Effect of propranolol on task performance in human volunteers.
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Biomedical subjects
Publications and source records attributed to C Adithan.
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The relationship between saliva and serum paracetamol levels was investigated in ten healthy male volunteers. The salivary and serum paracetamol levels showed significant correlation with each other. The salivary and serum paracetamol concentration ratio was highly dependent on sampling time. The salivary and serum paracetamol half-lives showed significant correlation with each other while the area under curve of paracetamol concentration in saliva and serum failed to show significant correlation.
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1. A pharmacokinetic study of antipyrine was performed in healthy volunteers and diabetic subjects, ten in each group. After a single oral dose of antipyrine (18 mg/kg) multiple samples of saliva were collected for the determination of antipyrine concentration and a pharmacokinetic analysis was carried out. 2. The mean salivary half-life of antipyrine was found to be significantly higher in patients with uncontrolled diabetes as compared to the healthy subjects. However, there was no significant difference in volume of distribution and metabolic clearance rates. 3. After 15 days of insulin therapy, there was a significant reduction in the mean half-life of antipyrine in the diabetic patients. The mean half-life of antipyrine in the patients with controlled diabetes was not significantly different from that of the normal healthy subjects. 4. There was no significant correlation between the salivary half-life of antipyrine and a 2 hour postprandial blood sugar level in the diabetic patients. 5. Our data suggest impaired hepatic microsomal enzyme activity in patients with uncontrolled diabetes which was corrected after 15 days of insulin therapy.
CYP2E1 and GSTP1 enzymes belong to phase I and phase II group of drug metabolizing enzymes respectively which are involved in the metabolic activation and detoxification of various potential genotoxic compounds. The functional polymorphism in these genes exhibit inter-individual variations in susceptibility towards various diseases and difference in therapeutic response. The variant sequences of these genes differ considerably between ethnic groups. Therefore, the objective of the study was to assess the prevalence of CYP2E1 & GSTP1 gene variants in healthy volunteers of Tamilnadu, a population of South India. The genotype distribution of CYP2E1*1B A2A2, A2A1 and A1A1 were 61%, 36% and 3% respectively. The distribution of CYP2E1*5B c1c1, c1c2 genotypes were 99.2%and 0.8%. CYP2E1*6 DD, DC and CC genotype frequencies were 72%, 25% and 3% respectively. The allele frequencies of CYP2E1*1B, CYP2E1*5B and CYP2E1*6 were A2- 0.79 A1- 0.21, c1-0.996 c2 - 0.004 and D- 0.84 C- 0.16 respectively. The genotypic distribution of GSTP1 (Ile/Val) were Ile/Ile - 44%, Ile/Val -47% and Val/Val- 9 % whereas, the allelic frequencies were 0.67 for Ile and 0.33 for Val allele. The molecular studies in these enzymes provide basis for further epidemiological investigations in the population where the functional mutations in the genes alter therapeutic response and acts as susceptibility markers for various clinical conditions.
BACKGROUND: Genotypes of the drug-metabolizing enzyme CYP2D6 influence plasma levels of 25% of commonly prescribed drugs. This is the first study in India to investigate the genotype-phenotype relationship of CYP2D6. AIM: To study the influence of some CYP2D6 genotypes on the metabolism of its substrate dextromethorphan in healthy South Indian volunteers and to assess the contribution of the CYP2D6*10 and CYP2D6*4 alleles. MATERIALS AND METHODS: Twenty-six subjects from a previous CYP2D6 genotyping study of healthy volunteers were included for phenotyping in this study. Selected volunteers belonged to any one of three genotype groups:Group I - two normal activity alleles, Group II - one reduced activity allele and one normal activity allele and Group III - one loss of function allele along with either a wild type or reduced activity allele. Volunteers were phenotyped for the CYP2D6 enzyme using dextromethorphan as probe drug. Concentrations of the parent drug and metabolite dextrorphan were estimated using high performance liquid chromatography. Metabolic ratios were calculated as the ratio of parent drug to metabolite in 0-8h urine samples. STATISTICAL ANALYSIS: Metabolic ratios from each genotype group were compared using the Mann-Whitney test at 5% significance, to observe their difference between genotype groups. RESULTS: The mean metabolic ratios+/-SD in Groups I, II and III were 0.0039+/-0.0031, 0.0032+/-0.0017 and 0.0391+/-0.0331 respectively. The mean metabolic ratio of Group III was significantly higher when compared with Groups I or II. In heterozygous individuals, the *1 or *2 alleles compensated for the reduced enzyme activity due to the *10 allele. However, if a heterozygous individual had a *4 allele, the reduced enzyme activity could not be compensated by the *1 or *2 alleles. CONCLUSIONS: The CYP2D6 enzyme activity was found to be decreased in individuals carrying *4 or *5 alleles. The *1 or *2 allele could compensate for the reduced function due to *10 allele, but not for the loss of function due to *4 allele.
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The endogenous creatinine clearance test was done in 14 Type I and 15 Type II poorly controlled diabetic patients and compared with respective age matched healthy volunteers. Type I diabetics had significantly lower creatinine clearance rate, body mass index and serum albumin levels when compared to their control group. In Type II diabetics these values remained unaltered. Both Type I and Type II diabetics had significantly higher blood sugar and glycosylated haemoglobin levels. The creatinine clearance rate had significant positive correlation with patients' body mass index and serum albumin levels. This suggests that the undernutrition of Type I diabetics may be responsible for the decreased creatinine clearance.
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