The in vivo response of Plasmodium falciparum parasites to amodiaquine or chloroquine was assessed in children with symptomatic malaria attending different health facilities in the Madang area. Among the 27 subjects who were completely followed up, 4 (15%) were infected with parasites fully susceptible and 23 (85%) with parasites exhibiting some degree of resistance. Out of the latter group, 52% were of RI level, 26% RII and 22% RIII. 14 subjects out of 42 (33%) failed to clear their parasitaemia by day 7 and 92 out of 134 (69%) had persistent or recrudescent parasitaemia at day 21. The level of in vivo resistance was similar for amodiaquine and chloroquine. 86% of the isolates tested in vitro showed resistance to amodiaquine, 86% to chloroquine and 7% to quinine. In ten years the prevalence of resistant isolates in vivo has increased from 47% to 85%. Of more concern is the shift from RI level of resistance to RII and RIII: the proportion of resistant strains that were RI dropped from 90% to 52% over the ten-year period. To determine if the standard antimalarial regimens are still appropriate, there is a need not only to assess the level of parasite resistance but also the prevalence of treatment failure in different parts of Papua New Guinea. PIP: The in vivo response of Plasmodium falciparum parasites to amodiaquine and chloroquine was assessed in children 1-9 years of age with symptomatic malaria recruited from health centers in Papua New Guinea's Madang area. Among the 27 children who were completely followed up, 4 (15%) were infected with fully susceptible parasites; in the remaining 23 cases (85%), there was some degree of resistance. 52% of parasites in the latter group were RI level, 26% RII, and 22% RIII. There was no correlation between level of resistance and age. 14 out of 42 children (33%) failed to clear their parasitemia by day 7 and 92 out of 134 (69%) had persistent or recrudescent parasitemia at day 21. Both amodiaquine and chloroquine had similar levels of in vivo resistance. 86% of isolates tested in vitro showed resistance to amodiaquine, 86% to chloroquine, and 7% to quinine. In 10 years, the prevalence of resistant isolates in vivo has increased from 47% to 85%. Of particular concern is the finding that the proportion of resistant strains that were RI dropped from 90% to 52% over this decade. The increase of resistance is attributed to indiscriminate use of 4-aminoquinolines in all cases of fever. Needed, to assess whether standard antimalarial regimens are still appropriate, is a review of treatment failure in different parts of Papua New Guinea.
Acute Disease ; Amodiaquine - therapeutic use ; Animals ; Antimalarials - therapeutic use ; Case-Control Studies ; Child ; Papua New Guinea ; Treatment Failure

Zika virus (ZIKV) is a mosquito borne pathogen, belongs to Flaviviridae family having a positive-sense single-stranded RNA genome, currently known for causing large epidemics in Brazil. Its infection can cause microcephaly, a serious birth defect during pregnancy. The recent outbreak of ZIKV in February 2016 in Brazil realized it as a major health risk, demands an enhanced surveillance and a need to develop novel drugs against ZIKV. Amodiaquine, prochlorperazine, quinacrine, and berberine are few promising drugs approved by Food and Drug Administration against dengue virus which also belong to Flaviviridae family. In this study, we performed molecular docking analysis of these drugs against nonstructural 3 (NS3) protein of ZIKV. The protease activity of NS3 is necessary for viral replication and its prohibition could be considered as a strategy for treatment of ZIKV infection. Amongst these four drugs, berberine has shown highest binding affinity of –5.8 kcal/mol and it is binding around the active site region of the receptor. Based on the properties of berberine, more similar compounds were retrieved from ZINC database and a structure-based virtual screening was carried out by AutoDock Vina in PyRx 0.8. Best 10 novel drug-like compounds were identified and amongst them ZINC53047591 (2-(benzylsulfanyl)-3-cyclohexyl-3H-spiro[benzo[h]quinazoline-5,1'-cyclopentan]-4(6H)-one) was found to interact with NS3 protein with binding energy of –7.1 kcal/mol and formed H-bonds with Ser135 and Asn152 amino acid residues. Observations made in this study may extend an assuring platform for developing anti-viral competitive inhibitors against ZIKV infection.
Amodiaquine ; Berberine ; Brazil ; Catalytic Domain ; Congenital Abnormalities ; Culicidae ; Dengue Virus ; Drug Design ; Flaviviridae ; Flavivirus ; Genome ; High-Throughput Screening Assays ; Humans ; Mass Screening* ; Microcephaly ; Molecular Docking Simulation ; Pregnancy ; Prochlorperazine ; Quinacrine ; RNA ; United States Food and Drug Administration ; Zika Virus* ; Zinc