Physical fitness in Indian women with epilepsy on anti-seizure medications and its association with reproductive status, quality of life and stigma: A cross-sectional study.

PURPOSE: To determine the status of physical fitness, reproductive abnormalities, QOL and epilepsy associated stigma in women with epilepsy (WWE) and their association with ASM therapy and seizure frequency. METHODS: This cross-sectional study included WWE of reproductive age (18-50 years) on antiseizure medications (ASMs) for at least three months before enrolment. Physical fitness was assessed using International Physical Activity Questionnaires (IPAQ) and Body composition analysis. Subjects were interviewed for menstrual abnormalities [menstrual disturbance or Polycystic Ovary Syndrome (PCOS)/hirsutism]. Validated questionnaires were used for assessment of, QOL (QOLIE-10) and Stigma in epilepsy (Epilepsy Stigma Scale). Sub-group analysis was done to compare the above parameters on the basis of a) type of therapy (mono or polytherapy), b) type of ASMs treatment (conventional, newer, or conventional + newer ASMs), and c) seizure type and (d) seizure frequency. Correlation and regression analysis were done to find out the association among different variables with physical fitness. RESULTS: The overall prevalence of poor physical fitness, reproductive abnormalities, worsened QOL and stigma in the enrolled WWE (n = 203) were 21.18 %, 20.19 %, 52.7 %, and 21.67 %, respectively. Sub-group analysis revealed that WWE on monotherapy (n = 99) had higher median IPAQ score (p = 0.002), comparatively less reproductive abnormalities (24.03 %, p = 0.008), and higher stigma (24.03 %, p = 0.04) than polytherapy group. WWE on conventional ASMs had significantly higher IPAQ scores compared to newer and conventional + newer ASMs groups (p = 0.02). The prevalence of poor physical fitness and stigma was significantly higher in WWE with higher number of seizures (p = 0.007, <0.001, respectively). No significant difference in QOL was observed on the basis of ASM type and therapy; however, WWE with generalized onset seizures had worsened QOL compared to those with focal onset seizures (p = 0.04). A significant negative correlation was found among seizure frequency and IPAQ score in WWE (p = 0.04). CONCLUSION: WWE on polytherapy were physically less active, higher occurrence of reproductive abnormalities, and stigma compared to the monotherapy group. WWE with higher seizure frequency had poor physical fitness, and higher stigma compared to those with lesser number of seizures. These findings may aid value in optimization of ASM treatment in WWE of reproductive age.

A Comparative Review of ICMR, WHO, and EMA Guidelines for Good Clinical Laboratory Practices.

With the advancement of clinical research and the increased burden on laboratory services, there is an unmet need for guidelines regarding proper laboratory functioning and reliable data generation. Several organizations from all over the world have published guidelines for these clinical and research laboratories. Good Clinical Laboratory Practices (GCLP) are stepwise procedures aimed at strengthening the quality of test results produced by all clinical laboratories engaged in human sample analysis. In this article, we attempt a comparison of the GCLP guidelines recently issued by the Indian Council of Medical Research with the guidelines released by the World Health Organization and the European Medicines Agency. Also, we have included and discussed several suggestions that, if included, will lead to the strengthening of the laboratory practices used for both research and patient care for overall improvement in the Indian healthcare system.

An update on efficacy and safety comparison of biologics in treatment of inflammatory bowel disease targeting TNF-α, interleukins, leukocyte trafficking, Janus-kinase, and sphingosine-1-phosphate receptor.

INTRODUCTION: Along with the rising prevalence of inflammatory bowel disease (IBD) [Crohn's disease (CD) and ulcerative colitis (UC)], biological therapies need an update/insight. AREA COVERED: This review included randomized controlled trials (RCTs) from PubMed database (2000-October 2022) of approved biologics and small molecules with primary outcome analysis on efficacy (clinical response/remission/mucosal healing) and/or adverse events (AEs). Considered for this review under biologics classes are TNF-α inhibitors, leukocyte trafficking inhibitors, and anti IL-12/IL-23; and under small molecules are Janus-kinase inhibitors, and sphingosine-1-phosphate receptor modulators. EXPERT OPINION: In CD, clinical response and remission were better with tofacitinib (61.23%) and infliximab (44.86%), respectively, in the induction phase, and these were better with ustekinumab in the maintenance phase. In UC, the maximum rate of response, remission, and mucosal healing were obtained with infliximab during the induction phase (67.49%, 35.99%, and 60.25%, respectively). During the maintenance phase, response rate was better with ustekinumab, but remission and mucosal healing were better with vedolizumab. The combined percentage of AEs was highest with infliximab (174.45%) and least with ozanimod (23.04%), and most commonly belonged to the 'infection and infestation system organ class (SOC).' These efficacy and safety analyses will help in the optimization of biologic treatment in IBD.

Identifying the core concepts of pharmacology education: A global initiative.

BACKGROUND AND PURPOSE: In recent decades, a focus on the most critical and fundamental concepts has proven highly advantageous to students and educators in many science disciplines. Pharmacology, unlike microbiology, biochemistry, or physiology, lacks a consensus list of such core concepts. EXPERIMENTAL APPROACH: We sought to develop a research-based, globally relevant list of core concepts that all students completing a foundational pharmacology course should master. This two-part project consisted of exploratory and refinement phases. The exploratory phase involved empirical data mining of the introductory sections of five key textbooks, in parallel with an online survey of over 200 pharmacology educators from 17 countries across six continents. The refinement phase involved three Delphi rounds involving 24 experts from 15 countries across six continents. KEY RESULTS: The exploratory phase resulted in a consolidated list of 74 candidate core concepts. In the refinement phase, the expert group produced a consensus list of 25 core concepts of pharmacology. CONCLUSION AND IMPLICATIONS: This list will allow pharmacology educators everywhere to focus their efforts on the conceptual knowledge perceived to matter most by experts within the discipline. Next steps for this project include defining and unpacking each core concept and developing resources to help pharmacology educators globally teach and assess these concepts within their educational contexts.

Effect of add-on alpha lipoic acid on psychopathology in patients with treatment-resistant schizophrenia: a pilot randomized double-blind placebo-controlled trial.

RATIONALE: Alpha lipoic acid is known to reverse NMDA receptor hypofunction in addition to dopamine receptor blockade activity. It also enhances neurotrophic factors and has antioxidant potential. These properties combined together may be beneficial for treatment-resistant schizophrenia (TRS). OBJECTIVES: This study evaluates the effect of alpha lipoic acid (ALA) on psychopathological scores (positive, negative, cognitive), neurotrophic factors and oxidative stress in TRS. METHODS: A pilot randomized double-blind placebo-controlled parallel design trial was conducted in 20 patients with TRS. After initial screening, participants were randomized into test (add-on ALA) and control (add-on placebo) groups. After recruitment, clinical evaluations with scale for assessment of positive symptoms and negative symptoms (SAPS and SANS), schizophrenia cognitive rating scale (SCoRS), UKU side effect rating scale were done. Serum levels of BDNF, MDA, and GSH were estimated. Patients were followed up for 8 weeks, and clinical and biochemical evaluations were repeated. Adherence to medication was evaluated at follow-up. RESULTS: A significantly greater improvement was found in SANS score in the test group when compared to control (Mann-Whitney U = 17.0; p = 0.021), whereas there was no significant improvement in SAPS score (Mann-Whitney U = 41.5; p = 0.780). A significant increase in BDNF levels was observed in the control group when compared to ALA (U = 20.0; p = 0.041). No significant differences were found between the test and control groups in serum MDA (U = 30.0; p = 0.221), serum GSH (U = 40.0; p = 0.683), and medication adherence rating scale (MARS) scores (U = 44.0; p = 0.934). CONCLUSIONS: ALA supplementation improved psychopathology and decreased oxidative stress in patients with TRS. This study thus shows the potential of adjunctive ALA in TRS. TRIAL REGISTRATION: The study was prospectively registered in Clinical Trial Registry of India (CTRI/2020/03/023707 dated 02.03.2020).

Efficacy and Safety of Adjunctive Serotonin-Dopamine Activity Modulators in Major Depression: A Meta-Analysis of Randomized Controlled Trials.

Serotonin-dopamine activity modulators (SDAMs) have been approved as an adjunctive treatment to antidepressants in patients with inadequate response. These drugs have been proposed to have a beneficial effect on cognition, sleep-related problems, and other affective symptoms in patients with depression. Previous studies have shown inconsistent evidence and have not reported a pooled effect of the 2 drugs of this class: aripiprazole and brexpiprazole. This meta-analysis evaluated the effect of augmentation with SDAM drugs in patients with major depression. The meta-analysis protocol was made as per Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol guidelines and registered in the International Prospective Register of Ongoing Systematic Reviews. The PubMed/MEDLINE, Cochrane Clinical Trial registry, and EudraCT databases were searched with prespecified search terms. A random-effects meta-analysis was performed using the meta package in R software. Fifteen studies were included in this meta-analysis. The random-effects model analysis observed a pooled effect of 1.55 (95%CI, 1.32-1.84; prediction interval, 0.95-2.55, z = 5.19 [P < .0001]) for remission between the SDAM and placebo groups. A pooled effect of 1.58 (95%CI, 1.37-1.83; prediction interval, 1.00-2.51, z = 6.34 [P < .0001]) for adverse events and 0.72 (95%CI, 0.48-1.08; prediction interval, 0.46-1.12; z = -1.58 [P = .113]) for serious adverse events was observed. No significant publication bias was noticed. The quality of the evidence was rated as high. Adjunct SDAM increased remission in patients and had no significant effect on serious adverse events compared to placebo. Therefore, we conclude that SDAM drugs can be an effective and safe antidepressant augmentation strategy in patients with major depressive disorder.

Questionnaire-based Pan-India survey for impact assessment of National Formulary of India.

OBJECTIVES: The National Formulary of India (NFI), a ready reckoner for medicines among healthcare-professionals aims for promoting rational drug use. This needs periodic update based on evidence-based medicines and suggestions from end-users. This study assessed the level of awareness among health-care professionals and sought suggestions for enhancement of utility/content of NFI. MATERIALS AND METHODS: This pan-India cross-sectional, questionnaire-based survey was conducted between November-2020 and March-2021. A Google-doc-based validated questionnaire (20 questions) was circulated through E-mail/social media groups and to 311 medical institutes/hospitals/clinics across India through the adverse drug reaction monitoring centers under the Pharmacovigilance Program of India. RESULTS: A total of 461 participants (39-interns, 167-resident doctors, and the rest practicing physicians/doctors) affiliated to 224 institutes/hospitals/clinics had responded. About 46% respondents consulted NFI for drug-related information and 82.3% stated that NFI provides balanced unbiased information. About 95% respondents were aware of NFI's content and 76% mentioned usefulness of NFI in their clinical practice; however, 34.4% had misconceptions about NFI, 28.7% had a false belief that NFI is a legal document to safeguard health-care providers and 22.2% had never used it. Suggestions to enhance NFI's utility included digital accessibility, incorporation of information like drugs for basic medical emergencies (71.3%), disposal of expired-pharmaceutical products (38.7%), pharmaceutical price control policy (36.3%), and drug-procurement practices in hospitals (35.6%). CONCLUSION: As per the survey findings, NFI is an effective tool for instant access to precise and unbiased drug-related information, and fostering rational use of drugs. Boosting its practical usefulness needs incorporation of suggested information, digital accessibility, and periodic update.

Chronic Neurological Disorders: Genetic and Epigenetic Markers for Monitoring of Pharmacotherapy.

INTRODUCTION: Chronic neurological diseases are a major cause of mortality and morbidity in the world. With increasing life expectancy in the developing world, the incidence and prevalence of these diseases are predicted to rise even further. This has also contributed to an increase in disability-adjusted life years (DALYs) for noncommunicable diseases. Treatment for such diseases also poses a challenge with multiple genetic and epigenetic factors leading to a varied outcome. Personalization of treatment is one way that treatment outcome/prognosis of disease can be improved, and pharmacogenomics plays a significant role in this context. METHODOLOGY: This article reviewed the evidence pertaining to the association of genetic and epigenetic markers with major neurological disorders like multiple sclerosis (MS), Alzheimer's disease (AD), and Parkinson's disease (PD), which are a major source of burden among neurological disorders. Types of studies included are peer-reviewed original research articles from the PubMed database (1999-2018). RESULTS: This study compiled data regarding specific genetic and epigenetic markers with a significant correlation between the clinical diagnosis of the disease and prognosis of therapy from 65 studies. In a single platform, this review highlights the clues to some vital questions, such as why interferon beta (IFN-ß) therapy fails to improve symptoms in all MS patients? why cholinesterase inhibitors fail to improve cognitive impairment in a subset of people suffering from AD? or why some individuals on levodopa (L-DOPA) for PD suffer from side-effects ranging from dyskinesia to hallucination while others do not? CONCLUSION: This article summarizes the genetic and epigenetic factors that may either require monitoring or help in deciding future pharmacotherapy in a patient suffering from MS, AD, and PD. As the health care system develops and reaches newer heights, we expect more and more of these biomarkers to be used as pharmacotherapeutic outcome indicators.

Pharmacodynamic and pharmacokinetic interactions of hydroalcoholic leaf extract of Centella asiatica with valproate and phenytoin in experimental models of epilepsy in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Centella asiatica (CA) is commonly used herbal medicine for treatment of epilepsy. CA has CYP2C9, CYP2D6 and CYP3A4 enzymes inhibition property and used as an adjuvant therapy with conventional antiepileptic drugs (AEDs). That may be responsible for herb-drug interaction. AIM OF THE STUDY: The present study was planned to evaluate interactions profile of hydroalcoholic extract Centella asiatica (HECA) with antiepileptic drugs in experimental models of epilepsy in rats. MATERIALS AND METHODS: Wistar rats (175-200 g) were used. In the pharmacodynamic interaction study, seizures were induced using pentylenetetrazole (PTZ) (60 mg/kg, i.p.) and maximal electroshock seizure (MES) (70 mA for 0.2 s). The therapeutic and sub-therapeutic doses of valproate (VPA) and phenytoin (PHT) were co-administrated with HECA in PTZ and MES model of seizures respectively. Behavioural parameters were assessed using elevated plus maze test and passive avoidance paradigm. Rat brain oxidative stress parameters were also assessed. In the pharmacokinetic interaction study, the serum levels of the VPA and PHT were estimated at different time intervals by HPLC and pharmacokinetic parameters were analyzed by WinNonlin software. RESULTS: The VPA and PHT produced complete protection against seizures in their therapeutic doses but not with sub-therapeutic doses. However, co-administration of HECA with a sub-therapeutic dose of VPA and PHT enhanced the protection of seizures and significantly (p < 0.001) attenuated the seizure induced oxidative stress and cognitive impairment. It also significantly increased (p < 0.001) serum levels of VPA and PHT. The alterations in pharmacokinetic parameters (maximum serum concentration, area under the curve, clearance) of AEDs were also found with co-administration of HECA. CONCLUSION: The results suggested that co-administration of HECA could improve the therapeutic efficacy of VPA and PHT. But, alteration in pharmacokinetic parameters revel that needs critical medical supervision to avoid any toxic reactions.

Antibody-drug conjugates, cancer immunotherapy, and metronomic chemotherapy as novel approaches in cancer management.

Treatment of cancer is a major challenge even though the pathophysiology is becoming clearer with time. A number of new chemical entities are developed to target cancer growth inhibition, but the targeted delivery of these products still needs novel research. This is of utmost importance not only for higher efficacy but also for a reduction in systemic toxicity and cost of treatment. Although multiple novel targets and molecules are being researched, most of them could not pass the regulatory approval process, due to low benefit-risk ratio and lack of target specificity. Failure of a majority of these drugs was in part due to their superiority claimed via surrogate markers. Despite these, currently, more than 100 chemotherapeutic agents are in practice. This review paper discusses in detail the molecular basis, drug discovery, and pros and cons over conventional treatment approaches of three novel approaches in cancer therapy, i.e., (i) antibody-drug conjugates, (ii) cancer immunotherapy, and (iii) metronomic chemotherapy. All the drugs developed using these three novel approaches were compared against the established treatment regimens in clinical trials with clinical end points, such as overall survival, progression-free survival, and quality of life.

Adjuvant role of Ocimum sanctum hydroalcoholic extract with carbamazepine and phenytoin in experimental model of acute seizures.

PURPOSE: This study assessed adjuvant potential of Ocimum sanctum hydroalcoholic extract (OSHE) with antiepileptic drugs (AEDs) carbamazepine (CBZ) and phenytoin (PHT) in maximal electroshock seizure (MES) model in male Wistar rats. MATERIAL AND METHODS: Pharmacodynamic effect of OSHE (1000 mg/kg) was assessed through seizure protection potential, neurobehavioral tests and oxidative stress estimation in MES model after 14 days administration of OSHE alone or combination with maximal (M) and sub-maximal (SM) dose of CBZ or PHT. Pharmacokinetic interaction of OSHE with AEDs was also assessed after 14 days of drug treatment. RESULTS: OSHE per se showed 50% protection against MES-induced seizures. Combination of OSHE with AEDs' SM dose enhanced its seizure protection potential. Significant reduction in duration of tonic hind limb extension was observed in CBZ-SM + OSHE as compared to control group (p = 0.006). Among neurobehavioral tests in Morris water maze test rats of CBZ-M + OSHE took significantly less time to reach the platform (p = 0.022) and spent more time in target quadrant (p = 0.016) as compared to other groups. Similarly, rats of PHT-SM + OSHE group spent significantly more time in the target quadrant (p = 0.013). In elevated plus maze test, CBZ-M + OSHE had significantly decreased transfer latency compared to other groups (p = 0.013). OSHE alone treated group had significantly lower oxidative stress as compared to other groups. No significant pharmacokinetic interaction was observed between OSHE and AEDs (CBZ, PHT). CONCLUSION: Ocimum's potential of enhanced seizure protection and neuroprotection along with minimal drug interaction with AEDs substantiate its adjuvant role in the management of epilepsy.

First-in-human dose: current status review for better future perspectives.

AIM: The aim of this article is to understand the pros and cons of various methods involved in first-in-human (FIH) dose calculation and act decisively in dose escalations when calculating the maximum tolerated dose. SUBJECTS AND METHODS: We reviewed early phase clinical trials for methods of FIH dose and dose-escalation steps and discuss them in line with existing guidelines. We also reviewed the clinical trial registry to recognize trends in trial registration in recent years and after a massive failure in a few trials. RESULTS: Phase 1 trials of TGN 1412 and BIA10-2474 would always be remembered as catastrophes for pharmaceutical development plans. Quite often than not, healthy human volunteers are the guinea pigs in this stage of drug development. And, the most important aspect of designing an early phase study is deciding upon the dose to be started with, apart from the selection of cohort and escalation steps. The common principles used for FIH dose calculation include no observed adverse effect level, minimum anticipated biological effect level, pharmacologically active dose, pharmacokinetic/pharmacodynamic approach, and similar drug comparison approach. CONCLUSION: Early phase clinical trials are basically foundation stones on which lies the entire onus of the later stages of development. Deciding FIH dose is a crucial step that necessitates the incorporation of detailed data from the preclinical stages and application of the most conservative approach for the safety/benefit of the volunteers in these studies.

Evaluation of adverse drug reaction profile of antiepileptic drugs in persons with epilepsy: A cross-sectional study.

INTRODUCTION: Newer antiepileptic drugs (AEDs) are preferred over conventional AEDs with the perception of better safety profile and efficacy though there is a lack of confirmatory evidence. The present study assessed the adverse drug reactions' (ADRs) profile of AEDs prescribed in persons with epilepsy (PWE) as per the System Organ Class (SOC) and compared them on the basis of demographics and treatment pattern. MATERIAL AND METHODS: This prospective, cross-sectional, and observational study was conducted in PWE attending Neurology Outpatient-Department from February 2016 to April 2019 who were presented with any ADR. World Health Organization-Uppsala Monitoring Centre (WHO-UMC) scale was used for the causality assessment of suspected ADRs. RESULTS: Among the 1011 PWE on AEDs, male:female ratio was 622:389, adult:pediatric ratio 736:275, and conventional:newer AEDs ratio 624:387. Among monotherapy PWE (47.1%), commonly used AEDs were levetiracetam (34.4%), valproic acid (22.9%), carbamazepine (18.3%), phenytoin (11.9%), and other AEDs (12.5%). A total of 1990 ADRs (1.96 ADRs per PWE) were reported as per SOC; among them, newer vs. conventional AEDs did not reveal any significant difference; however, monotherapy vs. polytherapy showed differences in nervous system disorders (p = 0.01) and skin and subcutaneous tissue disorders (p = 0.005). Causality assessment revealed 0.3% certain, 27.3% probable, 61.3% possible, and 11.1% unlikely association of ADRs with AEDs. Depending on the ADRs, there was either withdrawal of AED (0.9%), reduction in dose (48.4%), or continuation in the same dose as before (50.7%). CONCLUSION: The ADR analysis showed that newer AEDs were associated with a similar trend of ADRs as that of conventional AEDs. Thus, the choice among newer and conventional AEDs should preferably focus on the experience of better efficacy in addition to safety data.

Seizure recurrence risk in persons with epilepsy undergoing antiepileptic drug tapering.

OBJECTIVES: Antiepileptic drug (AED) tapering in persons with epilepsy (PWE) after 2-3 years of seizure freedom is still debatable because of the risk of seizure recurrence. Tapering patterns have wide variability and could impact seizure recurrence; this study aimed to find out the correlation between them. MATERIAL AND METHODS: This prospective, observational independent assessor study enrolled PWE undergoing AED tapering in a tertiary care hospital. Data collected included demography, seizure history, AED treatment, and investigational findings. Tapering pattern was assessed based on seizure-free period and AED dose before onset of tapering, dose reduction percentage and frequency, duration of tapering, and follow-up. These variables were compared among the PWE with seizure recurrence and no seizure recurrence. RESULTS: Among 408 enrolled PWE, 181 were on AED monotherapy: levetiracetam (73), valproate (45), carbamazepine (44), phenytoin (16), and clobazam (3). With a minimum 19 (maximum 41 months) follow-up, seizure recurrence was reported in 119 (29.2%) PWE. The seizure recurrence was not significantly different in-between mono and polytherapy groups; however, among monotherapy groups seizure recurrence was significantly higher (P = .023) in valproate (35.5%) followed by levetiracetam (28.8%) group. Parameters having significant association with seizure recurrence were duration of epilepsy (P = .03), frequency of seizures before control (P = .002), history of previously failed tapering (P = .04), and history of smoking/alcoholic/tobacco intake (P = .003). CONCLUSIONS: There is a wide variation in AEDs tapering pattern and seizure recurrence risk can be minimized by considering the risk factors like history of smoking/alcoholic/tobacco, longer duration of epilepsy, frequency of seizures before control, and previously failed tapering.

An interaction study of Ocimum sanctum L. and levetiracetam in pentylenetetrazole kindling model of epilepsy.

ETHNOPHARMACOLOGICAL RELEVANCE: Ocimum sanctum L. commonly known as tulsi (synonym of Ocimum tenuiflorum L.) is widely used in Ayurveda medicine and is having multitude neuromodulatory effect including the anticonvulsant effect in acute seizure models as per previous studies. In India, it is used for the treatment of epilepsy as traditional medicine. However, its role in chronic seizure model and interaction with newer antiepileptic drugs has not been investigated, which will enhance its translational value. AIM OF THE STUDY: Current study investigated the effect of Ocimum on chronic seizure model and its interaction with levetiracetam (LEV), a newer antiepileptic drug. MATERIALS AND METHODS: The adjuvant role of Ocimum sanctum hydroalcoholic extracts (OSHE) 1000 mg/kg along with LEV 300 mg/kg was studied in adult male Wistar rats with mean weight of 227.84 ± 21.68 g using pentylenetetrazole (30 mg/kg, i.p.) kindling (K) (with maximum 24 injections on alternate days and challenge on 7th-day). Along with seizure score, neurobehavioral, brain tissue oxidative stress and histopathology status were assessed. Pharmacokinetic interaction was assessed between LEV and OSHE after 14 days of drug treatment. RESULTS: K-LEV + OSHE had least seizure score during kindling and on the pentylenetetrazole-challenge test (p=0.031) than other kindling groups. Seizure protection was more in K-LEV + OSHE (85.72%) than others (K-LEV-42.86%, K-OSHE-42.86%, and K-Control-28.58%). Ocimum treated groups had better memory retention potential as evident from Morris water maze (MWM), passive avoidance test but not in an elevated plus maze test. Oxidative-stress was lower in Ocimum treated groups than K-Control group. As per histopathology, K-LEV + OSHE group had the least neuronal degeneration among kindling groups. There was no significant pharmacokinetic interaction between LEV and OSHE, except increased Tmax in LEV + OSHE group than LEV alone (p=0.009). CONCLUSIONS: Ocimum per se and combination with levetiracetam treatment exerted better seizure control, memory retention, oxidative stress reduction, and neuronal structure preservation than kindling control group. There was a very minimal drug interaction between Ocimum and LEV. So, Ocimum as an adjuvant to LEV may be shelpful in enhancing the antiepileptic effect and also in minimizing the adverse effects.

Assessment of psychiatric and behavioral adverse effects of antiepileptic drugs monotherapy: Could they have a neuroendocrine correlation in persons with epilepsy?

OBJECTIVE: The study investigated overall adverse event (AE) burden and specifically psychiatric and behavioral side effects (PBAEs) in persons with epilepsy (PWE) on antiepileptic drugs (AEDs) monotherapy. It also assessed their correlation with neuroendocrine and oxidative stress biomarkers. METHODS: This cross-sectional observational study was conducted at a tertiary care hospital between 2016 and 2018. Persons with epilepsy above 18 years on monotherapy of levetiracetam (LEV) and conventional AEDs {carbamazepine (CBZ), phenytoin (PHT), or valproate (VPA)} for at least 6 months were enrolled. Validated questionnaires, 'Mini-International Neuropsychiatric Interview (MINI 7.02)', 'Depression, Anxiety, and Stress Scale 21 (DASS-21)', 'Buss-Perry Aggression Questionnaire (BPAQ)', 'patient-weighted Quality of life Index in Epilepsy (QOLIE-10)', 'Pittsburgh Sleep Quality Index (PSQI)', and 'Liverpool Adverse Events Profile (LAEP)' were used to assess the PBAEs, quality of life, sleep quality, and AE profile. A subgroup of PWE recruited consecutively were considered for estimation of the following neuroendocrine biomarker levels: brain-derived neurotrophic factor (BDNF), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and total antioxidant capacity (TAC) which were then correlated with scores of above questionnaires. RESULTS: After screening 220 PWE, 163 PWE (58 on LEV and 105 on conventional AEDs) with a mean age of 29 ±â€¯10 years were enrolled. Mini-International Neuropsychiatric Interview revealed that LEV group had higher association with PBAEs and lower quality of sleep compared to conventional AEDs (p = 0.032 and 0.046, respectively). Other scales did not show significant difference between LEV and conventional AEDs. In the subset of PWE (n = 74, 36 on LEV and 38 on conventional AEDs), LEV group had more association with the PBAEs (p = 0.010), higher physical aggression and anger components of BPAQ (p = 0.03 and 0.02, respectively), and more AE (p = 0.049) than conventional AED group. However, there was no significant difference in neuroendocrine biomarker levels. CONCLUSION: Levetiracetam had a higher association with PBAEs and more AE when compared to conventional AEDs. There was no differential correlation of AEDs with the following neuroendocrine markers: BDNF, HVA, 5-HIAA, and TAC. These facts necessitate exploration of other mechanisms for LEV-induced PBAEs.

Methodological Characteristics of Clinical Trials: Impact of Mandatory Trial Registration.

PURPOSE: Numerous studies across multiple specialties have evaluated the impact of trial registration on quality of study reports and found significant improvements over several domains. However, the impact of mandatory trial registration on the quality of clinical trial protocols remains hitherto unexplored. METHODS: We carried out a retrospective cohort study of clinical trial applications submitted to drug regulatory authority of India for initial review with the objective of comparing methodological characteristics of their protocols. Since trial registration was made mandatory in the country in June 2009, we selected two study periods as between January 2007 to May 2009 (Period I) and July 2009 to December 2011 (Period II). Seventy-five protocols were randomly selected using a computer-generated list for each study period, making a total of 150 protocols. Data on twelve key methodological characteristics were collected including clearly defined primary outcomes, randomization, blinding, use of control group, statistical methods, handling of withdrawals amongst others. RESULTS: More than 3/4th of the trial applications in the two study periods were for new chemical entities and nearly 90% were pharmaceutical industry sponsored studies. Comparing the period before and after implementation of mandatory trial registration, description of clearly defined trial outcomes improved from nearly 42% to 80% (p<0.001), sample size justifications increased from 38% to 70% (p<0.001) and use of allocation concealment improved from 24% to 49% (p=0.001). Marked improvement was also noted for blinding, description of statistical methods and handling of withdrawals and dropouts. Remaining characteristics did not change significantly between the two study periods. The mean cumulative scores for the study protocols improved significantly from 7± 0.296 in the first period to 8.93± 0.346 (p<0.001) in the second period. CONCLUSIONS: Our study found a significant improvement in the methodological quality characteristics of the protocols particularly in elements related to minimization of bias and statistical methods, which could be attributed to mandatory trial registration. Overall, the significant improvement was limited to global clinical trials, and room for improvement was noted for two quality characteristics - proportion of randomized studies and trials adequately describing the generation of allocation sequence.

Pharmacokinetic and pharmacodynamic interaction of hydroalcoholic extract of Ocimum sanctum with valproate.

For effective control of seizures, antiepileptic drugs (AEDs) are administered at higher dose which is associated with several adverse effects. This study envisaged antiepileptic and neuroprotective potential of Tulsi, a commonly used herb for its immunomodulatory property. The optimal dose of Ocimum sanctum hydroalcoholic extract (OSHE) was determined using maximal electroshock seizure (MES)- and pentylenetetrazol (PTZ)-induced seizure models in Wistar rats (200-250g) after administering OSHE (200-1000mg/kg) orally for 14days. For interaction study, OSHE optimal dose in combination with maximum and submaximal therapeutic doses of valproate was administered for 14days. Serum levels of valproate were estimated using HPLC for pharmacokinetic study. For pharmacodynamic interaction, antiepileptic effect on above seizure models, neurobehavioral effect using Morris water maze, passive avoidance and elevated plus maze tests, and antioxidant capacity were assessed. Ocimum sanctum hydroalcoholic extract 1000mg/kg was found to be optimal providing 50% protection against both MES- and PTZ-induced seizures. Combination of OSHE with valproate did not alter antiepileptic efficacy of valproate significantly. However, the combination showed better memory retention potential in neurobehavioral tests and protection against oxidative stress compared with valproate-alone-treated groups. Pharmacokinetic parameters did not reveal any significant change in combination group compared with valproate alone. Ocimum, although having per se antiepileptic action, did not affect antiepileptic action of valproate in combination. However, combination treatment has an edge over valproate alone-better neurobehavioral function and reduced oxidative stress-predicting adjuvant potential of Ocimum in epilepsy treatment.

Impact of regulatory spin of pioglitazone on prescription of antidiabetic drugs among physicians in India: A multicentre questionnaire-based observational study.

Background & objectives: Pioglitazone was suspended for manufacture and sale by the Indian drug regulator in June 2013 due to its association with urinary bladder carcinoma, which was revoked within a short period (July 2013). The present questionnaire-based nationwide study was conducted to assess its impact on prescribing behaviour of physicians in India. Methods: Between December 2013 and March 2014, a validated questionnaire was administered to physicians practicing diabetes across 25 centres in India. Seven hundred and forty questionnaires fulfilling the minimum quality criteria were included in the final analysis. Results: Four hundred and sixteen (56.2%) physicians prescribed pioglitazone. Of these, 281 used it in less than the recommended dose of 15 mg/day. Most physicians (94.3%) were aware of recent regulatory events. However, only 333 (44.8%) changed their prescribing pattern. Seventeen of the 416 (4.1%) physicians who prescribed pioglitazone admitted having come across at least one type 2 diabetes mellitus patient (T2DM) who had urinary bladder carcinoma, and of these 13 said that it was in patients who took pioglitazone for a duration of more than two years. Only 7.8 per cent of physicians (n=58) categorically advocated banning pioglitazone, and the rest opined for its continuation or generating more evidence before decision could be taken regarding its use in T2DM. Interpretation & conclusions: Majority of the physicians though were aware of the regulatory changes with regard to pioglitazone, but their prescribing patterns were not changed for this drug. However, it was being used at lower than the recommended dose. There is a need for generating more evidence through improved pharmacovigilance activities and large-scale population-based prospective studies regarding the safety issues of pioglitazone, so as to make effectual risk-benefit analysis for its continual use in T2DM.