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Biomedical subjects

S K Gupta

Publications and source records attributed to S K Gupta.

At least 379 records · Page 21Linked to original sources
PubMed1995

Immunopharmacodynamic studies of cyclosporine in patients awaiting renal transplantation.

The immunopharmacodynamics of cyclosporine were investigated in eight hemodialysis patients awaiting renal transplantation. Cyclosporine was administered orally (10 mg/kg) and intravenously (4 mg/kg), with both administrations separated by at least one week. Plasma samples were processed at 37 degrees C and analyzed for specific cyclosporine and its four major metabolites (AM1, AM1c, AM9, and AM4N) using high-performance liquid chromatography. In addition, the in vitro immunosuppressive activity of these serial plasma samples was estimated as a relative percentage inhibition of third party mitogenic lymphocyte proliferation stimulated with phytohemagglutinin. The relationships between concentration and effect of cyclosporine versus time were noted. These results suggest that unchanged cyclosporine concentrations in plasma correlate with mitogen-induced lymphocyte suppression yielding significant immunosuppressant activity of cyclosporine. Control studies with plasma from healthy volunteers spiked with cyclosporine in the concentration range of 0-10,000 ng/mL were developed. A sigmoidal Emax model was fitted to the effect versus plasma concentration data. The ratio of effect versus predicted effect were calculated for intravenous cyclosporine dosing. There was a good correlation between the observed and predicted inhibitory effect.

Administration, Oral↗
PubMed1995

Comparison of the nicotine pharmacokinetics of Nicoderm (nicotine transdermal system) and half-hourly cigarette smoking.

Nicoderm, a nicotine transdermal system (NTS), provides a continuous, transdermal delivery of nicotine and is used as an aid to smoking cessation. In contrast, cigarette smoking yields nicotine concentrations in plasma that rise and fall with each cigarette. The primary objective of this study was to compare nicotine pharmacokinetics after treatment of subjects with either the NTS or controlled smoking. Fourteen healthy adult male smokers, who smoked at least 30 cigarettes per day, were entered into a randomized crossover design trial that compared the NTS, 21 mg/day applied for 24 hours, with half-hourly smoking during the day. Subjects abstained from smoking for 2 days, and were treated for 5 days with either the NTS (daily) or controlled smoking (30 cigarettes at half-hourly intervals on days 1 and 5; ad libitum smoking on days 2-4). Blood samples were obtained frequently on days 1 and 5 for analysis of nicotine and cotinine. Pharmacokinetic comparisons showed that nicotine Cmax, area under the curve (AUC)inf, and Cavg for the NTS were lower than corresponding values for controlled smoking; Cmax and Cavg values were approximately half those of smoking. Cmax and Cavg values for cotinine were similarly lower for the NTS compared to controlled smoking. For both treatments, plasma nicotine concentrations were higher on day 5 compared to day 1. Thus, the NTS provides concentrations of nicotine that are lower than smoking.

Administration, Cutaneous↗
PubMed1995

The effect of food, time of dosing, and body position on the pharmacokinetics and pharmacodynamics of verapamil and norverapamil.

To evaluate the influence of food, time of dosing, and body position on the steady-state pharmacokinetics of an osmotically controlled formulation of verapamil (COER-verapamil), each of 29 healthy men received one tablet a day at specified times in an open-label, multiple-dose, four-period, crossover study. The verapamil tablets were administered in a randomized, balanced, crossover design: 240 mg at 8:00 AM on an empty stomach, subjects remaining ambulatory; 240 mg at 8:00 AM on an empty stomach, subjects remaining supine for 8 hours; 240 mg at 10:00 PM with a standardized meal, subjects remaining supine for 8 hours; and 240 mg at 10:00 PM on an empty stomach, subjects remaining supine for 8 hours. Plasma verapamil concentrations were measured at steady state over the dosing interval. Steady-state plasma concentrations were achieved by the fourth administration of the drug. Neither food nor posture had any effect on the pharmacokinetics of verapamil or norverapamil, or on hemodynamic measurements. Time of dosing did affect the rate of appearance and elimination of verapamil, but had no effect on the extent of verapamil absorption, norverapamil appearance, or hemodynamic measurements.

Adult↗
PubMed1995

Comparison of the pharmacokinetics of two nicotine transdermal systems: nicoderm and habitrol.

This randomized, crossover study compared the nicotine and cotinine pharmacokinetic parameters and plasma concentration profiles of two different nicotine transdermal products: Nicoderm (Alza, Palo Alto, CA; and Marion Merrell Dow, Kansas City, MO) and Habitrol (Basel Pharmaceuticals, Summit, NJ). The two treatments were randomly assigned to each of 24 male smokers and worn for 24 hours each day for 5 days, with a 6-day washout between treatments. Plasma nicotine and cotinine concentrations were measured on day 1 and day 5 of each treatment. Mean delivered dose differed significantly between products, and the two products were not bioequivalent. The Nicoderm system provided higher mean plasma nicotine concentrations, particularly during the first 8 hours after system application. The mean steady state Cmax, AUC, and degree of fluctuation (DF) values were significantly greater for the Nicoderm system than for Habitrol. The mean nicotine tmax value for the Nicoderm system was significantly shorter (P < .001) than that for Habitrol (2.7 versus 8.6 hours). Steady state cotinine AUC values and plasma concentrations were significantly lower for Habitrol than for the Nicoderm system. The incidence of adverse events was similar for both products.

Administration, Cutaneous↗
PubMed1995

Evaluation of diurnal variation in fentanyl clearance.

Drug disposition kinetics are commonly assumed to be time-invariant as a first approximation. In a preliminary study, 6 healthy volunteers received a constant intravenous infusion of 50 micrograms/h for 48 hours; the serum fentanyl concentration at 36 hours was lower than that at 24 hours for all 6 subjects. This suggested possible diurnal variations in fentanyl clearance. In 2 subsequent studies, with healthy volunteers receiving short infusions of fentanyl (n = 9, 150 micrograms/h for 0.33 hours every 4 hours; n = 12, 150 micrograms/h for 0.33 hours every hour, respectively), the area under the serum fentanyl concentration curve appeared to be independent of the time of infusion. Thus, there was no evidence to support a large diurnal change in fentanyl clearance. The serum fentanyl concentration-time profiles, corrected for carryover from previous doses, within each study were superimposable. This suggests that there are no diurnal changes in the distribution kinetics of fentanyl.

Circadian Rhythm↗
PubMed1995

Effect of alosetron (a new 5-HT3 receptor antagonist) on the pharmacokinetics of haloperidol in schizophrenic patients.

Alosetron is under clinical development for the treatment of schizophrenia. This study evaluated the effect of oral alosetron dosing on the pharmacokinetics of haloperidol, the latter being administered daily to 13 schizophrenic patients for 56 days. Alosetron 1 mg daily or placebo was given by random assignment for 2 weeks. After a two-week alosetron washout period (during which patients received placebo), patients received the alternate treatment for another two weeks. Serial blood samples were collected for high-performance liquid chromatography determination of plasma haloperidol, reduced haloperidol, and alosetron at selected times for 24 hours after administration of haloperidol and alosetron on study days 21 and 49. Mean pharmacokinetic parameters of haloperidol in the presence of alosetron and placebo treatments were not significantly (P > .05) different: dose-normalized Cmax (6.40 versus 5.75 ng/mL), dose-normalized Cmin (2.00 versus 1.90 ng/mL), dose-normalized AUC (85.97 versus 68.48 ng.hr/mL), and CL/f (78.23 versus 104.7 L/hr). A two-compartment model was used to assess the concentration- and time-independent pharmacokinetics of haloperidol after multiple dosing. The model confirmed that there was no change in the pharmacokinetics of haloperidol when alosetron was administered concomitantly. Mean AUC ratios of reduced haloperidol to haloperidol (0.18) in the presence of alosetron were similar to values obtained in the absence of alosetron, indicating that alosetron had no influence on the metabolism of haloperidol. Mean pharmacokinetic parameters of alosetron were similar to those in previous studies in healthy subjects.

Adult↗
PubMed1995

Localization of epitopes for monoclonal antibodies at the N-terminus of the porcine zona pellucida glycoprotein pZPC.

Zona pellucida glycoproteins play an important role in fertilization. In this study, attempts have been made to identify and define epitopes of monoclonal antibodies (mAbs) possessing contraceptive efficacy in vitro. The porcine zona glycoprotein pZPC, a homologue of mouse/human ZP3, was reduced and alkylated and subsequently digested with trypsin. Reverse-phase HPLC of the tryptic digest yielded twenty two peaks (T1-T22). When tested against mAbs reactive against sequential determinants on pZPC, T11 was immunoreactive with two mAbs, mAb-455 and mAb-467, as shown by antigen inhibition ELISA. IC50 values of 3.1 nM and 8.6 nM were recorded versus mAb-455 and mAb-467 respectively, and approximated the IC50 values obtained with intact pZPC. Amino acid analysis, Edman degradation, and FAB-MS identified T11 as the N-blocked decapeptide pyro-Gln-Pro-Val-Trp-Gln-Asp-Glu-Gly-Gln-Arg derived from the N-terminus of pZPC. Synthesis of overlapping octapeptides further identified VWQDE and WQDE as the minimum motifs with antigenic activity for mAb-455 and mAb-467, respectively. Glycine replacement peptides confirmed residues W,Q,E as critical for binding mAb-455 and W,Q,D,E as critical for binding mAb-467. Both mAbs inhibited binding of boar sperm to zona-encased porcine oocytes. These results, the first to define peptide epitopes of porcine zona glycoprotein, will assist in the design of an immunocontraceptive vaccine based on synthetic peptides corresponding to pZPC or its homologues in other species.

Amino Acid Sequence↗
PubMed1995

Integrating parallelization strategies for linkage analysis.

We describe a second parallel implementation of the ILINK program from the LINKAGE package that improves on our previous implementation. To improve running time we integrated the strategy of parallel estimation of the gradient at a candidate recombination fraction vector with a previously implemented strategy for evaluating in parallel the likelihood at one vector. We also integrated an adaptive loadbalancing strategy in conjunction with our previous static loadbalancing strategy. We implemented a strategy for partitioning input pedigrees, but this slowed down the program; we give some evidence for what the problems are. To best exploit parallelism at all levels of the program and to take advantage of both coarse-grain and fine-grain parallelism it is necessary to combine multiple algorithmic strategies.

Algorithms↗
PubMed1995

Differentiation of absorption and first-pass gut and hepatic metabolism in humans: studies with cyclosporine.

The low and variable bioavailability of cyclosporine has been attributed to poor absorption. However, recent studies have suggested that intestinal first-pass metabolism exerts a significant effect on bioavailability. We describe theory and methods to differentiate the contribution from oral absorption and intestinal and hepatic metabolism to overall cyclosporine bioavailability. Analysis of data from previous studies in our laboratories shows that in the absence of intestinal metabolism, cyclosporine absorption from its presently available dosage form averages at least 65% +/- 12% in healthy volunteers and 77% +/- 19% in kidney transplant patients. Analysis also suggests that the extraction ratio for cyclosporine in the gut is approximately twice the hepatic extraction and that cyclosporine absorption does not present a problem, with an average of 86% of the drug absorbed intact from its commercially available product in healthy volunteers. The boundary condition analysis described should have broad application in the differentiation of factors responsible for poor bioavailability.

Administration, Oral↗
PubMed1995

Regulation of interleukin-8 receptor expression in human polymorphonuclear neutrophils.

Interleukin-8, a neutrophil chemotactic agent, is known to have an active role in the induction of inflammatory response in a number of diseases. Although the activity of IL-8 is known to be through a receptor (IL-8R) on the surface of neutrophils, no information is available regarding the regulation of the IL-8R expression. The present study demonstrates that serum activated LPS at a concentration of 10 ng/ml induces expression of functionally active IL-8R by 120% within 30 min through de novo protein synthesis. The upregulated receptors could be detected by anti-IL-8R antibody and could also be demonstrated by autoradiography with crosslinking 125I IL-8. The serum-activated LPS-stimulated neutrophils migrated faster and showed higher Ca2+ flux over the unstimulated cells. The LPS-induced receptors were downregulated rapidly, about 85% of the receptor activity being lost within 90 min of incubation at 37 degrees C. The downregulation could be partially prevented by treatment with a cocktail of protease inhibitors, suggesting the possible involvement of protease(s) in this process. Both EDTA (100 microM) and bestatin (40 microM) afforded almost complete protection of the receptor from proteolytic cleavage indicating that the enzyme involved is a metalloprotease, possibly an aminopeptidase. The study shows that stimulation of PMNs with LPS leads to induction of IL-8R expression enhancing the IL-8-mediated biological responses and also provides evidence for post-stimulatory restoration of receptor level on the neutrophil surface by proteolytic cleavage of the amino-terminal end of the receptor.

Antigens, CD↗
PubMed1995

Diagnostic utility of the estimation of mycobacterial Antigen A60 specific immunoglobulins IgM, IgA and IgG in the sera of cases of adult human tuberculosis.

SETTING: An ELISA assay based on mycobacterial Antigen A60 for the estimation of Mycobacterium-specific immunoglobulins in the serum has been used successfully for the rapid diagnosis of tuberculosis in studies done in the Western countries. There are hardly any similar large scale studies in India. OBJECTIVE: To evaluate the utility of this ELISA test for rapid diagnosis of different clinical forms of tuberculosis in an adult Indian population. DESIGN: ELISA test based on mycobacterial antigen A60 (Anda Biologicals, France) was used to estimate specific IgM, IgA and IgG antibodies in the sera obtained from 337 cases of tuberculosis and 131 controls in the population of Delhi (India). RESULTS: Of the 131 controls, only 9.9% were positive for IgM, 7.6% for IgG, 6.1% for IgA and 9.9% when an IgA and IgG combination was considered. Of 122 cases of active pulmonary tuberculosis, 41% were positive for IgM, 86.8% for IgA, 88.5% for IgG and a very high positivity (98.3%) was seen when IgA and IgG estimations were combined. A relatively low seropositivity was observed in 25 cases of pleural tuberculosis. The corresponding figures in 130 cases of extrapulmonary tuberculosis were 22.3%, 68.4%, 73.8% and 86.15%. When 60 cases of pulmonary tuberculosis who had been successfully treated with antituberculosis drugs were analyzed the rates of seropositivity fell to 11.6%, 46.6%, 58.3% and 66.6% respectively. CONCLUSION: Our findings point to a very good sensitivity (91.6%) and specificity (90.0%) of the test when combined IgA and IgG antibody titres are considered, to detect cases of adult tuberculosis. The role of IgM estimation can be restricted to the detection of cases of reactivation of tuberculosis.

Adult↗
PubMed1995

Nucleotide sequence of cDNA encoding bonnet monkey (Macaca radiata) zona pellucida glycoprotein-ZP3.

The cDNA encoding bonnet monkey zona pellucida ZP3 from bonnet ovary has been amplified by polymerase chain reaction. The ZP3 gene has an open reading frame of 1272 nucleotides encoding a polypeptide of 424 amino acid residues which shares 93.9% overall identity with human ZP3. Bonnet ZP3 has four potential attachment sites for N-linked sugar chains which are also conserved in human ZP3. Bonnet ZP3 has 14 cysteine residues compared with 15 in human ZP3. The highest disparity between these molecules was restricted to a domain represented by amino acid residues 370-398. These results have important implications for the use of bonnet monkey as an animal model for evaluation and development of contraceptive vaccine based on ZP3 for human use.

Amino Acid Sequence↗
PubMed1995

Evaluation of protein-A linked monoclonal antibody latex agglutination test for diagnosis of nuclear polyhedrosis virus (BmNPV) of silkworm Bombyx mori L.

The symptomology of BmNPV infection in Bombyx mori L depends on the stages of infection. Discernible symptoms develop at later stages of infection, which leads to improper diagnosis and poor crop yield with sericulturists. In the present study development of direct and protein-A linked monoclonal antibody latex (PALMAL) agglutination test for the detection of BmNPV infection in silkworm is described. Latex beads were precoated with protein-A and then sensitised with monoclonal antibody MA-231 (125 micrograms/ml). PALMAL test could detect 1 x 10(5) nuclear polyhedra/test and is ten times more sensitive than the direct agglutination test employing purified polyclonal antibodies. No agglutination was observed in presence of B. thuringiensis, S. marcescens, N. bombycis, group-A streptococci, Staphylococcus aureus, E. coli and normal haemolymph protein indicating the specificity of the test. Fifty haemolymph samples collected from the field were evaluated by PALMAL test. Twenty one samples having infection other than BmNPV, failed to show positive agglutination. Twenty five samples having > or = 5 x 10(6) BmNPV/ml showed positive agglutination. However, 4 samples having < 5 x 10(6) BmNPV/ml failed to show positive agglutination thereby indicating the limit of sensitivity of the assay.

Animals↗
PubMed1995

Improving the practical space and time efficiency of the shortest-paths approach to sum-of-pairs multiple sequence alignment.

The MSA program, written and distributed in 1989, is one of the few existing programs that attempts to find optimal alignments of multiple protein or DNA sequences. The MSA program implements a branch-and-bound technique together with a variant of Dijkstra's shortest paths algorithm to prune the basic dynamic programming graph. We have made substantial improvements in the time and space usage of MSA. The improvements make feasible a variety of problem instances that were not feasible previously. On some runs we achieve an order of magnitude reduction in space usage and a significant multiplicative factor speedup in running time. To explain how these improvements work, we give a much more detailed description of MSA than has been previously available. In practice, MSA rarely produces a provably optimal alignment and we explain why.

Algorithms↗
PubMed1995

Age and gender related changes in stereoselective pharmacokinetics and pharmacodynamics of verapamil and norverapamil.

1. Pharmacokinetics and pharmacodynamics of R- and S-verapamil and R- and S-norverapamil were studied at steady state following administration of 180 mg verapamil delivered by a controlled-release gastrointestinal therapeutic system (COER-verapamil). 2. Of the 30 young (19 to 43 years) and 30 elderly subjects (65 to 80 years) enrolled, approximately half of each age group were women; all subjects were healthy and none were smokers. 3. Mean R- and S-verapamil and R- and S-norverapamil Cmax, Cmin, and AUC values for elderly subjects were 1.2 to 2.2 times greater than those for young subjects; these differences were statistically significant at P < 0.05. Median tmax values for young and elderly subjects were not significantly different for any enantiomer. The mean half-life values of R- and S-verapamil for elderly subjects were approximately 20 h compared with approximately 13 h for young subjects, respectively. The mean half-life values of R- and S-norverapamil for elderly subjects were approximately 31 h and 20 h, respectively, compared with approximately 19 h and 21 h for young subjects, respectively. 4. In both age groups, the mean plasma verapamil concentrations of each enantiomer were higher for women than for men at all time points. 5. Mean arterial pressure (MAP) had a significant correlation to R- (r2 = 0.86) and S-verapamil (r2 = 0.87) concentration values that was not influenced by either gender or age of the patient. Change in PR-interval also had a significant correlation to R- and S-verapamil concentration values. However, the sensitivity of the response to changes in R- and S-verapamil concentration values in elderly subjects was about 1/5 of that in younger subjects.

Adult↗
PubMed1995

Sensitization to Ganoderma lucidum in patients with respiratory allergy in India.

Although human sensitization to basidiomycete Ganoderma has been reported in New Zealand, North America and Europe, hypersensitivity due to this fungi is not known in India, in spite of its prevalence in the atmosphere. We have studied the atmospheric concentration of Ganoderma in different localities within Delhi and the sensitization level to this fungi amongst the Indian population. Aerobiological sampling, using a Burkard personal slide sampler, was carried out in Delhi for 2 consecutive years (October 1989-September 1991). The sampler was operated at 10 day regular intervals for 10 min to trap the spores. The peak season for Ganoderma is recorded from July to September with highest average monthly catch of 336 spores/m3 in September 1991 from south Delhi. Antigenic extracts were prepared from both, the spores and whole body of Ganoderma lucidum. The results of intradermal skin tests conducted on 172 patients revealed that 28.48% and 17.44% of patients showed marked skin reactivity to spore and whole body extracts, respectively. A significant correlation (r = 0.963, P < 0.01) was found between intradermal and skin-prick tests. More than 80% of the intradermal test positive patients had significantly (P < 0.01) elevated IgE antibodies to the fungi in question. Thus, sensitization to Ganoderma lucidum has been reported for the first time in the atopic population of India.

Adult↗
PubMed1995

Argyrophilic nucleolar organizer regions (AgNORs) in breast lesions--a study on fine needle aspirates.

Nucleolar organizer region-associated proteins are argyrophilic and may be visualized by silver stains. This study is a prospective analysis of the AgNOR counts in a range of breast lesions seen in fine needle aspiration (FNA) smears. A total of 72 cases including ductal carcinomas (n = 24), fibrocystic change (n = 24), fibroadenoma (n = 16), proliferative lesions (n = 4) and miscellaneous lesions (n = 4) were studied. The ductal carcinomas showed higher AgNOR counts (mean 16.63 +/- 7.09) compared with the non-malignant lesions (mean 6.39 +/- 1.96), the difference being statistically significant. A cut off AgNOR score of 11 could reliably discriminate malignant from non-malignant lesions. In ductal carcinomas, the AgNOR scores showed a tendency to increase with higher grades of malignancy. There was no correlation with the presence or absence of lymph node metastases at the time of presentation. It is concluded that AgNOR counting, although tedious, is inexpensive, and provides useful information regarding cellular proliferation, and can supplement information obtained by more sophisticated techniques.

Adolescent↗