine ADRs were evaluated following the CTCAE criteria (version 5.0). Patients with gastric or colorectal carcinomas treated with three cycles of capecitabine were enrolled.

Results

We enrolled in this study 99 patients, predominantly male (50.5%), with a mean age of 58.4 years, and were of Caucasian ethnicity (51.5%). HFS in any cycle was found in 53 (53.5%) patients. Of these, ADRs grades 1 or 2 of were found in 47 (47.5%) and grades 3 or 4 were found in 3 (3%) patients. Neutropenia was found in 26 (26.26%) patients. The genotype and altered allele frequency are demonstrated in Table 1.

No significant association was found between the DPYD variants and HFS toxicity.

Conclusions

References

1. Mikhail S, Sun JF, Marshall J. Safety of capecitabine: a review. Expert Opinion Drug Safety. 2010;9:831–841. https://doi.org/10.1517/14740338.2010.511610

2. Gómez-Martín C, Sánchez A, Irigoyen A, et al. Incidence of hand–foot syndrome with capecitabine in combination with chemotherapy as first-line treatment in patients with advanced and/or metastatic gastric cancer suitable for treatment with a fluoropyrimidine-based regimen. Clin Transl Oncol. 2012;14:689–697. https://doi.org/10.1007/s12094-012-0858-3

3. Lam SW, Guchelaar H, Boven E. The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev. 2016;50:9–22. https://doi.org/10.1016/j.ctrv.2016.08.001

199

Exploring genetic markers for anti-TB therapy-induced adverse drug reactions: An in silico analysis

Kamal Kishor

IPFT

Introduction

Adverse drug reactions (ADRs) are associated with clinical morbidity and, in severe cases, even mortality. Globally billions of dollars are spent on managing these ADRs for common and uncommon diseases. Due to these reasons drug resistant strains have emerged and are now a serious challenge to TB eradication. To effectively deliver the available treatment regimen and ensure patient compliance it is important to manage ADRs more efficiently. Recent studies have demonstrated that drug outcomes are patient-specific and can, therefore be predicted. A few of these drugs, including a few administered for TB, have shown excellent correlation with response rates and development of ADRs.

Method

ADRs selected based on frequency of occurrence (≥1%). Anti-TB drugs were reviewed to identify the candidate genes (DMETs, HLA). Genes analysed with different web tools and databases to extract their SNPs. MAF >0.01 shortlisted using NCBI Gene and dbSNP databases (built 141). SNPs which lay in a functional domain of the gene were prioritized using SNPinfo web server (www.snpinfo.niehs.nih.gov/). Additionally, same analysis was done for Indian population.

Results

We identified 10 genes which maybe directly linked to ADRs to various anti-TB drugs, 4 of these have been documented earlier. Nearly 47 genes were identified for indirect association with ADRs by virtue of them being off-targets of the drugs. Lastly, 5 genes were reported for their allelic association with anti-TB DIH. To our knowledge, this is the first review reporting a list of possible genetic markers in context to TB ADRs to such a vast extent.

Conclusions

New gens are identified that may be associated potentially with anti-TB drug ADRs. This would translate into not just patient welfare but would also save billions of dollars spent annually on managing drug induced ADRs.

202

Clinical utility of pharmacogenetics-based treatment guidelines of Clinical Pharmacogenetics Implementation Consortium (CPIC) for depression in a central Indian population—A randomised double blind controlled trial

Shubham Atal, Abhijit Rozatkar, Ratinder Jhaj, Tamonud Modak, Jitendra Singh and Santenna Chenchula

All India Institute of Medical Sciences Bhopal

Introduction

Selective serotonin reuptake inhibitors (SSRIs) are considered first line treatment for Major depressive disorder (MDD), but substantial proportions of patients show unsatisfactory response. Genetic polymorphisms in CYP2D6 and CYP2C19 enzymes influence metabolism of SSRIs, affecting efficacy and adverse drug reactions (ADRs). CPIC guidelines provide therapeutic recommendations for selection and/or dosing of SSRIs in depression. There are no studies from Indian population to assess their applicability. This randomized controlled trial (RCT) evaluates the clinical effectiveness of pharmacogenetic testing guided prescription of SSRIs (PGxT) for MDD vs. standard clinician-based prescribing.

Methods

This RCT is being conducted since May 2023 with a target sample size of 200. Newly diagnosed, treatment-naïve patients aged 25–60 years of either sex with moderate-severe MDD (HDRS-17 score ≥17) are randomized 1:1 to PGxT or Usual treatment (UT) and patients and clinicians are kept blinded. Genotyping for CYP2D6 and CYP2C19 polymorphisms is performed using TaqMan-based assays. Treatment is adjusted according to CPIC guidelines in PGxT group. Primary outcomes are the response and remission rates, HDRS-17 score changes, and ADR frequency and FIBSER score at 4 and 8 weeks.

Results

This interim analysis of 90 patients (n = 44 PGxT and n = 46 UT group, CONSORT diagram), showed a significantly greater reduction in HDRS-17 scores in PGxT group (mean change: 14.07 ± 4.4) compared to the UT group (11.6 ± 5.7) and a significantly higher response rate (≥50% reduction in HDRS-17) (84.8% vs. 61.7%, OR 3.4, p = .03) at week 4. Remission rate (HDRS-17 ≤ 7) was also higher in PGxT group at week 8 (66.6% vs. 34.4%, OR 3.8, p = .048) (Figure 1). Additionally, there were significantly fewer ADRs in PGxT group (39.4% vs. 67.6% at week 4, p = .02; 37.0% vs. 69.0% at week 8, p = .003).

Conclusions

References

1. Hicks JK, Sangkuhl K, Swen JJ, et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of SSRIs. Clin Pharmacol Ther. 2015;98(2):127-134.

2. Bousman CA, Stevenson JM, Ramsey LB, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, CYP2C19, and SSRIs. Clin Pharmacol Ther. 2023;114(1):51-68.

3. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23(1):56-62.

251

Public knowledge and perceptions on pharmacogenetic testing

Noora Kulla^1,2, Kari Linden³, Nelli Halonen^1,2, Mikko Niemi^4,5,6 and Aleksi Tornio^1,2

¹Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku; ²Unit of Clinical Pharmacology, Turku University Hospital; ³University Pharmacy; ⁴Department of Clinical Pharmacology, University of Helsinki; ⁵HUS Diagnostic Center, HUS Helsinki University Hospital; ⁶Individualized Drug Therapy Research Program, University of Helsinki

Introduction

Pharmacogenetic testing is increasingly utilized in specific clinical situations. However, public awareness, knowledge and perceptions on pharmacogenetic testing are not well understood. Our aim was to investigate public knowledge of pharmacogenetics, as well as perceptions and possible experiences of pharmacogenetic testing. Furthermore, we evaluated the willingness of respondents to undergo pharmacogenetic testing, and recognized possible concerns related to the topic.

Methods

A web-based questionnaire was distributed in Finland to 270 000 adult-age pharmacy customers consented to receive electronic pharmacy newsletters. Previous knowledge or experience on pharmacogenetic testing was not expected from the respondents. General information on pharmacogenetic testing was provided along with the questionnaire.

Results

We received 6927 full responses in the survey with majority of the respondents being female (84%) and largest age group being 50–74 years (66%). At the time of answering, 96% of the respondents were using at least one prescription drug. Generally, respondents have positive perceptions and attitudes towards pharmacogenetic testing (Figure 1 Perceptions on pharmacogenetic testing). Majority (77%) of the respondents had not previously heard about pharmacogenetic testing, and only 2% had been tested for pharmacogenetic variants, most often by a public health care provider (46%). Up to 90% of the participants were at least somewhat likely willing to be tested for pharmacogenetic variants in distinct clinical situations, such as to decrease the risk for severe adverse drug reactions, or to explain lack of efficacy or sudden adverse drug reactions. Respondents mostly wanted physicians (96%) to have an access to the test results, followed by pharmacy professionals (57%). To explain test results to them, respondents preferred physicians (92%), followed by nurses (36%). Exploiting the test results and data protection were the most common concerns related to testing.

Conclusions

The survey results indicate a positive attitude towards pharmacogenetic testing among general population in Finland. Respondents were overall willing to take a pharmacogenetic test and they considered testing as a necessary tool in planning of their pharmacotherapy. Several concerns related to pharmacogenetic testing were frequently reported, indicating the need for patient education.

83

Comparative assessment of the risk of new-onset diabetes mellitus between proprotein convertase subtilisin/kexin type 9 inhibitors and statins: An analysis of FDA adverse event reporting system data

Saher Ahluwalia, Harmanjit Singh and Aaronbir Singh Randhawa

Government Medical College and Hospital, Chandigarh

Introduction

Statins are the cornerstone of lipid-lowering therapy but are associated with an increased risk of new-onset diabetes mellitus (NODM). With the introduction of PCSK9 inhibitors, such as alirocumab and evolocumab, as effective alternatives, it is crucial to assess their metabolic safety, particularly in relation to NODM. This study aimed to evaluate the risk of NODM due to PCSK9 inhibitors (alirocumab and evolocumab) and commonly prescribed statins (atorvastatin and rosuvastatin).

Methods

We conducted a retrospective analysis of FAERS data from Q4/2003 to Q2/2024, utilizing the OpenVigil 2.1 software for data extraction and analysis. Reports of NODM associated with alirocumab, evolocumab, atorvastatin, and rosuvastatin were identified (as primary suspects) using MedDRA Low-Level Term (LLT) classification terms ‘diabetes mellitus’, ‘diabetes mellitus inadequate control’, ‘type 2 diabetes mellitus’ and ‘diabetes mellitus non-insulin-dependent’, with an OR operator. Disproportionality analysis was employed, calculating Proportional Reporting Ratios (PRR), Reporting Odds Ratios (ROR), and chi-squared tests with Yates' correction. Evans' criteria (2001) were applied to assess the likelihood of a causal relationship between the drug and adverse event (an association was considered likely if more than two reports existed, the chi-squared value exceeded 4, and the PRR was greater than 2).

Results

Alirocumab was linked to 45 NODM events out of 74,206 reports, with a PRR of 0.58 (95% CI: 0.434–0.777), a ROR of 0.579 (95% CI: 0.432–0.776), and a chi-squared value of 13.297, indicating no significant association with NODM. Evolocumab was associated with 436 NODM events (PRR 0.637, 95% CI: 0.58–0.7; ROR 0.636, 95% CI: 0.579–0.699) and a chi-squared value of 89.558, similarly showing no significant association under Evans' criteria.

In contrast, atorvastatin had 4584 NODM events, resulting in a PRR of 17.813 (95% CI: 17.313–18.327), a ROR of 19.65 (95% CI: 19.043–20.277), and a chi-squared value of 68,638.02, fulfilling Evans' criteria for a likely causal link. Rosuvastatin, with 921 NODM events, showed a PRR of 5.669 (95% CI: 5.318–6.044), a ROR of 5.828 (95% CI: 5.456–6.227), and a chi-squared value of 3513.944, also indicating a significant association, though at a lower risk compared to atorvastatin.

Conclusion

This study did not find any significant association between PCSK9 inhibitors and NODM). In contrast, atorvastatin and rosuvastatin demonstrated a strong association with increased NODM risk. These findings suggest that PCSK9 inhibitors do not elevate the risk of NODM. Further studies are needed to confirm these findings in larger, controlled populations.

84

Assessing the risk of osteonecrosis of the jaw with bisphosphonate therapy: Insights from the FDA adverse event reporting system

Aaronbir Randhawa, Harmanjit Singh and Saher Ahluwalia

Government Medical College and Hospital, Sector 32, Chandigarh

Introduction

Osteonecrosis of the jaw (ONJ) is a rare but serious adverse event associated with bisphosphonate therapy. This study examines the risk of ONJ associated with four commonly used bisphosphonates: alendronate, pamidronate, risedronate, and zoledronate, utilizing data from the FDA Adverse Event Reporting System (FAERS) through OpenVigil 2.1.

Methods

We conducted a disproportionality analysis using OpenVigil 2.1 (from Q4/2003 to Q2/2024), focusing on the Medical Dictionary for Regulatory Activities (MedDRA) Lower-Level Term (LLT) “osteonecrosis of jaw” to identify cases associated with the bisphosphonates of interest (as primary suspects). The bisphosphonates analysed included alendronate, pamidronate, risedronate, and zoledronate and were investigated as primary suspect in causing ONJ. For each drug, chi-square values, relative reporting ratios (RRR), proportional reporting ratios (PRR), and reporting odds ratios (ROR) were calculated. Statistical significance was assessed using Evans criteria (n > 2, chi-square > 4, PRR > 2).

Results

Of the 14,096 total ONJ events reported in FAERS, 1391 were associated with alendronate. The disproportionality analysis yielded a chi-square value of 71,657.57, PRR was 59.116 (95% CI: 56.017–62.387) and the ROR was 62.80 (95% CI: 59.32–66.47), confirming a strong association between alendronate and ONJ. For pamidronate, 536 of the 14,096 total ONJ events were linked to the drug. The chi-square value for pamidronate was 85,513.08, PRR 167.966 (95% CI: 155.289–181.678) and the ROR was 204.69 (95% CI: 186.14–225.09), representing the highest association among the bisphosphonates studied, indicating a very strong association with ONJ. Zoledronate was associated with 2416 of the total ONJ events. The disproportionality analysis showed a chi-square value of 180,441.73, PRR 92.061 (95% CI: 88.255–96.032) with an ROR of 100.55 (95% CI: 96.08–105.23), also demonstrating a significant association with ONJ. Risedronate was linked to 309 of the total ONJ events, with a chi-square value of 5337.42, PRR 19.65 (95% CI: 17.576–21.969) and an ROR of 20.06 (95% CI: 17.90–22.48), indicating a statistically significant association with ONJ.

Conclusions

This study highlights a significant association between bisphosphonates and the risk of osteonecrosis of the jaw, particularly with pamidronate and zoledronate. These findings underline the importance of monitoring patients undergoing bisphosphonate therapy for the early signs of ONJ, particularly in high-risk cases.

85

Comparative risk of statin-induced diabetes mellitus: A disproportionality analysis of pitavastatin, rosuvastatin, and atorvastatin using FDA Adverse Event Reporting System (FAERS) data

Akanksha Mehra¹ and Harmanjit Singh²

¹University of New Haven; ²Government Medical College and Hospital

Introduction

Statins are widely prescribed for the management of hyperlipidaemia, but their association with the onset of diabetes mellitus (DM) has raised important clinical concerns. Pitavastatin is often considered to have a lower impact on glycaemic control compared atorvastatin and rosuvastatin. This study aims to evaluate and compare the risk of statin-induced DM among these three statins.

Methods

We conducted a disproportionality analysis using FDA Adverse Event Reporting System (FAERS) data from 2004Q1 to 2024Q2, accessed via OpenVigil 2.1. DM events were identified using MedDRA Low-Level Term (LLT) classification. The following events were used to search for associations: ‘diabetes mellitus’, ‘diabetes mellitus inadequate control’, ‘type 2 diabetes mellitus’ and ‘diabetes mellitus non-insulin-dependent’, with an OR operator applied between terms to capture all relevant cases. Only cases where the role of the drug was identified as the primary suspect were included in the analysis. The analysis applied the 2001 Evans criteria, which include report count >2, Proportional Reporting Ratio (PRR) > 2, and chi-squared value >4 to determine statistical significance. Additionally, we calculated the Reporting Odds Ratio (ROR) with 95% confidence intervals (CI).

Results

In this analysis, atorvastatin was associated with 4584 reported cases of DM out of a total of 74,206 adverse events. The PRR for atorvastatin was 17.81 (95% CI: 17.31–18.32), indicating a significant association with DM. The ROR was 19.65 (95% CI: 19.043–20.277). The chi-squared value with Yates' correction was notably high 68,638.02, indicating the statistical significance of the association.

For rosuvastatin, 921 cases of DM were reported out of 74,206 total DM events. The PRR was 5.669 (95% CI: 5.318–6.044), and the ROR was 5.828 (95% CI: 5.456–6.227), with a chi-squared value with Yates' correction of 3513.944, confirming a significant.

In contrast, pitavastatin was associated with only 3 reported cases of DM out of 74,206 total DM events. The PRR for pitavastatin was 0.979 (95% CI: 0.317–3.025), and the ROR was 0.979 (95% CI: 0.315–3.044), with a l chi-squared value of 0.062, indicating no significant risk of DM.

Conclusions

The analysis reveals that atorvastatin and rosuvastatin are associated with a significant increase in the risk of statin-induced DM. In contrast, pitavastatin showed the lowest risk and no significant association with DM, suggesting it may be a safer alternative for patients concerned about glycaemic control. These findings underscore the importance of individualized statin therapy, particularly for patients at high risk for diabetes.

88

Evolvement of spontaneous adverse event reporting after phosphodiesterase type 5 inhibitors became available as non-prescription drugs

Martin Michel¹, Mark Waring² and Amritdeep Gill³

¹University Medical Center, Johannes Gutenberg University; ²Mark Waring Pharmacovigilance Services; ³Opella, a Sanofi Company

Introduction

Phosphodiesterase type 5 inhibitors (PDE5Is) such as sildenafil and tadalafil were launched as prescription drugs in 1998 and 2002, respectively. After extensive market experience, they became non-prescription (non-Rx) or over-the-counter (OTC) medicines in several countries including the United Kingdom. Therefore, we aimed to assess if these switches from prescription to non-Rx status had any impact on the safety profile of these medicines.

Methods

Individual case safety reports (ICSRs) for sildenafil and tadalafil were retrieved from EudraVigilance (EU), FAERS (US, capturing ex-US ISCRs only when describing serious adverse drug reactions (ADRs)), and SMARS (New Zealand) for countries where these drugs switched to non-prescription status. Annual ICSR numbers, reporting rates (ICSRs per million sold tablets), and adverse event characteristics were analysed before and after the switch dates. The cut-off dates for our analysis were in spring 2024. Possible duplicates across databases were not categorically excluded but flagged and the effect of excluding these cases was explored in country-specific analyses. Annual reporting rates were calculated for Ireland, Norway, Poland and United Kingdom for 2014–2024 and for New Zealand for 2016–2024. Cases concerning children, females and/or treatment of pulmonary hypertension were excluded.

Results

Increases in annual ICSR numbers were observed over time for most countries. However, these trends coincided with increasing drug exposure and general increases in adverse event reporting. The EudraVigilance, FAERS and SMARS database included 1080 (763 from United Kingdom), 790 and 37 ICSRs for sildenafil; tadalafil had much smaller numbers based on becoming a non-RX drug in Poland in March 2022 and in United Kingdom in June 2023. ICSRs for sildenafil in EudraVigilance were rated as fatal, other serious, and non-serious in 4.0%, 41.1.% and 54.2%, respectively and numbers over time by country are shown in Table 1. When adjusted for exposure and probable duplicate reports, no clear increases in reporting rates were associated with the prescription status changes. Reported adverse events remained consistent with the known safety profiles. No trends in patient age or of concomitant use of contraindicated medications were identified.

Conclusion

The analysis was limited in some countries by low case counts, particularly for tadalafil, the presence of duplicate reports, and difficulty in classifying reports as originating from prescription vs. non-Rx or OTC use. With these limitations, we found no clear evidence that switches from prescription to non-Rx or OTC status were associated with increases in adverse events or new safety concerns.

102

Identification of a pharmacophore promoting dose-dependent fluoroquinolone antibiotic neuropsychiatric toxicity

Nathaniel Keymer², Alexander Tsai¹, Eunice Pak¹ and James Coulson¹

¹Cardiff University; ²National Poisons Information Service, Cardiff

Introduction

Fluoroquinolone antibiotics are associated with neuropsychiatric adverse events. The severity of toxicity has been reported to differ between medications within class. Structure-activity relationships have been identified which promote neurotoxicity in zebrafish.¹ We integrated adverse event data with prescribing data to estimate odds ratios to explore pharmacophore relationships to adverse neuropsychiatric events in humans.

Methods

The MHRA's Yellow Card Scheme collects reports of adverse events experienced by patients across the United Kingdom, available as the interactive drug analysis profile.² National Health Service, England, fluroquinolone prescription data was available from OpenPrescribing.³ We used these data to estimate odds ratios for neuropsychiatric events following human exposure to four fluoroquinolone antibiotics compared to amoxicillin.

Results

Odds ratios are presented in Table 1. These results demonstrate that substituents on the 1, 7 and 8 positions of the fluoroquinolone skeleton contribute to neuropsychiatric adverse events. The clearest comparison is between ofloxacin and levofloxacin. Levofloxacin is the S-conformer of the racemate ofloxacin. Patients are exposed to approximately twice as much levofloxacin when prescribed levofloxacin compared to a similar prescription of ofloxacin.⁴ The odds ratio for toxicity for levofloxacin was approximately twice that of ofloxacin. Steric bulk above the plane of the molecule at the 1 position contributes significantly to toxicity. Ciprofloxacin features a cyclopropyl group in the 1 position and has no hydrogen bond acceptor on the 8 position. The rotation of the cyclopropyl will cause it to spend time both above and below the plane of the molecule. By analogy with levothyroxine, which is conformationally locked above the plane, ciprofloxacin will cause toxicity only when the cyclopropyl is above the plane of the molecule. It is difficult to determine the effect of the lack of H-bond acceptor on position 8. Moxifloxacin features a cyclopropyl group on the 1 position, a H-bond acceptor on the 8 position and a larger tail on the 7 position. The large tail promotes toxicity and much more than makes up for the reduction in toxicity from the freely rotatable cyclopropyl on the 1 position. The H-bond acceptor on the 8 position is not locked into a ring, which may also contribute to the increase in toxicity.

Conclusion

A structure-activity relationship for the neuropsychiatric toxicity of fluoroquinolone antibiotics is proposed. Real-world toxicity and prescribing data can be leveraged to aid drug discovery and reduce harms associated with medicines.

References

1. Xiao C, Han Y, Liu Y, Zhang J, Hu C. Relationship between fluoroquinolone structure and neurotoxicity revealed by zebrafish neurobehavior. Chem Res Toxicol. 2018;31(4):238-50.

2. MHRA Interactive Drug Analysis Profile. Available at https://yellowcard.mhra.gov.uk/idaps

3. https://openprescribing.net

4. British National Formulary. Accessed on 30 August 2024 at https://bnf.nice.org.uk/treatment-summaries/quinolones/

174

Safety concerns following fentanyl patch fatalities reported by coroners in England, Wales, and Northern Ireland

Eman Mshari¹, Georgia C. Richards² and Caroline Copeland¹

¹Centre for Pharmaceutical Medicine Research, Institute of Pharmaceutical Science, King's College London; ²Institute of Pharmaceutical Science, King's College London

Introduction

Fentanyl deaths have increased by 5600% from 1 case in 1999 to 57 cases in 2022.¹ Research outside of the United Kingdom has found that pharmaceutical fentanyl patches have contributed to overdoses and misuse²; however, no systematic assessment of fentanyl patch-related deaths in the United Kingdom has been conducted. This study, therefore, aimed to identify safety issues reported by coroners following fentanyl patch fatalities by linking data from toxicology, coroners' reports and MHRA's Yellow Card Scheme.

Methods

A systematic retrospective case series was designed and registered on an open repository. Data from the National Programme on Substance Use Mortality (NPSUM), the Preventable Deaths Tracker (PDT), and MHRA's Yellow Card Scheme were searched to identify coroner reports and fatal adverse drug reactions involving fentanyl patches. Following systematic searches in each database, cases were manually screened to confirm eligibility. The data from NPSUM and PDT were compared to identify any duplicates. Each included case was categorised by the safety events reported by the coroner and the procurement of the patches. Descriptive analyses were conducted using IBM® SPSS™.

Results

There were a total of 710 fentanyl-related cases identified in NPSUM between 1997 and 1 July 2024, of which 89 (13%) involved fentanyl patches. In the PDT, there were 46 cases involving fentanyl between July 2013 and August 2024, of which 11 (24%) involved fentanyl patches. Comparing the cases in NPSUM and PDT, there were two duplicates, bringing the total number of unique fentanyl patch-related deaths reported by coroners to 98. In MHRA's Yellow Card Scheme database, there were 197 fatal adverse drug reactions involving fentanyl between 1996 and 19 May 2024, of which 82 (42%) involved transdermal patches. In NPSUM, the most common safety events were the wearing of duplicate patches (29%), oral ingestion (22%), inhalation of vapours following heating/smoking (9%), injection of extracted fentanyl (6%), unsafe disposal (4%), and hot baths and showers (3%).

Conclusion

This is the first study to combine data from multiple sources involving deaths from pharmaceutical products in England, Wales, and Northern Ireland. It highlights the need for enhanced pharmacovigilance for the prescribing of fentanyl patches and the importance of using coroner data to inform the safe use of medicines.

References

1. Office for National Statistics. Deaths related to drug poisoning in England and Wales: 2022 registrations. 2023; accessed 09/09/2024. https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/bulletins/deathsrelatedtodrugpoisoninginenglandandwales/2022registrations#drug-poisoning-deaths-by-english-region-and-in-wales

2. Nelson L, Schwaner R. Transdermal fentanyl: pharmacology and toxicology. J Med Toxicol. 2009 Dec;5(4):230-41. https://doi.org/10.1007/BF03178274

175

Assessment of intra- and inter-individual variability of a novel point-of-care assay for drug-induced liver injury

Luke Ockhuijsen¹, Kathleen Scullion¹, Iain MacIntyre¹, Sian Sloan-Dennison², Benjamin Clark², Paul Fineran³, Joanne Mair³, David Creasey⁴, Cicely Rathmell⁴, Karen Faulds², Duncan Graham², David Webb¹ and James Dear^1,5

¹Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute; ²Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde; ³Centre for Inflammation Research, Translational Healthcare Technologies Group, Institute for Regeneration and Repair; ⁴Wasatch Photonics; ⁵Centre for Precision Cell Therapy for the Liver, Lothian Health Board, Queens Medical Research Institute

Introduction

Drug-induced liver injury (DILI) has an annual incidence of 14–19 cases per 100,000 people. Common causes include paracetamol overdose and anti-tuberculosis drugs. A novel mechanistic DILI biomarker, cytokeratin-18 (K18), could improve outcomes by having superior diagnostic and prognostic properties compared to established biomarkers. A point-of-care assay to rapidly quantify K18 concentrations in blood to detect DILI is in development. This study examines the intra- and inter-individual variability of K18 in this novel assay compared to the current gold standard.

Methods

Repeat venous and capillary blood samples were collected from a diverse cohort of volunteers. A rapid paper-based lateral flow assay (LFA) was used to quantify K18 levels in capillary blood samples for volunteers and venous blood for other samples. Photographs of the LFAs were captured with a smartphone and analysed using image analysis software. Serum K18 concentrations were measured with the current gold standard method, a commercial ELISA, to compare variability. Repeat venous blood samples of older patients available from the PATH-BP trial¹ were analysed on the LFA in this study. K18 ELISA concentrations of used PATH-BP samples were previously determined in a PATH-BP sub-study.²

Results

The K18 LFA image analysis had higher intra- and inter-individual variability compared to the ELISA but this platform distinguished healthy volunteers from those with DILI. Higher signal intensities were observed in the LFA analysis for the spiked healthy volunteer samples mimicking DILI (Table 1) compared to the healthy volunteer and PATH-BP samples (Table 2).

Conclusions

The K18 LFA image analysis had higher intra- and inter-individual variability compared to the ELISA in volunteers without DILI. Determining the variability of this novel POC assay allows for a more robust assessment of its potential in a clinical setting for early DILI identification. Future research will focus on the application of the novel assay in DILI patients.

References

1. MacIntyre IM, Turtle EJ, Farrah TE, Graham C, Dear JW, Webb DJ. Regular acetaminophen use and blood pressure in people with hypertension: The PATH-BP trial. Circulation. 2022;145(6):416-423. https://doi.org/10.1161/circulationaha.121.056015

2. Scullion KM, MacIntyre IM, Sloan-Dennison S, et al. Cytokeratin-18 is a sensitive biomarker of alanine transaminase increase in a placebo-controlled, randomized, crossover trial of therapeutic paracetamol dosing (PATH-BP biomarker sub-study). Toxicol Sci. 2024; doi:10.1093/toxsci/kfae031