In Vivo and In Vitro Efficacy of Amodiaquine againstPlasmodium falciparumin an Area of Continued Use of 4‐Aminoquinolines in East Africa

Abstract

In light of reports of increasing resistance of parasites to amodiaquine in African countries in which Plasmodium falciparum is endemic as well as the paucity of recent in vitro sensitivity data, we assessed the in vivo and in vitro sensitivity to amodiaquine of P. falciparum isolates from 128 pediatric outpatients (0.5-10 years old) in Pingilikani, Kilifi District, Kenya, who were treated with amodiaquine (10 mg/kg/day for 3 days). The polymerase chain reaction-corrected parasitological cure rate on day 28 (by Kaplan-Meier analysis) was 82% (95% confidence interval [CI], 74%-88%). Twenty-six percent (17/66) of tested pretreatment P. falciparum field isolates had 50% in vitro growth inhibition at concentrations of N-desethyl-amodiaquine (DEAQ)-the major biologically active metabolite of amodiaquine-above the proposed resistance threshold of 60 nmol/L, but baseline median DEAQ 50% inhibitory concentration values were not associated with subsequent risk of asexual parasite recrudescence (29 nmol/L [95% CI, 23-170 nmol/L] and 34 nmol/L [95% CI, 30-46 nmol/L] for patients with and those without recrudescences, respectively). The median absolute neutrophil count dropped by 1.3 X 10(3) cells/microL (95% CI, -1.7 X 10(3) to -0.7 X 10(3) cells/microL) between days 0 and 28. The high prevalence of in vitro and in vivo resistance precludes the use of amodiaquine on its own as second-line treatment. These findings also suggest that the value of amodiaquine combinations as first- or second-line treatment in areas with similar patterns of 4-aminoquinoline resistance should be reassessed.

In Vitro Activities of Piperaquine, Lumefantrine, and Dihydroartemisinin in Kenyan Plasmodium falciparum Isolates and Polymorphisms in p fcrt and p fmdr1

“…From the field, blood samples were collected, placed in "transport medium" (containing RPMI medium and albumin), and taken to the laboratory for long-term culture adaption, and other isolates were cryopreserved in liquid nitrogen before adaption. The detailed description of this long-term parasite adaptation procedure is given elsewhere (32). Provision of informed consent for the original studies was ensured by the Kenya Medical Research Institute, Nairobi.…”

Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine

“…In Africa, where CQ-resistant strains of P. falciparum are now prevalent, AQ has remained sufficiently efficacious for the World Health Organization to recommend it as a partner in drug combinations including artemisinin combination therapy (ACT) (7). However, poor in vivo responses and outright failures of AQ against P. falciparum were described decades ago in India, Southeast Asia, the Philippines, South America, and Papua New Guinea (PNG) (8)(9)(10)(11)(12) and have been seen more recently in Africa (13,14).…”

Baseline In Vitro Activities of the Antimalarials Pyronaridine and Methylene Blue against Plasmodium falciparum Isolates from Kenya

“…As comparators, we have included the already-published data on the same isolates against CQ, LM, PIQ and QN, AQ, DEAQ, and DHA (13)(14)(15)27). Median IC 50 s for PRN and MB against the multidrug-resistant strain V1S were 12 and 1 nM, respectively, and values for the fully sensitive strain 3D7 were 8 and 2 nM, respectively.…”