Evaluation of the 2-Aminomethylphenol JPC-2997 in Aotus Monkeys Infected with Plasmodium falciparum.

Previously, we reported JPC-2997 [4-(tert-Butyl)-2-((tertbutylamino)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol] to possess high in vitro antimalarial activity against Plasmodium falciparum lines, low cytotoxicity in mammalian cell lines, a long blood elimination half-life in Aotus monkeys (10.8 days), and potent in vivo efficacy against animal malaria models (1). Herein, as planned by Birrell et al. (1), we report on the in vivo efficacy of JPC-2997 against the chloroquineand quinineresistant P. falciparum FVO strain in Aotus monkeys (2). As part of a malaria vaccine study of chemically attenuated parasites (CAP) in Aotus monkeys (3), various regimens of JPC2997 given alone (1and 3-day treatments) and JPC-2997 coadministered with artesunate (1and 3-day treatments) were used to treat monkeys that developed an FVO infection. Briefly, nonsplenectomized Aotus monkeys (n 9; body weight range, 0.98 kg to 1.55 kg) were inoculated intravenously with 1 10 to 4 10 parasites of the P. falciparum FVO strain. Three to 13 days after the onset of patency, monkeys were treated by orogastric intubation with either JPC-2997 alone or JPC-2997 plus artesunate. After treatment of the monkeys, thick and thin blood smears were examined daily by counting parasitized erythrocytes against 200 leukocytes or 10,000 erythrocytes. When no parasites were detected in 100 microscopic high-power ( 1,000) fields, follow-up blood thick smears were examined twice a week for 3 weeks after parasite inoculation and then approximately once a week up to at least day 60 after parasite inoculation. The study was approved by the AMI Animal Ethics Committee (protocol AEC 10-13). Regimens evaluated and parasite responses after treatment with JPC-2997 alone and in combination with artesunate are summarized in Table 1. The 1-day JPC-2997 (20 mg/kg of body weight) treatment cleared parasites as rapidly as the two 3-day treatment courses of JPC-2997 (10 or 20 mg/kg/day), with 99% reduction in parasitemia by day 3 after starting treatment. None of the 4 naive monkeys had a recrudescence after administration of the three JPC-2997 regimens. Previously, we reported that artesunate administered at 10 mg/kg daily for 3 days rapidly cleared parasites in Aotus monkeys infected with the P. falciparum FVO strain but that recrudescence occurred between days 9 and 20 (4). In the present study, a 1-day treatment of JPC-2997 (20 mg/kg) plus artesunate (10 mg/kg) administered to 4 monkeys (2 naive and 2 infected with CAP) with rising high parasitemia (range, 264.4 to 512.8 parasites 10/ l) cleared parasites by day 4 postdose, with no recrudescence observed over a 60-day follow-up period. Although the 1-day treat-