[Show abstract][Hide abstract] ABSTRACT: Context: Phenytoin (PHT) is one of the frontrunner drugs used as monotherapy in the management of epilepsy. It is also one of the most common drugs causing adverse drug reactions (ADRs). The aim of this study was to study the relationship between serum PHT levels and the age, gender, dosage and genetic polymorphisms in a North Indian population. This knowledge will help in devising drug dosage schedules in various sub‑groups of patients as well as in reducing its ADRs. Materials and Methods: A retrospective analysis of data of 6224 patients from 1998 to 2009 receiving PHT alone for greater than (>) 4 weeks was performed. Patients suspected of being non‑compliant, being overdosed or having a hepatic or renal
disorder were excluded from the study. Two thousand eight hundred and eighty‑eight patients fulfilling the inclusion criteria were divided into three groups: children (1–18 years), adults (19–60 years) and elderly (>60 years). Results: There was a male preponderance (80%) in all the groups. A significant difference was found in the mean dose between children and adults as well as between children and elderly (P = 0.00). Also, there was a significant difference in them mean concentration and dose ratio between children and adults (P = 0.00). However, a negative correlation was observed between the daily dose and dose ratio (r = ‑0.36, P = 0.00) that was highest (r = ‑0.58, P = 0.00) in the elderly. There was a significant gender difference in the mean dose in both children (P = 0.03) and adults (P = 0.00), whereas the mean concentration
differed in adults only. Every fifth patient was an intermediate metabolizer (IM) (CYP2C9*1/*3) and showed higher steady state drug levels (>17 mg/L) compared with extensive metabolizers (EMs) (<12 mg/L). The genetic difference between IM and EM was more prevalent in the dose ratio at maintenance dose, with a mean ± SD of 4.041 ± 1.288 mg/L/mg/kg in nine patients carrying the CYP2C9*1/*3 genotype compared with 2.145 ± 0.817 mg/L/mg/kg in 26 patients carrying the CYP2C9*1/*1 genotype (P = 0.00).
Conclusion: North Indian female children and male adults frequently attain a higher serum concentration with the same dose when compared to the other groups. Absence of poor metabolizers may be responsible for a lower number of cases exhibiting toxicity in our population; however, this needs elucidation in a larger number of patients.
Neurology India 03/2015; &§(2):202-208. DOI:10.4103/0028-3886.156281 · 1.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Even with numerous studies the cause of Parkinson's disease (PD) remains elusive. It has been hypothesized that interactions between genetic and environmental factors may play an important role in the pathogenesis of PD. Objectives: To examine the gene-gene and gene-environment interaction on PD risk with respect to gene polymorphism of cytochrome P450 2D6 (CYP2D6) and glutathione S-transferases pi 1 (GSTP1), organochlorine pesticides (OCPs) and metals. Methods: This study included 70 patients of PD and 100 age-matched controls. The restriction fragment length polymorphism was used for analysis of genetic polymorphism. OCPs and serum metal levels were estimated by using gas chromatography and an autoanalyser respectively. Results: The CYP2D6*4 mt and GSTP1 *B allelic variants were significantly associated with increase in PD risk. We found a statistically significant difference in β-hexachlorocyclohexane (β-HCH), dieldrin, 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (pp'-DDE) and copper levels between the patients and controls. We found significantly high levels of β-HCH, dieldrin and pp'-DDE in the CYP2D6*4 mt allelic variants, β-HCH and pp'-DDE in the GSTP1*B allelic variants and dieldrin in the GSTP1*C allelic variants when comparing CYP2D6*4 non-mt, GSTP1 non-*B and GSTP1 non-*C allelic variants in patients of PD respectively. Conclusion: This study demonstrates that the CYP2D6*4 and GSTP1 genes may be considered as candidate genes for PD and they may also interact with β- HCH, dieldrin and pp'-DDE to influence the risk for PD.
Current Aging Science 08/2014; 7(2). DOI:10.2174/1874609807666140805123621
[Show abstract][Hide abstract] ABSTRACT: Objectives:
Changes in lifestyle habits such as diet modification or supplementation have been indicated as probable protective factors for a number of chronic conditions including Alzheimer's disease (AD). With this background, we aim to hypothesize that whether C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene contributes towards the risk of developing AD and its association with vitamin B12 and folate levels.
Materials and Methods:
A case-control study comprising of total 200 subjects, within the age group of 50-85 years. Their blood samples were analyzed for serum folate, vitamin B12 levels, and MTHFR C677T polymorphism by restriction fragment length polymorphism (RFLP).
The mean plasma levels of vitamin B12 and folate were significantly lower in study group when compared to the control group (P < 0.001). Genotypic and allelic frequency of MTHFR gene in both groups was found to be significant (P < 0.05). The intergenotypic variations of vitamin B12 and folate were found to be significant (P < 0.001).
We concluded that the subjects with homozygous mutated alleles are more prone to AD and also pointed out the influence of presence/absence of MTHFR T allelic variants on serum folate and vitamin B12 levels.
Annals of Indian Academy of Neurology 07/2014; 17(3):308-12. DOI:10.4103/0972-2327.138510 · 0.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It has been assumed that the association between Alzheimer disease (AD) and pesticides may be stronger among genetically susceptible individuals. The aim of the study was to examine the genetic polymorphism in cytochrome P450 2D6 (CYP2D6) and glutathione S-transferases pi 1 (GSTP1) with respect to organochlorine pesticides (OCPs) and metals in AD.
This study included 100 patients with AD and 100 age-matched controls. The genetic polymorphisms were analyzed by restriction fragment length polymorphism. The OCPs and serum metal levels were determined using gas chromatography and an autoanalyzer, respectively.
We found a statistically significant association between AD and high levels of β-hexachlorocyclohexane (β-HCH; odds ratio [OR] = 2.064, 95% confidence intervals [95% CIs] = 1.373-3.102, dieldrin [OR = 2.086, 95% CI = 1.224-3.555], and copper [OR = 1.038, 95% CI = 1.012-1.064). The significant low level of magnesium (OR = 0.151, 95% CI = 0.047-0.489) even appears to have a protective role against AD. The GSTP1*B (P = .009) and GSTP1*C (P = .011) allelic variants were associated with increase in AD risk.
This study demonstrates that the GSTP1*B and *C allelic variants may be considered a candidate gene for AD. It can be suggested that although CYP2D6*4 polymorphism is not a risk of AD, the CYP2D6*4 and GSTP1 polymorphism may interact with β-HCH, dieldrin, and copper to influence the risk of AD.
Journal of Geriatric Psychiatry and Neurology 02/2014; 27(2). DOI:10.1177/0891988714522698 · 2.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epidemiologic findings suggest that lipids and alteration in lipid metabolizing protein/gene may contribute to the development of neurodegenerative disorders. The aim of the current study was to determine the serum lipid levels and genetic variation in two lipid metabolizing genes, low-density lipoprotein receptor-related protein-associated protein (LRPAP1) and apolipoprotein E (APOE) gene in Parkinson's disease (PD). Based on well-defined inclusion and exclusion criteria, this study included 70 patients with PD and 100 age-matched controls. LRPAP1 and APOE gene polymorphism were analyzed by polymerase chain reaction and restriction fragment length polymorphism, respectively. Fasting serum lipid levels were determined using an autoanalyser. The logistic regression analysis showed that high levels of serum cholesterol [odds ratio (OR) = 1.101, 95 % confidence interval (CI95%) = 1.067-1.135], LRPAP1 I allelic variant alone (OR = 2.766, CI95% = 1.137-6.752) and in combination with APOE ε4 allelic variant (OR = 4.187, CI95% = 1.621-10.82) were significantly associated with increase in PD risk. Apart from that, the high levels of LDL cholesterol appears to have a protective role (OR = 0.931, CI95% = 0.897-0.966) against PD. The LRPAP1 I allelic variant may be considered a candidate gene for PD, predominantly in patients having the APOE ε4 allelic variant.
[Show abstract][Hide abstract] ABSTRACT: Organophosphate (OP) poisoning is a common occurrence in the rural areas of developing countries like India. Acute cholinergic crisis is one of the important causes of mortality related to OP poisoning. Delayed peripheral neuropathy, extrapyramidal syndromes and neuropsychiatric manifestations are the major consequences of secondary neuronal damage. This case illustrates a 14-year-old girl who ingested 50 mL of OP pesticide and developed extrapyramidal symptoms in the form of parkinsonism and hand dystonia in spite of immediate medical attention. MRI of the brain with T2, fluid attenuated inversion recovery and diffusion-weighted sequences revealed bilateral symmetrical basal ganglia hyperintensities. Further follow-up revealed a significant clinical improvement with marked resolutions of the brain lesions. The reversible extrapyramidal symptoms with disappearance of neuroimaging findings without neuropathy or neuropsychiatric manifestations are unusual in OP poisoning.
Case Reports 01/2014; 2014. DOI:10.1136/bcr-2013-009752
[Show abstract][Hide abstract] ABSTRACT: The characteristic features of Madras motor neuron disease (MMND) are onset in the young in the first two decades, sporadic occurrence, facial and bulbar paralysis, sensorineural hearing impairment, asymmetrical weakness of limbs and pyramidal signs with a slow progression. The majority of the cases reported are from South India. MMND variant has the additional features of optic atrophy and cerebellar signs. We are reporting a 48 year old female of MMND who had persistent fasciculations of chin, with electromyographic features of fasciculations and fibrillations in mentalis muscle. Chin fasciculations, a rare clinical feature, is now described for the first time in Madras motor neuron disease adding a new feature to the clinical constellation of symptoms.
Neurology India 11/2013; 61(6):653-655. DOI:10.4103/0028-3886.125275 · 1.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The notion of potential existence of gene environment interaction (GxE) in Alzheimer’s disease (AD) has substantial impact on understanding the role of genetic and non-genetic contribution to this disorder. Keeping in mind this background we examined the genetic and environmental factors which may determine their relative contribution to AD. Based on well defined inclusion and exclusion criteria this study includes 70 AD patients and 75 age-matched controls. Organochlorine Pesticides (OCPs) were analyzed in blood by using gas chromatography and serum metals were analyzed by using an autoanalyser. The LRPAP1 and APOE gene polymorphism were determined by polymerase chain reaction and restriction fragment length polymorphism respectively. The frequency of APOE ε4 allele and LRPAP1 I allele were significantly high (p=0.000 for both allele) in AD patients as compared to controls. The significantly high levels of β-hexachlorocyclohexane (β-HCH) and dieldrin are risk factors for AD independent of the genetic risk factor, recording an odds ratio of 2.777 and 2.344 respectively. This study suggests that out of the environmental factors, high β-HCH levels were the best predictor of presence of AD independent of the genetic component and low levels of serum iron play a protective role against AD.
[Show abstract][Hide abstract] ABSTRACT: The cause of Parkinson's disease (PD) remains elusive, but environmental chemical exposures have been postulated to be involved in the etiology of PD. We examined the association between the persistent organochlorine pesticides (OCPs) and PD in the North Indian population. This case control study included 70 PD and 75 control subjects in the age group of 50 to 85 years. Blood samples were collected and high-purity grade hexane and acetone (2 : 1 ratio) were used for extraction of organochlorine residues. OCPs (hexachlorocyclohexane (HCH), aldrin, dieldrin, endosulfan, pp'-Dichlorodiphenyldichloroethylene (pp'-DDE), op'-DDE, pp'- Dichlorodiphenyltrichloroethane (pp'-DDT), op'-DDT, pp'-dichlorodiphenyldichloroethane (pp'-DDD) and op'-DDD) were quantitatively estimated by using gas chromatography. The most frequently detected OCP was dieldrin, which was present in 9.3% of control and 61.4% of PD. The strongest predictor was β-hexachlorocyclohexane (β-HCH), which reported an odds ratio of 2.566, indicating that for every additional one unit of β-HCH, patients had 2.566 times more chances of presence of PD. This study indicates that increased level of β-HCH and dieldrin may be associated with the risk of PD.
[Show abstract][Hide abstract] ABSTRACT: Neurocysticercosis (NCC) is an endemic parasitic infection of Asia, Africa, Latin America, and central Europe. Neuropsychiatric manifestations of the illness include epilepsy and behavioral disturbances. There is a dearth of systematic studies on psychiatric manifestations of NCC from various Asian counties. The present study assessed the prevalence of various psychiatric disorders in a cohort of patients with NCC attending a neurological service.
Detailed psychiatric assessment was carried out on 50 patients of NCC with epilepsy and 50 patients of epilepsy without any evidence of NCC. Comprehensive Psychopathological Rating Scale was used to elicit the symptoms. Cognitive functions were assessed using Mini Mental Status Examination. Psychiatric diagnoses were made as per International Classification of Diseases, 10(th) edition (ICD-10).
Sixty eight percent of the patients with NCC suffered from a psychiatric disorder, as compared to 44% of those without NCC (P=0.02). Major depression and mixed anxiety depression were the two most common diagnoses. None of the patients was to found to suffer from a psychotic disorder. The most frequent site of brain lesion of NCC was the parietal lobe, followed by frontal lobes and disseminated lesions. Left sided lesions were associated with greater psychiatric morbidity. Focal seizures with or without secondary generalizations were present more frequently in patients with NCC whereas primary generalized seizures were more common in patients with idiopathic epilepsy (P=0.05).
Psychiatric manifestations are more common in patients of epilepsy with NCC than those without NCC. The treating clinician need to be vigilant about the phenomenon.
Indian Journal of Psychiatry 03/2013; 55(3):264-267. DOI:10.4103/0019-5545.117146
[Show abstract][Hide abstract] ABSTRACT: Objectives:
The aim was to examine the gene environment (GxE) interaction with reference to APO E genotypes, serum lipids and organochlorine pesticides (OCPs) as one of the factors in the etiology of Alzheimer's disease (AD).
A case control study was used to examine, APOE HhaI polymorphism by polymerase chain reaction (PCR)/PCRrestriction fragment length polymorphism method, serum lipids by autoanalyser and OCPs by gas chromatography (GC).
APOE ∈4 allele frequency was significantly high (p=0.000, OR=5.73, CI=2.68-12.50) in AD as compared to controls. The serum cholesterol, β- hexachlorocyclohexane and dieldrin are risk factors for AD independent of the APOE ∈4 risk allele, recording an odds ratio of 1.16, 11.38 and 10.45 respectively.
GxE interactions exist with APOE ∈4 allele status that need to be considered for the study design and analysis of such data in future studies of AD.
American Journal of Alzheimer s Disease and Other Dementias 08/2012; 27(7):496-503. DOI:10.1177/1533317512456067 · 1.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) could result from a multifactorial process involving both genetic predisposition and exposure to environmental factors like pesticides. A case control study of 70 patients of AD and 75 controls was done to examine the association between organochlorine pesticides (OCPs) and risk of AD. OCPs (hexachlorocyclohexane (HCH), aldrin, dieldrin, endosulfan, pp'-dichlorodiphenyldichloroethylene (pp'-DDE), op'-DDE, pp'-dichlorodiphenyltrichloroethane (pp'-DDT), op'-DDT, pp'-dichlorodiphenyldichloroethane (pp'-DDD) and op'-DDD) were extracted from blood and quantitatively estimated using gas chromatography. A Mann-Whitney U test revealed significant difference in β-HCH levels (U = 1237.00, W = 4087.00, z = -6.296, p = 0.000, r = -0.71), dieldrin levels (U = 1449.00, W = 4299.00, z = -5.809, p = 0.000, r = -0.68) and pp'-DDE levels (U = 2062.00, W = 4912.00, z = -2.698, p = 0.007, r = -0.59) between AD patients and controls. In conclusion, this study supports epidemiological studies that associate exposure to pesticides with increased risk of AD, and we identified the specific pesticides β-HCH, dieldrin and pp'-DDE that are associated with the risk of AD in the north Indian population. However, further research is needed to establish the potential role of these OCPs as an etiologic agent for AD case.
[Show abstract][Hide abstract] ABSTRACT: The ATP-binding cassette (ABC) superfamily of transporters is known to efflux antiepileptic drugs (AEDs) primarily in the brain, gastrointestinal tract, liver, and kidneys. In addition, they are also known to be involved in estrogen disposition and may modulate seizure susceptibility and drug response. The objective of the present study was to investigate the role of genetic variants from ABC transporters in seizure control in epilepsy patients treated with monotherapy of first-line AEDs for 12 months.
On the basis of gene coverage and functional significance, a total of 98 single nucleotide polymorphisms from ABCB1, ABCC1, and ABCC2 were genotyped in 400 patients from North India. Of these, 216 patients were eligible for therapeutic assessment. Genetic variants were compared between the 'no-seizures' and the 'recurrent-seizures' groups. Bonferroni corrections for multiple comparisons and adjustment for covariates were performed before assessment of associations.
Functionally relevant promoter polymorphisms from ABCC2: c.-1549G>A and c.-1019A>G either considered alone or in haplotype and diplotype combinations were observed for a significant association with seizure control in women (odds ratio>3.5, P<10, power>95%). Further, low protein-expressing CGT and TGT (c.-24C>T, c.1249G>A, c.3972C>T) haplotypes were always observed to be present in combination with the AG (c.-1549G>A, c.-1019A>G) haplotype that was over-represented in women with 'no seizures'.
The distribution of the associated variants supports the involvement of ABCC2 in controlling seizures in women possibly by lowering of its expression. The biological basis of this finding could be an altered interaction of ABCC2 with AEDs and estrogens. These results necessitate replication in a larger pool of patients.
Pharmacogenetics and Genomics 06/2012; 22(6):447-65. DOI:10.1097/FPC.0b013e3283528217 · 3.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This article briefly outlines the proposed national epilepsy control program. The content of the article is based on four meetings held by invitation of the Ministry of Health. Invitees by ministry - Drs. D. C. Jain, M. Gourie Devi, V. Saxena, S. Jain, P. Satish. Chandra, M. Gupta, K. Bala, V. Puri, K. S. Anand, S. Gulati, S. Johri, P. S. Chandra, M. Behari, K. Radhakrishnan, D. Bachani. Presentations were made by Dr. M. Tripathi.The program will involve all neurologists across the country in teaching and training at state levels and a central monitoring committee.
Annals of Indian Academy of Neurology 04/2012; 15(2):89-93. DOI:10.4103/0972-2327.94989 · 0.60 Impact Factor