Antiepileptic-drug tapering and seizure recurrence: Correlation with serum drug levels and biomarkers in persons with epilepsy.

OBJECTIVES: Antiepileptic-drug (AED) serum level and inflammatory biomarkers are primarily monitored/assessed during epilepsy treatment for effective seizure control; however, their correlation with seizure recurrence (SR) following AED-tapering has not been established, and this is being investigated in this study. MATERIALS AND METHODS: This prospective observational study enrolled persons with epilepsy (PWE) on AED monotherapy and going to start tapering after being seizure-free for ≥2 years. Data regarding seizure episodes, AED-treatment, and adverse events (using Liverpool Adverse Event profile [LAEP]-score) were recorded. Serum AED levels using high-performance liquid chromatography and biomarkers levels through enzyme-linked immunosorbent assay kits were estimated at AED-tapering commencement and at 6 months/SR time. RESULTS: Among 129 enrolled PWE (levetiracetam [n = 52], valproate [n = 34], carbamazepine [n = 29], and phenytoin [n = 14]), SR occurred in 23.3% during follow-up (range 12-44 months). PWE with subtherapeutic serum AED level at the onset of tapering had higher SR (P = 0.004) than those with therapeutic or higher levels. Levetiracetam-treated PWEs with SR have significantly low AED levels than PWE with no-SR (P < 0.001). PWE had significantly raised inflammatory biomarkers (interleukin [IL]-1 ß, tumor necrosis factor [TNF]-α, IL-6, and high-mobility group box protein 1) and decreased IL-10 than healthy control subjects. SR and no-SR groups did not differ significantly in inflammatory markers except for higher IL-1 ß and TNF-α levels in SR group (P = 0.001, 0.02, respectively). Improvement in LAEP score was observed in follow-up visits without any difference between SR and no-SR groups. CONCLUSION: Low serum AED levels (especially levetiracetam) and raised levels of TNF-α and IL-1 ß during tapering commencement had a higher association with SR following AED-tapering.

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.

Validation of the Indian version of Neurological Disorders Depression Inventory for Epilepsy (NDDI-E).

PURPOSE: The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) is an efficient tool for rapid detection of depression, an important comorbid condition in persons with epilepsy (PWE). Since social and cultural differences can potentially affect the cutoff score of NDDI-E, in this study, the reliability and validity of the Indian version of the NDDI-E in PWE was determined. METHOD: After ethical clearance, 217 PWE above 18 years of age, on antiepileptic drugs (AEDs), attending neurology outpatient department (OPD) of All India Institute of Medical Sciences (AIIMS), New Delhi, India, were evaluated for depression using the NDDI-E (Indian version) and Mini International Neuropsychiatric Interview (MINI-Module A, version 6.0.0) as reference standard. Informed consent was taken before recruitment. Receiver operating characteristic (ROC) analysis and Cronbach's α, a measure of the internal consistency and reliability, were carried out to validate cutoff and questionnaire, respectively. RESULTS: Of the 217 PWE (112 males/105 females), mean age of 28.6 ±â€¯9.4 years, with generalized (69.1%) or focal seizures (30.9%), 41.5% and 10.6% were diagnosed with depression using MINI and NDDI-E Indian version (at cutoff >15), respectively. However, at a cutoff score of >11, the Indian version of NDDI-E had a sensitivity of 96.67%, a specificity of 84.25%, a positive predictive value of 81.31%, and a negative predictive value of 97.27%. ROC analysis showed an area under the curve (AUC) of 0.9547 (confidence interval (CI) 95% = 0.929-0.979; standard error (SE): 0.0127). With the Indian version of NDDI-E, the Cronbach's α value was 0.877. CONCLUSION: A periodic assessment of PWE using a quickly administrable and reliable tool for screening depression is highly desirable given the high incidence. In the Indian population with a cutoff of >11, NDDI-E is a reliable and valid instrument to screen depression in PWE.

Cost analysis study of neuropsychiatric drugs: Role of National List of Essential Medicines, India.

CONTEXT: This study investigated the cost variation among neuropsychiatric drugs prevalent in the Indian market with reference to the National List of Essential Medicines (NLEM, 2015). AIMS: To promote the rational use of medicines through cost variation analysis among drugs for neuropsychiatric disorders enlisted in NLEM and those not included in NLEM (NNLEM). STUDY DESIGN: This study included drugs used for epilepsy, migraine, psychosis, depression, generalized anxiety disorder (GAD), bipolar disorder, and obsessive-compulsive disorder (OCD). MATERIALS AND METHODS: The unit drug cost for the selected strengths of different manufacturers mentioned in the Current Index of Medical Specialities 2016 was used for calculating cost/defined daily dose (DDD). STATISTICAL ANALYSIS: Comparison was done among individual drugs and groups (NLEM and NNLEM) by cost/DDD in terms of interquartile range, percentage cost variation, and cost ratio. RESULTS: The cost variation is wide for neuropsychiatric drugs (maximum, 1724.3% for risperidone in NLEM, and 1780% for olanzapine in NNLEM). The drug-to-cost ratio is the highest (168.8 times) for bipolar disorder and the lowest (9.7 times) for GAD. The NLEM drugs were found to be more economical than the NNLEM drugs among antiepileptic drugs, antidepressants, and drugs for bipolar disorder; however, the reverse was noted for antimigraine drugs and drugs for GAD. Antipsychotic medications and drugs for OCD in the NLEM group have a wider range than in the NNLEM group. CONCLUSIONS: The NLEM group has economical drugs in some disease categories; there is a need to consider the cost effectiveness of all drug categories while revising the NLEM next time and attention should focus on drug price regulation policies to accomplish the goal of rational use of medicines.

Edaravone attenuates intracerebroventricular streptozotocin-induced cognitive impairment in rats.

Alzheimer's disease is a major cause of dementia worldwide. Edaravone, a potent free radical scavenger, is reported to be neuroprotective. The present study was designed to investigate the effect of chronic edaravone administration on intracerebroventricular-streptozotocin (ICV-STZ) induced cognitive impairment in male Wistar rats. Cognitive impairment was developed by single ICV-STZ (3 mg/kg) injection bilaterally on day 1. Edaravone (1, 3 and 10 mg/kg, orally, once daily) was administered for 28 days. Morris water maze and passive avoidance tests were used to assess cognitive functions at baseline and on days 14 and 28. ICV-STZ caused cognitive impairment as evidenced by increased escape latency and decreased time spent in target quadrant in the Morris water maze test and reduced retention latency in the passive avoidance test. STZ caused increase in oxidative stress, cholinesterases, inflammatory cytokines and protein expression of ROCK-II and decrease in protein expression of ChAT. Edaravone ameliorated the STZ-induced cognitive impairment. STZ-induced increase in oxidative stress and increased levels of pro-inflammatory cytokines (TNF-α, IL-1ß) were mitigated by edaravone. Edaravone also prevented STZ-induced increased protein expression of ROCK-II. Moreover, edaravone significantly prevented STZ-induced increased activity of cholinesterases in the cortex and hippocampus. The decreased expression of ChAT caused by STZ was brought towards normal by edaravone in the hippocampus. The results thus show that edaravone is protective against STZ-induced cognitive impairment, oxidative stress, cholinergic dysfunction and altered protein expressions. This study thus suggests the potential of edaravone as an adjuvant in the treatment of Alzheimer's disease.

Anticonvulsant activity of the antidepressant drug, tianeptine, against pentylenetetrazole-induced seizures mitigates cognitive impairment in rats.

Treatment of depression, a common comorbidity in patients with epilepsy, is restricted as certain antidepressants are considered to be proconvulsants. In contrast, anticonvulsant effects have been reported with some antidepressants. In the present study, the effect of tianeptine, an antidepressant, was evaluated against pentylenetetrazole (PTZ)-induced seizures, cognitive impairment and oxidative stress in rats. Tianeptine was administered in three doses (20, 40 and 80 mg/kg) 30 min before PTZ (60 mg/kg, intraperitoneally). MK801, an N-methyl-D-aspartate antagonist, and naloxone, an opioid receptor antagonist, were administered with tianeptine to evaluate the involvement of N-methyl-D-aspartate and opioid receptors, respectively. Morris water maze, elevated plus maze and passive avoidance tests were performed for behavioural assessment. Brain malondialdehyde and reduced glutathione levels were estimated as markers of oxidative stress. Tianeptine showed dose-dependent protection against PTZ seizures. Coadministration of tianeptine with MK801 potentiated the anticonvulsant effect of tianeptine. The protective effect of tianeptine against PTZ seizures was mitigated when tianeptine was administered with naloxone. Impairment of learning and memory by PTZ was prevented by tianeptine. Tianeptine also attenuated the seizure-induced increased oxidative stress. Thus, tianeptine showed an anticonvulsant effect along with amelioration of seizure-induced cognitive impairment and oxidative stress. Hence, tianeptine could be a useful drug in epileptic patients with depression, with the advantage of having both antidepressant and antiepileptic effects.

Low dose zinc supplementation beneficially affects seizure development in experimental seizure models in rats.

The role of zinc in seizure models and with antiepileptic drugs sodium valproate (SV) and phenytoin (PHT) was studied using experimental models of seizures in rats. Male Wistar rats, 150-250 g were administered zinc 2, 20, and 200 mg/kg, orally for 14 days. Sixty minutes after the last dose of zinc, rats were challenged with pentylenetetrazole (PTZ, 60 mg/kg, ip) or maximal electroshock (MES, 70 mA, 0.2 s duration). In another group, SV (150/300 mg/kg, ip) or PHT (40 mg/kg, ip) was administered after 30 min of zinc administration followed by seizure challenge. Zinc pretreatment at all doses had no effect on MES seizures. In PTZ seizures, with the lowest dose used, i.e., 2 mg/kg, a protective effect was observed. Neither the protection offered by the 100 % anticonvulsant dose of SV (300 mg/kg) in PTZ seizures was affected by pre-treatment with zinc nor a combination of subanticonvulsant dose of SV (150 mg/kg) and zinc offer any statistically significant advantage over either drug alone. The combination of phenytoin with zinc had no effect on any of the parameters tested. Apart from this, chronic zinc administration hampered development of chemically (PTZ)-kindled seizures in rats. Zinc supplementation is unlikely to have any undesirable effect when used in epileptics rather it may offer advantage in epileptic and seizure prone patients.

Pharmacovigilance practices for better healthcare delivery: knowledge and attitude study in the national malaria control programme of India.

Objective. With large scale rollout of artemisinin based therapy in the National Malaria Control Programme of India, a risk management plan is needed. This depends on adverse drug reaction (ADR) reporting by the healthcare professionals (HCPs). For the programme to be successful, an understanding of the mindset of HCPs is critical. Hence, the present study was designed to assess and compare the ADR reporting beliefs of HCPs involved in the National Malaria Control Programme of India. Methods. A cross-sectional survey was conducted amongst the HCPs who manage malaria up to the district level in India. A 5-point Likert scale-based questionnaire was developed as a study tool. Results. A total of 154 HCPs participated in the study (age: 42.4 ± 10.1 years with 33.8% being females). About 61% felt that only medically qualified HCPs are responsible for ADR reporting. Likeliness to report in future was mentioned by 45% HCPs. The knowledge score was relatively lower for life science graduates (P = 0.09). Knowledge correlated positively with attitude (r (2) = 0.114; P < 0.0001). Conclusion. Based on the caveats identified, a specific and targeted in-service education with hands-on training on ADR monitoring and reporting needs to be designed to boost real time pharmacovigilance in India.

miR-22 regulates expression of oncogenic neuro-epithelial transforming gene 1, NET1.

MicroRNAs control cellular processes by regulating expression of their target genes. Here we report that neuro-epithelial transforming gene 1 (NET1) is a target of tumor suppressor microRNA 22 (miR-22). miR-22 is downregulated in peripheral blood mononuclear cells derived from chronic myeloid leukemia (CML) patients and in CML cell line K562. NET1 was identified as one of the targets of miR-22 using both in vitro and in vivo experiments. Either mutations or naturally occurring single-nucleotide polymorphisms in NET1 3'-UTR that map at the miR-22 binding site were found to affect binding of miR-22 to NET1 mRNA. Over expression of NET1 in K562 cells resulted in increased proliferation. However decreased proliferation and alteration in cell cycle were observed on either overexpression of miR-22 or knockdown of NET1 expression respectively. We also found that overexpression of miR-22 or NET1 knockdown inhibits actin fiber formation, probably by downregulation of NET1 as NET1 knockdown also resulted in depletion of actin fiber formation. We suggest that the oncogenic properties of CML cells are probably due to deregulated expression of NET1 as a result of altered expression of miR-22.

Ethics Standards (HRPP) and Public Partnership (PARTAKE) to Address Clinical Research Concerns in India: Moving Toward Ethical, Responsible, Culturally Sensitive, and Community-Engaging Clinical Research.

Like other emerging economies, India's quest for independent, evidence-based, and affordable healthcare has led to robust and promising growth in the clinical research sector, with a compound annual growth rate (CAGR) of 20.4% between 2005 and 2010. However, while the fundamental drivers and strengths are still strong, the past few years witnessed a declining trend (CAGR -16.7%) amid regulatory concerns, activist protests, and sponsor departure. And although India accounts for 17.5% of the world's population, it currently conducts only 1% of clinical trials. Indian and international experts and public stakeholders gathered for a 2-day conference in June 2013 in New Delhi to discuss the challenges facing clinical research in India and to explore solutions. The main themes discussed were ethical standards, regulatory oversight, and partnerships with public stakeholders. The meeting was a collaboration of AAHRPP (Association for the Accreditation of Human Research Protection Programs)-aimed at establishing responsible and ethical clinical research standards-and PARTAKE (Public Awareness of Research for Therapeutic Advancements through Knowledge and Empowerment)-aimed at informing and engaging the public in clinical research. The present article covers recent clinical research developments in India as well as associated expectations, challenges, and suggestions for future directions. AAHRPP and PARTAKE provide etiologically based solutions to protect, inform, and engage the public and medical research sponsors.

Evaluation of the aphrodisiac activity of Tribulus terrestris Linn. in sexually sluggish male albino rats.

OBJECTIVES: To study the effect of acute and repeated dose administration of lyophilized aqueous extract of the dried fruits of Tribulus terrestris (LAET) on sexual function in sexually sluggish male albino rats. MATERIALS AND METHODS: Aphrodisiac activity of the test drug was evaluated in terms of exhibited sexual behavior. In order to assess the effect of chronic T. terrestris exposure on the hypothalamus--pituitary--gonadal axis, testosterone level estimation and sperm count were carried out. Twenty-eight-day oral toxicity studies were carried out to evaluate the long-term effects of the LAET administration on different body systems. RESULTS: A dose-dependent improvement in sexual behavior was observed with the LAET treatment as characterized by an increase in mount frequency, intromission frequency, and penile erection index, as well as a decrease in mount latency, intromission latency, and ejaculatory latency. The enhancement of sexual behavior was more prominent on chronic administration of LAET. Chronic administration of LAET produced a significant increase in serum testosterone levels with no significant effect on the sperm count. No overt body system dysfunctions were observed in 28-day oral toxicity study. CONCLUSIONS: Findings of the present study validate the traditional use of T. terrestris as a sexual enhancer in the management of sexual dysfunction in males.

Prescription practices and availability of artemisinin monotherapy in India: where do we stand?

BACKGROUND: The World Health Organization has urged all member states to deploy artemisinin-based combination therapy and progressively withdraw oral artemisinin monotherapies from the market due to their high recrudescence rates and to reduce the risk of drug resistance. Prescription practices by physicians and the availability of oral artemisinin monotherapies with pharmacists directly affect the pattern of their use. Thus, treatment practices for malaria, with special reference to artemisinin monotherapy prescription, in selected states of India were evaluated. METHODS: Structured, tested questionnaires were used to conduct convenience surveys of physicians and pharmacists in eleven purposively selected districts across six states in 2008. In addition, exit interviews of patients with a diagnosis of uncomplicated malaria or a prescription for an anti-malarial drug were also performed. Logistic regression was used to determine patient clinical care, and institutional factors associated with artemisinin monotherapy prescription. RESULTS: Five hundred and eleven physicians from 196 health facilities, 530 pharmacists, and 1,832 patients were interviewed. Artemisinin monotherapy was available in 72.6% of pharmacies and was prescribed by physicians for uncomplicated malaria in all study states. Exit interviews among patients confirmed the high rate of use of artemisinin monotherapy with 14.8% receiving such a prescription. Case management, i.e. method of diagnosis and overall treatment, varied by state and public or private sector. Treatment in the private sector (OR 8.0, 95%CI: 3.8, 17) was the strongest predictor of artemisinin monotherapy prescription when accounting for other factors. Use of the combination therapy recommended by the national drug policy, artesunate + sulphadoxine-pyrimethamine, was minimal (4.9%), with the exception of one state. CONCLUSIONS: Artemisinin monotherapy use was widespread across India in 2008. The accessible sale of oral artemisinin monotherapy in retail market and an inadequate supply of recommended drugs in the public sector health facilities promoted its prescription. This study resulted in notifications to all state drug controllers in India to withdraw the oral artemisinin formulations from the market. In 2010, artesunate + sulphadoxine-pyrimethamine became the universal first-line treatment for confirmed Plasmodium falciparum malaria and was deployed at full scale.

Analysis of the compliance of informed consent documents with good clinical practice guideline.

BACKGROUND: Informed consent document plays an integral part in the process of obtaining informed consent. Although India is fast gaining repute as a preferred clinical trial destination, only few studies have evaluated the compliance of informed consent documents with the Indian Good Clinical Practice guideline. METHODS: Retrospective analysis of consent documents submitted to the institutional ethics committee during the periods January 2007-July 2008 and August 2008-December 2009, for the inclusion of 14 essential information elements outlined in the Indian Good Clinical Practice guideline was carried out. Cumulative scores were given for compliance with the guideline and for vernacular translations of the consent documents. RESULTS: Majority of the informed consent documents analyzed were for academic projects in both periods. There was marked improvement in the documents in terms of compliance with Indian GCP in the period 2008-09. The mean cumulative score for consent documents for academic projects increased significantly from 7.00 ± 0.25 in 2007-08 to 8.57 ± 0.16 in 2008-09. The mean score for consent documents for pharmaceutical sponsored studies also increased from 10.23 ± 0.17 in 2007-08 to 11.31 ± 0.32 in 2008-09. Additionally, greater number of consent documents had been translated into vernacular language in the period 2008-29. CONCLUSIONS: The increased compliance with the good clinical practice guideline and improvement in the mean cumulative scores in 2008-09 was probably the outcome of greater awareness amongst the clinical researchers within the institute.

Reversible posterior leucoencephalopathy syndrome in an elderly male on sunitinib therapy.

AIMS: Reversible posterior leucoencephalopathy syndrome (RPLS) has been reported following the use of anti-vascular endothelial growth factor (VEGF) agents such as bevacizumab, sorafinib and sunitinib. In this report we present a case of RPLS that occurred in an elderly male on sunitinib therapy. METHODS: Other case reports of sunitinib-induced RPLS were reviewed and causality assessment was carried out using the World Health Organization-Uppsala Monitoring Centre criteria and the Naranjo algorithm. RESULTS: Only a few cases of sunitinib-induced RPLS had been reported previously and elevated blood pressure at presentation was common in most of the patients. Our case was clinically similar to the earlier reports and the adverse reaction had a 'probable' relationship with sunitinib intake. CONCLUSIONS: Physicians should monitor and manage elevated blood pressure in patients with sunitinib-induced RPLS.

India's growing participation in global clinical trials.

Lower operational costs, recent regulatory reforms and several logistic advantages make India an attractive destination for conducting clinical trials. Efforts for maintaining stringent ethical standards and the launch of Pharmacovigilance Program of India are expected to maximize the potential of the country for clinical research.

Anti-emetic effect of ginger powder versus placebo as an add-on therapy in children and young adults receiving high emetogenic chemotherapy.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) are major adverse effects of chemotherapy. Ginger has been used in postoperative and pregnancy-induced nausea and vomiting. Data on its utility in reducing CINV in children and young adults are lacking. PATIENTS AND METHODS: Sixty chemotherapy cycles of cisplatin/doxorubicin in bone sarcoma patients were randomized to ginger root powder capsules or placebo capsules as an additional antiemetic to ondensetron and dexamethasone in a double-blind design. Acute CINV was defined as nausea and vomiting occurring within 24 hr of start of chemotherapy (days 1-4) and delayed CINV as that occurring after 24 hr of completion of chemotherapy (days 5-10). CINV was evaluated as per Edmonton's Symptom Assessment Scale and National Cancer Institute criteria respectively. RESULTS: Acute moderate to severe nausea was observed in 28/30 (93.3%) cycles in control group as compared to 15/27 (55.6%) cycles in experimental group (P = 0.003). Acute moderate to severe vomiting was significantly more in the control group compared to the experimental group [23/30 (76.7%) vs. 9/27 (33.33%) respectively (P= 0.002)]. Delayed moderate to severe nausea was observed in 22/30 (73.3%) cycles in the control group as compared to 7/27 (25.9%) in the experimental group (P < 0.001). Delayed moderate to severe vomiting was significantly more in the control group compared to the experimental group [14/30 (46.67%) vs. 4/27 (14.81%) (P = 0.022)]. CONCLUSION: Ginger root powder was effective in reducing severity of acute and delayed CINV as additional therapy to ondensetron and dexamethasone in patients receiving high emetogenic chemotherapy (ClinicalTrials.gov identifier: NCT00940368).

Protective effect of curcumin against kainic acid induced seizures and oxidative stress in rats.

The effect of curcumin, a dietary antioxidant was studied against kainic acid (KA)-induced seizures and on markers of oxidative stress. Rats were administered KA (10 mg/kg, ip) and observed for behavioral changes, incidence and latency of convulsions and mortality over four hours. The rats were thereafter sacrificed for estimation of oxidative stress parameters; malondialdehyde (MDA) and glutathione (GSH). Curcumin was administered 30 min before KA at doses of 50, 100 and 200 mg/kg, ip. KA induced long-lasting seizures and associated symptoms. The brain level of MDA was significantly (P < 0.05) raised after KA administration (536 +/- 44 nmol/g wet tissue) as compared to saline treated group (200 +/- 36 nmol/g wet tissue) and significantly decreased the levels of GSH. Pretreatment with curcumin (100 and 200 mg/kg, ip) significantly increased the latency of seizures (120 + 20 min and 11 5+/- 5.7 min respectively) as compared to the vehicle treated KA group. Curcumin (100 and 200 mg/ kg, ip) significantly prevented the increase in MDA levels and ameliorated the fall in glutathione. Curcumin at the dose of 50 mg/kg had no effect on any of oxidative stress parameters. The study reports the potential antiepileptic effect of antioxidant curcumin.