Comparison of the Curative Antimalarial Activities and Toxicities of Primaquine and Its d and l Isomers

Abstract

This investigation was undertaken to determine whether either d-primaquine or l-primaquine has sufficient advantage over primaquine to warrant evaluation for curative activity in human volunteers infected with Plasmodium vivax. It was found: (i) that the capacities of the isomers and the racemate to cure infections with Plasmodium cynomolgi in rhesus monkeys were essentially identical; (ii) that the subacute toxicities of the isomers and racemate for this monkey were qualitatively the same, but that l-primaquine was three to five times as toxic as d-primaquine and at least twice as toxic as primaquine; and (iii) that the acute single-dose. toxicities of the isomers for mice were not only qualitatively different, but that the d isomer was at least four times as toxic as 1-primaquine. Since previous appraisals of curative activity and tolerability of 8-aminoquinolines in rhesus monkeys have correlated well with appraisals in human volunteers, attention was focused on results acquired with these test subjects. The relevant evaluations showed that d-primaquine had a therapeutic index at least twice that of primaquine. If this advantage carries over to man, problems that now complicate routine use of primaquine might be obviated. Therefore, a critical comparison of d-primaquine and primaquine in human volunteers seems indicated.

Antimalarial activity and inhibition of monoamine oxidases A and B by exo‐erythrocytic antimalarials

“…The finding of similar and relatively moderate inhibition of MAO A and B in vitro by 1A and 1B (Ki ranges 103-225/~M), enhanced 10-90-fold with 4, does not strongly support the concept that MAO A and B could catalyze their deamination to 3 in vivo at drug concentrations that give schizontocidal activity. Comparison of the optical isomers 1A and 1B of primaquine, favouring here the (-) isomer 1B as the less toxic compound, is offset by earlier reports showing that the (+) isomer 1A had a better therapeutic index in rhesus monkeys [16], with both 1A and 1B similarly inhibiting drug metabolism [17]. In view of the appearance of new and much improved antimalarials for radical cure and clearing of tissue parasites, such as 4 [12] or its 4-methyl-substituted analogues [18], further development of either (-)-primaquine (1B) or its (+) isomer 1A does in our opinion not seem warranted.…”

Primaquine revisited six decades after its discovery

“…Studies in mice indicated that the subacute toxicity of l-PQ is 3-5 times higher than that of d-PQ and 2 times less than PQ. The acute single-dose toxicity of the d-PQ was at least 4 times as toxic as l-PQ [98,99]. It is noteworthy that PQ is not a racemic mixture, because l isomer prevails over the d isomers.…”

“…As PQ has a stereogenic centre, it would be expectable that each isomer had different activities, considering the most probable involvement of enzymes in the drug's mechanism of action. Many scientists defended that PQ isomers have similar activity, based on the fact that both presented identical capacity for the radical cure of rhesus monkeys infected with sporozoites of P. cynomolgi [98]. Studies in mice indicated that the subacute toxicity of l-PQ is 3-5 times higher than that of d-PQ and 2 times less than PQ.…”

The Technology for Preparation of Generic (Monoenantiomeric) Antimalarial Drug Primaquine by Using Supercritical Fluid Chromatography. Separation of Primaquine from Quinocide: Simultaneous Resolution of the Enantiomers of Primaquine and Their Separation from Quinocide in One Run

“…However, the (+)-enantiomer is significantly more toxic than the (-)-enantiomer. In the rodent model described in [45,46], the (+)-enantiomer was more toxic than the (-)-enantiomer. The (-)-enantiomer of primaquine is transformed preferentially by mitochondrial enzymes though α-oxidation to (-)-carboxyprimaquine, which has a relatively low toxicity [47].…”