Current Clinical Pharmacology - Volume 15, Issue 2, 2020

Background: Self-Medication (SM) is a practice of using medications to treat selfdiagnosed symptoms without a legitimate prescription by a health care professional. Alongside posing a burden on a patient, SM practices are associated with certain unfavourable health conditions such as drug-resistance, adverse effects, drug-interactions, including death. Objective: To systematically review and quantify the prevalence of SM practices and its associated factors in India. Methods: A comprehensive systematic search was performed using scientific databases such as PubMed and Cochrane library for the peer-reviewed research articles that were conducted in India without any language and date restrictions. Studies which were cross-sectional by design and assessing the prevalence and predictors of SM practices in India were considered for the review, and all the relevant articles were screened for their eligibility. Results: Of 248 articles, a total of 17 articles comprising of 10,248 participants were included in the meta-analysis. Overall, the mean prevalence of SM practices in India was observed to be 53.57%. Familiarity with the medication appears to be a major reason to practice SM (PR: 30.45; 95% Confidence Interval [CI]: 17.08-43.82; 6 studies), and the practice was noticed more among individuals from a middle-lower class family with a prevalence rate of 26.31 (95%CI: 2.02-50.60; P<0.0001). Minor ailments were the primary reason for practicing SM (PR: 42.46; 95%CI: 21.87- 63.06), among which headache was the most commonly reported (PR: 41.53; 95%CI: 18.05-65.02). Conclusion: Self-medication practices are quite frequent in India. While NSAIDs and anti-allergens are the most frequently utilized self-medicated drugs used for headache and cold and cough.

Tenofovir Disoproxil Fumarate (TDF) and tenofovir Alafenamide (TAF) are prodrugs of tenofovir and have excellent long-term efficacy and tolerability for the treatment of HIV. An objective marker of adherence to tenofovir-based therapy could be clinically useful in supporting adherence to TDF-based HIV pre-Exposure Prophylaxis (PrEP) in populations in whom, self-report has been shown to be unreliable, and could play a role in resource-limited settings to support HIV and hepatitis B treatment adherence. A semi-quantitative high-performance liquid chromatographymass spectrometry method for tenofovir quantification of urine samples was developed. This assay detects tenofovir concentration in log10 levels between 1 and 10,000 ng/mL, and was shown to distinguish between recent adherence and low/non-adherence to both TDF and TAF, with a concentration of >1000 ng/mL, highly predictive of medication ingestion in the last 24-48 hours. This assay was validated relative to other markers of adherence including dried blood spot and selfreport in a highly adherent population of PrEP patients, and tenofovir was shown to be stable at room temperature in urine for at least 14 days. The assay was successfully used in a clinical setting to maintain high PrEP adherence and retention in care of 50 young men who have sex with men (MSM) over 48 weeks, to assess PrEP adherence in youth with mental health conditions, and to monitor drug levels relative to plasma levels in a case study of chewed TDF/FTC (tenofovir/emtricitabine) for PrEP. Further studies are underway to implement the tenofovir urine assay to monitor adherence and pre-exposure prophylaxis, nationally and internationally.

Background: Antibiotic therapies targeting multiple regenerative mechanisms have the potential for neuroprotective effects, but the diversity of experimental strategies and analyses of non-standardised therapeutic trials are challenging. In this respect, there are no cases of successful clinical application of such candidate molecules when it comes to human patients. Methods: After 24 hours of culturing, three different minocycline (Sigma-Aldrich, M9511, Germany) concentrations (1 μM, 10 μM and 100 μM) were added to the primary cortical neurons 15 minutes before laser axotomy procedure in order to observe protective effect of minocycline in these dosages. Results: Here, we have shown that minocycline exerted a significant neuroprotective effect at 1 and 100μM doses. Beyond confirming the neuroprotective effect of minocycline in a more standardised and advanced in-vitro trauma model, our findings could have important implications for future studies that concentrate on the translational block between animal and human studies. Conclusion: Such sophisticated approaches might also help to conquer the influence of humanmade variabilities in critical experimental injury models. To the best of our knowledge, this is the first study showing that minocycline increases in-vitro neuronal cell survival after laser-axotomy.

Background: There may be a possible link between the use of HAART and oxidative stress-related mitochondrial dysfunction in HIV patients. We evaluated the mitochondrial and oxidative impacts of short and long-term administration of HAART on HIV patients attending the Enugu State University Teaching (ESUT) Hospital, Enugu, Nigeria following short and long-term therapy. Methods: 96 patients categorized into four groups of 24 individuals were recruited for the study. Group 1 comprised of age-matched, apparently healthy, sero-negative individuals (the No HIV group); group 2 consisted of HIV sero-positive individuals who had not started any form of treatment (the Treatment naïve group). Individuals in group 3 were known HIV patients on HAART for less than one year (Short-term treatment group), while group 4 comprised of HIV patients on HAART for more than one year (Long-term treatment group). All patients were aged between 18 to 60 years and attended the HIV clinic at the time of the study. Determination of total antioxidant status (TAS in nmol/l), malondialdehyde (MDA in mmol/l), CD4+ count in cells/μl, and genomic studies were all done using standard operative procedures. Results: We found that the long-term treatment group had significantly raised the levels of MDA, as well as significantly diminished TAS compared to the Short-term treatment and No HIV groups (P<0.05). In addition, there was significantly elevated variation in the copy number of mitochondrial genes (mtDNA: D-loop, ATPase 8, TRNALEU uur) in the long-term treatment group. Conclusion: Long-term treatment with HAART increases oxidative stress and causes mitochondrial alterations in HIV patients.

Background: Group A β-hemolytic Streptococcus (GAS) and Group B streptococcus (GBS) are two common pathogens that are associated with many diseases in children. Severe infections as a result of these two streptococci are albeit uncommon but associated with high mortality and morbidity, and often necessitate intensive care support. This paper aims to review the mortality and morbidity of severe infection associated with GAS and GBS isolations at a Pediatric Intensive Care Unit (PICU). Methods: All children admitted to PICU of a teaching hospital between October 2002 and May 2018 with laboratory-proven GAS and GBS isolations were included. Results: There were 19 patients (0.7% PICU admissions) with streptococcal isolations (GAS, n=11 and GBS, n=8). Comparing to GAS, GBS affected infants were younger (median age 0.13 versus 5.47 years, 95% CI, 1.7-8.5, p=0.0003), and cerebrospinal fluids more likely positive (p = 0.0181). All GAS and GBS were sensitive to penicillin (CLSI: MICs 0.06 – 2.0 μg/mL), with the majority of GAS sensitive to clindamycin and erythromycin, and half of the GBS resistant to clindamycin and erythromycin. Co-infections were prevalent, but viruses were only isolated with GAS (p=0.024). Isolation of GAS and GBS was associated with nearly 40% mortality and high rates of mechanical ventilation and inotropic supports. All non-survivors had high mortality (PIM2) and sepsis scores. Conclusions: Severe GAS and GBS are rare but associated with high mortality and rates of mechanical ventilation and inotropic supports in PICU. The streptococci are invariably sensitive to penicillin. The high PIM2 and Sepsis scores suggest that prompt recognition of sepsis and the timely judicious institution of antibiotics and intensive care support may be life-saving for these devastating infections.

Background: Several drugs are used for treating IgA nephropathy (IgAN). We carried out a network meta-analysis evaluating these drugs. Methods: Electronic databases were searched for appropriate randomized clinical trials carried out in patients with IgAN. The primary outcome was proteinuria remission rates and there were several other secondary outcome measures. The risk of bias was assessed. Mixed treatment comparison estimates were modelled from direct and indirect comparison estimates. Grading of the evidence for key comparisons was carried out. Results: Fifty-seven clinical trials were included in the systematic review and 51 in the metaanalysis. Polyunsaturated fatty acids, corticosteroids/angiotensin receptor blockers (ARB), ARB, angiotensin converting enzyme inhibitors (ACEI), ARB/ACEI, corticosteroids/ACEI and hypolipidemics/ ARB were observed with significantly higher rates of proteinuria remission than the standard of care. Several benefits were observed with other drugs on the secondary outcome measures. A very low grade was observed for the interventions. Conclusion: We observed a few interventions to perform better in the management of IgAN. The results of this study will aid in further evaluation of such drugs that may assist in saving the resources and time. However, the readers should interpret the findings with great caution as the results might change with the advent of future head-to-head clinical trials.

Background: It is still controversial whether pomegranate causes drug interactions. Pomegranate juice has been shown to inhibit CYP3A in-vitro and animal studies. The coadministration of pomegranate juice with cyclosporine, a narrow therapeutic drug that is the substrate of CYP3A, might lead to drug toxicity. The objective of this study is to investigate the effect of pomegranate juice on the pharmacokinetics of cyclosporine in healthy Thai volunteers. Methods: The study design was an open-label, randomized, single dose, crossover study with a 2- week washout period. Each fasting subject received 2 microemulsion tablets of 100 mg of cyclosporine with 500 ml of pomegranate juice (test) or 500 ml of water (control). Serial blood samples were collected up to 24 h after dosing, and blood samples were analyzed for cyclosporine concentrations by using chemiluminescent microparticle immunoassay. Fourteen healthy volunteers completed the study. Results: The 90% confidence intervals for the test/control ratio using logarithmically transformed data of area under the concentration-time curve (AUC) from time zero until the last measured concentration (AUC0-t), AUC from time zero to infinity (AUC0-∞), and maximum concentration (Cmax) were 91.6-105.6, 92.0-105.2 and 82.3-102.5, respectively. The results were within the accepted bioequivalence range for narrow therapeutic index drugs (90-111% for AUC and 80-125% for Cmax). There were no differences in adverse event between the groups. Conclusion: Single dose administration of pomegranate juice with cyclosporine did not significantly affect the oral bioavailability of cyclosporine. However, further work is needed to thoroughly evaluate the effect of pomegranate on narrow therapeutic drugs.

Background: 2-iminobiotin (2-IB) is an investigational neuroprotective agent in development for the reduction of brain cell injury after cerebral hypoxia-ischemia. Objective: The present first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK) and -dynamics (PD) of 2-IB in healthy male subjects, intravenously infused with or without Captisol® as a solubilizing agent. Methods: This randomized, double-blind, placebo-controlled, dose-escalation study was executed in 2 groups of 9 healthy male subjects. A single dose of 2-IB 0.6 mg/kg or placebo was infused over periods between 15 min and 4 h, and repeated doses escalating from 0.6 mg/kg to 12 mg/kg, or placebo were infused every 4 h for 6 administrations in total. Results: Single and multiple doses of 2-IB up to 6 doses of 6 mg/kg with and without Captisol® were safe and well-tolerated in healthy male subjects. 2-IB proved to be a high-clearance drug with a volume of distribution slightly exceeding total body water volume, and with linear PK that appeared not to be affected by the presence of Captisol®. Conclusion: Sulfobutyletherbeta-cyclodextrin (SBECD) in Captisol® had a low-clearance profile with a small volume of distribution, with time-independent PK. Preliminary PD characterization of repeated iv dosing of 2-IB in an acute peripheral hypoxic ischemia model in healthy subjects did not reveal any notable effects of 2-IB, noting that this model was not selected to guide efficacy in the currently pursued indication of cerebral hypoxia-ischemia.

Background: Neonatal Respiratory Distress Syndrome (NRDS) is one of the most frequent causes of neonatal mortality especially in premature infants. Although it has been well established that maternal antenatal corticosteroid therapy has a positive effect on NRDS reduction, yet the effectiveness of this treatment in multifetal pregnancies is dubious. Objective: We aimed to investigate the effect of betamethasone therapy on the incidence of NRDS in multifetal pregnancies through a randomized controlled trial. Methods: 140 women with a multifetal pregnancy at less than 28 weeks’ gestational age were randomly allocated into intervention and control groups. Women at the intervention group received intramuscularly betamethasone (12 mg/kg/BW twice). Neonatal outcomes were evaluated between two groups of intervention and control, and two subgroups of preterm and term births. This study is registered with the Iranian Clinical Trials Registry, number IRCT20180227038879N1. Results: The incidence of NRDS was significantly lower in infants of betamethasone group than the ones in the control group (4.9% vs 18.1%, P=0.034) while it did not show a significant reduction in preterm infants compared to mature ones. Also, the intervention group presented a significant lower neonatal ventilation than the control group (47.2% vs 63.2%, P=0.041). Other neonatal outcomes, including age at birth, birth weight, Apgar score, NICU admission, and the number of mortalities were not significantly different between study groups. Conclusion: Betamethasone therapy during 28-32 weeks of gestation in multifetal pregnancies was associated with better neonatal outcomes through significant reductions in NRDS incidence and requiring ventilator treatment. However, betamethasone administration did not reduce the chance of NRDS in premature infants.