RETROSPECTIVE STUDY ON THERAPEUTIC DRUG MONITORING OF LAMOTRIGINE IN INDIAN EPILEPTIC PATIENTS

Objective: Antiepileptic drugs (AED) are administered either singly or in combination with other drugs. Their pharmacokinetics is influenced by drug-drug interaction & inter-individual variations. Lamotrigine (LTG) is a second order AED with similar constraints. Hence studying the relationship between lamotrigine dosage and plasma concentration was undertaken to offer assistance in therapeutic regimen. Methods: Pre-dose blood samples for lamotrigine estimation were obtained from 267 patients (138adults & 127children) including 2 pregnant women. Lamotrigine estimation was done by high performance liquid chromatography. Results: In our study more children (73%) than adults (34%) were on adjunctive therapy with inhibitors (valproic acid) or inducers (phenytoin, carbamazepine, oxcarbamazepine). Irrespective of co-therapy lamotrigine level within therapeutic range with an optimal seizure control was obtained only in 76% of children and 65% adults. In case of polytherapy with valproic acid, when lamotrigine dose was maintained similar or lower than monotherapy, lamotrigine levels were 105% and 65% higher in adults and children respectively. Increased volume as observed in pregnancy had a remarkable influence on lamotrigine level. An increase in drug dose with an increase in gestation was required in both pregnant women to maintain the plasma level. Conclusion: Inter-individual variations, co-medications and clinical conditions like pregnancy influence plasma lamotrigine level. Thus, drug monitoring is essential to obtain therapeutic efficacy for individual dose optimization

Prevalence of Metabolic Syndrome in Urban India

Background. Metabolic syndrome (MS) is characterised by a constellation of individual risk factors of cardiovascular disease. Materials and Methods. The current study was a population-based survey of cohort of subjects in the metropolitan city of Mumbai. A total of 548 subjects, who attended the CARDIAC evaluation camp, were recruited in the study. Participants with complete fasting lipid profiles, blood glucose, and known cardiac risk markers were evaluated. Results. On applying modified NCEP ATP III, we found out that nearly 95% of the subjects had at least one abnormal parameter. We found the prevalence of MS in our study population to be 19.52%. The prevalence of MS in males was almost double than females (P = .008). The overall prevalence of BMI (>23 kg/m2) was 79.01%. Increased hypertriglyceridemia and decreased levels of HDL-C were found to be more in males (P < .0001). Conclusion. The low percentage of subjects with normal and controlled parameters suggests that there is a need for awareness programs and lifestyle interventions for the prevention and control of MS

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

An in-house multilocus SNP genotyping assay for evaluation of complex genetic diseases

<p><b>Background:</b> With an increase in the discovery of newer genetic loci/polymorphisms in complex multifactorial diseases, there is also an increased need for methods that can simultaneously genotype multiple loci in a cost-effective manner. Using coronary artery disease (CAD) as a model, the study aimed to develop an in-house multilocus assay for simultaneous detection of 17 genetic variants in 11 genes implicated in CAD.</p> <p><b>Methods:</b> A multiplex polymerase chain reaction (PCR)-based reverse line blot hybridization (MPCR-RLBH) approach was used, where each DNA sample was amplified using two separate MPCRs, and the alleles were genotyped using covalently immobilized, amino-linked sequence-specific oligonucleotide probes using an enhanced chemiluminescence system. The assay performance was tested on 75 healthy controls and 75 angiographically proven CAD cases. Validation was done by automated Sanger sequencing.</p> <p><b>Results:</b> The assay could successfully discriminate both the alleles at <i>CETP</i> (I405V), <i>LPL</i> (D9N), <i>NOS3</i> (T-786G and E298D), <i>LIPC</i> (C-514T), <i>FGB</i> (G-455A), <i>ITGB3</i> (L33P), <i>AGT</i> (M235T), and <i>MTR</i> (A2756G) loci. Certain mutations included in this assay such as ins242G, ins397G, E387K, L393K in the <i>LDLR</i>; N291S in the <i>LPL</i>; D442G in the <i>CETP</i>; and T833C in the <i>CBS</i> genes were found to be absent. The genotype results obtained using this assay showed 100% concordance with sequencing.</p> <p><b>Conclusion:</b> The study demonstrated development and validation of a multiplex SNP genotyping assay that can be used to assess genetic risk factors in CAD. The assay provides a cost-effective alternative to expensive high throughput genotyping systems in common molecular research laboratories.</p

Association of <i>CYBA G640A</i> variation with coronary artery disease in Indians

<p><b>Introduction</b>: Oxidative stress induces atherosclerosis by triggering an inflammatory cascade within the vascular wall.</p> <p><b>Objective</b>: To investigate the role of pro-oxidant and antioxidant gene variations with CAD in Indian subjects.</p> <p><b>Materials & methods</b>: It’s a case-control study and genotyping for the variants <i>MPO G-463A, CYBA G640A, SOD2 Val16Ala</i> and <i>CAT C-262T</i> were performed by conventional PCR techniques.</p> <p><b>Results</b>: Only <i>CYBA G640A</i> variant allele was found to be significantly (<i>p</i> = 0.0075) associated with CAD.</p> <p><b>Conclusion</b>: Although <i>CYBA G640A</i> variation was found to be significant, a larger study is needed to validate these results and establish its role as a biomarker.</p

Platelet polymorphisms: frequency distribution and association with coronary artery disease in an Indian population

Platelets play a critical role in normal blood hemostasis and thrombus formation in myocardial infarction (MI). Several polymorphisms of genes involved in platelet activation and fibrinolysis have been reported to be associated with MI. The aim of the present study was to determine the frequency distribution and association of polymorphisms in these genes with coronary artery disease (CAD) among Indians. A case-control genetic association study was performed for polymorphisms in platelet glycoprotein receptors (GPIIb/IIIa [HPA1a/1b], GPIb-IX-V [VNTR], and GPIa/IIa [C807T]), fibrinogen &#946;-chain (BclI), &#945;-chain (A&#945;312), tissue plasminogen activator (tPA) [I/D] and plasminogen activator inhibitor-I (PAI-1) [4G/5G] in 473 healthy controls and 446 patients with stable and unstable angina. Genotyping was either by PCR-based restriction endonuclease digestion or allele-specific primers. The I allele frequency of the tPA I/D polymorphism was significantly higher in our patients (&#967;2=7.33, P&lt;0.01) and no other polymorphisms varied significantly between patients and controls. Also, none of the polymorphisms seemed to affect the severity of the disease, the only exception being the mutant alleles of &#946; chain of fibrinogen gene, which were significantly elevated in single vessel disease. This is the first study to evaluate the role of gene polymorphisms in both the thrombotic and fibrinolytic pathway in the Indian population and suggests that tPA I/D polymorphism confers CAD risk in our population