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1.
Indian J Lepr ; 88(2): 97-103, 2016 04.
Article in English | MEDLINE | ID: mdl-29757541

ABSTRACT

The study was undertaken in VSS Institute of Medical Sciences to observe the clinical, bacteriological and histological diagnosis of leprosy patients attending the hospital who consented to undergo slit skin smear (SSS) examination, punch biopsy and participate in the study. Fifty leprosy patients aged 5 to 70 years, which included 41 male and 9 female patients participated in the study. These included 4 TT, 24 BT, 2 BB, 5 BL and 15 ILL clinically diagnosed patients as per the IAL classification (1982 ). SSS were undertaken from 4 sites, stained with ZN stain and BI calculated as per Ridley Scale. Four patients were skin smear negative all TT). Of the 24 BT patients enrolled in the study, 11 were skin smear negative while 13 were smear positive (BI ranging from 1+ to 4+); Both the BB cases, all 5 BL cases, and all the 15 LL cases were smear positive (BI range 2+ to 6+). Histologically there was complete parity and correlation in.the TT group, while the correlation was observed to be 83%, 50%, 60%, and 93% in the clinically diagnosed BT, BB, BL and LL patients respectively. The sample size in the study was small, however, the overall bacteriological skin smear negativity/positivity correlation was observed to be 53.6% for paucibacillary (TT+BT) disease and 100% for MB (BB, BL and LL) disease Histological correlation was 100%, 83%, 50%, 60% and 93% respectively for clinically diagnosed TT, BT, BB, BL and LL disease. A sizeable number of BT patients were found to be bacteriologically positive and were therefore being treated with lesser number of drugs as well duration under programme conditions, Although there is inter-observer variation and overlapping of clinical and histological diagnosis in the borderline patients (BT, BB & BL), bacteriological and histological confirmation helps in deciding on adequate treatmeht and should be undertaken.


Subject(s)
Leprosy/diagnosis , Adolescent , Adult , Aged , Biopsy , Child , Child, Preschool , Female , Hospitals, University , Humans , India , Leprosy/pathology , Male , Middle Aged , Skin/pathology , Young Adult
2.
Int J Radiat Biol ; 81(3): 251-7, 2005 Mar.
Article in English | MEDLINE | ID: mdl-16019934

ABSTRACT

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.


Subject(s)
Amifostine/administration & dosage , Nanostructures , Radiation-Protective Agents/administration & dosage , Administration, Oral , Animals , Bone Marrow Cells/radiation effects , Cell Survival/radiation effects , Hematopoietic Stem Cells/radiation effects , Male , Mice
3.
AIDS Res Hum Retroviruses ; 17(17): 1569-84, 2001 Nov 20.
Article in English | MEDLINE | ID: mdl-11779345

ABSTRACT

Long-term use of HIV-1 protease inhibitors (PIs) is associated with a lipodystrophy syndrome. To delineate the associated mechanisms, adipogenesis was determined in 3T3-L1 cells in the presence or absence of either indinavir (2-50 microg/ml) or ritonavir (0.4-10 microg/ml). A concentration-dependent decrease in both lipid (4-59%) and triglyceride (11-49%) levels was seen after 10 days of exposure. Simultaneous treatment with TNF-alpha showed a synergistic suppression in lipid levels by 45-95% at 10 U/ml and almost complete suppression at 100 U/ml. The effect of PIs on insulin-induced lipogenesis was monitored by [(14)C)]glucose incorporation into lipids, which was suppressed by 21-86% in a concentration-dependent manner. Insulin-sensitizing agent, troglitazone (80 and 400 nM), effectively blocked the PI-mediated adipogenic suppression. Preadipocyte factor 1 gene (pref-1) expression, as monitored by RT-PCR, was downregulated (4- to 6-fold) within 48 hr after insulin stimulation; however, a smaller decrease (1.2- to 1.8-fold) was observed in PI-exposed cells. The decrease in proteolytic activity of matrix metalloproteases (MMP-2 and MMP-9) during adipogenesis was reversed on exposure to the PIs. Similarly, the plasminolytic activity was increased and plasminogen activator inhibitor (PAI) activity was decreased in supernatants from PI-treated cells. The insulin-mediated induction (3- to 4-fold) of PAI-1 and PAI-2 message was suppressed on exposure to PIs, which was reversed by troglitazone treatment. Thus, the HIV-1 PIs may suppress adipogenesis by disrupting the concerted actions of host proteases that regulate ECM integrity required for initiation of differentiation.


Subject(s)
Adipocytes/cytology , Cell Differentiation/drug effects , HIV Protease Inhibitors/pharmacology , Indinavir/pharmacology , Ritonavir/pharmacology , Tumor Necrosis Factor-alpha/pharmacology , Adipocytes/drug effects , Animals , Calcium-Binding Proteins , Cells, Cultured , Drug Synergism , Glucose/metabolism , Insulin/metabolism , Intercellular Signaling Peptides and Proteins , Lipid Metabolism , Membrane Proteins/drug effects , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Plasminogen Activator Inhibitor 1/metabolism , Plasminogen Activator Inhibitor 2/metabolism , Repressor Proteins/drug effects , Repressor Proteins/genetics , Repressor Proteins/metabolism , Triglycerides/metabolism
4.
Cancer Lett ; 160(2): 133-40, 2000 Nov 28.
Article in English | MEDLINE | ID: mdl-11053642

ABSTRACT

The antiapoptotic and mitogenic responses of metallothionein (MT) have been well documented in vitro. While MT protein overexpression, frequently encountered in a number of human primary tumors, has been shown to be correlated with disease progression, little information is available on the in vivo isoform expression of MT. In this study we have demonstrated the occurrence of MT proteins and further defined their differential expression profile in human primary renal cell carcinoma (RCC). Pooled normal human kidney RNA and paired biopsy specimens (tumor and control) obtained from 11 patients diagnosed with RCC with tumor grade ranging from 1-3 and a pathological staging of T2-T3 (N0M0) were used for the study. Samples were analyzed for the presence of MT protein using immunohistochemical (IHC) analysis and for MT isoform-specific mRNA expression by reverse transcriptase polymerase chain reaction. Metallothionein protein assumed both cytoplasmic and nuclear staining in cancer cells and was detected in eight of 11 samples (72%) with polyclonal antibodies. The immunoreactivity of MT protein, but not its cellular localization, in RCC specimens suggests a relationship between and advanced disease. While alterations in the basal level of expression of MT-1E, MT-1F and MT-1X genes remained unchanged, significant up-regulation of MT-2A and down-regulation of MT-1A and MT-1G transcripts was observed in RCC tissue specimens when compared with controls. Intriguingly, the paired RCC biopsy specimens had lower MT-1H transcripts than pooled normal human controls. We here provide the first report of the differential expression of MT isoforms in human RCC and that this data further support the role of MT-2A in tumorigenesis.


Subject(s)
Carcinoma, Renal Cell/genetics , Gene Expression Profiling , Kidney Neoplasms/genetics , Metallothionein/genetics , Adult , Aged , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Disease Progression , Female , Humans , Immunohistochemistry , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Male , Metallothionein/biosynthesis , Middle Aged , Neoplasm Staging , Protein Isoforms , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction
5.
Cancer Lett ; 155(1): 89-97, 2000 Jul 03.
Article in English | MEDLINE | ID: mdl-10814884

ABSTRACT

A series of title compounds has been synthesized and evaluated by the cytotoxicity assays conducted in vitro in seven human tumor cell lines, initially in MT-4 and H-9, followed by U-937, PM-1, MCF-7, Hep-3B, and K-562. These compounds were simultaneously compared with the existing clinical drug, busulfan and also with an experimental drug, hepsulfam. IC(50) values of these agents in T-cell lymphoma and leukemic cell lines indicate that two of these agents hexsulfamyl and octsulfamyl (compounds 3 and 4) were significantly more potent than busulfan and were comparable in antileukemic activity with hepsulfam. In order to determine the effect of these agents on normal proliferating cells, the toxicity of 3 and 4 was also determined in vitro against human peripheral blood mononuclear cells (PBMC) and against murine bone marrow progenitor cells. PBMC assay data indicate that these agents were generally less toxic than hepsulfam. The results of the colony forming unit-erythroid (CFU-E) and granulocyte-macrophage colony forming unit (CFU-GM) assays, however, indicate that these agents were more toxic than hepsulfam to erythroid progenitor cells than to granulocyte-macrophage progenitors. The toxicity of octsulfamyl was further assessed in vivo in normal Swiss mice by measuring drug-induced changes in hematological parameters, femoral bone marrow cellularity and splenic cellularity as well as hepatotoxicity and nephrotoxicity on day 7 and 14 following drug treatment at the dose of 1.0 mg/kg body weight from days 1 to 5. The results indicate that the compound did not adversely affect hematopoiesis. Marginal bone marrow suppression was observed on day 7, which gradually tends to reach normalcy on day 14. The other parameters were within normal limit.


Subject(s)
Alkanes/pharmacology , Antineoplastic Agents/pharmacology , Mesylates/pharmacology , Sulfones/pharmacology , Animals , Antineoplastic Agents, Alkylating/pharmacology , Bone Marrow/drug effects , Busulfan/pharmacology , Cell Survival/drug effects , Granulocytes/drug effects , Hematopoietic Stem Cells/drug effects , Humans , Inhibitory Concentration 50 , K562 Cells , Leukocytes, Mononuclear/drug effects , Macrophages/drug effects , Male , Mice , Tumor Cells, Cultured , Tumor Stem Cell Assay
6.
Bioorg Med Chem ; 6(5): 563-8, 1998 May.
Article in English | MEDLINE | ID: mdl-9629469

ABSTRACT

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.


Subject(s)
Adamantane/chemistry , Dihydropyridines/pharmacology , Radiation-Protective Agents/pharmacology , Animals , Cell Line , Cricetinae , Cricetulus , Dihydropyridines/chemical synthesis , Magnetic Resonance Spectroscopy , Male , Mice , Radiation-Protective Agents/chemical synthesis
7.
Cancer Res ; 58(11): 2335-8, 1998 Jun 01.
Article in English | MEDLINE | ID: mdl-9622069

ABSTRACT

The antiapoptotic response and enhanced cellular proliferation observed in neoplastic cells on overexpression of metallothionein (MT) have been well documented. We have investigated the mechanisms associated with this phenomenon by using MT inducers that increased MT transcripts and stimulated growth in MCF-7 cells. A MT antisense phosphorothioate oligonucleotide inhibited growth induction by >50%, suggesting a potential role of MT in mediating the mitogenic effects of these agents. Mobility shift assays using oligonucleotides encompassing the consensus nuclear factor kappaB (NFkappaB) binding site and anti-MT antibody revealed activation and a specific interaction of NFkappaB with MT. Cotransfection experiments using expression and reporter constructs demonstrated that MT caused transactivation of NFkappaB. Gel shift assays using purified proteins showed a specific interaction between MT and the p50 subunit of NFkappaB. These data indicate that MT may be involved in the interaction of NFkappaB with the DNA-binding domain and further suggest a potential role for NFkappaB in mediating the antiapoptotic effects of MT.


Subject(s)
Metallothionein/metabolism , Mitosis , NF-kappa B/metabolism , Apoptosis , Binding Sites , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , DNA/metabolism , Estradiol/pharmacology , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Metallothionein/genetics , Mitosis/genetics , NF-kappa B/genetics , Oligonucleotides, Antisense/metabolism , Transcriptional Activation , Tumor Cells, Cultured , Zinc Sulfate/pharmacology
8.
Cancer Gene Ther ; 4(3): 199-207, 1997.
Article in English | MEDLINE | ID: mdl-9171939

ABSTRACT

The association of increased metallothionein (MT) gene expression in breast cancer with metastasis and poor prognosis has led us to investigate the hypothesis that inhibition of MT gene expression may elicit antiproliferative effects in breast carcinoma MCF7 cells. To monitor the effect of downregulation of MT protein on growth, MCF7 cells were transiently transfected by electroporation with an 18-mer MT antisense phosphorothioate oligomer (AO) or an 18-mer random oligomer (RO). The MT-AO is complementary to the region 7 bases downstream from the AUG translational start site of the hMT-IIA gene. Transfection of MCE7 cells with the AO inhibited cell growth by 50-60% at 72 hours when compared to control cells or the cells transfected with RO. The AO-induced growth inhibition was associated with alterations in morphology suggestive of apoptotic cell death. This was further confirmed by DNA linker cleavage into oligonucleosomal fragments and decreased bcl-2 protein levels in AO-transfected cells as opposed to the RO-transfected cells. Reverse transcriptase polymerase chain reaction analysis showed that AO induced a 2-fold increase in the levels of c-fos and p53 transcripts in comparison to RO which had no significant effect. Conversely, c-myc transcripts were decreased by 2.5-fold in the AO-transfected cells when compared to the controls. Furthermore, MCF7 cells transfected with an expression plasmid pBAcNEO-sMT-IIA encompassing human MT-IIA cDNA, constitutively driven by beta-actin promotor, caused a 2.5-fold increase in intracellular levels of MT, as judged by PCR and western blot analysis, in comparison to the cells transfected with pBAcNEO plasmid. In contrast to the AO-induced growth inhibition, overexpression of cytoplasmic MT increased the cell multiplication by 2-fold compared with control cells or the cells transfected with the control plasmid 72 hours post-transfection. Moreover, the effects of AO on oncogene expression were reversed on increased expression of MT. These data suggest that overexpression of MT potentiates the growth of MCF7 cells, whereas downregulation of MT elicits antiproliferative effects.


Subject(s)
Apoptosis , Breast Neoplasms/genetics , Gene Expression Regulation, Neoplastic/drug effects , Metallothionein/genetics , Oligonucleotides, Antisense/pharmacology , Breast Neoplasms/pathology , Cell Division/genetics , DNA Fragmentation , DNA, Antisense/pharmacology , Down-Regulation/drug effects , Electroporation , Genetic Vectors , Humans , Metallothionein/metabolism , Metallothionein/physiology , Plasmids , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Proto-Oncogenes , RNA-Directed DNA Polymerase , Transfection , Tumor Cells, Cultured
9.
AIDS Res Hum Retroviruses ; 12(16): 1529-36, 1996 Nov 01.
Article in English | MEDLINE | ID: mdl-8911578

ABSTRACT

The trans-activator protein (Tat) of HIV-1 plays an important role in viral pathogenesis. Since Tat has been shown to alter expression of a number of host cellular genes, we have investigated the role of Tat in modulating gene expression and differentiation in hematopoietic progenitor cells. Tat protein was introduced in K562 cells, a human hematopoietic progenitor cell line, by either scrape-loading onto HeLa (HL)-tat cells or direct electroporation of an affinity-purified glutathione S-transferase (GST)-Tat fusion protein. Under these conditions, butyric acid-induced hemoglobin production in K562 cells was suppressed by 65 and 52%, respectively. However, coculturing with wild-type HeLa cells or electroporation with the control GST protein did not decrease hemoglobin production. To confirm the presence of bioactive Tat protein within K562 cells, the cells were transiently transfected with a pHIV/LTR-CAT prior to the introduction of Tat. A 30- to 40-fold induction in CAT gene expression was observed in the transfected K562 cells, which were either cocultured with HL-tat or were electroporated with GST-Tat. Simultaneous transient transfection of K562 cells with a TAR expression plasmid, to compete for the availability of Tat protein, significantly downregulated the HIV LTR trans-activation by Tat. In addition, overexpression of the TAR RNAs in K562 cells was able to downregulate the suppressive effect of Tat on butyric acid-induced differentiation. RT-PCR analysis of the total RNAs isolated from these cells demonstrated that Tat protein suppressed the butyric acid-induced gamma-globin gene expression by an average of 54% without affecting the level of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNAs. These data indicate that the viral Tat protein plays a significant role in abrogating erythroid differentiation in K562 cells.


Subject(s)
Butyrates/antagonists & inhibitors , Gene Products, tat/pharmacology , Hematopoietic Stem Cells/drug effects , Transcriptional Activation , Butyrates/pharmacology , Butyric Acid , Cell Differentiation/drug effects , Cell Division/drug effects , Cell Line , Gene Products, tat/antagonists & inhibitors , Globins/biosynthesis , HIV Long Terminal Repeat/drug effects , HIV-1/drug effects , Hemoglobins/biosynthesis , Humans , RNA/pharmacology , Trans-Activators/genetics , Trans-Activators/pharmacology , Transcriptional Activation/drug effects , tat Gene Products, Human Immunodeficiency Virus
10.
Prostaglandins ; 52(4): 249-59, 1996 Oct.
Article in English | MEDLINE | ID: mdl-8936581

ABSTRACT

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.


Subject(s)
Iloprost/analysis , Misoprostol/analysis , Animals , Chromatography, High Pressure Liquid , Iloprost/blood , Liver/chemistry , Mice , Misoprostol/blood , Molecular Structure , Prostaglandins/analysis , Prostaglandins/pharmacology , Rats , Reference Standards , Stereoisomerism
11.
Life Sci ; 59(16): 1323-9, 1996.
Article in English | MEDLINE | ID: mdl-8876661

ABSTRACT

The role of zinc and N-acetylcysteine (NAC) has been investigated in protecting the hematopoietic progenitor cells from zidovudine (AZT)-induced toxicity. Murine bone marrow progenitor cells (BMPC, 1x10(6)) were exposed to various concentrations (0.1-50 microM) of AZT in the presence and absence of zinc acetate (100 microM) or NAC (100 microM). The cell survival was determined by the colony forming assays of erythroid (CFU-E) and granulocytic (CFU-GM) lineage. The IC50 values of AZT in the presence of zinc were increased approximately 3-fold (from 3.0 to 9.5 microM) in the CFU-E assay and 7-fold (from 4.3 to 28.8 microM) in the CFU-GM assay whereas in the presence of NAC, the IC50 values were increased by 2- and 4-fold, respectively. To delineate the mechanism of significant protection of BMPC by zinc, the mRNA levels of metallothionein (MT) were monitored by using a 31-mer cDNA probe. Zinc produced a concentration-dependent increase in the MT mRNA levels in BMPC. These results suggest that zinc and NAC dietary supplementation can be conveniently used to reduce AZT-induced bone marrow toxicity.


Subject(s)
Acetylcysteine/therapeutic use , Antidotes/therapeutic use , Bone Marrow/drug effects , Zidovudine/adverse effects , Zinc/therapeutic use , Acetylcysteine/pharmacology , Animals , Antidotes/pharmacology , Cell Survival/drug effects , Female , Hematopoietic Stem Cells/cytology , Mice , Zinc/pharmacology
12.
Biochem Pharmacol ; 50(3): 413-9, 1995 Jul 31.
Article in English | MEDLINE | ID: mdl-7646543

ABSTRACT

To investigate the mechanisms that may be involved in zidovudine (AZT)-induced hematopoietic toxicity, spleen cells isolated from phenylhydrazine-treated anemic mice or murine bone marrow erythroid progenitor cells were treated with AZT (1-10 microM) for 24 hr. A concentration-dependent inhibition of the binding of 125I-labeled erythropoietin (Epo) was observed, suggesting down-regulation of Epo receptors. To determine if this effect is due to modulation of the levels of Epo receptor mRNA and to assess the effect of AZT on the expression of protooncogenes, mRNA levels were monitored by the slot blot hybridization technique. AZT caused a concentration-dependent inhibition in the levels of the mRNA of Epo receptors and c-fos, whereas the level of c-myc mRNA was unaffected. AZT also inhibited protein kinase C (PKC) activity in a concentration- and time-dependent manner, causing 50% inhibition at 10 microM within 3 hr. Simultaneous addition of Epo or interleukin-3 (IL-3) partially reversed the inhibitory effects of AZT on the levels of the mRNAs and on PKC activity; however, a combination of Epo and IL-3 was significantly more effective. These studies demonstrate that (i) AZT-induced down-regulation of Epo receptors and c-fos expression coupled with inhibition of Epo receptor-mediated signal transduction through PKC are significant contributory factors to AZT-induced erythroid toxicity, and (ii) these inhibitory effects can be overcome by treatment with a combination of Epo and IL-3.


Subject(s)
Erythroid Precursor Cells/drug effects , Erythropoietin/administration & dosage , Interleukin-3/administration & dosage , Zidovudine/toxicity , Animals , Down-Regulation , Drug Combinations , Erythroid Precursor Cells/metabolism , Erythropoietin/pharmacology , Genes, fos , Genes, myc , Mice , Protein Kinase C/antagonists & inhibitors , RNA, Messenger/analysis , Receptors, Erythropoietin/drug effects , Receptors, Erythropoietin/genetics , Zidovudine/antagonists & inhibitors
13.
Eur J Pharmacol ; 276(1-2): 21-6, 1995 Mar 24.
Article in English | MEDLINE | ID: mdl-7781691

ABSTRACT

Allicin, diallyl disulfide-oxide, an active ingredient released from garlic is a systemic vasodilator that acts by an unknown mechanism. In the present experiments, pulmonary vascular responses to allicin (0.1-1.0 mg) were studied in the intact-chest anesthetized cat and in the isolated lung of the rat under constant flow conditions. When baseline tone in the pulmonary vascular bed of the cat was raised with U46619 (11 alpha,9 alpha-epoxymethano-9 alpha,11 beta-dideoxyprostaglandin F2 alpha), intralobar injections of allicin produced dose-related decreases in pulmonary arterial pressure without changing left atrial pressure indicating that allicin had significant vasodilator activity in the pulmonary vascular bed when tone was increased experimentally. Allicin also decreased systemic arterial pressure in a dose-related manner. In terms of relative vasodilator activity in the cat, allicin was 100-fold less potent than sodium nitroprusside and many orders of magnitude less potent than isoproterenol. In the cat, vasodilator responses to allicin were unchanged by methylene blue or N omega-nitro-L-arginine methyl ester. Allicin also significantly diminished the pulmonary pressor response to ventilatory hypoxia in the isolated perfused rat lung. These data show that allicin has significant vasodilator activity in the pulmonary vascular bed of the cat and the rat. The present data suggest that pulmonary vasodilator responses to allicin are independent of the synthesis of endothelial-derived relaxing factor or the activation of soluble guanylate cyclase.


Subject(s)
Lung/drug effects , Sulfinic Acids/pharmacology , Vasodilator Agents/pharmacology , Animals , Arginine/analogs & derivatives , Arginine/pharmacology , Blood Pressure/drug effects , Cats , Disulfides , Female , Lung/blood supply , Male , Methylene Blue/pharmacology , NG-Nitroarginine Methyl Ester , Rats , Rats, Sprague-Dawley
14.
Clin Pharmacol Ther ; 56(3): 272-8, 1994 Sep.
Article in English | MEDLINE | ID: mdl-7924122

ABSTRACT

Zidovudine is metabolized to an inactive 5'-glucuronide and has a short plasma half-life requiring frequent dosing. The present study in six patients without symptoms who were infected with human immunodeficiency virus was undertaken to determine if coadministration of valproic acid which, like zidovudine, is metabolized by glucuronidation, would alter zidovudine disposition. Under steady-state conditions for both drugs, the plasma area under the curve for zidovudine increased twofold with a corresponding decline in its oral clearance when given with valproic acid. The mean 5'-glucuronide/zidovudine urinary excretion ratio was reduced by more than 50%, and the amount of unconjugated zidovudine recovered in urine increased by more than twofold. There was no significant increase in the plasma half-life of zidovudine. The effects of valproic acid on zidovudine glucuronidation were related to plasma valproic acid concentrations. Valproic acid inhibits glucuronidation of zidovudine and increases its oral bioavailability.


Subject(s)
HIV Infections/blood , Valproic Acid/pharmacology , Zidovudine/pharmacokinetics , Adult , Biological Availability , Drug Synergism , HIV Infections/drug therapy , Half-Life , Humans , Linear Models , Male , Middle Aged , Valproic Acid/blood , Zidovudine/analogs & derivatives , Zidovudine/blood , Zidovudine/therapeutic use
15.
Int J Radiat Oncol Biol Phys ; 29(2): 397-402, 1994 May 15.
Article in English | MEDLINE | ID: mdl-8195040

ABSTRACT

PURPOSE: Metallothionein (MT) has been shown to protect cells from the injurious effects of ionizing radiation. MT is an inducible protein and heavy metals can upregulate transcription of the MT gene. The present study was initiated to investigate regulation of MT mRNA synthesis in a human hepatocellular carcinoma (Hep3B) cell line. METHODS AND MATERIALS: MT levels in Hep3B cells were measured by the cadmium-hemoglobin assay. Zinc acetate was used as an inducing agent. Levels of the MT mRNA were determined by the slot blot hybridization technique. Cycloheximide was used as an inhibitor of protein synthesis and actinomycin D was used to block transcription. RESULTS: Zinc acetate (0.1 mM) treatment increased the intracellular levels of MT in Hep3B cells. MT levels peaked at 10 h and remained stable for up to 48 h. A time-dependent increase in the MT mRNA was also observed peaking at 16 h and then declining. Addition of cycloheximide and zinc acetate simultaneously, resulted in a decrease in the levels of MT, whereas MT mRNA levels were increased. There was no significant change in the decay rate of MT mRNA when the cells were treated with actinomycin D (7.5 micrograms/ml) either in the presence or absence of Zn. CONCLUSION: These results suggest that neither the increased synthesis of a metal regulatory factor (MRF) nor an increase in half-life of MT mRNA is involved in the mechanism of increased MT biosynthesis upon addition of Zn. These findings support the hypothesis that a preexisting MRF must complex with Zn to initiate increased transcription for MT.


Subject(s)
Carcinoma, Hepatocellular/metabolism , Gene Expression Regulation, Neoplastic , Liver Neoplasms/metabolism , Metallothionein/genetics , RNA, Messenger/analysis , Cycloheximide/pharmacology , Humans , Metallothionein/biosynthesis , Puromycin/pharmacology , Tumor Cells, Cultured
16.
Kidney Int ; 44(4): 734-40, 1993 Oct.
Article in English | MEDLINE | ID: mdl-8258950

ABSTRACT

The present studies were undertaken to assess the effects of 5'-N-ethylcarboxamideadenosine (NECA), an adenosine analogue, on erythropoietin (Epo) production. NECA (0.05 and 0.1 mumol/kg i.v.) produced significant increases in serum Epo levels (368.8 +/- 56.1 and 384.6 +/- 45.9 mU/ml, respectively) in exhypoxic polycythemic mice after a four hour exposure to hypoxia when compared with hypoxia controls (133.2 +/- 18.2 mU/ml). The hypoxic kidney Epo levels were 46.4 +/- 13.4 mU/kg kidney which were significantly higher than normoxic kidney Ep levels (< 1.24 mU/kg kidney). Theophylline (20 mg/kg i.p.), an adenosine receptor antagonist, significantly inhibited the stimulatory effects of NECA on serum Epo levels. In vitro cultures of an Epo producing hepatocellular carcinoma (Hep3B) cell line with NECA (> or = 10(-6) M) for 20 hours under hypoxic conditions (1% O2) produced significant increases in medium levels of Epo when compared with hypoxia controls. Hepatocellular carcinoma cells treated with NECA at a concentration range of 10(-7) M to 5 x 10(-5) M for one hour in a hypoxic atmosphere also had significantly higher cAMP levels than that of hypoxia controls. Scatchard analyses of [3H]NECA binding to membrane preparations of hepatocellular carcinoma cells showed low affinity binding sites with a dissociation-constant (Kd) of 0.44 microM and a binding capacity of 863 fmol/mg protein. These findings suggest that the increase in Epo production in response to NECA under hypoxic conditions can be attributed, at least in part, to stimulation of adenosine A2 receptors which is coupled to adenylyl cyclase activation.


Subject(s)
Adenosine/analogs & derivatives , Erythropoietin/biosynthesis , 8-Bromo Cyclic Adenosine Monophosphate/pharmacology , Adenosine/antagonists & inhibitors , Adenosine/pharmacology , Adenosine-5'-(N-ethylcarboxamide) , Animals , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Dose-Response Relationship, Drug , Erythropoietin/blood , Female , Hypoxia/blood , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Mice , Mice, Inbred Strains , Osmolar Concentration , Polycythemia/blood , Theophylline/pharmacology , Tumor Cells, Cultured/metabolism
17.
Antimicrob Agents Chemother ; 37(4): 818-24, 1993 Apr.
Article in English | MEDLINE | ID: mdl-8494380

ABSTRACT

The pharmacokinetics of two prodrugs of zidovudine (AZT), 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester and isoleucinyl ester (DPAZT and IAZT, respectively), were investigated in a rabbit model to determine their potential utility as drugs against human immunodeficiency virus. Drugs were administered by intravenous infusion over 5 min at doses equal to 10 mg of AZT per kg of body weight. The levels of the prodrugs and of released AZT in plasma, cerebrospinal fluid (CSF), and brain were determined by high-performance liquid chromatography analysis. DPAZT disappeared rapidly from plasma, whereas IAZT maintained a sustained level in plasma for up to 4 h. The levels in plasma of AZT released from DPAZT were consistently lower than the levels of AZT released from IAZT or AZT itself. At 75 min after infusion of AZT, DPAZT, and IAZT, the CSF plasma AZT ratios were 0.23, 0.30, and 0.25, while the brain/CSF AZT ratios were 0.32, 0.63, and 0.64, respectively. These results indicate that the administration of each of the prodrugs produced a higher concentration of AZT in the brain than did the direct administration of AZT. Both prodrugs therefore may be superior to AZT itself with respect to achieving anti-human immunodeficiency virus concentrations within the central nervous system.


Subject(s)
Brain/metabolism , Dihydropyridines/pharmacokinetics , Prodrugs/pharmacokinetics , Zidovudine/analogs & derivatives , Zidovudine/pharmacokinetics , Animals , Chromatography, High Pressure Liquid , Dihydropyridines/blood , Dihydropyridines/cerebrospinal fluid , Hydrolysis , Infusions, Intravenous , Male , Rabbits , Zidovudine/blood , Zidovudine/cerebrospinal fluid
18.
Antimicrob Agents Chemother ; 36(11): 2370-4, 1992 Nov.
Article in English | MEDLINE | ID: mdl-1489179

ABSTRACT

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.


Subject(s)
Fetus/drug effects , Pregnancy Complications/chemically induced , Pregnancy, Animal/drug effects , Zidovudine/toxicity , Animals , Bone Marrow/drug effects , Bone Marrow/embryology , Bone Marrow Cells , Erythroid Precursor Cells/drug effects , Erythropoietin/therapeutic use , Female , Fetal Diseases/prevention & control , Granulocytes/cytology , Granulocytes/drug effects , Hematocrit , Hematopoietic Stem Cells/drug effects , Interleukin-3/therapeutic use , Litter Size/drug effects , Liver/cytology , Liver/drug effects , Liver/embryology , Macrophages/cytology , Macrophages/drug effects , Male , Mice , Mice, Inbred Strains , Pregnancy , Pregnancy Complications/blood , Pregnancy, Animal/blood , Vitamin E/therapeutic use
19.
Biochem Pharmacol ; 44(6): 1009-12, 1992 Sep 25.
Article in English | MEDLINE | ID: mdl-1417927

ABSTRACT

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.


Subject(s)
Hematopoietic Stem Cells/drug effects , Receptors, Erythropoietin/drug effects , Zidovudine/pharmacology , Animals , Cell Differentiation/drug effects , Colony-Forming Units Assay , Didanosine/pharmacology , Dose-Response Relationship, Drug , Down-Regulation , Hematopoietic Stem Cells/metabolism , Male , Mice , RNA, Messenger/metabolism , Receptors, Erythropoietin/antagonists & inhibitors , Receptors, Erythropoietin/metabolism , Signal Transduction/drug effects
20.
Clin Pharmacol Ther ; 50(4): 442-9, 1991 Oct.
Article in English | MEDLINE | ID: mdl-1680594

ABSTRACT

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.


Subject(s)
HIV Seropositivity/metabolism , Ribavirin/pharmacokinetics , Administration, Oral , Adult , Biological Availability , CD4-Positive T-Lymphocytes/drug effects , Erythrocytes/metabolism , Humans , Infusions, Intravenous , Male , Middle Aged , Plasma/metabolism , Ribavirin/adverse effects , Ribavirin/blood , Time Factors
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