Pharmacogenetics of opioids: a narrative review.

Advances in the field of pharmacogenomics have resulted in the discovery of some important single-nucleotide polymorphisms which are found to be associated with opioid dose variability. This, to a large extent, explains genetic variability in the analgesic dose of opioids. These polymorphisms are found in various areas relevant to pain perception, including the nociceptive and antinociceptive pathways, drug receptors, drug-metabolising enzymes and drug efflux molecules. An in-depth knowledge of single-nucleotide polymorphisms can help clinicians to address interindividual variability in opioid dosing and requirements. In the era of precision medicine, these genetic markers can also help us to design prognostic tools to accurately predict the analgesic dose of opioids.

Genetic polymorphisms of drug-metabolizing phase I enzymes CYP2E1, CYP2A6 and CYP3A5 in South Indian population.

CYP2E1, CYP2A6 and CYP3A5 enzymes belong to phase I group of drug-metabolizing enzymes, which are involved in the metabolism of various compounds and xenobiotics. Presence of polymorphisms in the genes coding for these enzymes results in interindividual variations in drug metabolism, therapeutic response and susceptibility towards various diseases. The frequencies of these variants in genes differ considerably between ethnic groups. This study was carried out to estimate the allele and genotype frequencies of common variants in CYP2E1, CYP2A6 and CYP3A5 in South Indian population. Six hundred and fifty-two unrelated healthy volunteers of South Indian origin (Andhra Pradesh, Karnataka, Kerala and Tamil Nadu) were included in this study. Polymerase chain reaction-restriction fragment length polymorphism, allele-specific PCR, real-time PCR, SNaPshot and gene sequencing methods were used for the identification of gene polymorphisms. The frequencies of CYP2E1*1B, CYP2E1*5B and CYP2E1*6 alleles in South Indian population were 14.3, 1.3 and 22.4%, respectively. The frequencies of CYP2A6*2, CYP2A6*4A and CYP2A6*5 alleles were found to be 1, 8.9 and 0.7%, respectively. The distribution of CYP3A5*3 allele was 63.5%. There were no variant alleles of CYP3A5*2, CYP3A5*4 and CYP3A5*6 in South Indian population. The frequencies of CYP2E1, CYP2A6 and CYP3A5 in the South Indian population are distinct from Caucasians, Chinese, Japanese, African Americans and other compared populations. This is the first study conducted in the South Indian population with a larger sample size. The findings of our study provide the basic genetic information for further pharmacogenomic investigations in the population.

A study of adverse drug reactions in pediatric patients.

AIM: To study the adverse drug reaction (ADR) pattern in a pediatric population in a tertiary care hospital. MATERIALS AND METHODS: An observational study was done in the department of pediatrics in a tertiary care hospital. The ADRs occurring in the inpatient wards and outpatient department of pediatrics were actively monitored. The collected reports were analyzed for ADR pattern, drug groups, demographic profile, causality, severity, and preventability of the ADR. RESULTS: A total of 30 ADRs were documented during the mid period of 2009 among pediatric patients. Most of the ADRs (60%) occurred below the age of 1 year. Antibiotics comprised the major group of drugs causing ADRs (67%). Rashes and urticaria were the most common type of ADR (37%) followed by fever, anaphylactic shock, vomiting, chills, and rigors. A single case of death had been reported in the study period. There were more occurrences of ADRs with multiple drugs compared to single drug therapy. About 80% of the ADRs were of probable causality and 87% were of probable preventability. There were no mild reactions, with 77% of reactions being moderate and 23% of reactions being severe in the severity scale. CONCLUSIONS: ADRs occur more among infants and antibiotics were more commonly implicated. Most of the reactions were of moderate severity. This indicates the need for a rigid ADR monitoring among pediatric patients to ensure safety of drug therapy.

Influence of CYP2C9 gene polymorphisms on response to glibenclamide in type 2 diabetes mellitus patients.

PURPOSE: The antidiabetic drug glibenclamide is metabolized by the enzyme cytochrome P450 2C9 (CYP2C9) encoded by the polymorphic gene CYP2C9. Previous studies involving healthy volunteers have shown a significant influence of variant CYP2C9 genotypes on glibenclamide metabolism. The aim of this study was to investigate the influence of genetic polymorphisms of CYP2C9 on the response to glibenclamide and on glibenclamide plasma levels in type 2 diabetes mellitus patients. METHODS: The study cohort consisted of type 2 diabetes mellitus patients (n = 80) on regular therapy with glibenclamide either alone or with concomitant metformin. Plasma levels of glibenclamide were estimated by reverse phase high pressure liquid chromatography. The variant alleles of CYP2C9, namely CYP2C9 *2 and *3, were identified by PCR-restricted fragment length polymorphism. The plasma levels of glibenclamide and occurrences of hypoglycemic adverse effects with their severity were compared between the genotype groups. RESULTS: Of the 80 patients (61 males, 19 females), 78 were on concomitant treatment with two drugs, namely, glibenclamide and metformin, and two were on monotherapy with glibenclamide. There was a significant association (p < 0.001) between genotype status of CYP2C9 and the control of diabetes in patients receiving treatment with glibenclamide. There were no statistically significant differences in hypoglycemic adverse effects between the genotype groups. CONCLUSION: The type 2 diabetes mellitus patients participating in this study with variant genotypes of CYP2C9 were found to respond better to treatment with glibenclamide than those with the normal genotype. The variant genotype CYP2C9 *1/*3 did not significantly influence the hypoglycemic adverse effects among those patients on long-term glibenclamide treatment.

Adverse drug reaction profile of cisplatin-based chemotherapy regimen in a tertiary care hospital in India: An evaluative study.

AIMS: This prospective study was designed to monitor and analyze the pattern of occurrence of adverse drug reactions (ADRs) to cisplatin-based chemotherapy regimen in the cancer ward of a tertiary care hospital. MATERIALS AND METHODS: Cancer patients who received cisplatin-based cancer chemotherapy were monitored for adverse reactions. The collected reports were analyzed for demographic and drug details, causality, preventability and severity of adverse effects. Causality was assessed by the World Health Organization (WHO) causality assessment scale and Naranjo's Algorithm. Preventability and severity of ADRs were assessed by modified Schumock and Thornton scale, modified Hartwig and Siegel scale respectively. RESULTS: Among 51 patients, 48 developed ADRs to cisplatin chemotherapy. The reactions observed were nausea, alopecia, anorexia, vomiting, taste alteration, diarrhea, constipation, tinnitus, and hypocalcaemia. The WHO causality assessment scale indicated 69% "possible" and 31% "probable" but no "certain" reactions. Naranjo's Algorithm showed 62% "probable" and 38% "possible" reactions. Most of the reactions belonged to the category of "not preventable". Reactions like nausea and vomiting belonged to the category of "definitely preventable". Modified Hartwig and Siegel scale of severity assessment showed that most of the reactions were of "mild level 1" severity except for vomiting, diarrhea and hypocalcaemia, which were of "moderate level 3" severity. CONCLUSION: Cisplatin-based chemotherapy has a high potential to cause adverse effects. Most of the reactions were of milder nature but not preventable. The common adverse effects such as nausea and vomiting were preventable, but reactions like hypersensitivity reactions and anaphylaxis were not predictable.

Emerging trends of nanomedicine--an overview.

Nanotechnology is an emerging branch of science for designing tools and devices of size 1 to 100 nm with unique function at the cellular, atomic and molecular levels. The concept of using nanotechnology in medical research and clinical practice is known as nanomedicine. Nanoparticles possess some novel properties not seen with the macro molecules and they can be manipulated by attaching therapeutic components to help in diagnosis and treatment. They can also be used to probe cellular movements and molecular changes associated with pathological states. Nanodevices like carbon nanotubes to locate and deliver anticancer drugs at the specific tumour site are under research. Nanotechnology promises construction of artificial cells, enzymes and genes. This will help in the replacement therapy of many disorders which are due to deficiency of enzymes, mutation of genes or any repair in the synthesis of proteins. Currently nanodevices like respirocytes, microbivores and probes encapsulated by biologically localized embedding have a greater application in treatment of anaemia and infections. Thus in the present scenario, nanotechnology is spreading its wings to address the key problems in the field of medicine. Hence this review discusses in detail the applications of nanotechnology in medicine with more emphasis on drug delivery and therapy.

Novel applications of nanotechnology in medicine.

Current modalities of diagnosis and treatment of various diseases, especially cancer have major limitations such as poor sensitivity or specificity and drug toxicities respectively. Newer and improved methods of cancer detection based on nanoparticles are being developed. They are used as contrast agents, fluorescent materials, molecular research tools and drugs with targeting antibodies. Paramagnetic nanoparticles, quantum dots, nanoshells and nanosomes are few of the nanoparticles used for diagnostic purposes. Drugs with high toxic potential like cancer chemotherapeutic drugs can be given with a better safety profile with the utility of nanotechnology. These can be made to act specifically at the target tissue by active as well as passive means. Other modalities of therapy such as heat induced ablation of cancer cells by nanoshells and gene therapy are also being developed. This review discusses the various platforms of nanotechnology being used in different aspects of medicine like diagnostics and therapeutics. The potential toxicities of the nanoparticles are also described in addition to hypothetical designs such as respirocytes and microbivores. The safety of nanomedicine is not yet fully defined. However, it is possible that nanomedicine in future would play a crucial role in the treatment of human diseases and also in enhancement of normal human physiology.

Role of pharmacogenomics in drug discovery and development.

Pharmacogenetics and pharmacogenomics are two major emerging trends in medical sciences, which influence the success of drug development and therapeutics. In current times, though pharmacogenetic studies are being done extensively for research, its application for drug development needs to get started on a large scale. The major determinants of success of a new drug compound, viz safety and efficacy, have become more predictable, with the advent of pharmacogenetic studies. There is a need felt for pharmacogenomic studies, where the effects of multiple genes are assessed with the study of entire genome.Pharmacogenetic studies can be used at various stages of drug development. The effect of drug target polymorphisms on drug response can be assessed and identified. In clinical studies, pharmacogenetic tests can be used for stratification of patients based on their genotype, which corresponds to their metabolizing capacity. This prevents the occurrence of severe adverse drug reactions and helps in better outcome of clinical trials. This can also reduce attrition of drug compounds. Further, the variations in drug response can be better studied with the wider application of pharmacogenomic methods like genome wide scans, haplotype analysis and candidate gene approaches. The cost of pharmacogenetic testing has become very low, with the advent of newer high throughput genotyping systems. However, the cost of pharmacogenomic methods continues to be very high. As the treatment with several drugs is being more and more pharmacogeneticaly guided (e.g. warfarin and irinotecan), the FDA has laid down guidelines for pharmaceutical firms regarding submission of pharmacogenetic data for their drug products in labelling.

Influence of the CYP2C9 AND CYP2C19 polymorphisms on phenytoin hydroxylation in healthy individuals from south India.

BACKGROUND AND OBJECTIVES: Phenytoin, a widely used anti-epileptic drug, is metabolized mainly by CYP2C9 (90%) and partly by CYP2C19 (10%) to its major metabolite 5-(para-hydroxyphenyl)-5- phenylhydantoin (p-HPPH). The CYP2C9 and CYP2C19 genes encoding these enzymes are polymorphically expressed and most of the variants result in decreased metabolism of the respective substrates. The present study was undertaken to investigate the influence of the CYP2C9*2 and *3 as well as CYP2C19*2 and *3 variant genotypes on phenytoin hydroxylation in healthy subjects from south India. METHODS: A total of 27 healthy, unrelated, subjects were administered a single oral dose of 300 mg phenytoin. Four hours later, 5 ml of blood was collected and genotyped for CYP2C9*1, *2, *3, CYP2C19*1, *2 and *3 by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Phenytoin and the major metabolite p-HPPH were estimated by reverse phase HPLC. The metabolic ratio was calculated as concentration of phenytoin/p-HPPH. RESULTS: A significant correlation was observed between the CYP2C9 genotype and metabolic ratio of phenytoin/p-HPPH (r = 0.472, 95% CI 0.100 to 0.728; P = 0.01). While no association was found with CYP2C19 alone, a significant correlation was observed between the combined CYP2C9 and CYP2C19 genotypes and phenytoin metabolic ratio (r = 0.507, 95% CI 0.146 to 0.749; P< 0.01). INTERPRETATION AND CONCLUSION: CYP2C9*2 and *3 mutant alleles caused decreased hydroxylation of phenytoin in vivo, whereas the mutant alleles of CYP2C19 played only a minor role in the metabolism of phenytoin in subjects of our study. The results of present preliminary study needs to be confirmed with a larger sample.

Effect of slow and fast pranayams on reaction time and cardiorespiratory variables.

We planned to undertake a comparative study of the effect of short term (three weeks) training in savitri (slow breathing) and bhastrika (fast breathing) pranayams on respiratory pressures and endurance, reaction time, blood pressure, heart rate, rate-pressure product and double product. Thirty student volunteers were divided into two groups of fifteen each. Group I was given training in savitri pranayam that involves slow, rhythmic, and deep breathing. Group II was given training in bhastrika pranayam, which is bellows-type rapid and deep breathing. Parameters were measured before and after three week training period. Savitri pranayam produced a significant increase in respiratory pressures and respiratory endurance. In both the groups, there was an appreciable but statistically insignificant shortening of reaction time. Heart rate, rate-pressure product and double product decreased in savitri pranayam group but increased significantly in bhastrika group. It is concluded that different types of pranayams produce different physiological responses in normal young volunteers.