Combination of quinine, quinidine and cinchonine for the treatment of acute falciparum malaria: correlation with the susceptibility of Plasmodium falciparum to the cinchona alkaloids in vitro.

Thirteen patients with acute symptomatic uncomplicated falciparum malaria were enrolled in an open, randomized, phase 2, dose-finding clinical trial of a fixed dosage combination of quinine, quinidine and cinchonine (LA40221, Sanofi Recherche, France), which contained equal parts of the 3 alkaloids and was administered orally every 8 h in doses of 400 mg (7 patients) or 500 mg (6 patients) for 7 d. There was prompt clearance of parasitaemia and fever in all patients. The mean clearance times (+/- standard deviation) of parasitaemia, fever and other symptoms were 29 +/- 11.0 h, 10.7 +/- 4.1 h and 14.9 +/- 9.7 h respectively for the 400 mg dose group, and 35 +/- 20.0 h, 16 +/- 7.0 h and 17.6 +/- 8.7 h respectively for the 500 mg dose group. There was no recrudescence of parasitaemia during the 28 d observation period. Minor gastrointestinal side effects occurred in 2 patients, but there was no major side effect. Haematological, biochemical and other measurements were not adversely altered by treatment. QTc prolongation occurred in 3 patients--2 from the 400 mg and 1 from the 500 mg dose group. Testing in vitro against Plasmodium falciparum isolates from 47 patients (including the 13 patients enrolled in the trial) of the combination and its individual components suggested that the relative potencies in vitro, in decreasing order, were quinidine, LA40221, cinchonine and quinine. The minimum inhibitory concentrations were 0.32, 0.64, 0.64 and 1.28 mumol/litre of blood-medium mixture respectively, and the 50% inhibitory concentrations were 0.083, 0.11, 0.12 and 0.22 mumol/litre of blood-medium mixture. The respective 99% inhibitory concentrations were 0.27, 0.45, 0.50 and 1.20 mumol/litre of blood-medium mixture.