A review on role of metformin as a potential drug for epilepsy treatment and modulation of epileptogenesis.

BACKGROUND: Available anti-seizure medications (ASMs) target the symptomatology of the disease rather than any significant disease/epileptogenesis modifying actions. There are critical concerns of drug resistance and seizure recurrence during epilepsy management. So, drug repurposing is evolving as a paradigm change in the quest for novel epilepsy treatment strategies. Metformin, a well-known anti-diabetic drug has shown multiple pieces of evidence of its potential antiepileptic action. OBJECTIVE: This review elucidates various mechanisms underlying the beneficial role of metformin in seizure control and modulation of the epileptogenesis process. METHODS: Preclinical and clinical evidence involving metformin's role in epilepsy and special conditions like tuberous sclerosis have been reviewed in this paper. The putative mechanisms of epileptogenesis modulation through the use of metformin are also summarised. RESULTS: This review found the efficacy of metformin in different seizure models including genetic knockout model, chemical induced, and kindling models. Only one clinical study of metformin in tuberous sclerosis has shown a reduction in seizure frequency and tumor volume compared to placebo. The suggested mechanisms of metformin relevant to epileptogenesis modulation mainly encompass AMPK activation, mTOR inhibition, protection against blood-brain-barrier disruption, inhibition of neuronal apoptosis, and reduction of oxidative stress. In addition to seizure protection, metformin has a potential role in attenuating adverse effects associated with epilepsy and ASMs such as cognition and memory impairment. CONCLUSION: Metformin has shown promising utility in epilepsy management and epileptogenesis modulation. The evidence in this review substantiates the need for a robust clinical trial to explore the efficacy and safety of metformin in persons with epilepsy.

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.

Effect of ascorbic acid supplementation on pulmonary functions in healthy adults: a randomized controlled pilot study.

OBJECTIVES: The fact that oxidative stress plays an important role in the pathogenesis of various pulmonary diseases is supported by the beneficial effect of antioxidants. It is also well known that an altered oxidant-antioxidant balance after the age of 35 years increases the susceptibility to develop obstructive lung diseases later in life. Given this, the present study was designed to evaluate the effect of antioxidant supplementation on lung functions in healthy adults after the age of 35 years. METHODS: Persons of age ≥35 years (n=45) were randomized into three arms (each comprising 15 participants) to receive either no intervention (NI arm), ascorbic acid 250 mg daily (AA250 arm), or ascorbic acid 500 mg daily (AA500 arm) for 6 weeks. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC, and peak expiratory flow (PEF) were measured at baseline and 6 weeks. Persons of age group (20-30 years) were also enrolled in the study to compare their lung functions and cardiovascular parameters at baseline with those ≥35 years of age. All the adverse events experienced by participants were recorded. RESULTS: Baseline pulmonary functions were found to be comparable among the three study arms and compared to ≥35 years age group, these parameters were found to be better in the younger age group (20-30 years). Most of the pulmonary functions were comparable among the three study arms at 6 weeks. A significant improvement in PEF and % predicted PEF was noted in AA250 arm when compared to baseline values (p=0.049 and 0.026, respectively) and in participants with normal pulmonary functions when compared to those with reduced functions at baseline (p=0.059 and p=0.037). CONCLUSIONS: Although ascorbic acid did not affect most of the pulmonary functions in healthy adults, it improved PEF and % predicted PEF at a daily dose of 250 mg. In this regard, it was found effective in individuals with normal pulmonary indices at baseline.

Need for pharmacoeconomic consideration of antiepileptic drugs monotherapy treatment in persons with epilepsy.

OBJECTIVE: Newer antiepileptic drugs (AEDs) are expected to have less adverse effects (AEs) and drug interactions as compared to conventional AEDs but the high cost is the major limitation for their use. This study evaluated variation in the cost of treatment with newer and conventional AEDs through its correlation with treatment efficacy and AEs in persons with epilepsy (PWE). METHODS: This cross-sectional study included PWE (28.9 ± 9.9 years) having focal and generalized seizures on conventional [valproate, carbamazepine, phenytoin] or newer AEDs [levetiracetam, oxcarbazepine] for >6 months. Seizure frequency during the study (6 months) was compared to that within 6 months before the study. Other parameters assessed were Quality of life in epilepsy, Pittsburgh Sleep Quality Index, Gastrointestinal Quality of life Index, and Liverpool AEs Profile. The cost of treatment was determined as direct, indirect, and intangible costs. The incremental cost-effectiveness ratio (ICER) analysis was also performed. RESULTS: Out of 214 PWE, 51.4% were on newer AEDs. Newer and conventional AEDs did not differ significantly in seizure frequency reduction (60.29 vs. 53.09%), quality of life parameters, though these were improved significantly during the study period. The direct medical cost and total cost of treatment were lesser with conventional AEDs (p < 0.001 in both) than newer AEDs, but the intangible cost did not differ. The total cost of treatment was significantly influenced by factors (as per regression analysis) including the type of AEDs (significant difference between valproate, carbamazepine, and levetiracetam), frequency of seizures, cost of medicine (70.34% of total cost), hospital admission, and treatment of AEs. As per ICER, newer AEDs need an additional USD 8.39 per unit reduction in seizure frequency. CONCLUSION: Newer AEDs have comparatively better efficacy, though not significant than conventional AEDs. However, the additional cost per unit improvement is quite high with newer AEDs, necessitating pharmacoeconomic consideration in epilepsy treatment.

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.