The Repository Antimalarial Activities of 4,4'-Diacetyl-Aminodiphenylsulfone and Cycloguanil Pamoate (CI-501) in Monkeys Relative to Local Release Following Parenteral Administration

Abstract

Repository antimalarials were implanted subcu-taneously in dialysis sacks for various intervals to control the periods of local drug release. Challenges with Plasmodium cynomolgi tropho-zoites were used to assess drug efficacy. 4,4[image]-diacetylaminodiphenyl-aulfone (DADDS) and cycloguanil pamoate were given as lipid suspensions in doses of 50 mg/kg to six rhesus monkeys. When challenged with parasites 21 days later, two monkeys given DADDS showed strong protection. Two monkeys given cycloguanil pamoate alone, and two given it mixed with DADDS failed to develop patent infections or to yield positive subinoculations following the 21-day challenge. The sacks were removed from one monkey of each pair on day 49 and all were rechallenged on day 52. Typical acute infections developed in those without sacks but protection persisted in those with sacks. Assays of residual drug in the sacks indicated protection by 0.8 to 1.0 mg of drug/day. In-vitro observations confirmed that the drugs dialyze. DADDS was less effective in sacks than intramuscularly. It is concluded that repository action depends upon release from local rather than systemic reservoirs, which reduces the toxicological liabilities of the drugs.