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A phase I study of curdlan sulfate--an HIV inhibitor. Tolerance, pharmacokinetics and effects on coagulation and on CD4 lymphocytes.

Curdlan sulfate (CRDS) is a semi-synthetic sulfated polysaccharide which has anti-HIV activity in vitro, and inhibits attachment of the virus to T-cells. After two weeks of exposure of virus and cells to CRDS, there is complete inhibition of virus replication. CRDS is also active against cytomegalovirus. The favorable toxicological profile of CRDS in animals suggested clinical trials. In this study, doses of 0.014, 0.14, 0.42, 1.42, 2.84 and 4.26 mg/Kg (hereinafter referred to as 1, 10, 30, 100, 200 and 300 mg/body, respectively, for convenience) were administered to three HIV-positive patients at each dose level for four hours intravenously. Activated partial thromboplastin times (APTT) were measured hourly. Unexpectedly, single doses of CRDS produced marked, dose-related, increases in CD4 lymphocytes in HIV-infected patients. There were no clinical side effects seen at any dose tested. All laboratory parameters were normal except for prolongation of APTT in the 200 and 300 mg dose group. Two patients in the 300 mg dose group had a doubling of the APTT during the four hour infusion, which was the termination point of the trial according to the protocol. The half-life of CRDS was estimated to be 2 to 3 hours from the APTT data and from the blood level assays (not shown). CRDS was well tolerated in the study with the APTT levels being a convenient monitoring basis for dosing. Marked increases in CD4 levels were seen at higher doses, which, if confirmed and extended, may have therapeutic implications. CRDS is considered safe for multiple dosing with monitoring of APTT.