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Biomedical subjects

R P Sharma

Publications and source records attributed to R P Sharma.

At least 145 records · Page 8Linked to original sources
PubMed1989

Pharmacokinetics, tissue distribution, and placental permeability of all-trans- and 13-cis-N-ethyl retinamides in pregnant hamsters.

Retinamides have clinical applications in therapy of dermatologic disease, have cancer chemopreventive/chemotherapeutic activities, and possess larger therapeutic ratios than their acidic congeners. The N-ethyl-all-trans-retinamide (NERA) and its 13-cis congener (CNERA) failed to induce terata in hamsters, but an equivalent oral dose of all-trans- or 13-cis-retinoic acid was associated with a significant teratogenic response. Following intubation of 11.4 mg/kg of [3H]NERA or [3H]CNERA to pregnant hamsters during a sensitive stage of development, radioactivity accumulated in maternal bladder and liver. Although plasma concentrations of the parent retinamides declined to nondetectable levels within 12 hr of dosing, near-peak concentrations of retinamide metabolites persisted in maternal plasma until termination of the study (96 hr). Cis/trans isomerization of each retinamide at C13 occurred, but only 15-20% of the total dose could be accounted for as parent retinamide and its C13 isomer. The retinamides were not metabolized to detectable concentrations of circulating all-trans- or 13-cis-retinoic acid. Although the label associated with the retinamides and their biotransformation products crossed the placenta, there was no evidence for preferential accumulation in embryonic or fetal tissues. The results presented here show that the reduced teratogenic potency of retinamides compared to acidic retinoids cannot be ascribed to reduce placental transfer.

Animals↗
PubMed1989

Effects of aflatoxin B1 on murine lymphocytic functions.

We recently reported on the immunotoxic effects of Aflatoxin B1 (AFB1), a secondary fungal metabolite of Aspergillus flavus in mice. The present paper describes the effect of AFB1 on cellular functions in lymphocytes after in vivo or in vitro exposures. Male BALB/c mice received 0, 0.03, 0.145 or 0.7 mg/kg body weight of AFB1 for 4 weeks. A dose-related decrease in DNA synthesis in lymphocyte cultures with or without the mitogens (lipopolysaccharide, phytohemagglutinin, pokeweed mitogen and concanavalin A) was observed. No effects on protein or ribonucleic acid synthesis were observed. There were dose-dependent decreases in peripheral leucocyte counts and natural killer cell function. Splenic lymphocytes from normal mice cultured with 10(-6) to 10(-4) M AFB1 had decreased DNA synthesis at greater than 1 X 10(-5) M, a decreased protein synthesis at 10(-4) M and decreased RNA synthesis at greater than 2.5 X 10(-5) M. In vitro addition of AFB1 (greater than 50 microM) reduced generation of concanavalin A-induced suppressor cells. The results suggest that AFB1 had a direct and complex effect on lymphocytes and there is a differential sensitivity of various subpopulations.

Administration, Oral↗
PubMed1989

Diurnal alterations of catecholamines, indoleamines and their metabolites in specific brain regions of the mouse.

1. The diurnal variations of regional brain concentrations of dopamine (DA), norepinephrine (NE), serotonin (5-HT) and metabolites were determined in unperturbed male CD-1 mice. Determinations were made every 4 hr for 24 hr. 2. The most striking and significant variations in biogenic amines were seen in the hypothalamus, where concentrations of NE, DA and 5-HT varied in a rhythmic pattern and as much as two-fold during this period. 3. In some cases, daily alterations in parent biogenic amines were reflected by concurrent changes in their metabolites. 4. Since concentrations of neurotransmitters in the brain are often used as an indicator of stress and/or toxicity, these data should provide an accurate data base allowing for more accurate interpretation of results.

Animals↗
PubMed1989

Importance of hydroxyl radical in the vanadium-stimulated oxidation of NADH.

Vanadium compounds are known to stimulate the oxidation of NAD(P)H, but the mechanism remains unclear. This reaction was studied spectrophotometrically and by electron spin resonance spectroscopy (ESR) using vanadium in the reduced state (+4, vanadyl) and the oxidized state (+5, vanadate). In 25 mM sodium phosphate buffer at pH 7.4, vanadyl was slightly more effective in stimulating NADH oxidation than was vanadate. Addition of a superoxide generating system, xanthine/xanthine oxidase, resulted in a marked increase in NADH oxidation by vanadyl, and to a lesser extent, by vanadate. Decreasing the pH with superoxide present increased NADH oxidation for both vanadate and vanadyl. Addition of hydrogen peroxide to the reaction mixture did not change the NADH oxidation by vanadate, regardless of concentration or pH. With vanadyl however, addition of hydrogen peroxide greatly enhanced NADH oxidation which further increased with lower pH. Use of the spin trap DMPO in reaction mixtures containing vanadyl and hydrogen peroxide or a superoxide generating system resulted in the detection by ESR of hydroxyl. In each case, the hydroxyl radical signal intensity increased with vanadium concentration. Catalase was able to inhibit the formation of the DMPO--OH adduct formed by vanadate plus superoxide. These results show that the ability of vanadium to act in a Fenton-type reaction is an important process in the vanadium-stimulated oxidation of NADH.

Cyclic N-Oxides↗
PubMed1989

Immunotoxicological evaluation of toluene exposure via drinking water in mice.

Toluene is a known contaminant found in trace amounts in groundwater. Male CD-1 mice were exposed to 0, 17, 80, and 405 mg/liter toluene in drinking water for 4 weeks. Immune function assays were selected to evaluate specific humoral and cell-mediated immunity, interleukin-2 (IL-2) activity, hematology, along with general toxicity. Toluene produced an increase in liver weight and decrease in thymus mass at the highest dose. No effects on body weights and hematological parameters, including erythrocytes, leukocytes, and their differentials were noticed. Mitogenesis by lipopolysaccharide, pokeweed mitogen, concanavalin A, and phytohemagglutinin were suppressed in splenocytes from treated mice. Splenocyte lymphoproliferation to alloantigens decreased at the 405 mg/liter concentration only. Numbers of sheep red blood cell (SRBC)-specific plaque-forming cells decreased in the highest dosed animals; however, no significant change was observed in the serum alpha-SRBC antibody level. Toluene also adversely affected IL-2 synthesis at the 405 mg/liter concentration. Findings suggest that alteration of immune functions of mice ingesting toluene was generally evident at relatively high doses, except for splenic lymphocyte responses to selected mitogens.

Administration, Oral↗
PubMed1989

Construction of chickpea genomic library.

For construction of chickpea genomic library, DNA was isolated, purified on CsCl gradient and size fractionated into 15-20 Kb fragments after restriction with Sau 3A. These fragments were ligated to phage lambda (EMBL-3) vector and the recombinant molecules packaged in vitro into viable phage particles. The recombinant phages were obtained as phages on a P2 lysogen of E. coli (Spi- selection) and amplified to establish a permanent library. This is the first report of the construction of chickpea genomic library.

DNA↗
PubMed1989

Immunotoxic potential of N-ethyl, N-nitrosourea (ENU) in CD1 mice.

The immunotoxic potential of ENU, a potent and transplacental neurocarcinogen, was evaluated in male CD1 mice. The animals received i.p. injections of ENU--0, 2, 8 or 32 mg/kg body weight, in citrate-phosphate buffer, twice weekly for three weeks. Splenic lymphocytes were cultured in the presence of mitogens, lipopolysaccharide, pokeweed mitogen, concanavalin A and phytohaemagglutinin. Mixed lymphocyte cultures in the presence of allogeneic cells were also tested. Blastogenic response decreased in a dose-dependent manner, as measured by the 3H-thymidine uptake by splenocytes. Primary antibody production by splenic lymphocytes from animals challenged with a T-dependent antigen (sheep red blood cells) was stimulated at low doses but depressed at the highest dose group compared with the controls, whereas T-independent cell response showed no significant change. Our results suggest that exposure to repeated, low levels of ENU significantly alters the immune status of CD1 mice. The effects appear to be somewhat selective to T cell processes, based on in vivo responses to T-dependent and T-independent antigens.

Animals↗
PubMed1989

Trifluoperazine plasma levels and clinical response.

The authors studied 36 acutely psychotic inpatients who were diagnosed as having either a schizophrenic (N = 30) or other psychotic (N = 6) disorder. After a washout phase averaging 18 days, all patients were placed on trifluoperazine 5 mg orally twice a day. Plasma levels of trifluoperazine were obtained on days 11 and 15 of treatment and then compared with clinical response. After 2 weeks of treatment an inverted U-shaped relationship was found between change scores on the Brief Psychiatric Rating Scale and trifluoperazine plasma levels.

Adult↗
PubMed1988

Vanadium and lipid peroxidation: evidence for involvement of vanadyl and hydroxyl radical.

The present study was designed to determine which form of vanadium is involved in initiating conjugated diene formation in both purified and partially peroxidized fatty acids, and to determine if active oxygen radicals are involved in this process. We report that vanadyl is the active form of vanadium in initiating conjugated diene formation in micelles prepared from purified fatty acids or partially peroxidized fatty acids. Vanadate did not initiate conjugated diene formation in either case. Hydroxyl radicals were shown to be involved in the initiation of diene conjugation when vanadyl and hydrogen peroxide were added together in a reaction mixture. In this case, there was a rapid burst of conjugated diene formation which quickly leveled off. Using spin trapping techniques, hydroxyl radicals were shown to be generated in the vanadyl-catalyzed break-down of fatty acid hydroperoxides. A comparison was made between the ability of vanadyl or vanadyl chelates to decompose hydrogen peroxide and catalyze the decomposition of fatty acid hydroperoxides. It was found that strongly chelated vanadyl (vanadyl/EDTA) was much less effective in decomposing both hydrogen peroxide and fatty acid hydroperoxides than the weak vanadyl chelates (e.g., vanadyl/ADP). This study suggests a mechanism to explain the effects of vanadium on lipid peroxidation.

Electron Spin Resonance Spectroscopy↗
PubMed1988

The effect of diagnosis and age on the DST: a metaanalytic approach.

The authors present new data on the results of the pretreatment Dexamethasone Suppression Test (DST) in 164 drug-free inpatients, as well as on the effects of age on postdexamethasone cortisol values. Nonsuppression rates were 18% in schizophrenic patients (n = 44), versus 46% in patients with a major depression (n = 56). In addition, a significant correlation was found between age and the 4:00 PM postdexamethasone cortisol value among the depressed patients (r = 0.33). The authors then applied a metaanalysis to summarize 25 other studies that have addressed the schizophrenia/major depression dichotomy as it relates to the DST outcome. Nonsuppression rates were consistently different in schizophrenic patients (19%) when compared to patients with a major depression (51%) or normal controls (7%). These differences were highly significant as measured by the Mantel-Haenszel chi-square statistic. A metaanalysis applied to a series of correlations obtained from 14 other studies reporting an age/postdexamethasone cortisol relationship in affective patients indicated a modest, but significant correlation (r = 0.24) in a total of 1284 patients (p less than 1 x 10(-8)).

Adolescent↗
PubMed1988

Unusually high intake and fecal output of cadmium, and fecal output of other trace elements in New Zealand adults consuming dredge oysters.

The concentration of cadmium in the New Zealand dredge oyster Tiostrea lutaria (commonly known as a Bluff oyster) is sufficiently high so that the ingestion of just one oyster can more than double a normal daily dietary intake of cadmium for a New Zealand adult. A survey of 75 adults (18-76 years old) associated with the oyster fishing industry in Bluff, Southland, New Zealand, was carried out before and at the end of the oyster season. Preseason intakes (from dietary history questionnaires and from 3-day fecal collections) of cadmium, selenium, zinc, copper, and manganese were normal for a New Zealand adult not consuming Bluff oysters. The subjects were classified according to their reported average oyster consumption during the 6 months of the oyster fishing season; the subjects who consumed more oysters were more likely to smoke cigarettes. The end-season fecal output of cadmium confirmed the reported average oyster intakes: Category I (0-5 oysters/week): 15 +/- 8 (mean +/- SD) micrograms Cd/day; Category II (6-23 oysters/week): 84 +/- 134 micrograms Cd/day; Category III (24-71 oysters/week): 129 +/- 144 micrograms Cd/day; Category IV (72+ oysters/week): 233 +/- 185 micrograms Cd/day. The fecal output of selenium as well was increased by the consumption of many oysters but the fecal outputs of zinc, copper, and manganese were not. Using fecal cadmium excretion to predict dietary cadmium intake, 8-15% of the subjects in this study were identified as having an intake of cadmium which has been associated with an increased prevalence of tubular proteinuria. The highest individual daily fecal excretion of cadmium at the end of the season was 580 micrograms Cd/day, i.e., a daily excretion equivalent to more than 10 times above the weekly intake provisionally considered tolerable (400-500 micrograms Cd/week; WHO, 1972). Continued investigations on this population group will determine whether there are any health consequences of these extremely high cadmium intakes.

Adult↗
PubMed1988

Structure-activity relationships of retinoids in developmental toxicology. III. Contribution of the vitamin A beta-cyclogeranylidene ring.

The teratogenic potency of congeners of all-trans-retinoic acid (all-trans-RA) containing modifications or substitution of the naturally occurring beta-cyclogeranylidene ring was determined in Golden hamsters and compared to that of all-trans-RA. The following ring-modified retinoids were screened: phenyl (Ro 8-8717), furyl (Ro 8-9750), 4-methoxy-2,3,6-trimethylphenyl (Ro 21-6667), which also has a thiomethylene group in place of the trans-8,9 double bond of the etretin side chain, 4-hydroxy-2,3,6-trimethylphenyl (Ro 11-4768), 2-chloro-3,6-dimethyl-4-methoxyphenyl (Ro 12-0995), 2-(1-methoxyethyl)-5,5-dimethyl-1-cyclopentenyl (Ro 10-1770), 2-acetyl-5,5-dimethyl-1-cyclopentenyl (Ro 8-7699), and 10,11-epoxy-11,11-dimethyl (juvenile hormone III), which also has the bonds corresponding to the 7,8- and 11,12-double bond of the retinoid skeleton saturated. The retinoids Ro 12-4824, Ro 12-4825, and SRI2712-24 had C4-keto, C18-hydroxyl, and C18-methyl substituents, respectively. Motretinid (Ro 11-1430) had both 4-methoxy-2,3,6-trimethylphenyl ring and ethyl amide polar group modifications. Single oral retinoid doses administered to pregnant dams at 10:00 AM on Day 8 neither induced signs of hypervitaminosis A nor induced weight loss in any of the treated groups. Teratogenically active retinoids induced a malformation syndrome identical to that induced by all-trans-RA. At retinoid doses that were associated with malformations in all of the fetuses, embryolethality remained near that of vehicle-treated controls. The phenyl retinoid Ro 8-8717 was embryolethal but was not teratogenic. The ethyl amide derivative of the human and animal teratogen etretinate, motretinid, was teratogenic only at the highest dose administered, 350 mg/kg. The retinoids Ro 12-4824, Ro 12-4825, Ro 8-7699, and SRI 2712-24 were as potent as all-trans-RA. The chlorine substituted retinoid, Ro 12-0995, was sixfold more teratogenic than all-trans-RA, and the cyclopentene retinoid, Ro 10-1770, was 19 times more potent than all-trans-RA. The retinoids with furyl or epoxy group substitution for the cyclohexenyl ring were devoid of teratogenic activity up to equimolar doses of 75 mg/kg of all-trans-RA, and Ro 21-6667 was teratogenically inactive at a dose equivalent to 150 mg/kg of all-trans-RA. Major modifications of the beta-cyclogeranylidene ring can be made without altering teratogenic activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗