China
Africa
Explore chapters and articles related to this topic
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Amodiaquine is a 4-aminoquinoline derivative that has been widely used for treatment of malaria and is more active than the other 4-aminoquinoline, chloroquine, against Plasmodium falciparum parasites, which are moderately chloroquine resistant. Upon oral administration, amodiaquine is rapidly absorbed and extensively metabolized such that very little of the parent drug is detected in the blood. The main metabolite of amodiaquine is N-desethylamodiaquine with other minor metabolites being 2-hydroxyl-N-desethyl-amodiaquine and N-bis-desethylamodiaquine (Figure 3.87) (Churchill et al. 1985, 1986; Mount et al. 1986). The formation of N-desethylamodiaquine is rapid, while its elimination is very slow with a terminal half-life of more than 100 h (Laurent et al. 1993; Winstanley et al. 1987). Both amodiaquine and N-desethylamodiaquine have antimalarial activity, but amodiaquine is three times more active. Amodiaquine N-deethylation has been used as an alternative marker reaction for CYP2C8 because of its high affinity and high turnover rate (Km = 1.0 µM; Vmax = 2.6 pmol/min/pmol CYP2C8) (Li et al. 2002). N-Desethylamodiaquine is found to be CYP2C8 selective in the liver with a minor amount being formed by CYP2D6 and extrahepatic enzymes CYP1A1 and 1B1 (Li et al. 2002).
Treatment and prevention of malaria
Published in David A Warrell, Herbert M Gilles, Essential Malariology, 2017
David A Warrell, William M Watkins, Peter A Winstanley
The only 4-aminoquinoline in clinical use, other than chloroquine, is amodiaquine. It is rapidly and completely metabolized to desethyl-amodiaquine (DESAQ), which is equally active against the parasite. For these reasons, Churchill has suggested that amodiaquine should be considered a pro-drug for DESAQ. In many locations in Africa, amodiaquine is more effective than chloroquine for treating malaria, suggesting a possible difference in resistance mechanisms. However, it is now apparent that differences in efficacy between 4-aminoquinoline drugs and their metabolites largely reflect differences in liposolubility; the degree of cross-resistance correlates well with the octanol: water partition coefficient. Amodiaquine and chloroquine share the same resistance mechanism and, although the degree of cross-resistance to amodiaquine is relatively small, the degree of cross-resistance to DESAQ (the active moiety in vivo) is complete. Whether the greater efficacy of amodiaquine has significant operational usefulness is still an open question, given the dangers of severe toxic reactions associated with frequent dosage.
Amodiaquine
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Amodiaquine is a 4-aminoquinoline that has been used widely since the early 1950s to prevent and treat Plasmodium falciparum malaria. Amodiaquine is a 7-chloro-4-amino congener of chloroquine. Before the emergence of widespread resistance, it was mostly used in Africa for malaria monotherapy.
Current status of 4-aminoquinoline resistance markers 18 years after cessation of chloroquine use for the treatment of uncomplicated falciparum malaria in the littoral coastline region of Cameroon
Published in Pathogens and Global Health, 2022
Marcel Nyuylam Moyeh, Sandra Noukimi Fankem, Innocent Mbulli Ali, Denis Sofeu, Sorelle Mekachie Sandie, Dieudonne Lemuh Njimoh, Stephen Mbigha Ghogomu, Helen Kuokuo Kimbi, Wilfred Fon Mbacham
The results of this study showed a significant drop in the prevalence of markers of resistance to 4-aminoquinoline drugs. The K76T mutant allele was found in 97% of participants in samples collected just one year after the ban on chloroquine use [23] and by 2013, the proportion had dropped to 66.9% [24]. In the current study, the proportion has further dropped significantly to 25.1% (P < 0.00001). The rate of drop is small compared to data from Malawi Kublin et al. [25] just ten years after withdrawing chloroquine. This implies that almost 20 years down the line this reduction in prevalence in Cameroon does not seem to be at its lowest yet. This is probably because amodiaquine, which is another 4-aminoquinoline, was maintained as a partner drug to artesunate in treating uncomplicated falciparum malaria in Cameroon. In addition, in vivo results of clinical studies that were conducted in Malawi in 2006 showed that a 99% return to clinical efficacy was observed [17]. The significant drop in prevalence can be attributed in part to the removal of chloroquine pressure from the public or the high efficacy of ACTs to 4-aminoquinoline resistant parasites as well as selection of wild type alleles following treatment with artemether-lumefantrine (AL) [26–28]. These factors could have an additive effect explaining the drop. A similar trend was observed for alleles of the Pfmdr1 gene. Between 2003 and 2005, the prevalence of the mutant genotypes 86 N, 184 F and 1246Y were respectively 83.6%, 97.2% and 3.1% [23] but the figures dropped to 44.2%, 47.0% and 0.0% in samples collected between 2009 and 2013 [19]. In this study, carried out 8 years later, the results show that the 86Y, the 184 F and the 1246D mutant alleles were respectively 16.2%, 10.4% and 0.0%. This difference was observed to be highly significant (P≪0.00001).
Antimalarial drugs for treating and preventing malaria in pregnant and lactating women
Published in Expert Opinion on Drug Safety, 2018
Makoto Saito, Mary Ellen Gilder, Rose McGready, François Nosten
Amodiaquine is used as a treatment for uncomplicated falciparum malaria in combination with artesunate. Artesunate-amodiaquine (ASAQ) is available either as fixed-dose or non-fixed dose combination, with amodiaquine 10 mg base/kg/day given once daily for three days. ASAQ is recommended in the second and third trimesters by WHO [4]. Limited data from 24 pregnant women in the second and third trimesters indicated there were no clinically meaningful pharmacokinetic changes in pregnancy [73,74].
Zika virus pathogenesis and current therapeutic advances
Published in Pathogens and Global Health, 2021
Caroline Mwaliko, Raphael Nyaruaba, Lu Zhao, Evans Atoni, Samuel Karungu, Matilu Mwau, Dimitri Lavillette, Han Xia, Zhiming Yuan
Antivirals acting on host proteins interfere with different parts of the ZIKV life cycle, impairing viral replication. The first step in the ZIKV life cycle is binding of the virus to receptors (DC-SIGN, TYRO 3, AXL, TIM, and TAM) [35], followed by internalization by endocytosis to reach endosomes [37]. Different compounds have been developed using this target. Endocytosis and endosomal fusion (EEF) inhibitors include 25-hydroxycholesterol (25HC), a natural product of lipid metabolism shown to reduce viremia in mice and monkeys. Moreover, 25HC protected infected fetal mice from microcephaly [134]. Chloroquine, an antimalarial and anti-inflammatory drug, reduced ZIKV titers in ZIKV-infected cells and protected mouse neurospheres from morphological damage [108]. Arbidol, also known as umifenovir, an approved drug both in Russia and China, was shown to reduce viral titers in ZIKV with a micromolar effect [135]. Additionally, the drug also reduced viral multiplication in WNV and tick-borne encephalitis virus (TBEV) with a strong cell-dependent effect [135]. K22, a small compound inhibitor with potential activity against a broad range of coronaviruses, was also shown to inhibit ZIKV. K22 efficiently interfered with the replication of other flaviviruses, including JEV, WNV and, to a certain extent, Usutu virus (USUV), Wesselsbron virus (WESSV), hepacivirus (HCV), and bovine viral diarrhea virus (BVDV) [136]. Another EEF inhibitor is Tenovin-1, which inhibits ZIKV multiplication in primary fibroblasts [137]. A venom peptide, Ev37, from the scorpion Euscorpiops validusin inhibited ZIKV, DENV-2, hepatitis C virus (HCV) and herpes simplex virus type 1 (HSV-1) infections in a dose-dependent manner. The drug showed low cytotoxic effects in vitro; however, it had no effect on Sendai virus (SeV) or adenovirus (AdV) [138]. Finally, Amodiaquine, an antimalarial drug, was shown to exhibit antiviral activity in both ZIKV and DENV at a micromolar concentrations in vitro [139].