Association of ITPA 94C>A genetic polymorphisms with azathioprine induced adverse effects in the South Indian population.

OBJECTIVES: Azathioprine (AZA) is an effective immunosuppressant commonly used for malignancy and immune-mediated disorders. The association between genetic polymorphisms and AZA-induced adverse effects has not been elucidated. Hence this study aimed to evaluate the relationship between single nucleotide polymorphisms of ITPA (C94A) with azathioprine-induced adverse effects. METHODS: A cross-sectional study was performed on 120 patients who were on AZA therapy for immunobullous disorders and inflammatory bowel disease (IBD). Eligible patients were enrolled from outpatient Departments of dermatology and medical gastroenterology and five mL of blood was collected after obtaining written informed consent. DNA extraction and genotyping were done by phenol-chloroform method and real-time polymerase chain reaction (RT-PCR), respectively. RESULTS: The minor allele frequency of ITPA (A allele) was 30.8 %. The mutant genotypes of ITPA (C94A) were found to have no significant association with overall adverse effects in the South Indian patients on AZA therapy. CONCLUSIONS: We report no significant association between ITPA rs1127354 genetic polymorphism and adverse effects in the South Indian patients on AZA therapy.

Genetic polymorphisms of microsomal epoxide hydrolase and UDP-glucuronosyltransferase (UGT) and its effects on plasma carbamazepine levels and metabolic ratio in persons with epilepsy of South India: A cross-sectional genetic association study.

OBJECTIVES: Carbamazepine (CBZ), an anti-seizure drug, is widely prescribed for the management of focal seizures. At a given therapeutic dose, CBZ exhibits marked interindividual variation in the plasma CBZ levels. The aim wasto study the influence of EPHX1 c.337 T>C and UGT2B7*2 genetic polymorphisms on plasma carbamazepine (CBZ) levels in persons with epilepsy (PWE) from South India. METHODS: 115 PWE belong to South India origin who are on carbamazepine monotherapy were recruited. Genotyping of the two variants weredone using RT-PCR method. PWE who had seizure freedom for one year and their last dose which was not changed for one year duration were included and their plasma levels of CBZ and its active metabolite CBZ 10,11 epoxide were analysed by reverse phase HPLC. RESULTS: In EPHX1 c. 337 (T>C) polymorphism, the PWE carrying CC had lower plasma CBZ levels when compared to CT genotype (2.45 µg/ml vs 3.15 µg/ml. In UGT2B7*2, PWE carrying homozygous mutant TT had higher levels when compared with CT (3.09 µg/ml vs 2.74 µg/ml) genotype but found no statistical significance. Mutant genotype of EPHX1 (CC) had higher metabolic ratio compared to TT genotype (1.33 vs 1.17) but not found to be statistically significant. Mutant genotype of UGT2B7*2 (TT) was found to be having lower metabolic ratio when compared with CC genotype (1.18 vs 1.35; p value =0.08). CONCLUSION: PWE carrying EPHX1 c.337 T>C (rs1051740) and UGT2B7*2 (rs7439366) genetic polymorphisms did not affect the plasma CBZ levels and metabolic ratio of PWE of South Indian origin. However, this finding should be confirmed in a larger sample size which may help in optimization and personalized CBZ therapy in South Indians.

Impact of pharmacogenomics in achieving personalized/precision medicine in the clinical setting: a symposium report.

The Indo-Swiss symposium on pharmacogenomic strategies for the implementation of personalized medicine was conducted as part of the Jawaharlal Institute of Postgraduate Medical Education and Research Integrated Pharmacogenomics Program in Puducherry, India, on 19 November 2022. The symposium was conducted in hybrid mode. The theme of symposium was the impact of pharmacogenomics on the achievement of personalized medicine/precision medicine in the clinical setting. The symposium sought to promote interaction among the participants to initiate future collaborative research projects. The symposium also served as a platform for young researchers to present their research findings as posters to the audience.

Influence of EPHX1 c.337 T>C and UGT2B7*2 genetic polymorphisms on the requirement of carbamazepine maintenance dose in persons with epilepsy (PWE) of Southern part of India: a cross-sectional genetic association study.

OBJECTIVES: Carbamazepine (CBZ) is a first-line antiseizure drug used for focal onset seizures. It exhibits inter-individual variability in plasma carbamazepine levels and there are both genetic and non-genetic factors having a role in the requirement of CBZ maintenance dose. The aim was to study the influence of EPHX1 c.337 T>C and UGT2B7*2 genetic polymorphisms on CBZ maintenance dose requirement in persons with epilepsy. METHODS: Persons with epilepsy (PWE) of both gender of age 15-65 years on carbamazepine monotherapy who had been taking same maintenance dose for one year were eligible. Five milliliter of venous blood was collected in 10% EDTA under aseptic precautions. After centrifugation, the cellular component was used for DNA extraction and genotyping. For three genotypes of EPHX1 c.337 T>C and UGT2B7*2, the differences in mean carbamazepine dose were analyzed using Analysis of Variance (ANOVA). An unpaired t-test was used to draw a comparison between the genotypes and CBZ maintenance dose requirement for dominant and recessive models of EPHX1 c.337 T>C and UGT2B7*2. A value of p<0.05 was considered to be statistically significant. RESULTS: For UGT2B7*2 (rs 7439366), CT required a higher dose (CT 626 mg/day and TT 523 mg/day) but not found to be significant (p-value 0.167). PWE carrying CT genotype of EPHX1 c.337 T>C had 62 mg higher dose when compared to homozygous mutant CC (590 mg/day for CT and 528 mg/day for CC) but p-value was not found to be significant (p-value 0.835). CONCLUSIONS: The results of our study done in 115 PWE showed there was a lack of association between SNPs of EPHX1 c.337 T>C, UGT2B7*2 and CBZ maintenance dose requirement in Southern part of India and this finding has to be confirmed in a larger sample size.

Antibiotic-prescribing pattern in the outpatient departments using the WHO prescribing indicators and AWaRe assessment tool in a tertiary-care hospital in South India.

Context: Rational drug use has a great role of influence in health care. The fact sheet given by the World Health Organization (WHO) shows that around 50% of the drugs are prescribed, dispensed, and sold inappropriately. One of the major consequences of irrational drug use in infections is antibiotic resistance. Aim: The present study aims to assess the antibiotic-prescribing pattern by auditing the prescriptions in a teaching hospital. Settings and Design: A prospective cross-sectional study was conducted in the pharmacy of a teaching hospital to evaluate the prescriptions of the outpatient department. Materials and Methods: The prescriptions used to treat symptoms suggestive of infections were taken into consideration. A total of 1,000 prescriptions were analyzed. Data Analysis: The data was analysed using Microsoft Excel. Results: A total of 2,536 drugs were prescribed. The average number of drugs per prescription was 2.5. The percentage of encounters with antibiotics prescribed was 17.5%. The percentage of encounters prescribed with a generic name and with drugs from the essential drug list was 87.5% and 65%, respectively. There were no injections prescribed. Amoxicillin and ciprofloxacin were the most common antibiotics prescribed. The duration of the treatment was mentioned in all the prescriptions. Conclusions: Our study shows that the percentage of antibiotic usage is within the WHO standard value. The average number of drugs per prescription was slightly higher than the WHO value. Steps should be taken to improve the generic prescribing by the physicians.

Medicine Storage and Dispensing Facilities in Public Healthcare Pharmacies of Puducherry, India.

Background Large amounts of medicines are wasted during procurement, storage, distribution, and utilization. Proper procurement, storage, dispensing, and documentation of medicines are important aspects of pharmacy management. The World Health Organization (WHO) and the Indian Pharmaceutical Association (IPA) have developed guidelines for the storage and dispensing of medicines by pharmacists. This study was conducted to assess the storage and dispensing facilities of medicines in public healthcare pharmacies of Puducherry province in south India. Methodology A one-time survey was conducted in 10 public healthcare pharmacies by filling the checklist which was prepared based on the WHO and IPA guidelines. Results Facilities such as adequate surface area, storage area, reception area, and availability of water supply in dispensing area were available in 90% of surveyed pharmacies. The most common system used for the arrangement of medicines was alphabetical order (70%). In 80% of pharmacies, a sufficient number of shelves was available for storage of medicine, and in 90% of pharmacies, shelves were properly labeled. None of the pharmacies had separate storage facilities for expired medicines and narcotic drugs. Conclusions In Puducherry, pharmacy services are provided by qualified and experienced pharmacists. Although most of the surveyed pharmacies had all the required infrastructure and equipment facilities, few pharmacies need to improve their facilities to promote good drug-dispensing practices.

Assessment of medicine use based on WHO drug-use indicators in public health facilities of the South Indian Union Territory.

OBJECTIVE: To assess medicine use based on World Health Organization (WHO) core drug-use indicators in selected public health facilities of the South Indian Union Territory. METHODS: A prospective cross-sectional study was conducted for period of one year (from March 2019 to February 2020) in 10 selected public health facilities based on the WHO document How to investigate drug use in health facilities. Total 900 prescriptions were analysed to study prescribing, patient care and health facility indicators. The results were compared with the WHO standard measures. RESULTS: The overall average number of drugs per prescription was 3.2. Percentage of prescriptions with antibiotics and injections were found to be 36.6 and 11.4%, respectively. Percentage of drugs prescribed by generic name was 74.6%. Percentage of drugs prescribed from the National List of Essential Medicine was 93.3%. Average consultation and dispensing time were found to be 3.9 minutes and 49.3 seconds, respectively. The percentage of drugs dispensed in this study was 98.5 and 61.6% of medicines were properly labelled; 76.7% of patients had correct knowledge of each medicine dispensed to them. Mean availability of key essential medicine was 73.4%. CONCLUSION: Indicators such as percentage of drugs prescribed from the National List of Essential Medicine, availability of copy of essential medicine list and percentage of drugs dispensed were found to be as per WHO optimal value. Indicators such as average number of drugs per prescription, average consultation and dispensing time and percentage of medicines labelled were found below optimal value and need to be improved.

Availability of Key Essential Medicines in Public Health Facilities of South Indian Union Territory: One of the Crucial Components of Universal Health Coverage.

Introduction The supply of essential medicines is one of the vital components of primary health care. One of the important objectives of Indian health policy is to provide all the essential medicines at an affordable cost for the public. The performance of healthcare facilities is directly affected by the supply of essential medicines. This study was conducted to check the availability of key essential medicines in selected public healthcare facilities of the South Indian Union Territory. Methods A snapshot survey was conducted between March 2019 and February 2020 in 10 selected public health facilities to assess the availability of 50 key essential medicines. Percentage availability for all surveyed medicines for the individual facility as well as percentage availability of individual medicines in all surveyed health facilities was calculated. Results Percentage availability of 50 key essential medicines in 10 surveyed public health facilities was found in a range of 66 to 80%. Out of 50 medicines, 26 (52%) medicines were available in more than 80% of health facilities while six (12%) medicines were available in less than 30% of surveyed facilities. Conclusion This study reported the high availability of essential medicines in public health facilities as compared to similar studies done in other parts of India but the availability of some essential medicines was found sub-optimal and needs to be improved.

Frequency and risk factors of bleomycin-induced pulmonary toxicity in South Indian patients with germ-cell tumors.

AIM: Bleomycin, etoposide, and cisplatin (BEP) regimen is the standard treatment for germ-cell tumors (GCTs). Bleomycin-induced pulmonary toxicity (BPT) is fatal and dose-limiting toxicity associated with this regimen. In this study, we aimed to identify the frequency and risk factors of BPT in South Indian GCT patients receiving BEP regimen. PATIENTS AND METHODS: The study was carried out in the Department of Medical Oncology, Regional Cancer Centre at a tertiary care hospital in South India. All the patients with GCT (testicular and ovarian) who were receiving BEP regimen from December 2014 to May 2018 were included in the study. BPT was defined as the presence of radiological features and/or clinical symptoms during or post-treatment. RESULTS: BPT was observed in 11 (27%) patients of 41 analyzed patients. Five (12%) patients developed BPT during treatment whereas six (15%) patients developed BPT post-treatment. Cumulative bleomycin dose ≥240 mg (relative risk 3.8, confidence interval: 1.2-12.2,P =0.02) was found to increase the risk of BPT. Three-year overall survival in patients with and without toxicity was 82% and 93%, respectively. CONCLUSIONS: The frequency of BPT in the study population is 27%, and cumulative bleomycin dose ≥240 mg has been found to be associated with increased risk of developing BPT. BPT does not negatively impact survival outcome in GCT patients receiving BEP regimen.

Indo-Swiss symposium on advances in pharmacogenomic strategies for implementation of personalized medicine.

The Indo-Swiss symposium on advances in pharmacogenomic strategies for implementation of personalized medicine was conducted as a part of the JIPMER Integrated Pharmacogenomics Program (JIPP), held in Puducherry, India on 23 November 2019. The symposium focused on the growing contribution of pharmacogenomic information in designing treatment strategies and promoting better approaches to personalized medicine. The primary objective of this symposium was to bridge gaps in understanding the basics and recent advances in the field of pharmacogenomics. This symposium sought to promote interaction between the Indian and Swiss researchers to initiate future collaborative research projects. This symposium also served as a platform for young researchers to present their research findings as posters to the audience.

Variants in XPC, Noxa and TLR4 genes are not associated with bleomycin-induced lung injury in Hodgkin lymphoma patients.

Aim: Pulmonary toxicity is a well-known adverse reaction of bleomycin. In this study, we investigated the influence of XPC, PMAIP1/Noxa and TLR4 genetic variants on the development of bleomycin-induced lung injury (BILI) in south Indian patients with Hodgkin lymphoma. Materials & methods: Hodgkin lymphoma patients receiving adriamycin, bleomycin, vinblastine and dacarbazine regimen were recruited for the study and BILI was diagnosed based on symptoms and/or radiological signs. DNA samples were genotyped using real-time PCR. Results: A total of 78 patients were recruited in the study and BILI was observed in 17 (21.8%) patients. Polymorphisms in XPC, PMAIP1/Noxa and TLR4 genes were not associated with the development of BILI. Conclusion: The selected genetic polymorphisms do not predict the risk of BILI in south Indian population.

Influence of cytochrome P450 3A5 (CYP3A5) genetic polymorphism on dose-adjusted plasma levels of carbamazepine in epileptic patients in South Indian population.

AIM: The aim of the study was to compare the dose-adjusted plasma levels of carbamazepine (CBZ) among expressers and nonexpressers of cytochrome P450 3A5 (CYP3A5)* 3 genotypes. SUBJECTS AND METHODS: The study was carried out in 100 epileptic patients who were on CBZ monotherapy. Steady-state plasma CBZ levels were measured using reverse-phase high-performance liquid chromatography method, and genotyping of CYP3A5 was done using real-time polymerase chain reaction method. RESULTS: Patients inheriting CYP3A5*3/*3 variant (nonexpressers) had an increased plasma concentration of CBZ (4.86 µg/ml) when compared to patients inheriting either CYP3A5*1/*1 or CYP3A5*1/*3 (expressers) (4.3 µg/ml, P = 0.004). Nonexpressers had significantly increased plasma concentrations of CBZ when adjusted for dose and weight when compared to expressers (P < 0.002 and P < 0.001, respectively). The frequency of adverse reactions in expressers and nonexpressers was 12% and 9%, respectively. CONCLUSION: There is a significant influence of CYP3A5*3 genetic polymorphism (6986A>G) on dose-adjusted plasma levels of CBZ in epileptic patients in the South Indian population.

Influence of CYP2C9 genetic polymorphism and undernourishment on plasma-free phenytoin concentrations in epileptic patients.

The objective of this study was to study the effect of CYP2C9 genetic polymorphism and undernourishment on free phenytoin concentrations in epileptic patients. The study was done in 70 patients who were taking phenytoin therapy for the treatment of epileptic seizures. Genotyping of CYP2C9 (*2 and *3) was determined by the polymerase chain reaction-restriction fragment length polymorphism method. Bound and free plasma phenytoin was separated using equilibrium dialysis technique. Total and free phenytoin concentrations were measured by the reverse-phase high-performance liquid chromatography method. Patients were broadly classified into well-nourished and undernourished and further subclassified by CYP2C9 genotypes. In well-nourished groups (G1 to G3 group), free phenytoin concentrations were significantly higher in the heterozygous poor metabolizer of CYP2C9 genotype (G2) group (3.1 ± 0.62 µg/mL) and homozygous poor metabolizer of CYP2C9 genotype (G3) group (4.3 ± 1.76 µg/mL) when compared with patients with the wild-type CYP2C9 (G1) group (1.1 ± 0.72 µg/mL). Similarly, in undernourished patient groups (G4-G6 group), free phenytoin concentrations were significantly higher in the wild-type CYP2C9 (G4) group (2.5 ± 0.52 µg/mL), heterozygous poor metabolizer of CYP2C9 genotype (G5) group (4.3 ± 1.76 µg/mL), and homozygous poor metabolizer of CYP2C9 genotype (G6) group (8.2 ± 1.08 µg/mL) when compared with well-nourished patients with the wild-type CYP2C9 (G1) group (1.1 ± 0.72 µg/mL). The percentage increase in free phenytoin concentration by undernourishment, CYP2C9 allelic variants, and undernourishment cum CYP2C9 allelic variants were 127%, 290%, and 472%, respectively, compared with well-nourished patients with the wild-type CYP2C9 genotype (G1) group. The contribution of undernourishment and genetic factors (CYP2C9 allelic variant) for developing phenytoin toxicity was calculated to have an odds ratio of 37.3 (P < 0.0001). Undernourishment and variant CYP2C9 alleles elevate free phenytoin concentrations individually and in combination show additive effects.

Severe phenytoin toxicity in a CYP2C9*3*3 homozygous mutant from India.

The authors report an Indian adult female patient with a history of generalized tonic clonic seizures who developed severe features of phenytoin (DPH) toxicity on therapeutic dosage of this antiepileptic drug. Administration of 300 mg/day of DPH in this patient resulted in toxic symptoms associated with an excessive serum DPH concentration of 33 microg/ml. The PCR-RFLP analysis revealed a homozygosity involving CYP2C9*3*3. This mutation results in a marked decrease in the enzymatic activity (CYP2C9) and leads to a decreased clearance of the drug which can lead to severe acute and chronic toxicity. On switching the antiepileptic therapy from DPH to sodium valproate, there was reversal of both.

Allele and genotype frequency of MDR1 C3435T in Tamilian population.

The allele and genotype frequencies of MDR1 C3435T polymorphism were determined in 185 unrelated healthy Tamilians. The genomic DNA was extracted from peripheral leucocytes using phenol chloroform method and genotyped by PCR-RFLP method. The frequencies of MDR1 C3435 and T3435 alleles in Tamilian population were 0.46 and 0.54 respectively. The distribution of T3435 in this population was found to be greater than Africans and almost similar to Caucasians and Orientals. The distribution of CC, CT and TT genotypes was 0.18, 0.56 and 0.26 respectively. The frequency distribution of the CC genotype was lower in them when compared with Chinese and Africans whereas CT genotype was higher in comparison with all the major ethnic groups.