Journal of Pharmacy and Pharmaceutical Sciences最新文献

Introduction: Azathioprine (AZA) is an immunosuppressant approved for renal transplant rejection and rheumatoid arthritis. Recent FDA alerts have raised concerns about its link to intrahepatic cholestasis of pregnancy (ICP), a condition with serious maternal and fetal risks. This study used disproportionality analysis as a hypothesis-generating approach to evaluate the reporting association between AZA and ICP during pregnancy and to compare AZA with other drugs previously implicated in ICP.

Methods: A retrospective pharmacovigilance study was conducted using the FDA Adverse Event Reporting System (FAERS) reports from 1968 to Q2 2024. Disproportionality analysis was performed using reporting odds ratios (RORs), with statistical significance defined as a lower limit of the 95% confidence interval (CI) >1 and at least three unique cases. Subgroup analyses were conducted by pregnancy status and underlying autoimmune indications, and comparative analyses were performed against drugs previously reported to induce ICP.

Results: Among 35,576 AZA-related reports, 67 specifically documented ICP. A strong signal was detected for ICP ROR025 = 153.0; IC025 = 5.8; EBGM05 = 144.37), ranking among the highest AZA-associated adverse events. In pregnant women, ICP also showed a significant signal (ROR025 = 5.46; IC025 = 1.93; EBGM05 = 5.31). Subgroup analyses by indication revealed elevated risks in Crohn's disease (ROR025 = 66.99; IC025 = 4.8; EBGM05 = 64.73), and Colitis ulcerative (ROR025 = 9.01; IC025 = 1.95; EBGM05 = 9.95). Comparative analyses demonstrated that AZA had a higher proportion of ICP cases than other drugs reported to induce ICP.

Conclusion: This pharmacovigilance analysis identifies a disproportionality signal suggesting a possible association between AZA and intrahepatic cholestasis of pregnancy. These hypothesis-generating findings underscore the importance of cautious use and clinical vigilance when prescribing AZA to women of reproductive age.

Objective: Mutations in the tafazzin gene lead to impaired remodeling of cardiolipin, thereby impairing mitochondrial function and causing Barth syndrome (BTHS), a rare X-linked genetic disorder characterized by cardiomyopathy. Previous studies in a mouse model of BTHS, secondary to knockdown of Tafazzin (TazKD mice), also observed perturbations in mitochondrial substrate metabolism and a hypertrophic cardiomyopathy. BTHS may be characterized by increased cardiac ketone metabolism, as myocardial protein expression of the ketolytic enzyme, β-hydroxybutyrate dehydrogenase 1 (BDH1), was markedly increased in TazKD mice. We therefore determined whether increasing ketone supply in TazKD mice may have therapeutic utility against their cardiac abnormalities.

Methods: We treated TazKD mice and their wild-type littermates with either the sodium-glucose cotransporter-2 inhibitor, empagliflozin (10 mg/kg), or a ketone ester (KE; 1719 mg/kg) once daily for 7-week, and performed ultrasound echocardiography to assess cardiac structure and function.

Results: Treatment of TazKD mice with either empagliflozin or a KE increased circulating ketone levels. However, neither approach proved capable of alleviating the cardiac hypertrophy present in TazKD mice, as their increased left ventricular wall thickness and decreased left ventricular diameter remained comparable to that observed in vehicle control treated animals. We also observed that empagliflozin and KE treatment did not impact key markers of cardiac hypertrophy in TazKD mice.

Conclusion: Increasing circulating ketone levels did not alleviate the cardiac hypertrophy in TazKD mice, suggesting that such an approach would not improve outcomes in BTHS.

In paediatric wards, bisoprolol, betaxolol, or nadolol can be administered orally at non-licensed dosages. To provide paediatric patients with appropriate treatment, batches of beta-blocker oral suspensions must be compounded, which involves subsequent stability studies. A stability-indicating HPLC-UV method and microbiological analyses were validated. Experimental batches were compounded (betaxolol hydrochloride 1 mg.mL^-1, bisoprolol hemifumarate 0.5 mg.mL^-1 and nadolol 10 mg.mL^-1). Bisoprolol hemifumarate 0.5 mg.mL^-1 and nadolol 10 mg.mL^-1 needed the addition of citric acid (3 mg.mL^-1) and potassium sorbate (3 mg.mL^-1) to ensure preservative efficacy. Betaxolol hydrochloride 1 mg.mL^-1 was stable for 2 months when stored at 2-8  °C, for 1 month after opening at 2-8 °C, and for 15 days when stored at 25 °C/60% RH. Bisoprolol hemifumarate 0.5 mg.mL^-1 was stable for 2 months when stored at 2-8 °C, for 1 month after opening at 2-8 °C, and for 15 days when stored at 25 °C/60% RH. Nadolol 10 mg.mL^-1 was stable for 3 months when stored at 2-8 °C, for 1 month after opening at 2-8 °C, and for 15 days when stored at 25 °C/60% RH. Hospital pharmacies can compound batches of beta-blocker liquid oral suspensions and store them for secure dispensing and administration.

Medication waste is a significant global concern with environmental, economic, and healthcare implications. In Saudi Arabia, approximately 25.8% of dispensed medications are wasted, resulting in an annual cost of $150 million. Re-dispensing unused medications has been proposed to reduce this waste; however, its feasibility depends on public acceptance, regulatory frameworks, and assurances of safety. This study aimed to assess the Saudi public's willingness to accept re-dispensed medications returned unused to pharmacies and to identify factors influencing this willingness. A descriptive cross-sectional survey was conducted online across Saudi Arabia. The questionnaire, adapted from a validated tool by McRae et al. McRae et al. (Pharmacy (Basel), 2021, 9(2): 77) and translated into Arabic, explored demographics, medication practices, storage and disposal, and attitudes towards medication waste and re-dispensing. The survey was distributed via social media. Data were analyzed using SPSS version 29, including chi-squared tests and binary logistic regression. A total of 405 participants completed the survey, primarily female (64%) and aged 25-44 years (43%). About 64% reported having unused medications at home, most commonly stored in bedrooms (55.1%) and kitchens (53.6%). Disposal practices included keeping medicines for future use (62.5%), discarding them with household waste (45.7%), sharing them with others (21.5%), and returning unused medications to a pharmacy (8.4%). Approximately 60% were willing to accept re-dispensed tablets and 55% capsules, whereas fewer accepted other dosage forms. Key factors influencing acceptance included pharmacist verification of quality and integrity (79.3%), informed consent (77.3%), expiry dates (77%), and intact packaging (74.8%). Most participants (68.1%) indicated they would return unused medicines if a re-dispensing program were implemented, and half (50.6%) believed all medications, not only expensive ones, should be considered. Significant predictors of willingness included age (P < 0.001), employment status (P = 0.004), regular prescription use (P = 0.046), and concern about waste (P < 0.001). Younger participants showed higher acceptance, while employed individuals, retirees, and regular medication users were more hesitant. The findings indicate cautious yet notable public support for medication re-dispensing in Saudi Arabia, particularly for oral solid dosage forms, provided rigorous safety measures are assured. Policymakers should consider these insights to guide initiatives aimed at reducing medication waste.

Background: Hypoglycemia is a common yet underrecognized complication in patients with type 2 diabetes mellitus (T2DM), often linked with increased cardiovascular (CV) morbidity and mortality. Despite its clinical importance, there is a limited data on the association between hypoglycemia, CV events, and mortality among T2DM patients in Rwanda. This study investigated the occurrence of hypoglycemia and its association with CV diseases, morbidity, and mortality in T2DM patients attending two university teaching hospitals in Rwanda.

Methods: A retrospective study was conducted using secondary data from 267 T2DM patients attending Kigali University Teaching Hospital (CHUK) and Butare University Teaching Hospital between 2015 and 2020. Socio-demographic and clinical data, including anti-diabetic medications, hypoglycemia episodes, CV events, and comorbidities, were extracted from medical records and analyzed using Python. Binary regression was used to determine significant predictors of hypoglycemia.

Results: Hypoglycemia occurred in 112 (41.9%) patients during their hospitalization or hospital admissions. The use of insulin was significantly associated with hypoglycemia (OR = 1.590, CI: 1.100-2.290, p = 0.010). The mean age of patients who experienced hypoglycemia is 54.2 (±12.1) years. Hypoglycemia occurrence was higher in males (59.8%) group compared to females (40.2%) (p = 0.007). Cardiovascular conditions were common (73.8%), with hypertension being the most prevalent (85.4%). Insulin was the most frequently used anti-diabetic therapy (42.3%). A significant association was found between hypoglycemia and subsequent CV complications. Management of hypoglycemia predominantly involved the use of 50% dextrose solution.

Conclusion: Hypoglycemia is a frequent and clinically significant occurrence among T2DM patients in Rwanda, particularly associated with insulin therapy and CV comorbidities. Enhanced clinical monitoring and individualized treatment regimens are essential to mitigate hypoglycemia-related complications and reduce mortality. It is important to conduct a larger studies to support the evidence based findings and address the current methodological constraints.

Background/objectives: Optimal nutrition in very low birth weight (VLBW) infants is associated with improved clinical outcomes. When parenteral nutrition (PN) with a marketing authorisation is not appropriate, hospital pharmacies can prepare more suitable PN preparation. This corresponds to standard preparations (i.e., available at any time with a fixed composition) or individualised ones (i.e., available after a period of prescription, preparation, and pharmaceutical control). In France, 12 standard formulas to be compounded were proposed by a national consortium in 2018. The objective of the present study was to evaluate whether individualised PN preparations ordered in our hospital are substitutable by one of the 12 standard formulas.

Methods: All PN prescriptions for VLBW infants made in 2021 in our hospital were retrospectively extracted. For each prescription, the theoretical intakes that an infant would have received if a standard preparation had been administered were calculated. Standard and individualised preparations were compared using the Mann-Whitney U test for each component. Secondly, the relative difference between the expected intakes and effectively intakes was calculated for each component.

Results/discussion: Over the study period, 1708 prescriptions were identified (corresponding to 1708 PN individualised preparations). Most infants were extremely low birth weight infants. Based on the methods of comparison, none of the 12 standard formulas fitted with targeted intakes achieved with individualised PN preparations ordered, whereas prescriptions did fit with international guidelines.

Conclusion: The study highlights how it is difficult to establish nationally standard PN formulas for VLBW infants; the development of local standard formulas seems therefore relevant.

Objective: Despite the antioxidant, anti-inflammatory, and anti-cellular-aging activities of urolithin A (UroA), a naturally occurring postbiotic, its high lipophilicity hampers its pharmaceutical application. To overcome this limitation improving its stability and bioavailability, submicron emulsions (S-EMs) were designed.

Methods: Nineteen formulations (S-EM 1/S-EM 19) were prepared by two different methodologies. S-EMs were characterized evaluating macroscopical appearance and size distribution by photon correlation spectroscopy (PCS). One selected S-EM was loaded with UroA and characterized by PCS, transmission electron microscopy (TEM), small angle x-ray scattering (SAXS) and Fourier-transform infrared spectroscopy (FT-IR). Z potential, pH and syringeability were evaluated. UroA entrapment was studied efficiency by ultrafiltration and HPLC, while in vitro release by dialysis. Cytotoxicity was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) viability test on primary dermal human fibroblasts. The anti-inflammatory activity of S-EM-UroA was evaluated at 3, 6, and 24 h post-injection using the carrageenan-induced paw edema model in male C57BL/6 mice, and compared with UroA suspension and unloaded S-EM.

Results: The preformulative study enabled to select method and composition for S-EM preparation. S-EM 18 was selected for UroA loading (SEM-UroA), due to mean diameter, zeta potential, pH and syringeability suitable for intraperitoneal administration. The loading of UroA (0.2 mg/mL) did not influence S-EM physicochemical features, while maintaining technological properties for 3 months. In vitro drug release showed a biphasic profile, 2.35-fold faster in the case of SEM-UroA compared to the drug suspension. In vitro studies revealed absence of cytotoxicity at concentrations up to 5 µM. In vivo studies, conducted as a first step in assessing the potential of S-EM-UroA, demonstrated a dose-dependent anti-inflammatory effect. Specifically, S-EM-UroA at 2 mg/kg reduced paw edema at 24 h (p < 00.5; One-Way ANOVA followed by Tukey's test), and at 4 mg/kg significantly reduced edema at all time points (p < 0.01), whereas the UroA suspension or S-EM had no effect on carrageenan-induced paw edema at any time point.

Conclusion: These findings underscore the potential of UroA loaded S-EM as an effective delivery system, demonstrating its superiority over simple UroA suspensions in enhancing the systemic anti-inflammatory effects of the postbiotic.

Zaleplon (ZLP) is a commonly used sedative-hypnotic drug that has low oral bioavailability because of its poor water solubility and extensive hepatic metabolism. This study aimed to encapsulate ZLP into spanlastic nanovesicles to enhance its bioavailability via transdermal delivery. Using Span 60 and Tween 80, ZLP-loaded spanlastics were fabricated using thin film hydration technique according to 3² full factorial design. In the applied design, the influence of formulation variables on vesicle size, entrapment efficiency, and cumulative drug amount released over 24 h was investigated, leading to the identification of the optimal formulation. The optimized spanlastics were nanosized, spherical vesicles measuring 297.2 ± 8.17 nm, with an encapsulation efficiency of 65.75 ± 3.28% and a 24-hour drug release rate of 76.44 ± 5.66%. FT-IR studies revealed no significant chemical interactions between ZLP and the excipients used. HPMC K100M transdermal patches loaded with the optimized ZLP-spanlastics were formulated utilizing solvent casting technique. The patches were smooth and elastic with uniform drug content, ranging from 92.65 ± 2.54 to 96.12 ± 1.57%. The steady-state flux (Jss) of the spanlastic transdermal patch (ZLP-SP1) across rabbit skin was over 3.62 times higher than that of the control transdermal patch, indicating a significant enhancement in drug permeation. The investigated transdermal patches were stable under accelerated conditions with non-irritating properties. The in-vivo studies have shown that the pharmacokinetic parameters of ZLP oral suspension and ZLP-SP1 are significantly different, with the relative bioavailability of ZLP-SP1 being 2.681%. Therefore, these fabricated transdermal patches could be effectively used to treat insomnia.

A biowaiver generally refers to the request to waive an in vivo bioequivalence study. A biowaiver may be granted not only based on the Biopharmaceutics Classifications System (BCS) but also for many immediate-release dosage forms based on pre-defined criteria. The current paper summarises the results from a survey of the biowaiver requirements for cutaneous/topical products (topical solutions, gels, suspensions, ointments, and creams), ear/otic and ophthalmic solutions and suspensions, enemas in solution and suspension, and vaginal solid dosage forms and suppositories defined by the participants of the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Programme (IPRP). A review of the results from the survey indicates that there is a trend towards convergence when the dosage forms are less complex; however, the most common approach used by each of the participants was a case-by-case approach given that most participants do not have well-defined guidelines to support all possible scenarios. Notwithstanding the differences, disseminating information is the first step towards regulatory convergence regarding biowaivers for certain dosage forms and will be useful for pharmaceutical companies currently developing generic medicinal products for countries represented by IPRP participants.