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Comparative toxicity of nitrogen mustards (HN-1, HN-2 and HN-3) and sulphur mustard was carried o... more Comparative toxicity of nitrogen mustards (HN-1, HN-2 and HN-3) and sulphur mustard was carried out in mice. Based on LD 50, the toxicity pattern was HN-2 < HN-1 < HN-3 < sulphur mustard by percutaneous route whereas, by subcutaneous route the toxicity pattern was sulphur mustard < HN-3 < HN-2 < HN-1. Single dose of 1 LD 50 of nitrogen mustards and sulphur mustard was administered percutaneously and various oxidative stress parameters were also evaluated. The weight loss was more in HN-2 on day 3 and in sulphur mustard on day 7. There was a drastic fall of WBC count on day 3 in all groups with a recovery in nitrogen mustard groups on day 7. The RBC count and haemoglobin content showed a significant increase on day 7 in sulphur mustard group. The plasma enzymes (ALT, AST and ALP) showed an increase in all groups on day 3 and day 7. The hepatic GSH and GSSG contents were reduced and MDA content increased in all groups, with a further change in sulphur mustard on 7 day. Extensive DNA fragmentation was observed in all the nitrogen mustard groups compared to sulphur mustard group, on day 3. However, on the day 7 the DNA fragmentation was same in all groups. This study showed that the nitrogen mustards and sulphur mustard were extremely toxic by percutaneous route and caused oxidative stress. Sulphur mustard was more toxic by the percutaneous route and the effects were delayed and progressive.
Toxicology Letters, 2009
Nitrogen mustard (HN-2), also known as mechlorethamine, is an alkylating anticancer agent as well... more Nitrogen mustard (HN-2), also known as mechlorethamine, is an alkylating anticancer agent as well as blister inducing chemical warfare agent. We evaluated the cytoprotective efficacy of amifostine, DRDE-07 and their analogues, and other antidotes of mustard agents against HN-2. Administration of 1 LD50 of HN-2 (20 mg/kg) percutaneously, decreased WBC count from 24 h onwards. Liver glutathione (GSH) level decreased prominently and the maximum depletion was observed on 7th day post-HN-2 administration. Oxidised glutathione (GSSG) level increased significantly at 24 h post-administration and subsequently showed a progressive decrease. Hepatic malondialdehyde (MDA) level and percent DNA damage increased progressively following HN-2 administration. The spleen weight decreased progressively and reached a minimum on 3–4 days with subsequent increase. The antidotes were administered repeatedly for 4 and 8 days after percutaneous administration of single sublethal dose (0.5 and 0.25 LD50) of HN-2. Treatment with DRDE-07, DRDE-30 and DRDE-35 significantly protected the changes in spleen weight, WBC count, GSH, GSSG, MDA and DNA damage following HN-2 administration (0.5 and 0.25 LD50). There was no alteration in the transaminases (AST and ALT), and alkaline phosphatase (ALP) activities, neither with HN-2 nor with antidotes. The present study shows that HN-2 is highly toxic by percutaneous route and DRDE-07, DRDE-30 and DRDE-35 can partially protect it.
International Journal of Toxicology, 2010
The chemical warfare agents sulfur mustard (SM) and nitrogen mustards (HN-1, HN-2, and HN-3) are ... more The chemical warfare agents sulfur mustard (SM) and nitrogen mustards (HN-1, HN-2, and HN-3) are highly reactive vesicants. The study was planned to investigate the protective efficacy of amifostine, DRDE-07 and their analogues, and few conventional antidotes (30 minutes pretreatment) against dermally applied SM and nitrogen mustards in preventing hematological and biochemical changes in mice. Mustard agents (1.0 median lethal dose [LD 50 ]) induced a significant decrease in the body weight and spleen weight. A significant decrease in the white blood cell (WBC) count and an increase in serum transaminases and alkaline phosphatases (ALPs) were observed. A significant decrease in reduced (GSH) and oxidized glutathione (GSSG) and an increase in thiobarbituric acid reactive substances were also observed. All the mustard agents increased DNA fragmentation. The effects of SM were significantly ameliorated by DRDE-07 analogues, and with nitrogen mustards the protection was partial. Overall, DRDE-30 (propyl analogue) followed by DRDE-35 (butyl analogue) are favored as safer and better compounds.
Comparative toxicity of nitrogen mustards (HN-1, HN-2 and HN-3) and sulphur mustard was carried o... more Comparative toxicity of nitrogen mustards (HN-1, HN-2 and HN-3) and sulphur mustard was carried out in mice. Based on LD 50, the toxicity pattern was HN-2 < HN-1 < HN-3 < sulphur mustard by percutaneous route whereas, by subcutaneous route the toxicity pattern was sulphur mustard < HN-3 < HN-2 < HN-1. Single dose of 1 LD 50 of nitrogen mustards and sulphur mustard was administered percutaneously and various oxidative stress parameters were also evaluated. The weight loss was more in HN-2 on day 3 and in sulphur mustard on day 7. There was a drastic fall of WBC count on day 3 in all groups with a recovery in nitrogen mustard groups on day 7. The RBC count and haemoglobin content showed a significant increase on day 7 in sulphur mustard group. The plasma enzymes (ALT, AST and ALP) showed an increase in all groups on day 3 and day 7. The hepatic GSH and GSSG contents were reduced and MDA content increased in all groups, with a further change in sulphur mustard on 7 day. Extensive DNA fragmentation was observed in all the nitrogen mustard groups compared to sulphur mustard group, on day 3. However, on the day 7 the DNA fragmentation was same in all groups. This study showed that the nitrogen mustards and sulphur mustard were extremely toxic by percutaneous route and caused oxidative stress. Sulphur mustard was more toxic by the percutaneous route and the effects were delayed and progressive.
Toxicology Letters, 2009
Nitrogen mustard (HN-2), also known as mechlorethamine, is an alkylating anticancer agent as well... more Nitrogen mustard (HN-2), also known as mechlorethamine, is an alkylating anticancer agent as well as blister inducing chemical warfare agent. We evaluated the cytoprotective efficacy of amifostine, DRDE-07 and their analogues, and other antidotes of mustard agents against HN-2. Administration of 1 LD50 of HN-2 (20 mg/kg) percutaneously, decreased WBC count from 24 h onwards. Liver glutathione (GSH) level decreased prominently and the maximum depletion was observed on 7th day post-HN-2 administration. Oxidised glutathione (GSSG) level increased significantly at 24 h post-administration and subsequently showed a progressive decrease. Hepatic malondialdehyde (MDA) level and percent DNA damage increased progressively following HN-2 administration. The spleen weight decreased progressively and reached a minimum on 3–4 days with subsequent increase. The antidotes were administered repeatedly for 4 and 8 days after percutaneous administration of single sublethal dose (0.5 and 0.25 LD50) of HN-2. Treatment with DRDE-07, DRDE-30 and DRDE-35 significantly protected the changes in spleen weight, WBC count, GSH, GSSG, MDA and DNA damage following HN-2 administration (0.5 and 0.25 LD50). There was no alteration in the transaminases (AST and ALT), and alkaline phosphatase (ALP) activities, neither with HN-2 nor with antidotes. The present study shows that HN-2 is highly toxic by percutaneous route and DRDE-07, DRDE-30 and DRDE-35 can partially protect it.
International Journal of Toxicology, 2010
The chemical warfare agents sulfur mustard (SM) and nitrogen mustards (HN-1, HN-2, and HN-3) are ... more The chemical warfare agents sulfur mustard (SM) and nitrogen mustards (HN-1, HN-2, and HN-3) are highly reactive vesicants. The study was planned to investigate the protective efficacy of amifostine, DRDE-07 and their analogues, and few conventional antidotes (30 minutes pretreatment) against dermally applied SM and nitrogen mustards in preventing hematological and biochemical changes in mice. Mustard agents (1.0 median lethal dose [LD 50 ]) induced a significant decrease in the body weight and spleen weight. A significant decrease in the white blood cell (WBC) count and an increase in serum transaminases and alkaline phosphatases (ALPs) were observed. A significant decrease in reduced (GSH) and oxidized glutathione (GSSG) and an increase in thiobarbituric acid reactive substances were also observed. All the mustard agents increased DNA fragmentation. The effects of SM were significantly ameliorated by DRDE-07 analogues, and with nitrogen mustards the protection was partial. Overall, DRDE-30 (propyl analogue) followed by DRDE-35 (butyl analogue) are favored as safer and better compounds.