Current Reviews in Clinical and Experimental Pharmacology - Volume 17, Issue 2, 2022

We suggest that enteral formulation of escin could be used instead of enteral formulation if it is not available.

Background: The current recommendations of the American College of Cardiology/ American Heart Association and a previous Bayesian analysis clearly show a mortality benefit with the use of β- blockers in chronic HF, especially for bisoprolol, carvedilol, and sustained-release metoprolol succinate. Objective: The main objective was to report the evidence on the use of the afore-mentioned β-blockers in subjects with heart failure and to characterize the stages of heart failure in response to the four different β-blockers. Furthermore, it shed light on the patient’s satisfaction and improved quality of life using the afore-mentioned β-blockers in subjects with heart failure. Methods: The current perspective presented the clinical outcomes, including hospitalization, morbidity, mortality, patient’s satisfaction, and quality of life, of four beta (β)-blockers, namely bisoprolol, carvedilol, metoprolol succinate, and nebivolol in different stages of heart failure. Results: The use of these three agents should be recommended for all stable subjects with current or previous symptoms of heart failure and heart failure with reduced ejection fraction unless there is any contraindication. The fore-mentioned β-blockers (bisoprolol, carvedilol, and metoprolol succinate) can be initiated early, even in stable and symptom-free (at rest) subjects with heart failure. β-blockers in heart failure should be commenced at small doses and then titrated upward as tolerated to achieve the desired clinical effects on heart rate and symptom control. Conclusion: Cardiologists should weigh the benefit-risk in subjects with heart failure and other coexisting cardiovascular problems such as atrial fibrillation and diabetes.

Background: Assessing analgesic drugs developed over preceding 50 years demonstrated that very intensive efforts directed at diverse molecular pain targets produced thousands of PubMed articles and the introduction of more than 50 new analgesics. Nevertheless, these analgesics did not have a sufficiently broad spectrum of action and level of effectiveness to demonstrably affect the use of opioids or nonsteroidal anti-inflammatory drugs for the treatment of pain. Analgesics in current are only modestly effective in chronic pain (at least with respect to neuropathic pain), and the widespread application of mu-opioid receptor agonists for this purpose culminated in the global “opioid crisis”. The introduction of every new drug is regarded as an important success, at least initially. Assessing the merit of a new analgesic is extremely complicated. Objective: The aim of this article is to describe an approach that combines very different categories of drug evaluation – multifactorial approach for the assessment of new analgesics. It is based on conclusiveness of clinical trials, novelty of a drug’s molecular target, a drug’s commercial appeal, and the interest in a drug reflected by scientometric indices. Results: This approach was applied to analgesics developed in 1982-2016. It shows that although several new agents have completely novel mechanisms of action, all newly approved drugs, and drug candidates, demonstrated the same persistent problems: relatively low therapeutic advantage over previous treatment and narrow spectrum of use in different types of pain, compared to opioids or NSAIDs. Conclusion: The use of the suggested multifactorial approach to drug assessment may provide a better view of the whole spectrum of analgesics advantages and disadvantages.

The practice of medicine depends, over a long time, on identifying therapies that target an entire population. The increase in scientific knowledge over the years has led to the gradual change towards individualization and personalization of drug therapy. The hope of this change is to achieve a better clinical response to given medications and reduction of their adverse effects. Tailoring of medicine on the road of personalized medicine considers molecular and genetic mapping of the individual. However, many factors still impede the smooth application of personalized medicine and represent challenges or limitations in its achievement. In this article, we put some clinical examples that show dilemmas in the application of personalized medicine such as opioids in pain control, fluoropyrimidines in malignancy, clopidogrel as antiplatelet therapy and oral hypoglycemic drugs in Type2 diabetes in adults. Shaping the future of medicine through the application of personalized medicine for a particular patient needs to put into consideration many factors such as patient’s genetic makeup and life style, pathology of the disease and dynamic changes in its course as well as interactions between administered drugs and their effects on metabolizing enzymes. We hope in the coming years, the personalized medicine will foster changes in health care system in the way not only to treat patients but also to prevent diseases.

Background: Immunotherapy drugs, known as immune checkpoint inhibitors (ICIs), work by blocking checkpoint proteins from binding with their partner proteins. The two main pathways that are specifically targeted in clinical practice are cytotoxic T-lymphocyte antigen-4 (CTLA- 4) and programmed cell death protein 1 (PD-1) that showed potent immune-modulatory effects through their function as negative regulators of T cell activation. Methods: In view of the rapid and extensive development of this research field, we conducted a comprehensive review of the literature and updated on the use of CTLA-4, PD-1, and PD-L1 targeted therapy in the treatment of several types of cancer, including melanoma, non-small-cell lung carcinoma, breast cancer, hepatocellular carcinoma, Hodgkin lymphoma, cervical cancer, and head and neck squamous cell carcinoma. Results: Based on the last updated list released on March 2019, seven ICIs are approved by the FDA, including ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and cemiplimab. Conclusion: This review highlighted the most common adverse effects caused by ICIs which affect people in different ways.

The concept of ‘one size fits all’ - one treatment for patients with a particular disease, seems to be outdated. The advent of precision medicine has prompted profound changes in clinical research and it allows researchers to predict more accurately, the prevention and treatment strategies for a specific disease population. Novel study designs are, therefore, essential to establish safe and effective personalized medicine. Basket, umbrella and platform trial designs (collectively referred to as master protocols) are biomarker enrichment designs that allow for testing more than one hypotheses within a protocol, thus accelerating drug development. These trial designs tailor intervention strategies based on patient’s risk factor(s) that can help predict whether they will respond to a specific treatment. Basket trials evaluate therapy for various diseases that share a common molecular alteration, while umbrella trials evaluate multiple targeted therapies for a single disease that is stratified into subgroups based on different molecular alterations/ risk factors. These designs are complex and their major limitations stem from the fact that it would be inappropriate to completely replace histological typing with molecular profiling alone. However, in the upcoming decades, these trial designs are likely to gain popularity and improve the efficiency of clinical research. This article briefly overviews the characteristics of master protocol designs with examples of completed and ongoing clinical trials utilizing these study designs.

Background: The use of levetiracetam (LEV) has been increasing, given its favorable pharmacokinetic profile. Numerous population pharmacokinetic studies for LEV have been conducted. However, there are some discrepancies regarding factors affecting its pharmacokinetic variability. Therefore, this systematic review aimed to summarize significant predictors for LEV pharmacokinetics as well as the need for dosage adjustments. Methods: We performed a systematic search for population pharmacokinetic studies of LEV conducted using a nonlinear-mixed effect approach from PubMed, Scopus, CINAHL Complete, and Science Direct databases from their inception to March 2020. Information on study design, model methodologies, significant covariate-parameter relationships, and model evaluation was extracted. The quality of the reported studies was also assessed. Results: A total of 16 studies were included in this review. Only two studies were conducted with a two-compartment model, while the rest were performed with a one-compartment structure. Bodyweight and creatinine clearance were the two most frequently identified covariates on LEV clearance (CLLEV). Additionally, postmenstrual age (PMA) or postnatal age (PNA) were significant predictors for CLLEV in neonates. Only three studies externally validated the models. Two studies conducted pharmacodynamic models for LEV with relatively small sample size. Conclusion: Significant predictors for LEV pharmacokinetics are highlighted in this review. For future research, a population pharmacokinetic-pharmacodynamic model using a larger sample size should be conducted. From a clinical perspective, the published models should be externally evaluated before clinical implementation.

Background: Subacute granulomatous thyroiditis (SAGT) is an inflammatory disease due to viral infections. Glucocorticoids, especially prednisolone (PSL), are one of the first approaches in the treatment of patients with SAGT. To date, no study has determined the lowest effective dose of prednisolone with the lowest recurrence rate in the treatment of SAGT. This study aimed to use meta-analysis methods to identify the appropriate dosage of prednisolone with the lowest recurrence rate in the treatment of patients with SAGT. Methods: This study was conducted according to the PRISMA checklist in February 2021. Two independent researchers performed a search for relevant literature published before March 2021 in English databases, including Scopus, MEDLINE (via PubMed), Web of Science, Cochrane Library, Google Scholar, EMBASE, and also Persian electronic databases including SID, Iran medex, Magiran, and Irandoc. The search algorithm was initially developed by using a combination of MeSH terms, keywords, and also Boolean operators (“AND”; “OR”; “NOT”): Subacute thyroiditis, De Quervain Thyroiditis, Glucocorticoids, Prednisolone, Recurrence, and Meta-Analysis. All statistical analyses were performed using STATA 15.0 (StataCorp LLC, College Station, TX, USA) and SPSS 17.0. A random-effects model based on Metaprop was applied for the Meta-analysis. To assess heterogeneity between studies, the chi-squared test and I2 index were used, and for evaluating publication bias, funnel plots and Egger tests were performed. Results: The overall recurrence rate was 14.72% [95% CI: 9.63- 20.58] and there was a significant heterogeneity among the studies [I2 = 69.56%; P=0.000]. To evaluate the lowest effective dose of prednisolone, we divided the studies into two groups based on the mean initial dose of prednisolone: less than or equal to 20 mg/day (group one) and greater than 20 mg/day (group two). The recurrence rate in group 1 was 11% [95% CI: 5.7- 16.2] and in group 2 was 23.6% [95% CI: 11.5- 35.6]. Significant correlations were observed between the initial mean dose of PSL and recurrence rate (r= 0.71; P= 0.013). Begg’s funnel plot had no evidence of publication bias in these studies (p=0.160). Conclusion: According to the results of this meta-analysis, 15 to 20 mg/day of prednisolone is the most effective dosage with the lowest recurrence rate in the treatment of subacute Granulomatous thyroiditis.

Background: Several studies reported that abnormal behavior was noted in pediatric patients receiving several drugs, including neuraminidase inhibitors (NIs). However, the information on drugs associated with abnormal behavior in a real-world setting remains limited. The purpose of this study was to clarify the drugs associated with abnormal behavior using a spontaneous reporting system database. Methods: We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency were analyzed, and the reporting odds ratio at 95% confidence interval were calculated. Results: A total of 1,144 reports of abnormal behavior were identified. The signals were detected through the association of 4 neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir, and peramivir) with the abnormal behaviour. These signals were stronger for oseltamivir than other neuraminidase inhibitors. The signals were also detected for acetaminophen and montelukast. Conclusion: Our results should be able to raise physicians’ awareness of drugs associated with abnormal behavior, but further investigation of these medications is warranted.

Background: Patent Ductus Arteriosus (PDA) is associated with adverse clinical outcomes in very low birth weight (<1500g) infants. Objective: In our study, it was aimed to investigate the effect of gentamicin treatment, which is frequently used for early-onset sepsis on ductal patency. Methods: We performed a single-center retrospective review of charts of preterm infants <32 weeks gestation with birth weight <1500 grams born between June 1, 2015 and December 31, 2019 at the neonatal intensive care unit. All infants underwent an echocardiogram (ECHO) at 72 hours. To determine the effect of gentamicin treatment on hemodynamically significant PDA (hsPDA), we compared the frequency and duration of gentamicin administration between infants with hsPDA and without hsPDA. Results: During the study period, 792 patients were evaluated. Gentamicin was given to more infants with hsPDA than to those without hsPDA (89.2% vs. 64.6%, p<0.001), and the duration of therapy was longer in those infants with hsPDA (7 days vs. 9 days, p<0.001). The area under the curve for duration of gentamicin was 0.772 (%95 CI: 0.742-0.804, P=0.0001), sensitivity: 59 (%95 CI: 53-65), specificity: 82 (%95 CI: 78-88), with a cut-off day for duration of gentamicin >7 days. Conclusion: In our study, it was found that ductal contraction decreased and hsPDA rate increased as the rate and duration of gentamicin increased.

Background: Hepatitis C Virus (HCV) infection represents a global problem, and it is related to both hepatic and extra-hepatic manifestations (e.g., xerophthalmia). New direct-acting antivirals (DAAs), IFN-free treatments, are commonly used to manage HCV infection. However, the impact of new DAAs on dry eyes (xerophthalmia) is lacking. In this study, we evaluated its incidence in HCV patients and the effect of DAAs on this manifestation. Methods: We performed an observational open-label non-randomized study in HCV patients from 01 April 2018 to 01 June 2020. Results: Patients who satisfied the inclusion criteria underwent clinical and laboratory evaluation, Schirmer's test, and Break-up time test. Enrolled patients were divided in two groups: Group 1: HCV patients with xerophthalmia: 24 patients (16 male and 8 female), HCV-RNA 2,685,813 ± 1,145,698; Group 2: HCV patients without xerophthalmia: 35 patients (19 male and 16 female), HCV-RNA 2,614,757 ± 2,820,433. The follow-ups (3 and 6 months after the enrollment) documented an improvement in both eyes’ manifestations and HCV-infection (HCV-RNA undetected). Conclusion: In conclusion, in this study, we reported that xerophthalmia could appear in HCV patients, and DAAs treatment reduces this manifestation without the development of adverse drug reactions.