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Biomedical subjects

V Kishore

Publications and source records attributed to V Kishore.

At least 19 recordsLinked to original sources
PubMed2005

Radioprotection in mice following oral delivery of amifostine nanoparticles.

PURPOSE: Amifostine (Ethyol) is an approved cytoprotective agent prescribed to reduce certain side-effects in the chemotherapy of ovarian or non-small cell lung cancer, or in radiation treatment of head-and-neck cancer. The usefulness of this drug is further hampered, because it is not effective when given orally. The objective of this part of the project was to evaluate the radioprotective efficacy of orally active amifostine nanoparticles. MATERIALS AND METHODS: Radioprotective efficacy was evaluated by measuring the ability of the amifostine nanoparticles (equivalent to 500 mg/Kg) to inhibit whole-body gamma irradiation -induced injury in mice. All mice received acute whole-body gamma irradiation from a Cesium-137 source and the radioprotective efficacy of the formulation was determined by measuring 30-day survival at 9 Gy, bone marrow hemopoeitic progenitor cell survival at 9 Gy and 8 Gy, and intestinal crypt cell survival at 11 Gy. RESULTS: Thirty-day survival, hemopoietic progenitor cell survival, as well as the jejunal crypt cell survival were all significantly enhanced when the mice were treated orally with the amifostine nanoparticles 1 h prior to irradiation. CONCLUSIONS: These results clearly and unequivocally demonstrate that the amifostine nanoparticles developed in our laboratory provides significant protection from acute whole-body gamma irradiation injury in mice.

Administration, Oral↗
PubMed2000

Total synthesis and antifungal evaluation of cyclic aminohexapeptides.

The need for new therapies to treat systemic fungal infections continues to rise. Naturally occurring hexapeptide echinocandin B (1) has shown potent antifungal activity via its inhibition of the synthesis of beta-1,3 glucan, a key fungal cell wall component. Although this series of agents has been limited thus far based on their physicochemical characteristics, we have found that the synthesis of analogues bearing an aminoproline residue in the 'northwest' position imparts greatly improved water solubility (> 5 mg/mL). The synthesis and structure-activity relationships (SAR) based on whole cell and upon in vivo activity of the series of compounds are reported.

Acute Disease↗
PubMed1998

Synthesis and radioprotective effects of adamantyl substituted 1,4-dihydropyridine derivatives.

A series of 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diesters substituted at the N-1 and/or C-4 positions of the dihydropyridine ring was synthesized. The in vitro cytotoxicity and in vitro and in vivo radioprotective efficacy of these agents were evaluated in Chinese hamster (V-79) cells and CD2F1 male mice, respectively. Compounds with at least one adamantyl substituent afforded better radioprotection than those without this substituent. Substitution of an aromatic ring at the C-4 position of the dihydropyridine ring did not enhance the radioprotectant action of the compounds.

Adamantane↗
PubMed1996

Structure--activity relationships of the didemnins.

Bioactivities of 42 didemnin congeners, either isolated from the marine tunicates Trididemnun solidum and Aplidium albicans or prepared synthetically and semisynthetically, have been compared. The growth inhibition of various murine and human tumor cells and plaque reduction of HSV-1 and VSV grown on cultured mammalian cells were used to assess cytotoxicity and antiviral activity. Biochemical assays for macromolecular synthesis (protein, DNA, and RNA) and enzyme inhibition (dihydrofolate reductase, thymidylate synthase, DNA polymerase, RNA polymerase, and topoisomerases I and II) were also performed to specify the mechanisms of action of each analogue. Immunosuppressive activity of the didemnins was determined using a mixed lymphocyte reaction (MLR) assay. These assays revealed that the native cyclic depsipeptide core is an essential structural requirement for most of the bioactivites of the didemnins, especially for cytotoxicities and antiviral activities. The linear side-chain portion of the peptide can be altered with a gain, in some cases, of bioactivities. In particular, dehydrodidemnin B, tested against several types of tumor cells and in in vivo studies in mice, as well as didemnin M, tested for the mixed lymphocyte reaction and graft vs host reaction in murine systems, showed remarkable gains in their in vitro and in vivo activities compared to didemnin B.

Animals↗
PubMed1996

A high performance liquid radiochromatographic assay for the simultaneous analysis of iloprost and misoprostol.

A high-performance liquid chromatographic (HPLC) method utilizing ultraviolet absorbance coupled with radioisotove detection was developed for the precise and simultaneous determination of iloprost and misoprostol. This assay allows complete resolution of iloprost diastereoisomers and has a total run time of approximately twenty minutes. Samples were prepared for chromatographic analysis by extracting a mixture of tritiated drugs from rat plasma with acetonitrile. The resulting solutions were chromatographed on a reversed phase Zorbax Rx-C8 column using 0.02M potassium phosphate (pH 3.0), acetonitrile, and methanol (46:30:24, v/v) at a flow rate of 1.7 mL/min. 2-Naphthoic acid was employed as an internal standard. The correlation coefficient for varying concentrations of tritiated iloprost (12.7 Ci/mmol specific activity) from 2.18 ng/mL to 21.8 ng/mL was 0.995, and the correlation coefficient for concentrations of tritiated misoprostol (50 Ci/mmol specific activity) from 0.617 ng/mL to 6.17 ng/mL was 0.993. The high selectivity and sensitivity of this assay make it useful for the simultaneous quantitation of iloprost and misoprostol.

Animals↗
PubMed1996

Distribution and localization of monophosphoryl lipid A in selected tissues of the rat.

The distribution and cellular localization of Monophosphoryl Lipid A in the kidney, liver, lung, spleen, and stomach of rat were investigated by immunohistochemistry on paraffin embedded tissue sections. Rats were sacrificed 24h or 48h following intraperitoneal administration of MPL at a dose of 5mg/Kg. The presence of MPL in selected tissues was indicated by a positive reaction to MPL antibody. In the kidneys, MPL was found in collecting tubules and distal convoluted tubules in the medulla, whereas the glomerulus was essentially free of it. Regarding liver, MPL was found to be abundant in hepatocytes but only occasionally present in Kupffer cells. In lungs, both alveolar and bronchiolar macrophages were positive, indicating the lung can also serve as a possible site for the elimination of MPL. In spleen, endothelial cells and macrophages were positive for MPL. In stomach, MPL was detected in the gastric mucosa and vascular endothelial cells. In all the tissues studied the intensity of the peroxidase reaction was significantly weaker in 48h samples as compared to corresponding 24h samples indicating possible elimination of MPL from these tissues.

Adjuvants, Immunologic↗
PubMed1994

16-epiestriol: an anti-inflammatory steroid without glycogenic activity.

All of the steroidal anti-inflammatory drugs currently available are glucocorticoids. They exhibit both glycogenic and anti-inflammatory activities. These two activities are usually considered inseparable. This glycogenic activity is responsible for most of the adverse side effects that severely limit clinical use of currently available steroidal anti-inflammatory drugs. The purpose of this study was to determine if a steroid, 16-epiestriol, could exhibit significant anti-inflammatory activity without glycogenic activity. The anti-inflammatory activity of 16-epiestriol was determined using a modified Winter's carrageenin rat paw edema model. The glycogenic activity of 16-epiestriol was determined by a modification of Venning's methods on liver and plasma glucose concentrations. In each study, 16-epiestriol-treated animals were compared to untreated control and hydrocortisone-treated animals. In the anti-inflammatory study, 16-epiestriol was more than twice as effective as hydrocortisone, on an equimolar basis, in preventing edema. 16-Epiestriol exhibited no effect on the liver or plasma glucose concentration in the glycogenic study. 16-Epiestriol exhibited potent anti-inflammatory activity without glycogenic activity. 16-Epiestriol does not conform to classical steroidal structure-activity relationship theory.

Animals↗
PubMed1994

Pharmacokinetics and pharmacodynamics in copper deficiency. I. Antiinflammatory activity of aspirin.

The effect of nutritional copper (Cu) deficiency on the antiinflammatory activity and pharmacokinetics of aspirin (ASA) was investigated in rats. Male, weanling Sprague-Dawley rats were fed either a Cu-deficient (CuD) or Cu-sufficient (CuS) diet for 49-50 d. The antiinflammatory activity of ASA was studied using the carrageenan-induced paw edema (CPE) test. ANOVA analyses of edema volumes at 2, 3, 4, 5, and 21 h postcarrageenan indicated significant differences between groups. The percent inhibition of edema due to ASA treatment in CuS was lower than that in CuD rats at 5 h, AUC5h, and AUC21h. ASA was found to be significantly more effective in inhibiting the CPE in CuD rats when compared to the CuS rats. Thus, we hypothesized that the increase in ASA's antiinflammatory activity in CuD rats was a result of a decrement in its elimination during nutritional Cu deficiency. The elimination of ASA in CuD and CuS rats was studied using an iv dose of 200 mg/kg. Concentrations of ASA and salicylic acid (SA) were determined in blood; whereas the concentrations of SA, salicylic phenol-glucuronide (SPG), and salicyluric acid (SUA) were determined in urine by HPLC. The results of the pharmacokinetic analyses from blood and urinary data indicated no significant differences in the disposition of ASA between CuD and CuS rats. For instance, the total body clearance for ASA (mean +/- SD, mL/min/kg) was 37.9 +/- 9.4 and 38.5 +/- 13.9 (p > 0.05); and the volume of distribution (Vd) for ASA (mean +/- SD, mL/kg) was 385.5 +/- 110.3 and 397.1.1 +/- 137.9 (p > 0.05) for CuD and CuS groups, respectively. Thus, contrary to our hypothesis, the enhanced antiinflammatory activity of ASA in CuD rats does not appear to be mediated via a decrement in the elimination of the drug. In addition, plasma ASA-esterase activity was found to be independent of Cu nutritional status.

Analysis of Variance↗
PubMed1993

Immunosuppressive activity of [MeBm2t]1-, D-diaminobutyryl-8-, and D-diaminopropyl-8-cyclosporin analogues correlates with inhibition of calcineurin phosphatase activity.

Calcineurin, a Ca2+/calmodulin-dependent phosphatase, has recently been identified as a common target for cyclophilin A-cyclosporin A and FK506 binding protein 12-FK506 complexes. This study has examined the structure activity relationships of cyclosporin A (CsA) and three functionally distinct analogues, [MeBm2t]1-CsA, D-diaminobutyryl-8-CsA (Dab8-CsA), and D-diaminopropyl-8-CsA (Dap8-CsA). Immunosuppressive potency in T cell activation models, NF kappa B activation, and IL-2 mRNA transcription has been compared with analogue affinity for cyclophilin A and inhibition of calcineurin phosphatase activity. CsA, Dap8-CsA, and Dab8-CsA bind to cyclophilin A with a similar affinity (Ki 4 to 5 nM as measured by inhibition of prolyl cis-trans isomerase activity), however, Dap8-CsA and Dab8-CsA inhibit T cell activation less than CsA. Although [MeBm2t]-CsA has weak affinity for cyclophilin A (Ki 540 nM), its immunosuppressive potency is similar to that of CsA. Both cyclophilin A-CsA and cyclophilin A-[MeBm2t]1-CsA complexes inhibit calcineurin phosphatase activity in vitro (Ki 114 and 67 nM, respectively). In Jurkat cells exposed to CsA or the analogues for 2 h, endogenous calcineurin phosphatase activity in cell lysates was inhibited by CsA and [MeBm2t]1-CsA (drug concentrations causing 50% reduction in 32PO4 release of 8 and 55 nM, respectively) in proportion to inhibition of T cell activation, IL-2 mRNA transcription, and NF kappa B activation. Dap8-CsA and Dab8-CsA had a minimal effect on endogenous calcineurin phosphatase activity in Jurkat cell lysates. These findings correlate the functional activity of CsA and structural analogues with calcineurin phosphatase activity and support calcineurin as a target for drug action. The Dap8 and Dab8 modifications of CsA, occurring in residue 8, which is exposed to solvent in the cyclophilin A-CsA complex, appears to significantly alter complex affinity for calcineurin.

Amino Acid Isomerases↗
PubMed1991

Determination of kinetic constants for peptidyl prolyl cis-trans isomerases by an improved spectrophotometric assay.

The kinetic properties and substrate specificity of two well-characterized peptidyl prolyl cis-trans isomerases (PPIases), cyclophilin and the FK-506 binding protein (FKBP), have been previously examined [Fischer, G., Bang, H., Berger, E., & Schellenberger, A. (1984) Biochim. Biophys. Acta 791, 87-97; Harrison, R.K., & Stein, R.L. (1990) Biochemistry 29, 1684-1689; Albers, M.W., Walsh, C.T., & Schreiber, S. L. (1990) J. Org. Chem. 55, 4984-4986]. The chymotrypsin-coupled enzymatic assay employed in these studies suffers from two serious shortcomings. Due to the low equilibrium population of the X-cis-Pro-Phe-pNA isomer (the PPIase substrate), in conjunction with the low solubility of p-nitroaniline generated by chymotrypsin hydrolysis, substrate concentrations in the saturating region are not experimentally attainable. Secondly, the uncatalyzed cis-trans isomerization obscures the interpretation of the initial velocity. As a result of these limitations, the steady-state kinetic parameters (Km,Kcat) have not been determined. Here we introduce an improved version of the spectrophotometric assay and report for the first time the Michaelis constants and turnover numbers for both PPIases with established substrates. The improvements in the experimental conditions originate in a medium-induced increase in the equilibrium population of the cis X-Pro conformer and in conducting the assay at 0 degrees C to suppress the uncatalyzed thermal isomerization. In addition, we present a rigorous mathematical model of the spectrophotometric progress curves that accounts for the contributions of the residual background rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Isomerases↗
PubMed1990

Isotope-edited NMR of cyclosporin A bound to cyclophilin: evidence for a trans 9,10 amide bond.

The binding of a 13C-labeled cyclosporin A (CsA) analog to cyclophilin (peptidyl prolyl isomerase) was examined by means of isotope-edited nuclear magnetic resonance (NMR) techniques. A trans 9,10 peptide bond was adopted when CsA was bound to cyclophilin, in contrast to the cis 9,10 peptide bond found in the crystalline and solution conformations of CsA. Furthermore, nuclear Overhauser effects (NOEs) were observed between the zeta 3 and epsilon 3 protons of the methylleucine (MeLeu) residue at position 9 of CsA and tryptophan121 (Trp121) and phenylalanine (Phe) protons of cyclophilin, suggesting that the MeLeu9 residue of CsA interacts with cyclophilin. These results illustrate the power of isotope-edited NMR techniques for rapidly providing useful information about the conformations and active site environment of inhibitors bound to their target enzymes.

Amides↗
PubMed1990

Nutritional copper deficiency does not affect sponge granuloma formation in the rat.

Sponge granuloma formation was compared in copper-deficient and copper-sufficient rats following feeding of respective diets for 20, 40, or 60 d. Body weight, total blood hemoglobin, and activities of ceruloplasmin and Cu, Zn-superoxide dismutase in plasma were monitored to ascertain copper deficiency. Mean granuloma weights (mg +/- SEM) in copper-deficient and copper-sufficient groups of rats, respectively, were as follows: 37 +/- 2 and 38 +/- 2 after 20 d, 22 +/- 2 and 23 +/- 2 after 40 d, and 19 +/- 1 and 21 +/- 1 after 60 d on respective diets. Thus, nutritional copper deficiency did not have an effect on sponge granuloma formation in the rat.

Animals↗
PubMed1990

Effects of copper aspirinate and aspirin on tissue copper, zinc, and iron concentrations following chronic oral treatment in the adjuvant arthritic rat.

Concentrations of copper, zinc, and iron were analyzed and compared in a number of tissues of adjuvant arthritic rats following 22 d of chronic treatment (per os) with either vehicle, aspirin or copper aspirinate, at doses of 100 mg/kg, 200 mg/kg, or 400 mg/kg. Such chronic treatment resulted in a negative balance in copper, zinc, and iron in many tissues. Among the tissues examined, liver and kidney exhibited the greatest changes in metal concentrations; brain and skeletal muscle exhibited the least. Arthritis-induced changes in the concentrations of all three metals in the liver were reversed upon treatment with aspirin. Treatment with copper aspirinate, on the other hand, resulted in an extremely high accumulation of copper in the liver. Arthritis-induced changes in copper, zinc, and iron concentrations in the pancreas and copper concentration in the plasma were generally not reversed upon treatment with either aspirin or copper aspirinate. Among the three metals examined, the degree of change observed as a result of drug treatments was greatest for iron and least for zinc. Finally, it appeared that the effects of aspirin and copper aspirinate on tissue metal concentrations were independent of the antiarthritic effects of these compounds.

Administration, Oral↗
PubMed1989

Effects of adjuvant arthritis on copper, zinc, and iron metabolism in the rat.

In a study on the effects of adjuvant arthritis on copper (Cu), zinc (Zn), and iron (Fe) metabolism in the rat, most significant changes were observed in the liver and pancreas where arthritis caused a large increase in the concentrations of all three metals. Results also indicated that although arthritis-induced changes in metal concentrations were highly correlated to inflammation and occurred in selected tissues only, these changes were not selective for copper.

Animals↗