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Biomedical subjects

A K Thakur

Publications and source records attributed to A K Thakur.

At least 19 recordsLinked to original sources
PubMed1994

Chronic effects of atrazine on estrus and mammary tumor formation in female Sprague-Dawley and Fischer 344 rats.

The chronic effects of dietary administration of atrazine at levels as high as 400 ppm on selected endocrine and tumor profiles were evaluated in Fischer 344 and Sprague-Dawley female rats. The study showed that lifetime dietary administration of atrazine at a maximum tolerated dose (MTD) to Sprague-Dawley female rats caused (1) lengthening of the estrous cycle, (2) increased number of days in estrus or under the influence of exposure to estrogen, (3) earlier onset of galactocele formation, and (4) earlier onset of mammary and pituitary tumor formation but not an increased incidence of mammary and pituitary tumors when compared to concurrent control rats. Fischer 344 female rats fed atrazine at an MTD exhibited slightly lengthened estrous cycles, but no effects were observed on estradiol or progesterone levels, or on the onset or incidence of mammary tumors. These results support a hypothesis that high-dose atrazine administration in Sprague-Dawley females is related to an acceleration of age-related endocrine changes leading to an earlier onset and/or increased incidence of mammary tumors. This endocrine-mediated response, which appears to be unique to the Sprague-Dawley female rat, occurs only at or above a threshold dose (the MTD) that interferes with normal estrous cycling, promoting prolonged exposure to endogenous estrogen.

Animals↗
PubMed1994

On definition and use of the term bioavailability.

In common usage, the rate of absorption of an active ingredient or its therapeutic moiety is generally not mentioned in the context of bioavailability. In this communication it is shown that exclusion of the rate of absorption may have serious consequence on the interpretation of bioavailability depending on the underlying model for the system under study. In the case of endogenous substances, the term "bioavailability" is ambiguous unless one specifies whether it refers to availability of the exogenous substance only or the sum total of the exogenous and endogenous substances.

Absorption↗
PubMed1991

Intravenous clomipramine and obsessive-compulsive disorder.

A 62 year old woman presented with a long history of obsessive-compulsive disorder, the symptoms of which were not adequately controlled by oral clomipramine. The patient was started on intravenous clomipramine. Drug levels of both clomipramine and its active metabolite desmethylclomipramine were measured. Symptoms were controlled during her hospital stay. A three year follow-up report indicated the patient is doing well with no evidence of obsessive-compulsive or depressive symptoms. A discussion of the blood levels obtained and the caution to be exercised during intravenous administration is presented.

Clomipramine↗
PubMed1989

Echocardiographic detection of cardiac involvement in chronic renal failure.

The aim of this work was to determine the incidence of occult cardiac involvement in chronic renal failure (CRF). 50 adult patients (42 male, 8 female) were subjected to echocardiography (by both M-mode and 2D methods). Pericardial effusion was detected in 15 patients (30%), 2 patients (4%) had dilated left ventricles with poor contractility and sluggish interventricular septum (IVS) movement, suggesting cardiomyopathy. 1 patient (2%) had cardiac calcification involving the aortic valve, 32 patients (64%) had normal echo findings. These findings suggest that echocardiography is an invaluable tool in detecting early cardiac abnormalities in C.R.F., especially in diagnosing small asymptomatic pericardial effusion and cardiac calcification.

Adult↗
PubMed1988

Structural requirements for binding of nonsteroidal anti-inflammatory drugs to human serum albumin.

The binding of representative chemical classes of nonsteroidal anti-inflammatory drugs (NSAIDs) to human serum albumin (HSA) was investigated by equilibrium dialysis. Warfarin enantiomers were used as specific markers in displacement studies. Data were analyzed by a computerized nonlinear least squares approach designed for binding of small ligands to macromolecules at equilibrium. The binding data indicated comparable affinities to the primary site by the warfarin enantiomers, phenylbutazone, and meclofenamate sodium. Naproxen, sulindac, and zomepirac showed lower affinity by one order of magnitude. The displacement data revealed stereoselectivity. The R(+) isomer was displaced to a significantly greater extent than the S(-) isomer by meclofenamate sodium, while the reverse was observed for phenylbutazone. Naproxen displaced both isomers to the same extent. No significant displacement of either isomer was seen with sulindac or zomepirac. Examination of the chemical structures of the high affinity compounds indicated the common feature of a hydrophobic area bearing a widely delocalized negative charge. Hydrophobic binding of these compounds to HSA at the warfarin site is possibly stabilized by the attraction of the delocalized negative charge to the basic lysine and arginine residues adjoining the lone tryptophan.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1987

Unscheduled DNA synthesis: some statistical thoughts.

Statistical interpretation of results of experiments involving unscheduled DNA synthesis is examined from a design standpoint. Most appropriate methods currently in use are evaluated and some modifications and extensions are suggested. Concerns about replication and/or interaction errors are evaluated and methods for their appropriate handling are discussed. It is suggested that methods incorporating both dose-response and heterogeneity statistics should be considered in treating results from unscheduled DNA synthesis experiments. Proper designs for such experiments are emphasized.

DNA Repair↗
PubMed1986

A two-year drinking-water study of dichloromethane in rodents. I. Rats.

In order to evaluate its toxicity and carcinogenic potential, dichloromethane (DCM) at levels of 0, 0, 5, 50, 125 and 250 mg/kg body weight/day was administered in deionized water to a total of 500 Fischer 344 rats of each sex for 104 wk. An additional group received a level of 250 mg/kg body weight/day for 78 wk followed by a 26-wk recovery period during which only deionized water was presented. Kills were performed at 26-wk intervals. Statistically significant effects on body weight, water consumption and food consumption were observed at the two highest dose levels. Minimal effects were noted on the haematological and serum chemistry parameters monitored. Treatment-related hepatic changes were observed histomorphologically in both sexes after 78 wk of treatment. These changes consisted of an increased incidence of foci/areas of cellular alteration and of fatty change at all dose levels except the lowest. A decrease in the severity of fatty change was observed in the recovery group, but no difference was noted in the incidence of cellular alteration. An increased incidence of hepatic tumours noted in females treated at 50 and 250 mg/kg/day was within the range of historical control incidences. In view of an unusually low incidence of similar tumours in the concurrent control groups and the absence of an increased incidence of hepatic tumours in the group treated at 125 mg/kg/day, the effect seen at 50 and 250 mg/kg/day was not considered to be attributable to DCM treatment. Under the experimental conditions of this study, there was a no-observable-effect level of 5 mg/kg/day in both males and females.

Administration, Oral↗
PubMed1986

A two-year drinking-water study of dichloromethane in rodents. II. Mice.

To investigate its carcinogenic potential, dichloromethane (DCM) was administered at levels of 0, 0, 60, 125, 185 and 250 mg/kg body weight/day to a total of 1000 B6C3F1 mice in deionized drinking-water for 104 wk. The high-dose male and female mice showed a transitory increase in mean leucocyte counts. Treatment-related toxic changes were noted in both male and female livers at the highest dose. There was a slight elevation of proliferative hepatocellular lesions in the treated males but no dose-related trend was apparent and the effect was absent in the females. Neoplastic lesions observed in the study were homogeneous among all groups and were within the range of incidence in historical controls. The results of this study demonstrated a toxicological no-observable-effect level (NOEL) for DCM of 185 mg/kg body weight/day in both sexes.

Administration, Oral↗
PubMed1985

Tests of homogeneity and trend with medians.

Algorithms for tests of homogeneity and trend with medians are presented. Under certain conditions the tests are more efficient than many standard nonparametric tests on one-way classification designs. Computationally the tests are very simple and could be performed by hand or with the help of a calculator. Application to certain types of data derived in cytogenetics is pointed out with an example.

Animals↗
PubMed1985

Some readily available computer programs for special types of statistical analyses.

A list of readily available computer programs for analysis of different types of experimental data is compiled. Some of these programs have been tested by the author for accuracy, and yet several others need to be checked by the users against existing tables and documents. The errors, to the author's knowledge, have been pointed out. Many of these programs may be used as subroutines in analyzing data derived from experiments in cytogenetics as well as other fields.

Computers↗
PubMed1985

A FORTRAN program for testing trend and homogeneity in proportions.

A FORTRAN program is provided for testing linear trend and homogeneity in proportions. Trend is evaluated by the Cochran-Armitage method and homogeneity is tested by an overall X2 test as well by multiple pairwise comparisons by the Fisher-Irwin exact method. The program should be easy to implement on any size of computer with a FORTRAN compiler.

Biometry↗
PubMed1984

A FORTRAN program to perform the nonparametric Terpstra-Jonckheere test.

The present FORTRAN program performs the nonparametric Terpstra-Jonckheere test of significance on ordered alternatives. The program is short, simple and easy to use and can be implemented on any machine including a desk-top microcomputer. When groups are ordered, the test provides more power than the Kruskal-Wallis H-test and similar multiple comparison tests.

Computers↗
PubMed1983

Gamma-aminobutyric acid and benzodiazepine receptors in an animal model of fulminant hepatic failure.

Hepatic encephalopathy (HE) is a syndrome of generalized neural inhibition, which complicates both acute and chronic liver failure. Since gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter of the brain and HE is associated with increased responsiveness to certain drugs (benzodiazepines and barbiturates) that mediate neural inhibition by binding to the GABA receptor complex on postsynaptic neural membranes, the status of this receptor complex in HE was investigated. Fulminant hepatic failure was induced in rabbits by the intravenous injection of galactosamine hydrochloride. Neural membranes were isolated from the brains of normal rabbits, rabbits in hepatic coma, and rabbits with another type of metabolic encephalopathy, uremic coma. To characterize GABA and benzodiazine receptors, measurements were made of the specific binding to neural membranes of 3H-GABA and 3H-flunitrazepam, respectively. Computer-assisted Scatchard plot analysis of the binding data suggested the presence of two independent receptors for GABA and a single class of receptor for benzodiazepines. Hepatic coma was associated with no changes in the affinities of these receptors but with significant increases in their densities: 0.34 vs. 0.60; 1.1 vs. 2.2; and 4.6 vs. 7.3 pmol/mg of membrane protein for the high-affinity GABA, low-affinity GABA and benzodiazepine receptors, respectively. Uremic coma was associated with no changes in the affinities or densities of GABA receptors. On the basis of these findings, it is suggested that (1) increased numbers of GABA receptors in liver failure may potentiate neural inhibition by increasing the sensitivity of the brain to GABA and (2) increased responsiveness to the sedative-hypnotic effects of benzodiazepines in liver failure may be mediated by increased numbers of receptors for this class of drug, permitting increased drug effect.

Animals↗
PubMed1982

Quantitative description of the binding of GM1 oligosaccharide by cholera enterotoxin.

We present a quantitative molecular interpretation of binding between the five B subunits of cholera enterotoxin and the oligosaccharide of ganglioside GM1, based on the currently accepted quaternary structure of the toxin and principles of multiple equilibria. A sequential binding equation is derived and fitted to published binding data obtained by equilibrium dialysis. In one study of binding to reduced toxin (I), intact toxin (II), and isolated B subunits (III) at low concentrations, analysis by the Hill equation suggested that binding was positively cooperative and that there were only four binding sites per toxin molecule; individual affinity constants could not be estimated because of the empirical nature of the Hill equation. Our analysis suggests that the evidence for positive cooperativity is stronger for I and III than for II. Affinity constants for the first binding step are about 2.0-2.1 microM-1 for I and 2.5-2.7 microM-1 for II and III; those for the second binding step are about 3.5-5.0 microM-1 and for I and III, but only 2.5 microM-1 for II. Constants for later binding steps are apparently within the range of 2-7 microM-1. Predictions of the sequential model at higher ligand concentrations diverge substantially from those of the Hill equation, and are supported by data obtained at higher protein and ligand concentrations. Thus all available equilibrium dialysis data are consistent with a single set of affinity constants and with the hypothesis of five equivalent binding sites.

Binding Sites↗
PubMed1981

A computer program for estimating LD50 and its confidence limits using modified Behrens-Reed-Muench cumulant method.

A FORTRAN IV program is developed for simple and quick estimation of LD50 and its confidence intervals from quantal dose-response data. The algorithm is based on a modification of the Behrens-Reed-Muench cumulant method. Under ideal experimental design, the method produces results comparable to the ones by statistically more accurate maximum likelihood method using the Logit or the Probit transformation. The procedure, as implemented, can also be easily performed on a small hand-held calculator.

Computers↗
PubMed1980

Quantitative characterization of hormone receptors.

Most workers characterize steroid (and other hormone) receptors by graphical analysis of Scatchard plots or by simple linear regression. Unfortunately, these methods are suboptimal from a statistical point of view. The Scatchard plot, B/F vs. [Bound], does not satisfy the assumptions underlying simple linear regression: both variables are subject to error, and these errors are intimately interdependent. Accordingly, nether B/F nor [Bound] is an appropriate independent variable. Furthermore, both variables (B/F and [Bound] show non-uniformity of variance. Thus, even when the Scatchard plot is liner, one should estimate the binding parameters (affinity, K, and binding capacity, R) by means of weighted nonlinear least-squares regression, using the Total ligand concentration as the independent variable, and either B/T or [Bound] as the dependent variable. In the case of a nonlinear Scatchard plot, one should also use weighted nonlinear least-squares curve fitting to estimate the K and R values for the high and low affinity classes of sites. Allowing the computer program to provide the best estimate of the nonspecific or nonsaturable binding is also desirable. The program should provide estimates of the standard errors and/or 95% confidence limits for the estimated parameters, and the joint 95% confidence limits for K and R. One should routinely attempt to fit several models of varying degrees of complexity (e.g., 1,2, or 3 classes of sites), provide estimates of the goodness-of-fit for each, and then select the best model by statistical criteria. Sometimes, we encounter Scatchard plots that are obviously nonlinear but provide insufficient information within any one experiment to permit reliable characterization of two or more classes of sites. In this case, we may employ any of several alternative techniques, including 1) use of the " limiting slopes" technique to obtain approximate estimates of parameters; 2) use of a Continuous Affinity Distribution, with consideration of only the receptors with an affinity above an arbitrarily selected cutoff value of k; 3) use of a Discrete Affinity Distribution, by assigning values to the affinities (K19 K2) based on prior information, and then estimating the binding capacities; 4) pooling information over several specimens within an assay or over several assays by use of normalizing or scaling factors. The best estimates of these scaling factors can be obtained by the use of a general least-squares method for pooling data from different specimens or experiments. A series of computer programs to perform these analyses has been developed. They have been applied successfully to analysis of steroid receptors in specimens from breast carcinoma.

Breast Neoplasms↗