Clinical Pharmacology : Advances and Applications最新文献

Primary central nervous system lymphoma (PCNSL) is a rare, aggressive, extranodal lymphoma exclusively located in the central nervous system. High-dose methotrexate (HD-MTX)-based chemotherapy combination regimens are now the standard of care for the upfront treatment of PCNSL and are used in a salvage setting but are toxic and cumbersome to administer because of the need for inpatient supportive care. While the incidence of PCNSL is increasing in the aging population, a significant proportion of patients are unable to follow HD-MTX protocols owing to performance status and organ dysfunction. Consolidative autologous stem cell transplant or whole-brain radiation therapy improves progression-free survival at the cost of short- and long-term toxicities. Induction of low toxicity and consolidative and salvage therapeutic options are lacking. Due to its unique biology, PCNSL presents an exciting opportunity for the development of novel therapies with improved efficacy and toxicity. In this review, we focus on the biology of PCNSL and novel chemotherapeutics, including targeted and immunotherapeutic agents as well as cellular therapies. Expert Opinion summary: Given the lack of low-toxicity standard treatments for PCNSL, the outcomes for aging PCNSL patients remain suboptimal. Current research has focused on introducing targeted immunotherapies into the induction, salvage, and consolidation treatments of PCNSL.

Purpose: This study aimed to assess the real-world impacts of non-cardiac drug-induced QTc interval prolongation and identify associated risk factors in acute care settings.

Patients and methods: A cross-sectional study reviewed medical charts of 7,778 patients admitted to tertiary teaching hospitals from January 2016 to December 2022. Patients on CredibleMeds-listed QTc-prolonging non-cardiac drugs were identified, excluding those with congenital long QTc syndrome or on QTc-prolonging cardiac medications. Data collection involved reviewing medication charts and recording demographic and clinical data, including comorbidities and laboratory values. A logistic regression analysis was performed to address confounders, and known risk factors, calculating Odds Ratios (OR) and 95% confidence intervals (CI). Statistical analysis used SPSS Version 21.0, with p < 0.05 indicating significance.

Results: Out of 7,778 screened patients, 151 met the inclusion criteria. Among these, 75.5% demonstrated prolonged QTc values. The study identified 42 distinct medications associated with QT interval prolongation, categorized into six therapeutic groups. Proton pump inhibitors (PPIs) were the most common cause of non-cardiac drug-induced QTc interval prolongation, with esomeprazole representing 46.5% of the cases. Antimicrobial medications followed, with azithromycin at 9.6% and piperacillin-tazobactam at 6.1%. The multivariate analysis revealed that heart failure was significantly associated with QTc prolongation odd ratio (OR) 4.98 with 95% confidence interval CI [1.58 to 17.35], while other factors such as age, BMI, and certain comorbidities did not show a statistically significant impact.

Conclusion: The findings highlight the significant risk associated with the in-hospital administration of QTc-prolonging non-cardiac medications, particularly among patients with heart failure. Future research should aim to include a larger patient population and employ comprehensive data collection methods across multiple centers to enhance the robustness and generalizability of the findings.

Glofitamab is a novel bispecific antibody targeting CD20×CD3, capable of simultaneously targeting CD20 and CD3 to activate T cells and release cytotoxic proteins that kill cancer cells. Cytokine release syndrome (CRS) is one of the most common adverse events observed in clinical trials of glofitamab. In most cases, CRS is mild, transient, and manageable with appropriate treatment. This paper reports a case of persistent CRS in a patient with mantle cell lymphoma following glofitamab treatment and reviews the relevant literature for reference.

Introduction: Rifampicin is a crucial first-line anti-tuberculosis drug that has been extensively studied through population pharmacokinetic (popPK) analyses. This study aims to construct a comprehensive rifampicin popPK model repository to support model-informed individualized therapy.

Methods: A systematic review was conducted using PubMed, Web of Science, and Embase databases up to September 2023 to retrieve popPK model articles on rifampicin. Extracted data included basic information, dosing regimens, sampling strategies, model parameters, and covariate details. Non-English studies, non-parametric models, and duplicates were excluded. The repository was built using R package mrgsolve, and a Shiny application was developed for simulation and individualized dosing predictions.

Results: A total of 29 studies were included in the rifampicin model repository: 23 on adults, 5 on pediatrics, 1 on both populations, and 1 on pregnant women. Most rifampicin popPK models were one-compartment linear elimination models, with transit compartment or lagged absorption models improving drug absorption fitting. An allometric growth model based on fat-free mass (FFM) might improved model fit. Postmenstrual age (PMA) significantly impacted elimination in pediatric patients. All models underwent internal validation, with three studies validated externally. Significant variations in exposure predictions were observed among models, indicating challenges in achieving therapeutic targets under standard treatment.

Discussion: The model repository provides a comprehensive resource for exploring various models and their application in different populations, supporting individualized rifampicin therapy. Further research is needed for special populations and to determine whether weight or FFM is more rational for dosing. External validation is essential for model development.

Introduction: Malaria remains a persistent challenge in global health, disproportionately affecting populations in endemic regions (eg, sub-Saharan Africa). Despite decades of international collaborative efforts, malaria continues to claim hundreds of thousands of lives each year, with young children and pregnant women enduring the heaviest burden. This concise review aimed to provide an up-to-date assessment of malaria vaccines progress, challenges, and future directions.

Methods: A PubMed/MEDLINE search (2015-2024) was conducted to identify studies on malaria vaccine development, implementation barriers, efficacy, and vaccination hesitancy. Clinical trials, reviews, and global health reports were included based on relevance to the review aims. No strict inclusion criteria were applied, and selection was guided by key review themes and policy relevance.

Results: The introduction of pre-erythrocytic malaria vaccines (RTS,S/AS01 and R21/Matrix-M), represents an important milestone in malaria control efforts with promising results from the erythrocytic vaccine RH5.1/Matrix-M in recent clinical trials. However, the approval of these vaccines is accompanied by significant challenges such as the limited efficacy, the complexity of multi-dose regimens, and numerous barriers to widespread implementation in resource-limited settings. The review identified the complex challenges to broad malaria vaccination coverage, including logistical barriers, healthcare infrastructure effect, financial limitations, malaria vaccine hesitancy, among other obstacles in malaria-endemic regions. Promising developments in malaria vaccination, such as next-generation candidates (eg, mRNA-based vaccines), hold the potential to offer improved efficacy, longer-lasting protection, and greater scalability. There is a critical need to integrate malaria vaccination efforts with established malaria control interventions (eg, insecticide-treated bed nets, vector control strategies, and anti-malarial drugs).

Conclusion: Achieving sustained control of malaria morbidity and mortality will require strong global collaboration, sufficient funding, and continuous efforts to address inequities in access and delivery of malaria control measures including the malaria vaccines.

Crotalidae polyvalent immune Fab (CroFab) is an antivenin that is FDA approved and commonly used to treat envenomations caused by North American pit vipers. Although CroFab has been widely used since the early 2000s, hypersensitivity reactions like type I, type IV, and angioedema have been reported in the literature. We present a case of CroFab induced hypersensitivity reaction in a 41-year-old male shortly after starting CroFab infusion. Furthermore, this patient developed anaphylaxis symptoms including: difficulty breathing, oropharyngeal edema, dysphagia, wheezing, and chest tightness. This was resolved upon stopping CroFab infusion and administering epinephrine, methylprednisolone, diphenhydramine, and famotidine. The reaction occurred again when CroFab was re-introduced despite infusing it at a much slower rate. Interestingly, this patient successfully tolerated crotalidae immune F(ab')2 (equine) antivenom (ANAVIP) upon switching him from CroFab. Hypersensitivity reactions to CroFab can be life-threatening and warrant immediate attention and treatment in a multidisciplinary setting.

Introduction: Curcumin is an extract from herbal plants that has been implicated in the treatment of any disease, including oral disease. There are various types of curcumin formulation as the option of the therapy. The aim of this review is to describe the curcumin mechanism in reducing the severity, pain score, and oral lesion size as the therapeutic effects.

Methods: This systematic review used the Preferred Reporting Items for Systematic Review and Meta Analysis (PRISMA) guidelines. Databases used for articles include PubMed, Science Direct, and Scopus with inclusion criteria published from 2014 to 2024, full text, in English, and randomized controlled trial (RCT).

Results: The present study included 21 RCTs with a total of 1244 individuals. In this study, curcumin was most commonly used for oral submucous fibrosis, with 9 studies demonstrating that curcumin has anti-inflammatory properties and inhibits collagenase. All studies demonstrate that curcumin produces significant results in the management of oral disease. The remain studies showed curcumin has antioxidant, inhibit collagenase, antifungal, and wound healing properties for oral leukoplakia, recurrent aphthous stomatitis (RAS), oral lichen planus (OLP), and denture stomatitis.

Conclusion: Curcumin has anti inflammatory, antioxidant, inhibit collagenase, antifungal, and wound healing properties for reducing the severity of lesion, pain score and oral lesion size as the therapeutic effects in the patients with oral disease including OSMF, mucositis, leukoplakia, RAS, OLP, and denture stomatitis.

Various repurposing drugs have been tested for their efficacy on coronavirus disease 2019 (COVID-19), including antimalarial drugs. During the pandemic, Chloroquine (CQ) and Hydroxychloroquine (HCQ) demonstrated good potential against COVID-19, but further studies showed both drugs had side effects that were more dangerous than the efficacy. This made World Health Organization (WHO) ban the usage for COVID-19 patients. In this context, there is a need to explore other antimalarial drugs as potential therapies for COVID-19. This study provides a descriptive synthesis of clinical trials evaluating antimalarial drugs for COVID-19 treatment conducted after the withdrawal of CQ and HCQ. The method was a literature study using the keywords "antimalarial", "COVID-19", "SARS-CoV-2", "clinical trial", and "randomized controlled trial" on the MEDLINE, Scopus, and Cochrane databases. Inclusion criteria were published clinical trials with randomized controlled trials (RCTs) on the efficacy and safety of single antimalarial drugs for COVID-19, published in English and excluding combination therapies. The results showed 3 antimalarial drugs, namely Quinine Sulfate (QS), Atovaquone (AQ), and Artemisinin-Piperaquine (AP), had gone through clinical trial to assess efficacy and safety against COVID-19 patients. Out of the 3 drugs, only AP showed significant results in the primary outcome, which was the time required to reach undetectable levels of SARS-CoV-2. Furthermore, the intervention group took 10.6 days, and the control group took 19.3 days (p=0.001). Based on this review, AP showed significant potential as a therapy in the fight against COVID-19.

Background: Heparin and its derivates, including unfractionated heparin (UFH) and low molecular weight heparin (LMWH), are among the most commonly used anticoagulants. Nonetheless, their use has been associated with hyperkalemia.

Objective: To determine and compare the incidence, magnitude, and potential risk factors of hyperkalemia in patients receiving UFH versus LMWH in a real-world clinical setting.

Methods: A retrospective observational study was conducted involving all adult hospitalized patients who received UFH, dalteparin or enoxaparin. Electronic medical records were reviewed over a 12-month period, collecting data on demographic, laboratory, comorbidity, and medication-related variables. Data were analyzed using multivariate logistic regression.

Results: A total of 929 patients met the eligibility criteria, with a mean age of over 40 years across all groups. Of these, 56.3%, 17.2%, and 15.7% experienced hyperkalemia with UFH, dalteparin and enoxaparin, respectively. The incidence of hyperkalemia was significantly higher with UFH compared to enoxaparin and dalteparin (p<0.001). Diabetes mellitus was associated with a higher incidence of hyperkalemia (OR 1.79, 95% CI 1.241-2.581, p=0.002), as was the concomitant use of co-trimoxazole (OR 2.244, 95% CI 1.137-4.426, p=0.02). Whilst chronic kidney disease and the use of two or more hyperkalemia-inducing agents were not statistically significant, they were retained in the model as they were associated with more than a 10% increase in the odds of hyperkalemia.

Conclusion: Heparin (UFH, LMWH) administration was associated with a risk of hyperkalemia particularly in patients with diabetes mellitus and those concurrently receiving co-trimoxazole.

Dexmedetomidine is a selective and potent α₂-adrenoceptor agonist used for sedation, analgesia, and anxiolysis, with minimal respiratory depression; therefore, it is widely used in clinical practice. Transient hypertension has been reported to be an indication for the use of dexmedetomidine. The authors report three female patients who experienced hypertensive crisis when used atropine to treat bradycardia caused by dexmedetomidine. The transient hypertension is a relatively common side effect of dexmedetomidine, hypertensive crisis seen with coadministration of atropine is much less frequently reported. This is the first report to describe the use of atropine to treat bradycardia induced by dexmedetomidine, which may cause severe hypertension in female patients. They discuss the reason for and treatment of hypertension caused by administration of atropine and dexmedetomidine together and review the relevant literature.