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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Allele and genotype distributions of DNA repair gene polymorphisms in South Indian healthy population.

Various DNA repair pathways protect the structural and chemical integrity of the human genome from environmental and endogenous threats. Polymorphisms of genes encoding the proteins involved in DNA repair have been found to be associated with cancer risk and chemotherapeutic response. In this study, we aim to establish the normative frequencies of DNA repair genes in South Indian healthy population and compare with HapMap populations. Genotyping was done on 128 healthy volunteers from South India, and the allele and genotype distributions were established. The minor allele frequency of Xeroderma pigmentosum group A (XPA) G23A, Excision repair cross-complementing 2 (ERCC2)/Xeroderma pigmentosum group D (XPD) Lys751Gln, Xeroderma pigmentosum group G (XPG) His46His, XPG Asp1104His, and X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphisms were 49.2%, 36.3%, 48.0%, 23.0%, and 34.0% respectively. Ethnic variations were observed in the frequency distribution of these polymorphisms between the South Indians and other HapMap populations. The present work forms the groundwork for cancer association studies and biomarker identification for treatment response and prognosis.

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.

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.

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.

Clinical trials in India: Where do we stand globally?

AIMS: To evaluate the trend of clinical trials in India over the last 4 years compared to the well-established countries using clinical trial registries since the advent of clinical trial registry of India (CTRI). MATERIALS AND METHODS: The data of clinical trials registered in India, United States (US), and European Union (EU) were obtained from websites of CTRI, clinicaltrial.gov and EU clinical trial registry, respectively from July 20, 2007 to August 29, 2011 for a period of 4 years. Trials registered in Australia, Canada, China, and Japan were obtained from WHO's international clinical trial registry platform for the same period. We used search words for the common diseases such as diabetes, hypertension, etc.. RESULTS: The total number of clinical trials registered during the study period was 67,448 across seven study nations. Clinical trials from India constituted only 2.7% of the total number of trials carried out, compared to US constituting 47% of the total number of trials registered, followed by 18% from EU and 11% from Japan. However, India, China, and Japan have been found to show an increase of 3.7%, 5.1%, and 13.1% increase in the number of trials registered in 2011 compared to 2007. In contrast, US and EU showed a decline of 11.3% and 11.95% respectively in the total number of trials registered in 2011 compared to 2007. CONCLUSIONS: Although India shows gradual increase in trials registered since the advent of CTRI, still it continues to lag behind established countries in clinical research.

Haplotype structures and functional polymorphic variants of the drug target enzyme aromatase (CYP19A1) in South Indian population.

CYP19A1 gene product aromatase (CYP19A1) is a 58-kDa protein and belongs to the member of the cytochrome P450 superfamily, which facilitates the bioconversion of estrogens from androgens. Single-nucleotide polymorphisms (SNPs) of CYP19A1 affect the activity of the enzyme and have been implicated in the association of estrogen-dependent disease, prognosis, therapeutic efficacy, and toxicity of third-generation aromatase inhibitors (AIs). Based on ethnicity, the frequency distribution of CYP19A1 alleles will differ, and until now, no data are available for Indians. Using qRT-PCR with TaqMan assays, the frequencies of functionally important polymorphic variants of CYP19A1 gene were determined in 163 healthy subjects of South Indian origin. The observed frequencies of the CYP19A1 minor alleles for the SNPs rs4646 (T), rs10046 (T), rs700519 (T), rs700518 (G), rs727479 (G), rs4775936 (T), rs10459592 (G), rs749292 (A), rs6493497 (T), and rs7176005 (A) are 41.1 (35.8-46.4), 20.0 (15.6-24.3), 33.7 (28.6-38.9), 17.8 (13.6-21.9), 25.8 (21.0-30.5), 19.9 (15.6-24.3), 33.7 (28.6-38.9), 24.9 (20.2-29.5), 35.9 (30.7-41.1), and 35.9 (30.7-41.1), respectively. Strong linkage disequilibrium existed between CYP19A1 SNPs, and sixteen different haplotype structures with a frequency >1% were derived from all the 10 SNPs tested. The most common being the haplotype (H1) GCTATCTGTG with a frequency of about 17.8%. Gender-specific assessment showed significant difference in the allele frequency for rs749292 (p < 0.04), and greater inter-ethnic variation was detected in the distribution of CYP19A1 variants except for rs727479. Our results could provide preliminary insight for further pharmacogenetic investigations of AIs as well as for subsequent molecular epidemiological studies on the contribution of these variants to the occurrence and development of estrogen-dependent disease in South Indians.

The dawn of hedgehog inhibitors: Vismodegib.

Cancer, one of the leading causes of death worldwide is estimated to increase to approximately 13.1 million by 2030. This has amplified the research in oncology towards the exploration of novel targets. Recently there has been lots of interest regarding the hedgehog (Hh) pathway, which plays a significant role in the development of organs and tissues during embryonic and postnatal periods. In a normal person, the Hh signaling pathway is under inhibition and gets activated upon the binding of Hh ligand to a transmembrane receptor called Patched (PTCH1) thus allowing the transmembrane protein, smoothened (SMO) to transfer signals through various proteins. One of the newer drugs namely vismodegib involves the inhibition of Hh pathway and has shown promising results in the treatment of advanced basal-cell carcinoma as well as medulloblastoma. It has been granted approval by US Food and Drug Administration's (US FDA) priority review program on January 30, 2012 for the treatment of advanced basal-cell carcinoma. The drug is also being evaluated in malignancies like medulloblastoma, pancreatic cancer, multiple myeloma, chondrosarcoma and prostate cancer. Moreover various Hh inhibitors namely LDE 225, saridegib, BMS 833923, LEQ 506, PF- 04449913 and TAK-441 are also undergoing phase I and II trials for different neoplasms. Hence this review will describe briefly the Hh pathway and the novel drug vismodegib.

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.