Carrier-linked primaquine in the chemotherapy of malaria.

The antimalarial effect of intravenously administered primaquine (PQ) can be improved and its toxicity diminished by linking it to a macromolecular carrier protein. A thiol-containing primaquine derivative 8-[[4-(2-amino-3-mercaptopropionamido)-1-methylbutyl]amino]-6- methoxyquinoline was synthesized. This compound could readily be linked via a disulfide bond to a carrier protein containing (pyridyldithio)propionate groups. The derivative was coupled to serum albumin as well as to serum albumin that contained covalently linked lactose residues. The protein-drug conjugates were tested for their antimalarial activity in mice inoculated with Plasmodium berghei. The causal prophylactic activity of the conjugate with the lactosaminated serum albumin was 2 times higher than that of the free drug; the mean causal prophylactic doses (CPD50) were 6 and 13 mg of primaquine base/kg, respectively. Moreover, its acute lethal toxicity had decreased at least 6.5-fold (mean lethal dose (LD50) greater than 85 mg of primaquine base/kg). The therapeutic index of this conjugate was at least 12 times higher than that of the free drug. This allowed the administration of a dose that cured 100% of the animals (17.5 mg of primaquine base/kg), in a single injection. With unmodified serum albumin the conjugate showed an increased therapeutic efficacy (the CPD50 was approximately 10 mg of primaquine base/kg) and a strongly reduced lethal toxicity.