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Biomedical subjects

K C Agrawal

Publications and source records attributed to K C Agrawal.

At least 19 recordsLinked to original sources
PubMed1992

Zidovudine-induced blockade of the expression and function of the erythropoietin receptor.

Treatment of bone marrow progenitor cells (BMPC) with zidovudine (AZT) at various concentrations (0.5 to 20 microM) in vitro for 24 hr caused a concentration-dependent decrease in erythropoietin (Epo) receptor expression. The decrease in Epo receptors correlated with a decline in mRNA levels of the receptor. These results suggest that AZT-induced down-regulation of Epo receptor expression followed by loss of Epo-receptor mediated signal transduction is a significant contributory factor to AZT-induced erythroid toxicity.

Animals↗
PubMed1992

Amelioration of zidovudine-induced fetal toxicity in pregnant mice.

The effects of zidovudine (AZT) on the fetus were investigated in pregnant mice by using parameters such as the number of fetuses, fetal size, and the fetal hepatic cell clonogenic assay. AZT caused dose-dependent toxicity to the fetus upon administration via drinking water to pregnant mice from days 1 to 13 of gestation. At the 0.5-mg/ml dose level, AZT caused a decrease in the number of fetuses to 12 from an average of 16.5 in control animals, and the fetal size (crown-rump length) was reduced from 10.5 to 8.5 mm. The CFU of the erythroid progenitor cell colonies derived from the fetal hepatic cells were decreased to 38% of that of the control, and the hematocrit dropped to 33.5 +/- 1.7 from a control value of 42.6 +/- 2.5. Concomitant administration of erythropoietin, vitamin E, or interleukin-3 to the AZT-treated pregnant mice caused a significant reversal in the AZT-induced toxicity to the fetus and to the mother's bone marrow. The success of therapeutic intervention was demonstrated by (i) restoration of the number of fetuses to the level of untreated controls, (ii) an increase in the size of fetuses to normal values, and (iii) an increase in hematocrit to > 40. The results suggest that AZT is toxic to the fetus in a dose-dependent manner and that treatment with erythropoietin, vitamin E, or interleukin-3 can ameliorate the AZT-induced fetal toxicity.

Animals↗
PubMed1991

Effect of zidovudine (AZT) on reproductive and hematopoietic systems in the male rat.

The effects of Zidovudine (AZT) on parameters of the reproductive and hematopoietic systems of male rats were evaluated and compared to those of the controls. Young male Wistar rats were divided into three groups. The control rats (Group 1) received no drug. AZT was administered via drinking water to rats in Groups 2 and 3 (0.1 mg/mL Group 2, and 1.0 mg/mL Group 3) for 4 weeks. Daily water intake and weekly body weight were monitored. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), prolactin (PRL) and intratesticular T levels were determined by specific radioimmunoassays. Serum AZT was measured by HPLC. Bone-marrow toxicity was monitored by colony-forming units of erythroid (CFU-E) and granulocyte-macrophage (CFU-GM) assays. The body weight of all rats increased 2-fold in four weeks, and no significant differences were observed between control and treated groups. Ventral prostate (VP) weight decreased significantly (P less than 0.05) by 32% in Group 2 and 27% in Group 3 rats, compared to the control group. Seminal vesicle (SV) weight decreased by 20% in Group 2 (NS) and 30% in Group 3 (P less than 0.05) rats. No significant differences were observed in testes weight or in the intratesticular sperm count between control and AZT-treated groups. Serum T levels (ng/mL) decreased significantly in Group 2 rats (2.8 +/- 0.4 in control to 1.7 +/- 0.2, P less than 0.05) but recovered (2.6 +/- 0.5) in Group 3 when compared to Group 1 (control). Serum LH and PRL levels showed a significant increase (P less than 0.05) in Group 3 compared to control or Group 2 rats. Serum FSH and intratesticular T levels showed no significant change. A significant (P less than 0.05) dose-dependent decrease in CFU-E and in CFU-GM was observed in AZT-treated rats compared to controls. These results demonstrate that the effects of AZT on the reproductive system in the male rat are more subtle and complex, compared to its significant effects on bone-marrow. This suggests that important interactions may exist between the endocrine and hematopoietic systems.

Animals↗
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

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↗
PubMed1979

Potential radiosensitizing agents. Dinitroimidazoles.

New compounds of the nitroimidazole series have been synthesized as radiosensitizers which selectively sensitize hypoxic cells to the lethal effect of radiation. The reaction of 2,4(5)-dinitroimidazole (2) with chloroethanol or hydrochloric acid yielded 4(5)-nitro-5(4)-chloroimidazole (3), which upon reaction with ethylene oxide yielded the 4-nitro-5-chloroimidazole-1-ethanol (6). Reaction of 2 with ethylene oxide resulted in a mixture of two compounds, the 2,4-dinitroimidazole-1-ethanol (4) and 2,3-dihydro-5-nitroimidazo[2,1-b]oxazole (5). The structure of the new heterocyclic compound 5 was confirmed by 1H NMR, mass spectrum, and X-ray crystallography. These agents were tested for their ability to sensitize hypoxic Escherichia coli cells to killing by ionizing radiation. Compound 4 was found to be the most active agent of this series of compounds.

Chemical Phenomena↗
PubMed1978

Relationship between structure and antineoplastic activity of arylsulfonylhydrazones of 2-formylprydine N-oxide.

The effects of various structural modifications on the antineoplastic activity of the benzenesulfonylhydrazone of 2-formylpyridine N-oxide have been ascertained in mice bearing either Sarcoma 180 or leukemia L1210. To accomplish this a variety of derivatives substituted at the aldehyde proton, the aryl ring, and the 4 position of the pyridine nucleus were synthesized. Antineoplastic activity was retained when nitro, amino, chloro, bromo, fluoro, and methoxy groups were introduced into either the meta or para positions of the phenyl ring of the parent compound. In addition, substitution of the terminal phenyl group by a pyridine ring or by a bulky aromatic ring such as alpha-naphthyl, beta-naphthyl, or fluorenyl did not abolish the marked antitumor activity expressed by this class of agents. Insertion of a nitro function or a morpholino group in the 4 position of the pyridine nucleus of the benzenesulfonylhydrazone of 2-formylpyridine N-oxide resulted in two potent anticancer agents, while the introduction of a chloro function in the 4 position led to a pronounced decrease in biological activity. Furthermore, the essentiality of the aldehydic proton for tumor-inhibitor activity was demonstrated by the inactivity of two derivatives in which the aldehydic proton was replaced by a methyl group or by an oxygen atom.

Animals↗
PubMed1978

The Woodlawn mental health studies: tracking children and families for long-term follow-up.

Elementary school children in a large public urban school system (Chicago) can be tracked into adolescence, together with their families, by using student numbers established by the Chicago Public Schools. This paper reports on the linkage between a psychiatric follow-up study and the data bank of the Chicago Public Schools. The authors were able to find information about the location and grade placement of 87% of an urban ghetto neighborhood's first grade children after a seven to ten-year lapse in contact. The children about whom information was found did not differ from those missing in the early measures of their school achievement and psychological wellbeing. However, first grade measures of school success of failure did relate to grade placement of children ten years later, as did first grade ratings of bizarreness.

Chicago↗