Chloroquine-enhancing effectiveness

Chlorphenamine enhances the efficacy of chloroquine in acute uncomplicated falciparum malaria, but the disposition of chloroquine in these circumstances is unpredictable. Chloroquine (25 mg/kg) was given orally over 3 days in combination with chlorphenamine to Nigerian children with parasitemia (45). The peak whole blood chloroquine concentration was increased and the time to peak concentration shortened. In small trials there seemed to be an increase in QT interval with this combination, but less than with halofantrine (46). However, in other studies, the addition of chlorphenamine to chloroquine did not amplify the cardiac effects of chloroquine (46). 

Ferroquine possesses planar chirality due to the non-symmetrical 1,2-substitution of the ferrocene entity, and the pure enantiomers (+)35 and (—)35 were obtained by enzymatic resolution using the Candida rugosa lipase as a biocatalyst. The enantiomeric purity levels exceed 98%. However, the two optical isomers display identical activity in vitro at the nanomolecular level. In vivo, however, either of the enantiomers alone is less active than the racemic mixture against both chloroquine-sensitive and chloroquine-resistant strains. In addition, (4-)35 displays better curative effects than (—)35, suggesting different pharmacokinetic properties. The reasons for the enhanced behavior of racemic ferroquine have not yet been elucidated. It is still not clear whether 35 is oxidized by the parasite to give the ferricinium ion, thus initiating Fenton-type reactivity. Such a hypothesis is reasonable, given that reactive oxidative species can escalate in cancer cells due to the malfunction of mitochondria. ... 

To disrupt the endosomal-lysosomal membranes, exogenous agents such as chloroquine, glycerol, fusogenic peptides, and inactivated adenoviruses have often been employed. These agents enhance the efficiency of gene transfer but have some inherent problems. For example, whereas chloroquine has received FDA approval for the treatment of malaria, it is toxic to many cell types in vitro. In high doses, chloroquine may lead to a variety of undesirable side effects in the... 

A study in healthy subjects found that intramuscular promethazine hydrochloride 25 mg, given with intramuscular chloroquine phosphate 200 mg increased the AUC of chloroquine and its metabolites by 85%. This may be due to promethazine enhancing the absorption of chloroquine from the injection site or displacing it and its metabolites from binding sites in the blood. The initial rate of excretion of chloroquine and the total drug excreted within 3 hours was unaffected by promethazine. The increased bioavailability of chloroquine may improve its therapeutic effects but could also increase toxicity. In vitro and animal studies suggest the combination may be effective in the treatment of uncomplicated chloroquine-resistant malaria. More study is needed. For mention that chloroquine may increase chlorpromazine levels, see Phenothiazines + Antimalarials , p.759. 

The interplay of antiparasitic drugs and metal complexes may give a synergistic effect and the way activity is affected is shown by the unusual result that a chloroquine adduct of rhodium acetate, Rh2-(acetate)4(chloroquine)], is more active in vitro in T, rhodesiense than either component [98]. This complex is also as active in malaria in vivo as the free chloroquine, although no enhancement over free drug is seen [98]. An interesting historical note to the metallation of trypanocidal drugs is that the platinum salt of Salvarsan was reported by Ehrlich in 1915 in one of his last papers [99]. 

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