Amodiaquine antimalarial

El-Ashry et al. [36] studied the complex formation between the bromophenol blue, primaquine, and other important aminoquinoline antimalarials. The colorimetric method used was described as simple and rapid and is based on the interaction of the drug base with bromophenol blue to give a stable ion-pair complex. The spectra of the complex show maxima at 415 420 nm with high apparent molar absorptivities. Beer s law was obeyed in the concentration range 1-8,2-10, and 2-12 pg/mL for amodiaquine hydrochloride, primaquine phosphate, and chloroquine phosphate, respectively. The method was applied to the determination of these drugs in certain formulations and the results were favorably comparable to the official methods. 

Toxicity by metabolism is not confined to the liver since oxidative systems occur in many organs and cells. Amodiaquine is a 4-aminoquinoline antimalarial that has been associated with hepatitis and agranulocytosis. Both side-effects are probably triggered by reactive metabolites produced in the liver or in other sites of the body. For instance polymorphonuclear leucocytes can oxidize amodiaquine. It appears that amodiaquine is metabolized to a quinone imine by the same pathway as that seen in... 

Antimalarial drugs are designed to prevent or treat malaria. Antimalarial drugs currently used for treatment for prophylaxis are mefloquine, primaquine, chloroquine, pyrimethamine, amodiaquin, quinine/quinidine, chloroguanide. 

Amodiaquine (Camoquin) is another 4-aminoquinoline derivative whose antimalarial spectrum and adverse reactions are similar to those of chloroquine, although chloroquine-resistant parasites may not be amodi-aquine-resistant to the same degree. Prolonged treatment with amodiaquine may result in pigmentation of the palate, nail beds, and skin. There is a 1 2000 risk of agranulocytosis and hepatocellular dysfunction when the drug is used prophylactically. 

Metabolism of the antimalarial amodiaquine provides quinone-imine, which is an electrophilic metabolite responsible for hepatotoxicity and agranulocytosis. These side effects have severely restricted the clinical use of amodiaquine. Replacement of the phenolic hydroxyl by a fluorine prevents the oxidation process. Then Af-dealkylation becomes the major process. This has led to further refinements, with the preparation of the Af-fbutyl analogue, a compound that resists metabolic side chain cleavage and has an excellent in vitro and in vivo profile (Figure 3.16). ... 

Ginsburg, H. Famin, O. Zhang, J. Krugliak, M. Inhibition of glutathione-dependent degradation of heme by chloroquine and amodiaquine as a possible basis for their antimalarial mode of action. Biochem. Pharmacol, 1998, 56(10) 1305-1313. 

Antimalarials amodiaquine, chloroquine, chlorproguarril, cin-chonidine, cinchonine, primaquine, proguarril, pyrimethamine, quinine... 

Chloroaniline (133) is the starting point for biguanidine therapeuticals including the antimalarial proguanil (Paludrine) (134). Metabolism of 134 affords dihydrodiazine (135). Another useful antimalarial is the 4-aminoquinoline known as amodiaquin (136). 

The principle of making depot preparations by esterification is widely applied not only to steroid hormones, but also to other drugs (e.g vitamin K, the tranquillizer fluphenazine, and the antimalarial amodiaquine (Fig. 35)158,159> and in the field of pesticides to the weedkiller dichlorophenoxyacetic acid. 

Key among the factors contributing to increasing malaria mortality and morbidity is the widespread resistance of Plasmodium falciparum to conventional antimalarial dmgs, such as chloroquine, sulfadoxine-pyrimethamine and amodiaquine (7). 

As a response to increasing levels of antimalarial resistance. The World Health Organization (WHO) recommends that treatment policies in all countries experiencing resistance of Plasmodium falciparum to conventional monotherapies should be combination therapies, preferably those containing artemisinin derivatives. Currently WHO recommends the following therapeutic options artesunate-sulfadoxine/pyrimethamine, artesunate-amodiaquine,... 

Naisbitt DJ et al. Metabolism-dependent neutrophil cytotoxicity of amodiaquine A comparison with pyronaridine and related antimalarial drugs. Chemical Research in Toxicology, 1998, 11 1586-1595. 

The synthesis of various 4-aminoquinoline antimalarials may be achieved by nucleophilic reaction of 91 with desired amines. Scheme 2 outlines the preparation of chloroquine (3) and amodiaquine (8) starting from 4,7-dichloroquinoline (91) [134-136]. 

Soon after the Second World War (1943), a large number of compounds were synthesized and tested for antimalarial actions, and these eventually gave birth to a host of potent drugs like, chloroquine, proguanil, comoquine and amodiaquine, etc. 

Amodiaquine (AQ), a 4-aminoquinoline antimalarial which is elfective against many chloroquine-resistant strains of Plasmodium falciparum, produces idiosyncratic toxicity in man. Clinical use of AQ has been severely restricted because of life-threatening agranulocytosis and hepatotoxicity seen in about 1 in 2,000 patients during prophylactic administration (Hatton et al. 1986 Larrey et al. 1986 Neftel et al. 1986). The metabolism of AQ has been clearly implicated and there is potential for designing out the toxicity. 

O Neill PM, Mukhtar A, Stocks PA et al (2003) Isoquine and related amodiaquine analogues a new generation of improved 4-aminoquinoline antimalarials. J Med Chem 46 4933-4945 Ormerod LP, Skinner C, Wales J (1996) Hepatotoxicity of antitulxaculosis drugs. Thorax 51 111-113... 

Amodiaquine hydrochloride is an antimalarial of low toxicity and is three to four times as active as quinine as a suppressive drug against Plasmodium vivax and Plasmodium falciparum infections (44,45,46). In therapeutic doses amodiaquine hydrochloride is generally well tolerated but may occasionally give rise to side-effects, including nausea, vomiting. 

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