Association of CYP19A1 gene variations with adjuvant letrozole-induced adverse events in South Indian postmenopausal breast cancer cohort expressing hormone-receptor positivity.

PURPOSE: Musculoskeletal adverse events (MS-AEs) and vasomotor symptoms (VMSs) are the major side-effects of newer generation non-steroidal aromatase inhibitor (AI), letrozole. Single-nucleotide polymorphisms (SNPs) in CYP19A1 gene coding for the enzyme aromatase are related to AI treatment-associated adverse drug reactions. Therefore, we aimed to determine whether SNPs in the CYP19A1 gene are associated with adjuvant letrozole-induced 'specific' AEs in postmenopausal hormone receptor-positive (HR+) breast cancer patients. METHODS: Genomic DNA was isolated from 198 HR+ breast cancer patients by the phenol-chloroform method, and eleven SNPs in the CYP19A1 gene were genotyped by TaqMan genotyping assays on the qRT-PCR system. Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0, and the data were analyzed using SPSS v19.0 and Haploview v4.2 statistical software. RESULTS: Subjects carrying the genetic variants of CYP19A1 gene SNP rs700519 had significantly higher odds (OR 2.33; 95% CI [1.29-4.20], P = 0.0057) of MS-AEs under dominant statistical effect. The frequency of the two distinct haplotypes that include the variant allele 'T' at rs700519 locus, H5-GCTATCTGGCG (P = 0.042) and H11-GCTATTGCACG (P = 0.013) were significantly higher in patients with musculoskeletal toxicity than in those without MS-AEs and thus predisposing to MS-AEs. Similarly, H6-GCCAGCTGGCG (P = 0.037) haplotype exhibited higher frequencies in patients presented with VMSs. However, no such association was observed between CYP19A1 genotypes and VMSs. CONCLUSIONS: To the best of our knowledge, this is the first study assessing the impact of CYP19A1 genetic variations with adjuvant letrozole treatment-associated AEs in Indian women. Genetic variations in the CYP19A1 gene is associated with letrozole-induced AEs and warrants further investigation in larger cohorts to validate this finding.

Single nucleotide polymorphism of CYP3A5*3 contributes to clopidogrel resistance in coronary artery disease patients among Tamilian population.

Clopidogrel is an antiplatelet drug. It is used for the treatment as well as for the prophylaxis of coronary artery disease. Clopidogrel resistance is an emerging problem in clinical settings. The aim of the present study was to evaluate the effect of CYP3A5*3 genetic polymorphism on clopidogrel resistance. One hundred and forty-seven patients from outpatient Department of Cardiology on 75 mg/day of clopidogrel as maintenance dose were recruited from April 2010 to July 2011. All subjects gave written informed consent to participate in the study. DNA extraction was performed using phenol chloroform extraction procedure and genotyping by standard Taqman based RT-PCR method. Platelet aggregation was done at the end of 7th and 14th day by using chronolog lumi Aggregometer which is expressed as impedance in ohms. Impedance values of >5 ohms at the end of 6 min were considered as clopidogrel resistance. Subjects (N = 147) were analysed for CYP3A5*3 polymorphism, of which 49 (33%) were found to be clopidogrel resistant. Homomutants of CYP3A5*3 gene had 2.78 (0.97-7.98; p < 0.05) fold risk and heteromutants had 2.4 (0.93-6.46; p < 0.05) fold risk of developing clopidogrel resistance. Carriers of defective allele G of CYP3A5*3 had higher propensity to cause clopidogrel resistance with an odds ratio of 1.63. Variant alleles and genotypes of CYP3A5*3 polymorphism contributed significantly to clopidogrel resistance with a higher odds ratio. Thus, pharmacogenomics paves way for the emergence of stratified medicine in clopidogrel therapy and personalised pharmacotherapy in ischaemic heart disease.

Newer antipsychotics and upcoming molecules for schizophrenia.

BACKGROUND: The management of schizophrenia has seen significant strides over the last few decades, due to the increasing availability of a number of antipsychotics. Yet, the diminished efficacy in relation to the negative and cognitive symptoms of schizophrenia, and the disturbing adverse reactions associated with the current antipsychotics, reflect the need for better molecules targeting unexplored pathways. PURPOSE: To review the salient features of the recently approved antipsychotics; namely, iloperidone, asenapine, lurasidone and blonanserin. METHODS: We discuss the advantages, limitations and place in modern pharmacotherapy of each of these drugs. In addition, we briefly highlight the new targets that are being explored. RESULTS: Promising strategies include modulation of the glutamatergic and GABAergic pathways, as well as cholinergic systems. CONCLUSIONS: Although regulatory bodies have approved only a handful of antipsychotics in recent years, the wide spectrum of targets that are being explored could eventually bring out antipsychotics with improved efficacy and acceptability, as well as the potential to revolutionize psychiatric practice.

Inter and intra-ethnic differences in the distribution of the molecular variants of TPMT, UGT1A1 and MDR1 genes in the South Indian population.

Molecular variants of polymorphic drug metabolizing enzymes and drug transporters are attributed to differences in individual's therapeutic response and drug toxicity in different populations. We sought to determine the genotype and allele frequencies of polymorphisms for major phase II drug-metabolizing enzymes (TPMT, UGT1A1) and drug transporter (MDR1) in South Indians. Allelic variants of TPMT (*2,*3A,*3B,*3C & *8), UGT1A1 (TA)6>7 and MDR1 (2677G>T/A & 3435C>T) were evaluated in 450-608 healthy South Indian subjects. Genomic DNA was extracted by phenol-chloroform method and genotype was determined by PCR-RFLP, qRT-PCR, allele specific PCR, direct sequencing and SNaPshot techniques. The frequency distributions of TPMT, UGT1A1 and MDR1 gene polymorphisms were compared between the individual 4 South Indian populations viz., Tamilian, Kannadiga, Andhrite and Keralite. The combined frequency distribution of the South Indian populations together, was also compared with that of other major populations. The allele frequencies of TPMT*3C, UGT1A1 (TA)7, MDR1 2677T, 2677A and 3435T were 1.2, 39.8, 60.3, 3.7, and 61.6% respectively. The other variant alleles such as TPMT*2, *3A, *3B and *8 were not identified in the South Indian population. Sub-population analysis showed that the distribution of UGT1A1 (TA)6>7 and MDR1 allelic variants differed between the four ethnic groups. However, the frequencies of TPMT*3C allele were similar in the four South Indian populations. The distribution of TPMT, UGT1A1 and MDR1 gene polymorphisms of the South Indian population was significantly different from other populations.

Potassium channels in health, disease & development of channel modulators.

Ion channels present in the plasma membrane and intracellular organelles of all cells, play an important role in maintaining cellular integrity, smooth muscle contraction, secretion of hormones and neurotransmitters. Among the ion channels, potassium channels (K(+)) are the most abundant having important role in cardiac repolarization, smooth muscle relaxation and insulin release. These are also involved in the regulation of physiological functions like gastrointestinal peristalsis. These channels are the most diverse of all ion channels and are coded by at least 75 genes. Moreover, these have different subunits which co-assemble to form diverse functional channels. Abnormalities in K(+) channels are associated with diseases like long QT syndrome, Anderson Tawil syndrome, epilepsy, type 2 diabetes mellitus, etc. A number of naturally occurring as well as synthetic compounds have been identified that modulate the opening and closure of K(ATP) Channels. Some of the currently available K(+) channel modulators like sulphonylureas, minoxidil, amiodarone, etc. lack tissue selectivity and have adverse effects. Hence, the success of K(ATP) channel modulators depend on their tissue selectivity. Molecular level studies are needed to understand the type of K(+) channels as this can lead to the development of newer drugs with tissue selectivity for various diseases.

Role of ion channel modifiers in reversal of morphine-induced gastrointestinal inertia by prokinetic agents in mice.

Prokinetic drugs like mosapride, domperidone etc, are used to treat gastrointestinal delay. Though the receptor-mediated actions of these agents have been studied, involvement of ion channels in reversing morphine-induced gastrointestinal inertia by prokinetic agents has not been explored. Charcoal meal test was used to measure small intestinal transit (SIT) in adult male Swiss albino mice. Animals were given ion channel modifiers and prokinetic drugs intragastrically. Reversal of morphine-induced gastrointestinal delay by mosapride was decreased significantly by CaCl2, minoxidil and glibenclamide. Similarly, domperidone's effect on morphine was decreased by CaCl2, nifedipine, minoxidil and glibenclamide significantly. The results reveal that ion channel modifiers counteract the prokinetic effects of mosapride or domperidone.

Oxaliplatin-induced Peripheral Neuropathy in South Indian Cancer Patients: A Prospective Study in Digestive Tract Cancer Patients.

PURPOSE: The aim of the current study is to report our prospective experience on the prevalence of oxaliplatin-induced peripheral neuropathy (OXAIPN) in patients with digestive tract cancers treated with oxaliplatin-based combination therapy. MATERIALS AND METHODS: A total of 219 patients scheduled to be treated with oxaliplatin-based combination therapy were prospectively examined at baseline and follow-up during the therapy between November 2014 and December 2016. The incidence of acute OXAIPN was measured using a descriptive questionnaire (yes/no question) based on sum of number of symptoms present and NCI-CTCAE version 4.03 was applied to clinically grade the severity of chronic OXAIPN. RESULTS: Acute and chronic OXAIPN was found in 108 of 219 (49.3%) and 127 of 219 (58%) patients, respectively. Out of 11 acute OXAIPN symptoms, the vast majority of patients manifested cold-induced pharyngolaryngeal (63.8%) dysesthesias or perioral (61.1%) paresthesias. Development of acute OXAIPN was predictive of subsequent development of chronic OXAIPN (P = 0.0001). All the patients received a median cumulative dose of 780 mg/m2 (range: 130-1040 mg/m2). There was a significant correlation between the patients who received the median cumulative dose and the development of chronic OXAIPN. The incidences of OXAIPN in patients with median cumulative dose of ≤780 mg/m2 was 51/120 (42.5%) and >780 mg/m2 was OXAIPN 76/99 (76.7%) (P = 0.0001). CONCLUSION: The current study results demonstrate that the vast majority of patients who receive oxaliplatin-based combination chemotherapy will manifest acute OXAIPN that may contribute to the development of chronic peripheral neuropathy on repeated courses of drug administration.

Atorvastatin Induced Adverse Drug Reactions among South Indian Tamils.

INTRODUCTION: Atorvastatin is the most widely used statin world-over. Although atorvastatin is beneficial in reducing cardiovascular morbidity and mortality, they are associated with Adverse Drug Reactions (ADRs) which are under-recognized as well as under-reported. There is no data on safety of atorvastatin in ethnic populations like South Indian Tamils and hence the need for this study. AIM: To report the Adverse Events (AEs) associated with atorvastatin use, their causality and severity in dyslipidemic south Indian Tamils. MATERIALS AND METHODS: This cross-sectional study was carried out on 304 dyslipidemic Tamils. Those on any lipid lowering therapy within one month before study enrolment, those with contraindications to statin therapy, hypothyroid patients, those with LDL cholesterol >250 mg/dL or serum triglycerides >400 mg/dL and patients who were on drugs which modulate Cytochrome P 450 3A4/5 (CYP3A4/5) activity were excluded from the study. Causality assessment for atorvastatin induced AEs were done using Naranjo adverse drug reaction probability scale criteria and severity assessment was done using Hartwig scale. AEs which were causally related to atorvastatin use were reported as ADRs. RESULTS: One hundred and eighty three AEs were noted among 145 (47.7%) patients, during the course of first 45 days of atorvastatin therapy. AEs were probably due to atorvastatin in 11% of the patients and possibly due to atorvastatin in 89%. Most common ADRs were myalgia (41%), followed by nervous system ADRs (35.5%) and gastrointestinal ADRs (14%). CONCLUSION: Myalgia was the most common cause for atorvastatin discontinuation which might place these individuals at an increased risk of cardiovascular morbidity and mortality. Measures to identify and address atorvastatin induced myalgia should be given priority.

A Polymorphism Located Near PMAIP1/Noxa Gene Influences Susceptibility to Hodgkin Lymphoma Development in South India

Background: Single nucleotide polymorphisms (SNPs) in DNA repair and Toll-like receptor (TLR) genes have been reported to be associated with Hodgkin Lymphoma (HL) risk. Since such associations may be ethnicity dependent, polymorphisms in TLR4 rs1554973, Xeroderma pigmentosum C (XPC) rs2228000, rs2228001 and a variant near PMAIP1/Noxa gene rs8093763 were here investigated with regard to HL susceptibility in a south Indian population. Normative frequencies of SNPs were established and compared with data for 1000 genome populations. Methods: We conducted a case control study consisting of 200 healthy volunteers and 101 cases with HL. DNA samples were genotyped using real-time PCR. Linkage disequilibrium (LD) analysis between rs2228000 and rs2228001 was performed using HaploView (version 4.2). Results: Among the studied variants, we observed that a variant rs8093763 located near PMAIP1/Noxa gene was associated with HL risk (OR=1.72 and 95% CI=1.004-2.93). The major allele frequencies of XPC (rs2228000 and rs2228001), TLR4 (rs1554973) and PMAIP1/NOXA (rs8093763) variants were 79%, 66%, 67% and 59% respectively. The studied frequencies were significantly different from 1000 genome populations. Conclusion: The results suggest that a variant rs8093763 located near the PMAIP1/Noxa gene may modify risk of HL. We found variation in distribution of polymorphic frequencies between the study population and 1000 genome populations. The results may help identify individual risk of development of HL in our south Indian population.

Effect of Vitamin D Supplementation on Vascular Functions and Oxidative Stress in Type 2 Diabetic Patients with Vitamin D Deficiency.

BACKGROUND: Vitamin D levels are reported to have an inverse liaison with the risk of cardiovascular diseases. Hence, we aimed to evaluate the effect of Vitamin D supplementation on changes in vascular functions and oxidative stress in type 2 diabetic patients with Vitamin D deficiency. SUBJECTS AND METHODS: One hundred and three patients with type 2 diabetes attending endocrinology outpatients department in a tertiary care hospital were screened for Vitamin D deficiency. Patients with serum 25-hydroxy Vitamin D levels <20 ng/ml were considered as deficient and were administered 60,000 IU of oral Vitamin D3 weekly for 8 weeks. In these patients, parameters of vascular functions (carotid-femoral pulse wave velocity, brachial-ankle pulse wave velocity, and arterial stiffness index) and oxidative stress (serum malondialdehyde levels and total antioxidant status) were measured at baseline and after 8 weeks of oral Vitamin D supplementation. RESULTS: Among 103 patients with type 2 diabetes, 75 (72.82%) were found to have Vitamin D deficiency. Amidst these patients, carotid-femoral pulse wave velocity (991.6 ± 161.82 vs. 899.29 ± 151.86, P < 0.001), right brachial-ankle pulse wave velocity (1446.16 ± 204.33 vs. 1350.8 ± 178.39, P < 0.001), and left brachial-ankle pulse wave velocity (1493.81 ± 219.65 vs. 1367.61 ± 220.64, P < 0.001) showed a significant reduction following Vitamin D supplementation. Further, these patients were found to have significant fall in serum malondialdehyde levels with rise in total antioxidant status ensuing Vitamin D supplementation. CONCLUSION: The present study shows that oral Vitamin D supplementation of 60,000 IU/week for 8 weeks significantly improves vascular functions and reduces oxidative stress in type 2 diabetic patients with Vitamin D deficiency.

Association of Voltage-Gated Sodium Channel Genetic Polymorphisms with Oxaliplatin-Induced Chronic Peripheral Neuropathy in South Indian Cancer Patients

Oxaliplatin is a platinum drug active against digestive tract cancers. Among its side effects, peripheral neuropathy is one of the dose-limiting toxicities. This affects around 50 to 70% of patients but the pathophysiology of development of oxaliplatin-induced peripheral neuropathy (OXAIPN) remains unclear. Sodium channels (SCNAs) play major role in neuronal electrical signaling processes and mutations in SCNAs lead to various neuronal diseases involving the central and peripheral nervous systems. In this study, we evaluated whether SCNA genetic variants might be associated with risk of chronic OXAIPN in patients with digestive tract cancers treated with oxaliplatin. Methodology: Blood samples from 228 digestive tract cancer patients who had received oxaliplatin in adjuvant and neoadjuvant or metastatic settings were obtained and genomic DNA was extracted by phenol-chloroform extraction. Genotyping was performed with the real-time polymerase chain reaction (RT-PCR) using validated real-time TaqMan single nucleotide polymorphism (SNP) genotyping assays. Neuropathy was evaluated and graded according to National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.03. Results: We found that the rs6746030 polymorphic variant of SCN9A was significantly associated with a higher incidence of chronic OXAIPN (GA+AA vs GG: OR=1.8, 95% CI=1.04-3.4, P=0.04; dominant model) while the rs6754031 variant was linked with a lower incidence (OR=0.45, 95% CI=0.22-0.77, P=0.005; dominant model). The SCN 10A polymorphic variant was associated with severity of chronic OXAIPN (P=0.006, OR=2.0, 95% CI=1.2 - 3.3). Conclusion: The results of the present prospective study provide evidence in support of a causal relationship between chronic OXAIPN and voltage gated sodium channel polymorphisms. However, further studies from independent groups are required to validate these results.

Drug information center as referral service in a South Indian tertiary care hospital.

OBJECTIVE: The objective of this study is to assess the various aspects of drug information services (DISs) provided in the DI center of a tertiary care hospital. MATERIALS AND METHODS: DI queries received from various departments from April 2013 to May 2017 were included in the study. Various aspects such as year- and department-wise distribution, reason for sending the queries, mode of receipt and reply, time taken for reply, number of visit for bedside examination of patients, and number of references given per query were analyzed. All the results are expressed in numbers and percentages. RESULTS: Fifty-five DI queries were received during the study period. Most of the queries were received from Department of Orthopedics (26, 47.27%), followed by Neurology (4, 7.27%). Most common mode of receipt of queries (41, 74.55%) was by Cross-reference form not case record form followed by phone calls (8, 14.55%) and outpatient department (OPD) case sheet (6, 10.9%). CRF with attached opinion was the most common mode of reply (41, 74.55%) followed by phone calls (7, 12.73%), and OPD case sheets (6, 10.9%). The most common reason for sending queries was antimicrobials-related problem (25, 45.46%), followed by the use of anticoagulants (13, 23.63%). Most of the queries were replied within 24 h (31, 56.36%), followed by 48 h (14, 25.45%). Out of 41 CRF received for in-patients, bedside examination was requested in 23 (56.09%) CRF. There was an increasing trend in the number of queries received every year with more queries received during 2016 (23, 41.82%). CONCLUSIONS: DIS if utilized properly can be used as a referral service such as other specialties in a tertiary care hospital.

Effect of metformin on exercise capacity in metabolic syndrome.

OBJECTIVE: Metabolic syndrome is a constellation of risk factors with increased predilection towards occurrence of cardiovascular diseases. Currently physical exercise and management with metformin are the prevailing treatment modalities for metabolic syndrome. Patients with metabolic syndrome have been found to have reduced exercise capacity over a period of time. Likewise metformin has been shown to decrease exercise capacity among healthy volunteers. Hence this study aims to evaluate the effect of metformin on the exercise capacity of patients with metabolic syndrome. DESIGN: Prospective study with 6 weeks follow up. METHODS: Newly diagnosed patients with metabolic syndrome and to be started on Table Metformin 500mg twice a day were recruited for the study after obtaining written informed consent. Cardiopulmonary Exercise Testing (CPET) was done at baseline before the subjects were started on metformin and after 6 weeks of treatment using cardiopulmonary exercise testing apparatus (ZAN600). RESULTS: Fifteen treatment naïve patients with metabolic syndrome completed six weeks of therapy with metformin. In these patients oxygen uptake [VO2] showed statistically significant decrease from 1.10±0.44 at baseline to 0.9±0.39 (l/min) after six weeks of treatment with metformin [mean difference of -0.20 (-0.31 to -0.09); P=0.001]. Similarly oxygen uptake/kg body weight [VO2/Kg] showed a significant decrease from 14.10±4.73 to 11.44±3.81 (mlkg-1min-1) at the end of six weeks of treatment [mean difference of -2.66 (-4.06 to -1.26); P=0.001]. CONCLUSION: Six weeks of treatment with metformin significantly decreases exercise capacity in newly diagnosed patients with metabolic syndrome.

Effect of insulin on small intestinal transit in normal mice is independent of blood glucose level.

BACKGROUND: Insulin is the drug of choice in the management of diabetes mellitus (DM). About 76 % of diabetic patients suffer from gastrointestinal (GI) disorders. Therapy of DM with insulin primarily involves lowering of elevated blood glucose levels. Hence, on any organ in addition to insulin's effect, hypoglycaemic effect also prevails. A systematic study exploring the effect of insulin on small intestinal transit in normal laboratory animals is lacking. Hence, in the present study, the possible effect of insulin with or without associated hypoglycaemia on small intestinal transit in normal mice was examined. RESULTS: Insulin in all the doses tested (2 mu, 2 m and 2 U/kg) elicited a significant acceleration of SIT. The lower doses of insulin (2 mu and 2 m U/kg) produced significant acceleration of SIT and were associated with normal blood glucose levels. However, the highest dose of insulin (2 U/kg) produced an acceleration of SIT that was associated with significant fall in blood glucose levels. Further, the 2 m and 2 U doses of insulin significantly elevated serum insulin and C-peptide levels. CONCLUSION: Insulin at the lowest dose produced an acceleratory effect on SIT that was independent of blood glucose and serum insulin levels in normal mice.

An inherent acceleratory effect of insulin on small intestinal transit and its pharmacological characterization in normal mice.

AIM: To study an inherent effect of insulin on small intestinal transit and to explore involvement of various systems/mechanisms in normal mice. METHODS: Insulin at the doses of 2 microU/kg, 2 mU/kg, 2 U/kg or vehicle was subcutaneously administered to four groups of overnight fasted normal male mice. Blood glucose (BG) levels were measured 2 min before insulin administration and 2 min before sacrificing the animals for the measurement of small intestinal transit (SIT). Charcoal meal was administered (0.3 mL) intragastrically 20 min after insulin administration and animals were sacrificed after 20 min and SIT was determined. For exploration of the various mechanisms involved in insulin-induced effect on SIT, the dose of insulin which can produce a significant acceleration of SIT without altering BG levels was determined. The following drugs, atropine (1 mg/kg), clonidine (0.1 mg/kg), ondansetron (1 mg/kg), naloxone (5 mg/kg), verapamil (8 mg/kg) and glibenclamide (10 mg/kg), were administered intravenously 10 min prior to the administration of insulin (2 microU/kg). RESULTS: The lower doses of insulin (2 microU/kg and 2 mU/kg) produced a significant acceleration of SIT from 52.0% to 70.7% and 73.5% without lowering blood glucose levels (P < 0.01), while the highest dose of insulin (2 U/kg) produced a fall in blood glucose levels which was also associated with significant acceleration of SIT (P < 0.01). After pretreatment of insulin (2 microU/kg) group with atropine, insulin could reverse 50% of the inhibition produced by atropine. In clonidine-pretreated group, insulin administration could reverse only 37% of the inhibition produced by clonidine and inhibition of SIT was significant compared with vehicle + insulin-treated group, i.e. from 74.7% to 27.7% (P < 0.01). In ondansetron-pretreated group, insulin administration could produce only mild acceleration of SIT (23.5%). In naloxone-pretreated group, insulin administration could significantly reverse the inhibition of SIT produced by naloxone when compared with naloxone per se group, i.e. from 32.3% to 53.9% (P < 0.01). In verapamil-pretreated group, insulin administration could only partially reverse the inhibition (65%). In glibenclamide-pretreated group, insulin administration produced further acceleration of SIT (12.2%). CONCLUSION: Insulin inherently possesses an acceleratory effect on SIT in normal mice. Adrenergic and cholinergic systems can play a significant role. Calcium channels and opioidergic system can play a supportive role; in addition, enhancement of endogenous insulin release can augment the effect of exogenously administered insulin on SIT.

Comparison of ranolazine and trimetazidine on glycemic status in diabetic patients with coronary artery disease - a randomized controlled trial.

INTRODUCTION: Cardiovascular diseases have become the leading cause of death around the globe and diabetes mellitus (DM) is considered to be a coronary artery disease (CAD) risk equivalent. Ranolazine, an anti anginal drug has been found to reduce Glycated haemoglobin (HbA1c) in diabetes patients with chronic angina. However the effect of another antianginal drug trimetazidine, on glycemic status is not clear. AIM: To compare the effect of ranolazine and trimetazidine on glycemic status in diabetic patients with CAD. SETTINGS AND DESIGN: Patients diagnosed with CAD and diabetes mellitus attending Cardiology Out Patient Department (OPD), Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India were recruited for this randomized open label parallel arm trial. MATERIALS AND METHODS: The study conducted from January-2012 to April-2013 had 47 eligible patients diagnosed with CAD and diabetes mellitus. They were randomized to receive either ranolazine 500 mg BD or trimetazidine 35 mg BD for 12 weeks. HbA1c levels, fasting blood glucose (FBG), lipid profile, QT and QTc intervals were measured at baseline and after 12 weeks. STATISTICAL ANALYSIS: Unpaired t-test was used to compare the baseline characteristics of between the groups while comparison within the groups were done using Paired t-test. Wilcoxon and Mann Whitney U-tests were used for non parametric data. Graph pad instat version-3 was used for statistical analysis. Values were expressed as mean ± SD. A p < 0.05 was considered statistically significant. RESULTS: The study could not find any change in HbA1c levels in both ranolazine and trimetazidine groups. The adverse effects reported from patients on ranolazine include angina, constipation, postural hypotension, headache, dizziness, nausea and weakness while patients on trimetazidine complained of constipation, weakness, palpitations, angina, dizziness, nausea, dyspepsia, headache, gastric discomfort, joint pain, etc. CONCLUSION: In patients with chronic angina and diabetes mellitus Ranolazine 500mg BD and Trimetazidine 35mg BD did not show any effect on HbA1c and fasting blood glucose lebel.

Polymorphic genetic variations of cytochrome P450 19A1 and T-cell leukemia 1A genes in the Tamil population.

Aromatase inhibitors (AIs) are anti-neoplastic drugs widely used for the treatment of endocrine responsive breast carcinoma in postmenopausal women. Drug disposition, efficacy and tolerability of these agents are influenced by germ-line polymorphisms in the sequence of the genes encoding CYP19A1 and TCL1A proteins. In the current work, we aimed to determine the haplotype structures, linkage disequilibrium (LD) patterns, and allele and genotype frequency distribution of pharmacologically important variants from two genes (CYP19A1 and TCL1A) in Tamil population and assessed their ethnic differences. DNA derived from peripheral leukocytes of 111 healthy subjects were genotyped for 15 pharmacogenetic variants by real time thermocycler through allelic discrimination method using TaqMan 5' nuclease genotyping assay. The polymorphic variant allele frequencies of CYP19A1 were 42.3% (rs4646, T), 18% (rs10046, T), 36% (rs700519, T), 16.7% (rs700518, G), 26.1% (rs727479, G), 18% (rs4775936, T), 32% (rs10459592, G), 15.3% (rs1062033, C), 33.8% (rs749292, A), 40.1% (rs6493497, T) and 40.1% (rs7176005, G). TCL1A gene allele frequencies were 26.1% (rs7158782, G), 27% (rs7159713, G), 21.2% (rs2369049, G) and 27.5% (rs11849538, G). Comparing our data across the 5 HapMap populations (CEU, GIH, HCB, JPT and YRI) huge inter-ethnic differences were exhibited in the variant allele frequencies, LD patterns and haplotype blocks. Our results emphasize the importance of normative frequency documentation and will offer significant clinical relevance in personalizing AIs therapy.

Pattern of Adverse Drug Reactions Reported with Cardiovascular Drugs in a Tertiary Care Teaching Hospital.

BACKGROUND: Cardiovascular diseases (CVD) are one of the leading causes of non-communicable disease related deaths globally. Patients with cardiovascular diseases are often prescribed multiple drugs and have higher risk for developing more adverse drug reactions due to polypharmacy. AIM: To evaluate the pattern of adverse drug reactions reported with cardiovascular drugs in an adverse drug reaction monitoring centre (AMC) of a tertiary care hospital. SETTINGS AND DESIGN: Adverse drug reactions related to cardiovascular drugs reported to an AMC of a tertiary care hospital were included in this prospective observational study. MATERIALS AND METHODS: All cardiovascular drugs related adverse drug reactions (ADRs) received in AMC through spontaneous reporting system and active surveillance method from January 2011 to March 2013 were analysed for demographic profile, ADR pattern, severity and causality assessment. STATISTICAL ANALYSIS USED: The study used descriptive statistics and the values were expressed in numbers and percentages. RESULTS: During the study period, a total of 463 ADRs were reported from 397 patients which included 319 males (80.4%) and 78 females (19.6%). The cardiovascular drug related reports constituted 18.1% of the total 2188 ADR reports. In this study, the most common ADRs observed were cough (17.3%), gastritis (7.5%) and fatigue (6.5%). Assessment of ADRs using WHO-causality scale revealed that 62% of ADRs were possible, 28.2% certain and 6.8% probable. As per Naranjo's scale most of the reports were possible (68.8%) followed by probable (29.7%). According to Hartwig severity scale majority of the reports were mild (95%) followed by moderate (4.5%). A system wise classification of ADRs showed that gastrointestinal system (20.7%) related reactions were the most frequently observed adverse reactions followed by respiratory system (18.4%) related adverse effects. From the reported ADRs, the drugs most commonly associated with ADRs were found to be enalapril (17.5%), atorvastatin (14.9%), aspirin (8.4%) and metoprolol (8.4%). CONCLUSION: The cardiovascular drug related adverse effects constituted 18.1% of the total ADRs reported during the study period. Cough, gastritis, fatigue and myalgia by enalapril, aspirin, ß-blockers and atorvastatin respectively were found to be the most commonly reported ADRs among the cardiovascular drugs.

Genotype, allele and haplotype frequencies of four TCL1A gene polymorphisms associated with musculoskeletal toxicity in the South Indian descent.

INTRODUCTION: Decline in circulating estrogen levels causes lessening of bone mass accompanied with musculoskeletal pain, which is the primary cause of treatment discontinuation in patients taking aromatase inhibitors. Evidence from recent genome-wide association studies (GWAS) suggests that the genetic variability underlying TCL1A gene increases the risk of aromatase inhibitors (AIs) - induced musculoskeletal toxicity. Currently, no data is available on the frequency distribution of TCL1A gene polymorphisms in Indians. METHODS: In this pilot study, we used TaqMan fluorescent probes to assess the genotypes of four TCL1A gene polymorphisms associated with musculoskeletal toxicity in 247 healthy homogenous South Indian subjects on real time thermocycler. Haplotype estimation and pairwise linkage disequilibrium (LD) analysis were executed by Haploview. RESULTS: The incidence of polymorphic variant allele (G) frequencies of rs7158782, rs7159713, rs2369049 and rs11849538 were 22.1%, 23.5%, 18.2% and 22.9% in the study population, respectively. The polymorphisms were found to be in complete LD with each other. Four different haplotypes, each of which having a frequency of above 1% were inferred in South Indians using an expectation-maximization algorithm. Notably, three haplotypes were found to be population specific viz H4 A-A-A-G (1.2%) for South India, H5 G-G-A-C (1.3%) for JPT and H6 G-G-G-C (40.4%) for YRI. Further, H3 G-G-A-G (2.3-16.3%) haplotype occurs primarily in Asians and is virtually absent in Africans. Overall, the genetic variability and haplotype profile of South Indian population revealed significant inter-racial variability compared with HapMap data. CONCLUSION: This documentation contributes for further investigations on the pharmacogenetics of AIs in South Indians.

Frequency distribution of DNA repair genes ERCC1 and ERCC2 polymorphisms in South Indian healthy population.

DNA repair genes are crucial in maintaining the integrity of the whole genome. Single nucleotide polymorphisms (SNPs) in DNA repair genes have been attributed to the development of various cancers. SNPs of DNA repair genes (ERCC1 and ERCC2) have been implicated in the causation of various cancers as well as inter-individual variability in the therapeutic outcomes of platinum based therapy. Thus establishing the frequency of these functional SNPs in the healthy population is of significance. The present study was aimed to establish the allele and genotype frequencies of ERCC1 (19007C>T, rs11615; 8092C>A, rs3212986) and ERCC2 (Asp312Asn, rs1799793) genes in South Indian healthy population and to compare the data from HapMap populations. The study population consisted of 128 healthy South Indian unrelated individuals of either sex aged between 18 and 60 years. Standard phenol-chloroform method was used to extract DNA from peripheral leukocytes. The genotype of DNA repair gene polymorphisms was determined by quantitative real-time polymerase chain reaction using TaqMan genotyping assay. The observed frequency of the studied polymorphisms followed Hardy-Weinberg equilibrium (p>0.05). The frequencies of the minor alleles of the SNPs rs11615 (T), rs3212986 (A) and rs1799793 (A) were 43.8%, 29.3% and 35.6%, respectively. Gender-based analysis showed no significant difference in the frequency pattern. The observed allele and genotype frequencies showed significant ethnic difference between South Indians and other HapMap populations. This is the first study to provide the normative frequency data of allele and genotype distribution of three SNPs of ERCC1 and ERCC2 in South Indian healthy population. It might be useful in future genotype-phenotype association studies, especially for predicting the efficacy and adverse events of platinum based drugs.