Computational identification and analysis of deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) in the human POR gene: a structural and functional impact.

Cytochrome P450 oxidoreductase (POR) protein is essential for steroidogenesis, and POR gene mutations are frequently associated with P450 Oxidoreductase Deficiency (PORD), a disorder of hormone production. To our knowledge, no previous attempt has been made to identify and analyze the deleterious/pathogenic non-synonymous single nucleotide polymorphisms (nsSNPs) in the human POR gene through an extensive computational approach. Computational algorithms and tools were employed to identify, characterize, and validate the pathogenic SNPs associated with certain diseases. To begin with, all the high-confidence SNPs were collected, and their structural and functional impacts on the protein structures were explored. The results of various in silico analyses affirm that the A287P and R457H variants of POR could destabilize the interactions between the amino acids and the hydrogen bond networks, resulting in functional deviations of POR. The literature study further confirms that the pathogenic mutations (A287P and R457H) are associated with the onset of PORD. Molecular dynamics simulations (MDS) and essential dynamics (ED) studies characterized the structural consequences of prioritized deleterious mutations, representing the structural destabilization that might disrupt POR biological function. The identified deleterious mutations at the cofactor's binding domains might interfere with the essential interactions between the protein and cofactors, thus inhibiting POR catalytic activity. The consolidated insights from the computational analyses can be used to predict potential deleterious mutants and understand the disease's pathological basis and the molecular mechanism of drug metabolism for the application of personalized medication. HIGHLIGHTSNADPH cytochrome P450 oxidoreductase (POR) mutations are associated with a broad spectrum of human diseasesIdentified and analyzed the most deleterious nsSNPs of POR through the sequence and structure-based prediction toolsInvestigated the structural and functional impacts of the most significant mutations (A287P and R457H) associated with PORDMolecular dynamics and PCA-based FEL analysis were utilized to probe the mutation-induced structural alterations in PORCommunicated by Ramaswamy H. Sarma.

Prothrombotic Factors Have Significant Association with Arterial and Venous Strokes in Indian Tamilians.

BACKGROUND: Prothrombotic factors have been correlated with vascular events in young patients, with recurrent strokes, and with venous thromboembolisms. However, their prevalence in adult strokes, in healthy populations, and in specific ethnic groups is not well defined. We investigated the association of prothrombotic factors with strokes in a South Indian Tamil population. METHODS: In this hospital-based cross-sectional study, plasma homocysteine (Hcys), protein C and protein S activity levels, activated protein C resistance (APCR) as a surrogate for factor V Leiden (FVL), fibrinogen, and antithrombin III (ATIII) were determined from 75 consecutive patients with ischemic stroke (IS), 25 with cortical venous thrombosis (CVT), and 75 healthy control participants. The Student t test or Mann-Whitney U test was used for comparing prothrombotic factor levels between the stroke and control groups. The χ2 or Fisher exact test was used for comparisons of proportions of thrombophilia and estimation of odds ratios. Mid-P correction was done for multiple estimations. RESULTS: Hcys levels in patients with IS were significantly higher compared with those in healthy control participants (P = 0.02). Proportions of ATIII deficiency and hyperfibrinogenemia were significantly higher in the IS group, and no healthy control participants had hyperfibrinogenemia. Protein C deficiency was more frequent in those with IS (17%; P < 8 × 10-5) and CVT (P < 10-7) compared with healthy control participants, and protein C activity levels (P = 0.016) were also significantly lower in patients with CVT. Other parameters had no significant associations with IS and CVT. The frequency of protein S deficiency was high in healthy control participants (60%) and in both patients with IS (45%; P = 0.1) and patients with CVT (48%; P = 0.4). No patients or control participants had abnormal APCR. CONCLUSIONS: In Tamilian participants, several prothrombotic factors were associated with IS. Protein C deficiency alone was associated with CVT. Replication of the pattern in genetically linked populations around the world may affect management of stroke in those populations.

Insight into the structural and functional analysis of the impact of missense mutation on cytochrome P450 oxidoreductase.

Cytochrome P450 oxidoreductase (POR) is a steroidogenic and drug-metabolizing enzyme. It helps in the NADPH dependent transfer of electrons to cytochrome P450 (CYP) enzymes for their biological activity. In this study, we employed integrative computational approaches to decipher the impact of proline to leucine missense mutation at position 384 (P384L) in the connecting/hinge domain region which is essential for the catalytic activity of POR. Analysis of protein stability using DUET, MUpro, CUPSAT, I-Mutant2.0, iStable and SAAFEC servers predicted that mutation might alter the structural stability of POR. The significant conformational changes induced by the mutation to the POR structure were analyzed by long-range molecular dynamics simulation. The results revealed that missense mutation decreased the conformational stability of POR as compared to wild type (WT). The PCA based FEL analysis described the mutant-specific conformational alterations and dominant motions essential for the biological activity of POR. The LIGPLOT interaction analysis showed the different binding architecture of FMN, FAD, and NADPH as a result of mutation. The increased number of hydrogen bonds in the FEL conformation of WT proved the strong binding of cofactors in the binding pocket as compared to the mutant. The porcupine plot analysis associated with cross-correlation analysis depicted the high-intensity flexible motion exhibited by functionally important FAD and NADPH binding domain regions. The computational findings unravel the impact of mutation at the structural level, which could be helpful in understanding the molecular mechanism of drug metabolism.

Effects of genetic polymorphisms in Vitamin D metabolic pathway on Vitamin D level and asthma control in South Indian patients with bronchial asthma.

OBJECTIVES: The study was designed to evaluate the single-nucleotide polymorphisms (SNPs) of genes involved in Vitamin D actions (rs2228570) and metabolic pathways (rs2248137 and rs10766197) and their associations with serum 25-hydroxy Vitamin D (25(OH)D) level and asthma control in South Indian patients with bronchial asthma. MATERIALS AND METHODS: One hundred and two patients of South Indian origin with bronchial asthma either naive to inhaled corticosteroids (ICSs) or not receiving ICS for ≥1 month were included and were treated with ICS (beclomethasone 200 µg twice daily) for 8 weeks. One hundred and one unrelated healthy South Indians were used as controls. Pulmonary function test and fractional exhaled nitric oxide were used to assess asthma control. Serum 25(OH)D levels (chemiluminescence immunoassay) and SNPs in Vitamin D pathway (real-time polymerase chain reaction) were assessed. The associations of SNPs and serum 25(OH)D with asthma control was determined using linear regression. All analyses were performed using SPSS (version 19) and "SNPStats." P < 0.05 was considered as statistically significant. RESULTS: Vitamin D receptor (VDR) polymorphism (rs2228570) was found to be protective against asthma (P = 0.022), while there were no significant associations between the other two SNPs and asthma. Similarly, poor correlation and insignificant associations between the SNPs and serum 25(OH)D levels were observed in both cases and controls. There were also insignificant associations between the SNPs and asthma control. CONCLUSION: VDR polymorphism (rs2228570) was found to be protective against asthma in South Indians, while other genes involved in the metabolic pathway of Vitamin D did not show associations with asthma.

Vascular endothelial growth factor (VEGF) gene polymorphisms (rs699947, rs833061, and rs2010963) and psoriatic risk in South Indian Tamils.

BACKGROUND: Psoriasis is a chronic inflammatory disease of the skin. Vascular endothelial growth factor (VEGF), a pro-angiogenic factor, is involved in the pathogenesis of psoriasis. Being highly polymorphic, several SNPs of VEGF have been reported to be associated with increased risk of psoriasis. OBJECTIVES: We determined the association of VEGF gene polymorphisms with risk of psoriasis in South Indian Tamils. METHODS: 300 cases of psoriasis and 300 controls were recruited in this case-control study. Genotyping of SNPs of VEGF gene was done using Taqman 5' allele discrimination assay. Estimation of VEGF levels in plasma was done by ELISA. RESULTS: VEGF (rs2010963) polymorphism and the CTC haplotype were found to confer an increased risk of psoriasis. However, two other VEGF SNPs, rs833061, and rs699947, showed no association with psoriasis susceptibility. VEGF levels were higher in patients with psoriasis, as compared with controls and significantly correlated with disease severity. CONCLUSIONS: Our results indicate that VEGF (rs2010963) polymorphism and CTC haplotype of the VEGF SNPs (rs699947, rs833061, and rs2010963) confer an increased risk of psoriasis in the South Indian Tamil population. Plasma VEGF levels are higher in patients with psoriasis, as compared with controls and are significantly correlated with disease severity.

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.

Association of C-Reactive Protein (rs1205) Gene Polymorphism with Susceptibility to Psoriasis in South Indian Tamils.

INTRODUCTION: Psoriasis is a multi-factorial heritable T-helper Th-1/Th-17 mediated inflammatory disease, affecting the skin. It is associated with co-morbidities such as Cardiovascular Disease (CVD). C-Reactive Protein (CRP) is a good inflammatory marker. CRP rs1205 polymorphism is associated with circulating plasma CRP levels. Although there is association between the rs1205 Single Nucleotide Polymorphism (SNP) and CVD, there are no prior reports regarding the association of CRP rs1205 SNP with psoriasis susceptibility. AIM: To study the association of the genetic variant rs1205 in the CRP gene with susceptibility to the disease and protein levels in South Indian Tamils with psoriasis. MATERIALS AND METHODS: In this case-control genetic study, 300 cases of psoriasis and 300 age and gender matched controls were genotyped for CRP SNP rs1205 using Taq Man 5'allele discrimination assay at Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India from February 2014 to January 2016. Plasma high sensitivity (hs)-CRP levels were estimated by ELISA. Disease severity was assessed by Psoriasis Area Severity Index (PASI). RESULTS: CRP genetic variation rs1205 was not associated with psoriasis risk in our South Indian Tamil population. However, the circulating levels of hs-CRP was significantly higher in patients with psoriasis, as compared with controls (p < 0.0001) and the protein levels were significantly associated with disease severity, as assessed by PASI scoring. No genotype was found significantly associated with PASI or CRP levels. CONCLUSION: Our results suggest that plasma CRP levels are higher in patients with psoriasis and correlate with disease severity, whilst CRP rs1205 is not associated with susceptibility to psoriasis in South Indian Tamils.

Role of CYP2C19 gene polymorphism in acute alcohol withdrawal treatment with loading dose of diazepam in a South Indian population.

PURPOSE: Alcohol dependence is a public health problem worldwide, commonly associated with withdrawal symptoms for which diazepam is a frequently used drug. We studied the effect of CYP2C19 gene polymorphisms on diazepam loading dose requirement and time to reversal of acute alcohol withdrawal symptoms. We also studied the influence of the polymorphism in this gene on the persistent symptoms after loading dose of diazepam. METHODS: Sixty-nine patients who reported to the psychiatry department with symptoms of alcohol withdrawal diagnosed by DSM-IV criteria were included for the study. A 10-mg loading dose of diazepam was administered iv after baseline assessment of withdrawal severity using CIWA-Ar scoring. The patients were assessed for improvement of the symptoms every two hourly and 20 mg oral diazepam was given based on improvement of symptoms. Genotyping for CYP2C19*2, CYP2C19*3 and CYP2C19*17 was done by PCR-RFLP and RT-PCR methods. RESULTS: The diazepam dose requirement as well as the time required for reversal of acute symptoms was not statistically different among the different genotype groups. Similarly, the frequency of patients with persistent symptoms after successful treatment of the acute episode was not different among the groups. However, the total diazepam dose requirement was influenced by baseline CIWA-Ar scores (adjusted OR 0.21, p = 0.026). In addition, the odds of treatment with a lower dose (10 mg) of diazepam were higher in smokers (adjusted OR 5.22, p = 0.025) and patients with other addiction (adjusted OR 9.26, p = 0.026). CONCLUSION: We found that CYP2C19 polymorphism did not have any significant effect on the diazepam dose requirement, time duration needed for successful treatment or on the persistent symptoms after loading dose of diazepam in South Indian population. However, diazepam dose requirement was influenced by baseline CIWA-Ar score, smoking status and other comorbid addictions.

Relation between serum prolactin levels and antipsychotic response to risperidone in patients with schizophrenia.

BACKGROUND: Hyperprolactinemia is commonly seen in patients with schizophrenia on risperidone. Dopamine receptor blockade plays a major role in risperidone induced hyperprolactinemia. However, limited studies are available with inconsistent results on antipsychotic response to risperidone and prolactin elevation. Therefore, we aimed to study the change in serum prolactin levels and response to risperidone and to test the association between DRD2 genetic variants and prolactin levels in schizophrenic patients treated with risperidone. METHODS: A prospective study comprising of 102 patients with schizophrenia were recruited. Prolactin levels and Positive and Negative Syndrome Scale (PANSS) score were recorded at baseline and after four weeks of risperidone treatment. Prolactin concentrations were measured by standard method Advia-Centaur® Chemiluminescence immuno assay method. Taq1A DRD2 genotyping was performed by qRT-PCR. RESULTS: The mean±SD prolactin levels (ng/ml) were increased after four weeks of treatment in both responders (males 21.66±15.15 to 41.63±18.73; p<0.01 females 51.92±40.89 to 122.35±52.16; p<0.01) and non-responders group (males 23.89±14.85 to 37.45±13.5; p<0.01 females 39.25±26.94 to 91.13±54.31; p<0.01). Patients with increased prolactin concentration were 4.6 fold higher in responders (OR 4.60; 95%CI 1.376-15.389; p-value 0.01) compared to non-responders. Ninety-six patients were genotyped for Taq1A DRD2 gene (AA=9, AG=46, GG=41) and found no association (p=0.6) between genetic variants and response to risperidone. CONCLUSION: Patients were showing more than 20% increase in prolactin levels had a better chance of responding to risperidone therapy. Taq1A DRD2 gene did not show any association with prolactin elevation and response to risperidone.

Clinical Utility of Fractional exhaled Nitric Oxide (FeNO) as a Biomarker to Predict Severity of Disease and Response to Inhaled Corticosteroid (ICS) in Asthma Patients.

INTRODUCTION: Bronchial asthma is a common chronic inflammatory airway disease diagnosed and is based on symptomatic history and Pulmonary Function Tests (PFT). Fractional exhaled Nitric Oxide (FeNO) is exclusively a non-invasive biomarker of on-going eosinophilic airway inflammation which remains unpredictable only with PFTs. FeNO measurement is recommended in predicting asthma severity and Inhaled Corticosteroid (ICS) response but further research is required to understand its clinical utility and agreement with current recommendations in a specific population. AIM: To estimate FeNO levels in Tamilian patients with mild-to-moderate persistent asthma and to correlate with disease severity and ICS response. MATERIALS AND METHODS: The study was a prospective cohort with a single group of 102 persistent asthma patients under standard ICS regimen for 8 weeks (follow-up period). PFT and FeNO were measured using portable spirometry and chemiluminescence based exhaled breath analyser, at baseline and during follow-up visits. Based on PFT and FeNO parameters, the study population was sub-grouped with respect to asthma severity (as mild, moderate and moderately severe), FeNO cut-off (> or < 50ppb) and ICS response classification (good vs poor ICS responders). RESULTS: Significant decrease in mean FeNO levels were found in mild, moderate and moderately severe asthmatic groups following ICS treatment (90.15±27.36, 75.74±31.98 and 77.18±32.79 ppb) compared to similar baseline FeNO levels (103.03±34.08, 91.38±37.60 and 97.90±43.84 ppb) in all the above groups. Similarly, significant decrease in mean FeNO levels was found - FeNO>50ppb, good and poor ICS responders groups, in post- ICS treatment (89.63±24.04, 77.90±31.12 and 86.49±32.57 ppb) compared to baseline levels (110.183±1.23, 97.12±42.04 and 99.68±34.71 ppb). CONCLUSION: The observed baseline FeNO values in all groups as stated above did not show significant difference to differentiate asthma severity or ICS responders groups. The present study results do not support the predictive association of baseline FeNO levels with asthma severity and future ICS response, but the decrements in FeNO levels on ICS treatment, supports its clinical utility in monitoring of ongoing airway inflammation and understanding treatment response rate.

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.

A study to explore the correlation of ABCB1, ABCG2, OCT1 genetic polymorphisms and trough level concentration with imatinib mesylate-induced thrombocytopenia in chronic myeloid leukemia patients.

PURPOSE: Imatinib mesylate is presently the first-line treatment for chronic myeloid leukemia (CML). Therapeutic drug monitoring (TDM) and pharmacogenetic screening is warranted for better management of imatinib therapy. The present study was framed to explore the influence of common drug transporter gene polymorphisms of ABCB1, ABCG2, OCT1 and trough level concentration on commonly occurring adverse events in CML patients treated with imatinib mesylate. METHODS: A total number of 111 patients in chronic phase (Philadelphia chromosome +ve) were included in the study. The plasma drug concentration of imatinib was estimated using LC-MS/MS method. RESULTS: The mean ± SD trough level concentration of imatinib mesylate was found to be 1430.7 ± 438.7 ng/ml. The trough level concentration at steady state (Cmin.ss) was significantly higher in patients with grade 2-4 thrombocytopenia compared with patients without the adverse event (P value 0.033). CONCLUSION: The drug level of imatinib in plasma correlates with the severity of thrombocytopenia, which adds to the utility of TDM in the management of CML patients.

Influence of Sokal, Hasford, EUTOS scores and pharmacogenetic factors on the complete cytogenetic response at 1 year in chronic myeloid leukemia patients treated with imatinib.

Imatinib mesylate is currently considered the first-line treatment for chronic myeloid leukemia (CML). Sokal, Hasford and EUTOS are the three major risk categorization scores available for CML patients. The present study aimed to explore the influence of three risk score, genetic polymorphisms of ABCB1, OCT1, ABCG2 and trough level concentration on complete cytogenetic response at 1 year and overall survival. The mean time period of follow-up was 53.05 months, and the overall survival was 94.6%. The Sokal score (P 0.014), Hasford score (P 0.016) and MDR1 C3435T (P 0.001) tend to influence the overall survival in the patients. The patients who had better overall survival had early complete cytogenetic response (P 0.0003). The ABCG2 C421A was the covariate which had correlation with the complete cytogenetic response. A perceptive approach incorporating pharmacogenetic evaluation with major risk categorization score at the initial stage will help in ensuring better treatment success in CML patients treated with imatinib.

Prehypertension status, cardiometabolic risks, and decreased baroreflex sensitivity are linked to sympathovagal imbalance in salt-preferring individuals.

Salt preference has been reported to cause sympathovagal imbalance (SVI) and prehypertension. We investigated the role of inflammation, insulin resistance (IR), hyperlipidemia, and oxidative stress (OS) in genesis of SVI and cardiovascular (CV) risks in salt-preferring prehypertensives. The subjects were divided into no-salt-preferring (NSP, n = 87) and salt-preferring (SP, n = 89) group based on their preference for salted food. Body mass index (BMI), blood pressure (BP) variability parameters including baroreflex sensitivity (BRS), heart rate variability (HRV) indices, autonomic function tests, IR, lipid risk factors, inflammatory and OS markers, and renin were measured in both the groups. Based on the contribution of various cardiometabolic risks to low-frequency-high-frequency (LF-HF) ratio of HRV, the marker of SVI was assessed by multiple-regression analysis. Prediction of prehypertension status by the LF-HF ratio was assessed by bivariate logistic regression. BMI, heart rate, BP parameters, cardiac output, total peripheral resistance, LF-HF ratio, IR, atherogenic index, inflammatory, and OS markers were significantly increased, and BRS was significantly decreased in the SP group compared with the NSP group. There was an independent association of IR, atherogenic index, markers of inflammation and OS, and BRS with the LF-HF ratio in SP subjects, and the LF-HF ratio had significant prediction of prehypertension status in these subjects. It was concluded that IR, low-grade inflammation, atherogenic lipid profile, and OS contribute to SVI in SP subjects. Decreased BRS (the marker of CV risk) is linked to SVI, and SVI predicts prehypertension status in SP subjects.

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.

Adverse drug reactions of imatinib in patients with chronic myeloid leukemia: A single-center surveillance study.

OBJECTIVE: To monitor the adverse drug reactions (ADRs) associated with imatinib treatment in patients with chronic myeloid leukemia (CML) in a tertiary care hospital. MATERIALS AND METHODS: The study was carried out by the Departments of Pharmacology and Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India. The study was carried out from March 2012 to February 2014. The ADRs were reported in a suspected Adverse Drug Reaction Reporting form, provided by the Central Drugs Standard Control Organization (CDSCO), Ministry of Health and Family Welfare, Government of India. The ADRs were analyzed for their pattern, causality and severity. RESULTS: A total of 326 ADRs from 81 patients were reported during the study period. The hematological toxicities were much more prominent than the non-hematological toxicities in this study. The prevalence of thrombocytopenia (21.17%) was higher compared with other reactions. Further analysis showed that most of the ADRs were mild to moderate in nature. The causality assessment revealed that the majority of the ADRs belonged to the possible category. CONCLUSION: The present study in a tertiary care hospital suggests that hematological toxicities are predominant in CML patients treated with imatinib mesylate. The blood and lymphatic system (38.96%) was the most affected, with imatinib therapy and thrombocytopenia (21.17%) being the most commonly encountered ADRs in the present study. Thorough monitoring of ADRs is warranted for better treatment outcomes.

Anticancer drug induced palmar plantar erythrodysesthesia.

BACKGROUND: Palmar plantar erythrodysesthesia (PPE) is a dose limiting toxicity of anticancer agents. In some cases it may mandate for discontinuation of anticancer agents. Evaluation of data of PPE among reported adverse drug reactions (ADRs) from the Department of Medical Oncology could quantify the burden. AIM: To evaluate and analyse the PPE among reported ADRs from medical Oncology. MATERIALS AND METHODS: The data of all cases of reported PPE were collected during January 2012 to September 2013 and were analysed with WHO causality assessment scale. The severity was clinically graded. The follow-up data regarding outcome of ADRs were also noted. RESULTS: During the study period of 21 months a total of 1418 ADRs have been reported from 1076 patients. Among them PPE was reported from 31 cases (2.9%). Majority (32.2%) of these patients were on chemotherapy for breast cancer. Patient's age ranged from 17 to 68 y and the median age was 50 y. There were 18 female (58%) and 13 male patients (42%). Capecitabine was the leading drug involved in PPE, reported with 20 cases (64.5%), and followed by docetaxel with 5 cases (16.1%). Majority (67.7%) of the reactions was categorized as certain and 64.5% was grade II severity clinically. CONCLUSION: Our findings show that PPE accounts for 2.9% of total reported ADRs from Medical Oncology during 21 months. Majority of the reactions were classified as certain. Capecitabine is commonly implicated drug.

Allele and genotype frequency of a genetic variant in ataxia telangiectasia mutated gene affecting glycemic response to metformin in South Indian population.

UNLABELLED: Allele and genotype frequency of a genetic variant in ATM gene affecting glycemic response to metformin in South Indian population. CONTEXT: The novel polymorphism in ATM gene (rs11212617), which is implicated to have association with metformin response, exhibits inter-ethnic variability in the allele and genotype frequency distribution. AIMS AND DESIGN: The objective of the present study is to establish the allele and genotype frequency of rs11212617 single nucleotide polymorphism in ATM gene, in South Indian population and to find if this variant has any role in the etiology of type 2 diabetes mellitus. MATERIALS AND METHODS: The study was performed in 2 cohorts of populations, 112 healthy volunteers and 118 type 2 diabetes mellitus patients. Genomic deoxyribonucleic acid (DNA) was extracted from peripheral blood leucocytes by phenol-chloroform method and genotyping was performed by real-time polymerase chain reaction using TaqMan assay. RESULTS: In South Indian population, the frequency of major A allele was 0.65 and the minor C allele was 0.35. AA and CC are the homozygous genotypes with frequency of 0.39 and 0.09 respectively. The frequency of heterozygous genotype AC (0.52) was found to be higher than the homozygotes. There was no significant difference in the frequency distribution in the diabetic population, which implies that this variant does not have any causative role in the disease etiology. The frequency distributions were found to be significantly different from the distributions in other ethnic populations such as Caucasians, Chinese, Japanese and Africans. But there was no significant difference when compared with the Gujarati Indians of Houston. CONCLUSION: The frequency distribution of this novel variant in South Indian population forms a framework for further gene disease association studies to establish the association of this variant with metformin response. Our study could not find any association of this variant with respect to the disease etiology.

Oyster shell calcium induced parotid swelling.

A 59 year old female consumer was started on therapy with oyster shell calcium in combination with vitamin D3 and she presented with swelling below the ear, after two doses. She stopped the drug by herself and the swelling disappeared in one day. She started the drug one day after recovery and again she developed the swelling. She was advised to stop the drug with a suggestion to take lemon to enhance parotid secretion and the swelling subsided. Calcium plays major role in salivary secretion and studies have shown reduced parotid secretion in rats, deficient of vitamin D. But in humans involvement of calcium and vitamin D3 in parotid secretion is unknown. However, the patient had no history of reaction though she had previously taken vitamin D3 with calcium carbonate which was not from oyster shell. Hence, we ruled out vitamin D3 in this reaction and suspecting oyster shell calcium as a culprit. This adverse drug reaction (ADR) was assessed using World Health Organization (WHO) causality assessment, Naranjo's and Hartwig severity scales. As per WHO causality assessment scale, the ADR was classified as "certain". This reaction was analyzed as per Naranjo's algorithm and was classified as probable. According to Hartwig's severity scale the reaction was rated as mild. Our case is an example of a mild but rare adverse effect of oyster shell calcium carbonate which is widely used.

Effect of eNOS polymorphisms on salbutamol evoked endothelium dependent vasodilation in South Indian healthy subjects.

BACKGROUND: The model of pulse plethysmograph using inhalational salbutamol 400 mcg is studied well to assess endothelium dependent vasodilation. Endothelial nitric oxide synthase (eNOS) gene polymorphism may influence the response to salbutamol in healthy subjects. AIM: To find the effect of polymorphisms 894G>T and -786T>C of eNOS gene on endothelium dependent vasodilation in healthy subjects. MATERIALS AND METHODS: One hundred and two south Indian healthy subjects of either sex, aged between 18 to 35 years were recruited for the study. The digital volume pulse (DVP)was measured by pulse plethysmograph before and after salbutamol 400mcg inhalation. Three predose and five postdose recordings of DVP were measured. The average change in the DVP parameters namely reflection index (RI) and stiffness index (SI) were determined. The eNOS894G>T and -786T>C gene polymorphism were genotyped using polymerase chain reaction followed by restriction fragment length polymorphism. The percentage changes in RI and SI from predose baseline recordings were calculated and compared between the genotype groups. RESULTS: The genotype and allele frequency of study subjects were in Hardy-Weinberg equilibrium. The changes in DVP parameters were not significantly different between the genotype groups. CONCLUSION: eNOS polymorphism do not affect salbutamol evoked endothelium dependent vasodilation in the model of pulse plethysmograph in healthy subjects.