Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel immunosuppressant, succinyl acetone (4,6-dioxoheptanoic acid), was studied in dogs. Results with bolus intravenous injections at doses ranging from 50 to 1600 mg/kg showed dose-dependent alpha and beta half-lives, ranging from 30 to 80 min and 7 to 27 hr, respectively. Results suggested that continuous i.v. infusion was necessary to maintain constant plasma levels. Four dogs were given 9.2 Gy total-body irradiation and autologous marrow transplants along with continuous i.v. infusion of succinyl acetone at 50, 100, 200, or 400 mg/kg/day for 21 days, and all four had rapid, sustained hematopoietic engraftment. However, two of the four dogs receiving 200 and 400 mg succinyl acetone/kg/day, respectively, developed bilateral hind-limb ataxia, with histologically confirmed cerebellar lesions in the dog given the higher dose, thus establishing a potential dose-limiting neurotoxicity. Prevention of graft-versus-host disease was studied in recipients of allogeneic marrow. Dogs were given 9.2 Gy TBI, followed by hematopoietic grafts from unrelated DLA-nonidentical or DLA-haploidentical littermate dogs. Succinyl acetone was given as continuous infusion for 21 days after transplant at doses of 100-300 mg/kg/day. Starting succinyl acetone on the day of marrow infusion in four dogs failed to prevent rapid onset of acute GVHD, and dogs survived no longer than controls. Starting succinyl acetone 3 days before transplant delayed the onset of acute GVHD and prolonged survival significantly compared with that of dogs not given postgrafting immunosuppression (P = 0.008); survival was comparable to that in previously reported dogs given either methotrexate or cyclosporine as postgrafting immunosuppression (P = 0.88 and 0.99, respectively). Seven of the sixteen allogeneic recipients developed evidence of neurotoxicity during succinyl-acetone infusion. Neurological dysfunctions were manifested by hind-limb ataxia and posterior paresis. In conclusion, succinyl acetone significantly delayed the onset of GVHD and prolonged survival of DLA-nonidentical marrow graft recipients but did not induce graft-host tolerance and was associated with dose-limiting neurotoxicity.
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PMID:Pharmacologic, toxicologic, and marrow transplantation studies in dogs given succinyl acetone. 144 Aug 68

The efficacy of succinyl acetone (SA, 4,6-dioxoheptanoic acid) was explored in the allogeneic rat bone marrow transplant model of graft-vs.-host disease. Lethally irradiated Wistar Furth rats receiving Fischer 344 allogeneic bone marrow and spleen cells developed severe GVHD, resulting in mortality at 25-45 days posttransplant. Treatment for 14 days with 250 mg/kg/day of SA by Alzet osmotic pumps implanted subcutaneously 3 days before cell transfer prevented GVHD and produced long-term survivors that were allogeneic hematopoietic chimeras. SA doses below 250 mg/kg/day and treatment for less than 14 days were less efficacious. Initiation of SA therapy could be effectively delayed up to 7 days after BMT. Pharmacokinetic studies with i.v. bolus administration in normal CD rats revealed a plasma mean residence time that increased with dose and a systemic clearance that decreased with dose. Three dose-dependent half lives were apparent (ca. 7-18 min, 0.8-3 hr, and 12 hr). The s.c. bioavailability was ca. 82%. Relatively constant plasma SA levels were obtained with s.c. Alzet osmotic pumps, indicating no change in clearance with continuous exposure. Allogeneic BMT exerted no major influence upon SA clearance. These studies show that SA is a robust therapeutic agent that suppressed GVHD in the allogeneic rat BMT model under a variety of circumstances.
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PMID:Suppression of graft-versus-host disease by succinyl acetone in a rat allogeneic bone marrow transplantation model. 843 89