THE CLINICAL TRIAL OF EIGHTEEN ANALOGUES OF PAMAQUIN (PLASMOCHIN) IN VIV AX MALARIA (CHESSON STRAIN) 1

Abstract

Eighteen 8-aminoquinolines have been studied for antimalarial activity in human vivax malaria (Chesson strain) and for their clinical toxicity. SN-9972, SN-13,274, SN-13,276 and DR-15,302 apparently cured 2 or more patients when admd. concurrently with quinine. They are all secondary amines. The alkyl substituent of the terminal amine nitrogen is isopropyl in 4 of these drugs and normal propyl in the 5th. All 5 compounds possess 5 carbons in the inter-nitrogen aliphatic chain; in 3 of them it is a secondary amyl and in 2 it is normal amyl. All have a 6-methoxy group on the quinoline nucleus. On an equal weight basis these drugs have greater therapeutic efficacy than pamaquin. SN-13,276 (pentaquine) has been the most extensively studied drug of this group. On an equal wt. basis it has greater curative activity and lower toxicity than pamaquin (plasmochin). The therapeutic effectiveness of drugs was demonstrated both by immediate effect on relapse ratio and by effect on subsequent latent intervals. Drug regimes which produced a high percentage of cures tended to prolong subsequent latent intervals in relapses, and the prolongation was more or less proportional to the lowering of the relapse ratio. No serious toxicity has been encountered in clinical tests on these regimes. The most prominent symptoms have been abdominal pain, anorexia, nausea and vomiting. Cyanosis has occurred when methemoglobinemia exceeded 5 or 6% of the total hemoglobin. Mild drug fever, leukocytosis and leukopenia have been observed. The only 8-aminoquinolines that have not caused significant methemoglobinemia at any dosage level studied are SN-191, SN-13,619, SN-13,694, and SN-13,697. Three of these (SN-191, SN-13,619, and SN-13,697) have no 6-methoxy radical on the nucleus. The 4th has a chloro substituent in the 5 position as well as a 6-methoxy. Diminution in height of the T waves in the limb leads of the electrocardiogram was also observed.