Meso 2,3-dimercaptosuccinic acid (DMSA) and monoisoamyl DMSA effect on gallium arsenide induced pathological liver injury in rats.

The effect of meso 2,3-dimercaptosuccinic acid (DMSA) and monoisoamyl DMSA (MiADMSA) on gallium arsenide (GaAs) induced liver damage was studied. The oral feeding rat model was used in this study. The animals were exposed to 10 mg/kg GaAs, orally, once daily, 5 days a week for 24 weeks and treated thereafter with single oral daily dose of either 0.3 mmol/kg DMSA or MiADMSA for two course of 5 days treatment. The animals were sacrificed thereafter. Lipid peroxidation was assessed by measuring liver thiobarbituric acid reactive substance (TBARS). Liver damage was assessed by number of biochemical variables and by light microscopy. The activity of superoxide dismutase (SOD) and delta-aminolevulinic acid dehydratase (ALAD) beside reduced glutathione (GSH) concentration was measured in blood. Exposure to GaAs produced a significant reduction in GSH while, increased the oxidized glutathione (GSSG) concentration. Hepatic glutathione peroxidase (GPx) and catalase activity increased significantly while level of serum transaminase increased moderately. Gallium arsenide exposure also produced marked hepatic histopathological lesions. Overall, treatment with MiADMSA proved to be better than DMSA in the mobilization of arsenic and in the turnover of some of the above mentioned GaAs sensitive biochemical alterations. Histopathological lesions also, responded more favorably to chelation treatment with MiADMSA than DMSA.

Reversal of gallium arsenide-induced suppression of the antibody-forming cell response by vehicle supernatants. I. Pharmacokinetics after in vitro and in vivo exposure.

Exposure of splenocytes in vivo or in vitro to gallium arsenide (GaAs) dose-dependently suppresses the ability of these cells to produce antibody after in vitro immunization with sheep red blood cells. In addition, it has been demonstrated that GaAs exerts immunosuppressive effects early (36 hr) in the generation of a primary antibody-forming cell (AFC) response. The objective of this study was to determine if the GaAs-induced suppression was produced as a result of a GaAs-induced alteration in the secretion of soluble mediators. Supernatants from in vivo and in vitro vehicle (VH)-exposed splenocyte cultures time-dependently reversed GaAs-induced suppression of the in vitro-generated primary AFC response produced by both in vitro (50 microM) and in vivo (200 mg/kg) exposure to GaAs. Supernatants from in vitro GaAs-exposed cells suppressed the VH response 40, 89 and 93% at 24, 36 and 48 hr, respectively. Using the arsenic-binding compound meso-2,3-dimercaptosuccinic acid (100 microM), it was determined that the suppression of the VH response by supernatants from in vitro GaAs-exposed cultures was confounded by the presence of free arsenic in the in vitro GaAs-exposed culture supernatant. In contrast, suppression of in vivo VH-exposed AFC responses by supernatants from in vivo GaAs-exposed cells was not seen. The time-dependent reversal of immunosuppression produced by in vivo or in vitro exposure to GaAs, by supernatants from in vivo and in vitro VH-exposed cells mimics the reported kinetics of suppression by addition of GaAs to antibody cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversal of gallium arsenide-induced suppression of the antibody-forming cell response by vehicle supernatants. II. Nature and identification of reversing factors.

Previous studies have demonstrated that several immunological events which are T cell mediated are significantly suppressed by a single exposure to gallium arsenide (GaAs). In addition, in the in vitro-generated antibody-forming cell (AFC) response supernatants from vehicle (VH) cultures were able to time-dependently reverse suppression induced by either in vivo (200 mg/kg) or in vitro (50 microM) exposure to GaAs. The present studies were designed to determine the nature and identification of the reversing factors present in VH supernatants. VH supernatants (25-100%) were able to dose-dependently reverse suppression of the AFC response (from 45% suppression to 48% enhancement of the VH response) induced by GaAs exposure (200 mg/kg). Concentration of 24-hr VH supernatants and treatment with proteinases revealed that the reversing factors were protein in nature with a molecular weight between 5,000 and 50,000 Da. This molecular weight range encompasses many of the lymphokines known to be necessary for the generation of an immune response. In antibody cultures exposed either in vivo or in vitro to VH or GaAs, HT-2 bioassay and antigen capture enzyme-linked immunosorbent assays demonstrated that GaAs exposure alters production of interleukin (IL)-2, IL-4, IL-5 and IL-6. Interestingly, the alterations in lymphokine production differed between the exposure regimes. Direct addition of IL-2 to antibody cultures resulted in a dose-dependent (6.25-50 ng/ml) reversal of GaAs-induced suppression (in vivo exposure) and was also dependent on the concentration of GaAs (50-200 mg/kg). IL-4 suppressed the VH AFC response and failed to reverse GaAs suppression.(ABSTRACT TRUNCATED AT 250 WORDS)

Gallium nitrate (NSC-15200) induced toxicity in the rat: a pharmacologic, histopathologic and microanalytical investigation.

Administration of gallium nitrate to rats resulted in the formation of renal precipitates which occluded tubular lumina. When analyzed with a combination of scanning electron microscopy and x-ray energy spectrometry, these precipitates were found to contain gallium complexed with calcium and phosphate. Injection of gallium nitrate also resulted in hypercalciuria, although serum calcium levels remained unaltered. Administration of an osmotic diuretic, isosorbide, prior to gallium treatment resulted in the formation of fewer renal precipitates and histopathologic changes than in the nondiuresed animals. Diuresis did not alter gallium serum pharmacokinetics, the 24 hour cumulative renal excretion of gallium or the extent of the drug-induced hypercalciuria. However, isosorbide pretreatment significantly reduced the urinary concentrations of both gallium and calcium. The data presented indicate that diuresis reduces the severity of gallium-induced renal lithiasis and subsequent renal accumulation of gallium by diluting the urinary concentration of gallium and calcium thereby lowering the incidence of interaction of these two elements within the kidney tubule.

Evaluation of gallium-67 in the diagnosis of bronchial carcinoma.

Twenty-four patients with carcinoma of the bronchus had lung scans performed with gallium-67. The results were compared with corresponding chest radiographs. In four patients who had been treated with radiotherapy or cytotoxic drugs, there was no uptake of isotope in the lesion. The isotope, however, identified the neoplasm accurately in 17 out of the 20 cases (85%). The relative distribution of isotope in neoplastic tissue and adjacent inflammatory reaction is discussed as well as those cases in which either the radiograph or the scan failed to demonstrate the malignant lesion. Gallium scanning in this study failed to indicate the extension of growth into the mediastinal glands.