Biomedical subjects

K C Agrawal

Publications and source records attributed to K C Agrawal.

At least 37 records · Page 2Linked to original sources

PubMed1991

Pharmacokinetics and long-term tolerance to ribavirin in asymptomatic patients infected with human immunodeficiency virus.

Single-dose and steady-state pharmacokinetics of the antiviral agent ribavirin were studied in seven male, asymptomatic, human immunodeficiency virus-seropositive subjects. After a single 400 mg intravenous infusion, mean terminal plasma half-life (t1/2) was 27.1 hours, mean volume of distribution was 802 L, and mean total plasma clearance was 26.1 L/hr. Renal clearance was 39% of total clearance and it exceeded creatinine clearance. Oral bioavailability was 44.6%. With long-term dosing (400 mg orally twice a day) ribavirin accumulated, reaching steady state in 2 to 4 weeks in plasma and red blood cells. Red blood cell concentrations greatly exceeded plasma concentrations (60:1). Plasma concentrations at steady state (trough) were 10- to 14-fold higher than the corresponding single-dose concentrations. The terminal t1/2 (washout) after 16 weeks greatly exceeded the t1/2 observed after a single oral dose (151 versus 29.6 hours). Ribavirin-induced reductions in hemoglobin ranging from 0.8 to 3.5 gm/dl were well tolerated. There was no significant reduction in CD4 lymphocytes during treatment with ribavirin for 16 weeks in subjects who had more than 200 CD4 cells at entry and who also remained free of opportunistic infections during 24 weeks of observation.

Administration, Oral↗

PubMed1991

Protection of zidovudine-induced toxicity against murine erythroid progenitor cells by vitamin E.

The ability of vitamin E (alpha-tocopherol) to stimulate erythroid progenitor cells was investigated in an attempt to identify ways to ameliorate zidovudine (azidothymidine, AZT)-induced anemia. In vitro, alpha-tocopherol acid succinate (ATS), upon incubation with murine bone marrow cells at concentrations of up to 4 micrograms/ml, caused a dose-dependent increase in erythroid colony-forming unit (CFU-E)-derived colonies. This increase was equivalent to the effect demonstrated by 50 mU of recombinant human erythropoietin (rhEpo) or 200 U of recombinant interleukin 3 (rIL-3). For in vivo studies, anemia was produced in CD-1 male mice by administering AZT in drinking water (1.5 mg/ml). Treatment with vitamin E (50 mg/kg body weight) or Epo (0.4 U per mouse) was initiated 24 h later and continued for five consecutive days. Seventh day bone marrow cells from femurs were assayed for CFU-E-derived colonies. Both vitamin E and Epo significantly increased the number of CFU-E-derived colonies by 75% and 86% of control, respectively, indicating that these agents were approximately similar in protecting the bone marrow from AZT-induced toxicity.

Anemia↗

PubMed1990

Synthesis and biological evaluation of prodrugs of zidovudine.

A series of prodrugs of zidovudine (AZT) has been synthesized in an effort to enhance the uptake of the prodrugs by the HIV-1 infected cells and to increase the plasma half-life of AZT. The 5'-OH function of AZT was esterified with various acids in the presence of DCC and 4-(dimethylamino)pyridine (DMAP). The prodrug moieties included (a) morpholine and N-phenylpiperazine-1-acetic acid, (b) 1,4-dihydro-1-methyl-3-nicotinic acid, (c) retinoic acid, and (d) certain amino acids. The anti-HIV-1 activity of the esters was determined in peripheral blood lymphocytes. The IC50 for AZT in this system was 0.12 microM whereas for prodrugs it ranged from 0.05 to 0.2 microM. The prodrugs were generally less cytotoxic than AZT except the retinoic acid ester. In vitro hydrolysis of the various esters in human plasma indicated that these agents were relatively stable toward plasma esterases with t1/2 ranging from 10 to 240 min. Drug uptake studies in H9 cells with radiolabeled analogues demonstrated that the retinoic acid ester achieved approximately 4-fold higher intracellular concentration than [3H]AZT. However, 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester (5) was the most active agent of this series and had a higher therapeutic index than AZT.

Animals↗

PubMed1990

Sickle haemoglobin, G-6PD deficiency and malaria in western Orissa.

Sixty cases of malaria were screened for sickle haemoglobin and G-6PD deficiency. Plasmodium vivax was detected in 40 (66%) and Plasmodium falciparum in 21 (35%) cases, with six of the latter having cerebral manifestation. Sickle Hb was found in 7 (11.5%) patients and G-6PD deficiency in 3 (5%) cases. Both patients with SS disease had vivax malaria, while of 5 with sickle cell trait 3 had only vivax, one only falciparum and one mixed infection. Amongst G-6PD deficient patients one had vivax and two falciparum malaria. One of the latter had both SC trait and G-6PD deficiency. Thus, adult persons with SS disease or SC trait were not found to be resistant to either vivax or falciparum malaria. A high frequency (5%) of G-6PD deficiency amongst malaria patients warrants a caution against indiscriminate use of 8-aminoquinoline drugs.

Adolescent↗

PubMed1989

Increased therapeutic efficacy of zidovudine in combination with vitamin E.

Antiviral activity and bone marrow toxicity of 3'-azido-3'deoxythymidine (Zidovudine; AZT) was evaluated in the presence of alpha-D-tocopherol acid succinate (ATS) in the MT4 cell line and in murine hematopoietic progenitor cells, respectively. At varying concentrations (.016 to .125 microM) of AZT, addition of ATS (5 to 15 micrograms/ml) showed a dose-dependent increase in anti-HIV activity. The ED90 of AZT in this test system was 0.37 microM, whereas in the presence of ATS (15 micrograms/ml) it was 0.06 microM, thus producing an approximately 6-fold increase in anti-HIV activity. In contrast, in murine bone marrow cells, ATS (4 micrograms/ml) showed significant protection (p less than 0.05) against AZT-induced toxicity as measured by CFU-E and CFU-GM assays. The IC50 values in the presence and absence of ATS for CFU-E were 3.7 and 1.5 microM, whereas for CFU-GM were 6.0 and 2.7 microM, respectively. Overall, these data suggest that AZT in combination with ATS has greater therapeutic efficacy against HIV-1.

Cell Line↗

PubMed1989

Modulation of prostaglandin biosynthesis in hypoxic murine mammary adenocarcinoma cells by misonidazole.

Resistance of hypoxic cells to radiation and chemotherapy remains a major limitation to effective therapy of solid tumors. Misonidazole, a 2-nitroimidazole analogue, has been studied extensively as a radiosensitizer of hypoxic cells and has been shown to undergo bioreductive metabolism to exert preferential cytotoxicity against hypoxic cells. We have investigated the effects of misonidazole on the biosynthesis of prostaglandins (PGs) in a murine mammary adenocarcinoma cell line (No. 4526) under aerobic and hypoxic conditions in attempts to exploit modulation of PG levels under hypoxia as a means of improving therapeutic approaches for the treatment of solid tumors. We report a time-dependent inhibition of PG biosynthesis by the suspended cells under hypoxia induced by flushing sealed vials with N2 (1.5 liters/min). After 30 min of hypoxia, PG formation was inhibited by 50%. Indomethacin was able to further inhibit the PG formation in a concentration-dependent manner under hypoxia. Misonidazole, however, selectively increased the PGE2 biosynthesis under hypoxia by 49% at 100 microM. This increase was concentration dependent over the range of 25 to 100 microM and was blocked by indomethacin (0.1 microM). Imidazole, the heterocyclic moiety in misonidazole without the nitro function, had no effect on PG biosynthesis at these concentrations. These data suggest that arachidonic acid metabolism is sensitive to the differential oxygen levels which exist within solid tumors and that PG levels may be modulated by electron-affinic agents in hypoxic tumor cells.

Adenocarcinoma↗

PubMed1989

A pro-drug of zidovudine with enhanced efficacy against human immunodeficiency virus.

In an attempt to alleviate the drug-related toxicity of zidovudine in patients with AIDS, a pro-drug of zidovudine, 5'-[(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)oxy]-3'-azido-2',3'- dideoxythymidine (DP-AZT), has been evaluated. Cellular uptake by H9 cells and peripheral blood lymphocytes (PBL) with zidovudine and DP-AZT showed at least a 50% greater intracellular concentration of DP-AZT within 2 hr. DP-AZT was significantly less toxic to murine bone marrow cells as measured by CFU-E assay. The ED50 concentration to inhibit the production of HIV specific p24 antigen was 0.05 microM for DP-AZT whereas zidovudine required 0.125 microM. These results demonstrated that DP-AZT has a higher therapeutic ratio than zidovudine as an anti-HIV-1 agent.

Animals↗

PubMed1989

Anti-HIV drugs: comparative toxicities in murine fetal liver and bone marrow erythroid progenitor cells.

The toxicity of anti-HIV drugs, 3'-azido-3'-deoxythymidine (zidovudine, AZT), 2',3'-dideoxycytidine (DDC), 2',3'-dideoxy-2',3'-didehydrothymidine (d4T) and ribavirin was studied in vitro in murine fetal liver cells (FLC) and in bone marrow cells. These studies indicate that d4T is the least toxic drug and ribavirin is the most toxic agent in both models. However, the murine FLC system was found to be a more sensitive model for the assessment of toxicity of anti-HIV agents towards erythroid progenitor cells as indicated by the IC50 values.

Animals↗

PubMed1989

Inhibition of GSH-dependent PGH2 isomerase in mammary adenocarcinoma cells by allicin.

We have reported that allicin, a constituent of garlic oil, has no effect on the activities of platelet cyclooxygenase or thromboxane synthase, or vascular PGI2 synthase. The effect of allicin on glutathione (GSH) dependent PGH2 to PGE2 isomerase is unknown. We therefore studied the effect of allicin on PGE2 biosynthesis in a murine mammary adenocarcinoma cell line (No 4526). Intact or sonicated cells were incubated with either 14C-arachidonic acid (AA) or 14C-PGH2, respectively. Following metabolism, products were extracted, separated by TLC and analyzed by radiochromatographic scan. PGE2 was predominantly formed with minimal amounts of PGF2 alpha and PGD2. Formation of 6-keto-PGF1 alpha or TXB2 was not detected indicating the absence of TXA2 and PGI2 synthase activity. Indomethacin and ibuprofen inhibited the PGE2 formation (p less than 0.05). The enzymatic PGE2 formation in sonicates was blocked by depletion of the cellular non-protein thiols by buthionine sulfoximine and was shown to be dependent on GSH. Allicin, over the range of 10-1000 microM, inhibited the formation of PGE2 in cells exposed to 2.0 microM 14C-AA for 20 min. and in sonicated cells incubated with 20.0 microM 14C-PGH2 for 2 min (p less than 0.05). Allicin did not alter cyclooxygenase-mediated oxygen utilization in ram seminal vessicle microsomes, suggesting that allicin selectively inhibits the GSH-dependent PGH2 to PGE2 isomerase in this adenocarcinoma cell line.

Adenocarcinoma↗

PubMed1988

Role of nonprotein thiols in enzymatic reduction of 2-nitroimidazoles.

The role of nonprotein thiols (NPSH) in the enzymatic reduction of the nitro function in 2-nitroimidazoles (2-NI) has been investigated. The addition of NPSH has been shown previously to protect cells from the hypoxic cytotoxicity of 2-NI, whereas depletion of NPSH enhances the hypoxic cytotoxicity. In this report, we have investigated the effects of thiol depleting agents, N-ethylmaleimide (NEM) and diethyl maleate (DEM), on the enzymatic reduction of the nitro group. Cytosolic and microsomal fractions of rat hepatic tissue and xanthine oxidase were employed as sources of nitro reductases. Addition of NPSH caused an enhancement in the reduction of the nitro group of 2-NI; cysteine was significantly more effective than glutathione (GSH) in stimulating the enzymatic reduction. The reduction of the nitro function was decreased markedly in the presence of NEM or DEM. Addition of cysteine or GSH reversed the inhibition with NEM. Both NEM and DEM also attenuated the enhancement of reduction observed after the addition of NPSH. These results suggest that the addition of NPSH facilities the reduction of the nitro function to the reduced intermediates that may be inactivated by an excess of NPSH, whereas the depletion of NPSH allows the accumulation of the toxic nitro radicals causing increased cytotoxicity.

Animals↗

PubMed1988

The pharmacological effects of allicin, a constituent of garlic oil.

Garlic has been used in herbal medicine for thousands of years. While garlic oil contains many components and has been widely studied, the pharmacology of pure allicin, a constituent of garlic oil, is not well understood. We report that allicin inhibits human platelet aggregation in vitro without affecting cyclooxygenase or thromboxane synthase activity or cyclic adenosine monophosphate (AMP) levels. Allicin does not alter the activity of vascular prostacyclin synthase. However, it inhibits ionophore A23187-stimulated human neutrophil lysosomal enzyme release. In vivo allicin dilates the mesenteric circulation of the cat independent of prostaglandin release or a beta adrenergic mechanism.

Animals↗

PubMed1986

Radiosensitization, pharmacokinetics, and toxicity of a 2-nitroimidazole nucleoside (RA-263).

A 2-nitroimidazole nucleoside, 1-(2',3'-dideoxy-alpha-D-erythro-hex-2'-enopyranosyl)-2-nitroimida zole (RA-263), has been investigated for its radiosensitization, pharmacokinetics, and toxicity properties. The in vitro radiosensitization tests against hypoxic Chinese hamster (V-79) cells demonstrated that RA-263 was a more potent radiosensitizer than misonidazole and at 2 mM concentration approached the oxic curve. Significant in vitro radiosensitization activity was also observed in EMT6 mammary tumor cells. The in vitro cytotoxicity data suggested that RA-263 is considerably more toxic to hypoxic cells than misonidazole. The increased cytotoxicity may be related to its higher depletion of nonprotein thiols (NPSH) than misonidazole. The combined effects of radiosensitization and hypoxic cell toxicity were measured by preincubation of the V-79 cells for 4 h under hypoxic conditions before irradiation. The results demonstrated a synergistic response by causing a significant decrease in the extrapolation number with loss of shoulder of the radiation survival curves. The in vivo radiosensitization experiments conducted by the in vivo-in vitro cloning assay with the EMT6 mammary tumor indicate that RA-263 is an effective sensitizer. Pharmacokinetic data suggested that RA-263 was eliminated from plasma by a rapid alpha phase and a slower beta phase with T 1/2 of 36 and 72 min, respectively. The concentration in the brain was approximately one-sixth of tumor concentration, suggesting that RA-263 is excluded from the CNS. Moreover, RA-263 was two times less toxic than misonidazole on equimolar basis by acute LD50 tests. This agent was also significantly less mutagenic than misonidazole in a strain of Escherichia coli.

Animals↗

PubMed1985

Potential radiosensitizing agents. 7. 4(5)-Iodo-5(4)-nitroimidazole derivatives.

A series of 4(5)-iodo-5(4)-nitro-1-substituted-imidazoles has been synthesized and tested for their ability to selectively radiosensitize hypoxic Chinese hamster cells (V-79) to the lethal effect of radiation. The reaction of 4(5)-iodo-5-(4)-nitroimidazole with 1,2-epoxy-3-methoxypropane and ethyl alpha-chloroacetate produced two isomeric products in each case, which were identified by their NMR spectra. The ethyl esters were further reacted with 3-picolylamine to produce corresponding amides. The 5-iodo-4-nitroimidazole-1-N-(3-picolyl)acetamide on further reaction with m-chloroperbenzoic acid produced the corresponding N-oxide. These compounds were generally more toxic to V-79 cells than the 2-nitroimidazole derivatives and were found to be more effective radiosensitizers in vitro. The 5-iodo-4-nitroimidazole derivatives were more efficient as sensitizers than the 4-iodo-5-nitroimidazole derivatives, and the sensitizing efficiency of this class of agents was found to have significant correlation with their partition coefficients.

Animals↗

PubMed1984

Pharmacokinetic studies of amino acid analogues of 2-nitroimidazole, new hypoxic cell radiosensitizers.

A series of new analogues of 2-nitroimidazole has been synthesized by inserting various amino acids at 1-position through an amide bond. The ethyl esters of N-alpha-[(2-nitro-1-imidazolyl)acetyl]-L-phenylalanine and N-alpha-[2-nitro-1-imidazolyl)acetyl]-L-tyrosine were found to be the most effective radiosensitizers in vitro against hypoxic Chinese hamster (V-79) cells. The sensitizer enhancement ratios (SER) of these derivatives were 2.2 and 2.3 respectively at 1 mM concentration after 2 hr exposure under hypoxia. However, the free acid of phenylalanine analogue was less active as a radiosensitizer and required 5 mM concentration to produce SER of 1.9. In contrast, the free acid of tyrosine analogue was inactive in this test system. The pharmacokinetic studies with the esters revealed their rapid hydrolysis in serum to the corresponding acids within 5 minutes as detected by HPLC. The pharmacokinetic parameters were therefore determined by employing the free acid analogues and solubilizing them as their sodium salts. The drugs were administered intraperitoneally at 0.5 mg/g dose level to C-57 mice bearing B16 melanoma. These agents were cleared from the plasma rapidly with an apparent t 1/2 of 18.8 and 15.6 min respectively. Peak tumor concentration of approximately 217 micrograms/g was achieved within 15 min with phenylalanine analogue. The tumor to brain ratio was 10:1 suggesting that this agent is excluded from CNS and that the phenylalanine analogue should be considered a potentially less neurotoxic radiosensitizer than misonidazole.

Amino Acids↗

PubMed1983

Potential radiosensitizing agents. 6. 2-Nitroimidazole nucleosides: arabinofuranosyl and hexopyranosyl analogues.

New 2-nitroimidazole nucleosides have been synthesized as radiosensitizers of hypoxic mammalian cells in an attempt to reduce the neurotoxicity and to increase the therapeutic efficacy of this class of agents. The trimethylsilyl derivative of 2-nitroimidazole was condensed with 1-bromo-2,3,5-tri-O-benzoylarabinofuranose in the presence of mercuric cyanide to yield anomeric isomers of arabinofuranosides, which were separated by preparative thin-layer chromatography. Reaction of 2-deoxy-1,3,4,6-tetra-O-acetyl-D-glucose or 3,4,6-tri-O-acetyl-D-glucal with 2-nitroimidazole in the presence of an acid catalyst produced alpha and beta isomers of 2',3'-dideoxy-D-erythro-hex-2'-enopyranosides and an isomeric 3-substituted 1,2,3-trideoxy-D-erythro-hex-1-enopyranose. Hydrolysis of the esters was accomplished with sodium methoxide in methanol at 0 degrees C. The radiosensitizing efficacy of these agents was determined against Chinese hamster (V-79) cells in vitro. The 1-(2',3'-dideoxy-alpha-D-erythro-hex-2'-enopyranosyl)-2-nitroimidazole was the most active agent of this series and was found to be superior to misonidazole as a radiosensitizer.

Animals↗

PubMed1982

Potential Radiosensitizing Agents III: 2-Nitro-4-acetylimidazole analogs.

New analogs of 2-nitroimidazole have been synthesized in an effort to minimize the toxicity and increase selective sensitization of hypoxic mammalian cells toward lethal effects of ionizing radiation. 2-Nitro-4(5)-acetyl-5(4)-methylimidazole was synthesized from the corresponding 2-amino analog and then reacted with oxiranes to produce the corresponding 1-substituted 2-propanol and 3-methoxy-2-propanol derivatives. The biological results of radiosensitizing activity of these agents against Chinese hamster cells (V-79) indicated that the 3-methoxy-2-propanol derivative was a more effective radiosensitizer than misonidazole in vitro. Evaluation of the acute toxicity of these agents as determined by LD50 demonstrated no significant difference between these agents and misonidazole suggesting that the 3-methoxy-2-propanol analog may possess a therapeutic advantage over misonidazole.

Animals↗

PubMed1982

Potential radiosensitizing agents. 4. 2-Nitroimidazole nucleosides.

A series of 2-nitroimidazole nucleoside analogues has been synthesized as potential radiosensitizers in an effort to reduce neurotoxicity and increase therapeutic efficacy. The 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl and glucothiopyranosyl analogues of 2-nitroimidazole were synthesized by condensation in the presence of stannic chloride and mercuric cyanide. The deacetylation of these esters was carried out with sodium methoxide at 0 degree C. Condensation of the trimethylsilyl derivative of 2-nitroimidazole with methyl 2-deoxy-2-chloro-4,7,8,9-tetra-O-acetyl-N-acetyl-alpha-D-neuraminate was achieved in the presence of mercuric bromide. These agents were tested for cytotoxicity and radiosensitization in vitro against Chinese hamster (V-79) cells under oxic and hypoxic conditions. The thioglucose and sialic acid analogues were found to be active radiosensitizers.

Animals↗

PubMed1982

Potential radiosensitizing agents. 5. 2-Substituted benzimidazole derivatives.

A series of 2-substituted benzimidazoles and their derivatives have been synthesized and tested for their ability to selectively sensitize hypoxic Chinese hamster cells (V-79) toward the lethal effect of ionizing radiation. These compounds were prepared by reacting the 2-substituted benzimidazoles with 1,2-epoxy-3-methoxypropane in the presence of potassium carbonate. Reaction of the 2-nitro and 2-methylfonyl analogue with the epoxide also yielded a cyclized material, which was confirmed to be a benzimidazo[2,1-b]oxazole. In an attempt to increase the electron affinity, 5- or 6-nitro-2-substituted-benzimidazoles were also synthesized and then reacted with the epoxide to yield the corresponding 1-substituted derivatives. The results of the biological tests for the radiosensitizing activity of these agents against Chinese hamster cells (V-79) in culture indicated that the 2-nitro-substituted analogues were the most effective sensitizers in this series.

Animals↗