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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↗
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↗
PubMed1978

Hypoxic radiosensitizers: prospects for effective compounds with fewer toxic side-effects.

Several radiosensitizing chemicals, including a family of simple nitroimidazoles, were examined in E. coli and compared with misonidazole for toxic side-effects on endpoints such as mutagenesis, cell killing and inhibition of the synthesis of the inducible enzyme beta-galactosidase. While all the compounds were similar to misonidazole or better in radiosensitization, marked differences in the various side effects were found. There results show that for E. coli it is possible to find compounds that sensitize as well as misonidazole but which have decreased mutagenicity and fewer other side-effects. Of the compounds examined, KA121 (2,5-dinitroimidazole) is the most promising for future study because it combines good radiosensitization with low mutagenicity and toxicity.

Escherichia coli↗
PubMed1977

Tetramisole analogues as inhibitors of alkaline phosphatase, an enzyme involved in the resistance of neoplastic cells to 6-thiopurines.

A series of tetramisole derivatives was synthesized and tested for inhibitory activity against alkaline phosphatase which was partially purified from a murine ascitic neoplasm resistant to 6-thiopurines (Sarcoma 180/TG). These agents included derivatives substituted with halogens, CH3, or NO2 groups at either the meta or para position of the phenyl ring of tetramisole and 2,3-dehydrotetramisole. The phenyl ring of tetramisole and 2,3-dehydrotetramisole was also replaced by a naphthyl ring, and the phenyl ring of 2,3-dehydrotetramisole was substituted by a thienyl ring system. The presence of both the thiazolidine and dihydroimidazole rings of tetramisole was found to be essential for enzyme inhibitory activity. Substitution of a naphthyl for the phenyl group and dehydrogenation at the 2,3 position of the thiazolidine ring were found to significantly enhance inhibitory activity for alkaline phosphatase. Tests employing (S)-(-)-6-(4-bromophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole oxalate in combination with 6-thioguanine demonstrated that the inhibitor of alkaline phosphatase was capable of increasing the toxicity of 6-thioguanine to Sarcoma 180/TG cells in tissue culture.

Alkaline Phosphatase↗
PubMed1977

4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone, a second-generation antineoplastic agent of the alpha-(N)-heterocyclic carboxaldehyde thiosemicarbazone series.

4-Methyl-5-amino-1-formylisoquinoline thiosemicarbazone (MAIQ-1) was studied to determine its potential for clinical trail as a second-generation antineoplastic agent of the alpha-(N)-heterocyclic carboxaldehyde thiosemicarbazone class. MAIQ-1 was shown to be among the most potent known inhibitors of the major target for the expression of antineoplastic activity by this class of agents, the enzyme ribonucleoside diphosphate reductase, requiring only 0.06 micronM for 50% inhibition. This potency at the enzymatic level was consistent with its antineoplastic activity against the murine neoplasms Sarcoma 180, Leukemia L1210, Leukemia P388, and the B16 melanoma. The acetylation of the 5-amino group of the model substrate 5-amino-1,4-dimethylisoquinoline was lower than that of 5-amino-1-methylisoquinoline when incubated with acetyl-coenzyme A and rat liver homogenate. This finding suggests that the presence of the 4-methyl function offers steric hinderance to enzymatic substitution of the adjacent 5-amino group. In vivo metabolism of MAIQ-1 in mice, studied with [3'-14C]MAIQ-1 showed that relatively slow excretion of this agent occurred, since the cumulative urinary excretion of radioactivity was only 35% in 48 HR. About 51% of excreted urinary radioactivity was present in chromatograms in an area corresponding to the iron chelate of MAIQ-1, and only a minor quantity of material migrating like acetylated MAIQ-1 was present in urine, a finding consistent with enzymatic data with liver homogenates. The results indicate that MAIQ-1 has the antineoplastic activity, enzyme inhibitory potency, and relative resistance to metabolic inactivation required of an agent of this class for clinical trials.

Animals↗
PubMed1976

Synthesis of site-directed chelating agents II: 2-formyl-3-hydroxy-4,5-bis (hydroxymethyl)pyridine thiosemicarbazone.

2-Formyl-3-hydroxy-4,5-bis(hydroxymethyl)pyridine thiosemicarbazone was synthesized in an attempt to direct the chelating potential of this agent to the active site of the zinc-requiring enzyme pyridoxal phosphokinase. Evaluation of the antineoplastic activity of this agent in the sarcoma 180 and L-1210 leukemia systems in mice showed potent activity. The presence or absence of pyridoxine hydrochloride in the diet did not influence the degree of inhibition of the growth of sarcoma 180 ascites cells. In addition, 2-formyl-3-hydroxy-4,5-bis(hydroxymethyl)pyridine thiosemicarbazone was inactive against a subline of sarcoma 180 resistant to 1-formylisoquinoline thiosemicarbazone, suggesting that the former agent may have a biochemical mechanism of action similar to that of the latter. In keeping with this expectation, 2-formyl-3-hydroxy-4,5-bis(hydroxymethyl)pyridine thiosemicarbazone inhibited the synthesis of DNA but not of RNA or protein in sarcoma 180 ascites cells in vitro.

Animals↗
PubMed1976

Antineoplastic and biochemical properties of arylsulfonylhydrazones of 2-formylpyridine N-oxide.

The structural parameters necessary for the antineoplastic potency of a new class of anticancer agents, arylsulfonylhydrazones of 2-formylpyridine N-oxide, were examined in mice bearing Sarcoma 180 ascites cells. The findings indicated that (a) replacement of the pyridine ring with benzene, quinoline, or isoquinoline resulted in loss of activity (b) movement of the formylhydrazone side chain from the 2 to the 3 or 4 positions of the pyridine N-oxide produced inactive agents (c) the pyridine N-oxide function was essential for anticancer activity, except for 4-substituted derivatives which were active without the N-oxide group, (d) replacement of the SO2 group by CO resulted in complete loss of activity, and (e) a carbon atom could be inserted between the SO2 and aryl ring with retention of anticancer potency. One of the most active members of this series, 1-oxidopyridine-2-carboxaldehyde p-toluenesulfonylhdrazone, exhibited antineoplastic activity against a broad spectrum of transplanted tumors including Sarcoma 180, Hepatoma 129, Ehrlich carcinoma, leukemia L1210, and a subline of Sarcoma 180 resistant to alpha-(N)-heterocyclic carboxaldehyde thiosemicarbazones. This agent caused inhibition of thymidine-3H and uridine-3H incorporation into DNA and RNA, respectively, of Sarcoma 180 ascites cells; protein biosynthesis was relatively insensitive to the action of this compound.

Animals↗
PubMed1976

Potential antitumor agents. 14. 4-Substituted 2-formylpyridine thiosemicarbazones.

A series of 4-substituted 2-formylpyridine thiosemicarbazones has been synthesized which contain a tertiary N at the 4 position. These materials were obtained by reacting 4-nitro-2-picoline N-oxide, either directly or after conversion to the corresponding 4-chloro derivative, with a variety of secondary amines. Rearrangement of the 4-substituted 2-picoline N-oxides with Ac2O yielded respective methyl acetates, which upon acid hydrolysis, MnO2 oxidation, and reaction with thiosemicarbazide resulted in the desired compounds. An alternate procedure which consisted of reacting 4-chloro-2-formylpyridine ethylene acetal with various amines, followed by hydrolysis and reaction with thiosemicarbazide, was also employed. Introduction of an alkyl group at the 3 position of the pyridine ring of 4-morpholino-2-formylpyridine thiosemicarbazone was achieved by utilizing 2,3-dimethyl-4-nitropyridine N-oxide; this material was converted to the corresponding 4-chloro derivative which was then subjected to nucleophilic substitution. 4-Morpholino-2-formylpyridine thiosemicarbazone was the most active antineoplastic agent of this series in mice bearing Sarcoma 180 ascites cells and was significantly superior to 5-hydroxy-2-formylpyridine thiosemicarbazone in this test system.

Animals↗