Amodiaquine, toxicity

The drug resembles very similar to chloroquine mechanistieally and it does not possess any added advantages over the other 4-aminoquinoline drugs. It has been demonstrated amply that the hydroquinone (phenol) amine system rapidly gets oxidized to a eorresponding quinone-imine system, either accomplished via antioxidatively and/or metabolically and the resulting product may be solely responsible for the ensuing amodiaquine toxicity. 

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... 

Amodiaquine and chloroquine have been compared in an open, randomized trial in uncomplicated falciparum malaria in Nigerian children (1). The doses were amodiaquine (n = 104) 10 mg/kg/day for 3 days and chloroquine n = 106) 10 mg/kg/day for 3 days. After 28 days, the cure rate was significantly higher with amodiaquine than chloroquine (95% versus 58%). The rates of adverse events, most commonly pruritus (10%) and gastrointestinal disturbances (3%), were similar in the two groups. Cross-resistance between the two aminoquinolines is common, and there are concerns regarding toxicity of amodiaquine with repeated use. 

The other 4-aminoquinolines, hydroxychloroquin, HCQ, and amodiaquine, are of use primarily as alternatives to CQ, offering no advantages in terms of resistance, although HCQ may be somewhat less toxic. 

Several 4-aminoquinolines have now been tested and hydroxychloroquine sulphate (Plaquenil XLV, R =Et, R =CH2-CH2-OH), a closely related derivative of chloroquine, is known to possess antirheumatic properties similar to those of chloroquine . Amodiaquine (Camoquin, XLVl, R=NEt2) also possesses activity but seems to be too toxic for routine use . . . However, the closely-related amopyroquin (Propoquin, XLVI, R=pyrrolidino) appears to possess desirable clinical activity without serious toxicity . Drugs of the 4-aminoquinoline type in most frequent use are chloroquine phosphate, 250-500 mg daily, chloroquine sulphate, 200-400 mg daily, and hydroxychloroquine sulphate, 400-600 mg daily . A striking feature of this therapy is that beneficial effects are often not apparent until... 

Amodiaquin (10), 4-aminoquinoline which contains 3-diethylaminomethyl-4-hydroxyphenylamino and chloro groups, was synthesized and found to be more potent against P. falciparum than chloroquine. However it is more hepatotoxic than chloroquine and produces granulocytosis. One of the N-ethyl substituents of chloroquine is 0-hydroxyIated to produce hydroxychloroquine (11), which has similar efficient activity against falciparum malaria, and is less toxic than chloroquine. This compound is preferred over chloroquine in the treatment of rheumatoid arthritis and lupus erythematosus. 

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. 

Chloroquine and other aminoquinolines are used in the prophylaxis or therapy of malaria and other parasitic diseases. Chloroquine and hydroxychloroquine are also used in the treatment of rheumatoid arthritis. Drugs in this class include chloroquine phosphate (Aralen ), amodiaquine hydrochloride (Camoquin ), hydroxychloroquine sulfate (Plaquenil ), mefloquine (Lariam" ), primaquine phosphate, and quinacrine hydrochloride (Atabrine ). Chloroquine overdose is common, especially in countries where malaria is prevalent, and the mortality rate is 10-30%. Quinine toxicity is described on p 326. 

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. 

A method is described for evaluating the relative toxicity of amodiaquine in rats on the basis of effect on growth, lethal effects, production of pathological changes, and the concentration of drug in blood or plasma. The test can be completed in fourteen days (50). 

Amodiaquine is bioactivated by CYP2C8 to N-desethyl-amodiaquine (DEAQ) which concentrates in blood cells [3 ]. DEAQ, similar to chloroquine, inhibits the digestion of haemoglobin and inhibits glutathione-dependent destruction of ferriprotoporphyrin IX, causing toxicity due to accumulation of the peptide [4 ,5 ]. 

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