Effect of monodesethyl amodiaquine on human polymorphonuclear neutrophil functions in vitro

Abstract

We have previously observed that the antimalarial drug amodiaquine impairs the human polymorphonuclear neutrophil (PMN) oxidative burst in vitro. However, the drug acted at a concentration of 100 ,ug/ml, far higher than that which is achievable therapeutically. Since amodiaquine is extensively metabolized into monodesethyl amodiaquine, we investigated whether the metabolite modified PMN functions at lower concentrations than amodiaquine does. Monodesethyl amodiaquine strongly depressed PMN chemotaxis and phagocytosis at concentrations as low as 10 ,ug/ml. This inhibition was reversed by washing out the drug. The PMN oxidative burst was markedly depressed by monodesethyl amodiaquine, whatever the assay technique (luminol-amplified chemiluminescence, lucigenin-amplified chemiluminescence, myeloperoxidase activity) or stimulus used (opsonized zymosan, phorbol myristate acetate, formylmethionyl leucyl phenylalanine). There were extreme interindividual variations in sensitivity to the depressive effect of monodesethyl amodiaquine when the PMN oxidative burst was assayed in terms of luminol-amplified chemiluminescence or lucigeninamplified chemiluminescence. PMN samples were divided into two groups on the basis of the MIC of the drug: 60% of the samples were "highly sensitive," being strongly inhibited at concentrations as low as 0.1 ,ug/ml (obtained during therapy), whereas the "moderately sensitive" samples were inhibited at concentrations of 10 ,ig/ml and above. The difference between the two groups was highly significant. This PMN sensitivity to the inhibitory effect of the drug was not related to intrinsic oxidative metabolism. Our data indicate that monodesethyl amodiaquine, the main metabolite of amodiaquine, has a far stronger inhibitory effect on various PMN functions in vitro than the parent drug, warranting relevant in vivo studies.Immunosuppression is the hallmark of many protozoal diseases, including malaria, as shown in animal models and in Plasmodium falciparum-infected patients (20,33), and may lead to fatal secondary infections (17). Polymorphonuclear neutrophils (PMNs) play a crucial role in the resolution of bacterial infections, and recent in vitro data suggest that these cells could also be of critical importance in natural resistance to parasitic infections, in particular, malaria (4,18,21,41). Parasite killing appears to be mediated partly by oxygen intermediates (7) and partly by non-oxygen-dependent systems (18,19). Oxygen derivatives form a potent anti-P. falciparum system (29), and the combination of oxygen-dependent components of the microbicidal system with certain antimalarial drugs potentiates the inhibition of the growth of P. falciparum (30). It is thus of major interest to determine whether the drugs given for the treatment or prophylaxis of malaria may depress PMN functions, especially their oxidative burst. Indeed, we and others (3,9,11,15,16,23) have observed that most antimalarial drugs in use are able to depress PMN functions, although, in general, they do so at concentrations f...

Amodiaquine Metabolism is Impaired by Common Polymorphisms in CYP2C8: Implications for Malaria Treatment in Africa

“…6,40,41 Mechanisms of AQ toxicity are not known, but both AQ and DEAQ led to inhibitory effects on bone marrow progenitor cells and neutrophil function in vitro. [42][43][44][45][46] Additionally, several lines of evidence suggest that AQ toxicity is mediated through the production of an immunologically reactive quinoneimine, 47,48 a finding supported by the demonstration of anti-AQ antibodies in individuals with AQ-associated toxicity. [49][50][51] Importantly, DEAQ is less readily activated to immunologically reactive compounds compared with AQ.…”

Interference of Antibacterial Agents with Phagocyte Functions: Immunomodulation or "Immuno-Fairy Tales"?

“…Although the immunomodulatory profile of any drug encompasses its effect on specific and nonspecific immune mediators, owing to the key role of the phagocyte in innate and adaptive defenses and homeostasis, this cell is a major target for immunomodulation. The relevant literature has been periodically reviewed (16,25,113,140,197,199,202,203,205,208,236,330,386,417), reflecting a gradual change from basic, fundamental, and sometimes controversial observations (considered epiphenomena of antibacterial activity) to serious, well-founded tests of the effects of some antibacterial agents in noninfectious diseases.…”

“…Aminoglycosides interfere with bacterial protein synthesis by acting on the 30S ribosomal subunit. There are controversial data on the inhibitory effect of aminoglycosides at therapeutic concentrations on PMN chemotaxis, oxidative metabolism, and yeast killing (16,42,197,236). Various mechanisms have been advanced, based on analyses performed in cell-free or nonphagocyte systems; they include binding to negatively charged membrane phospholipids leading to membrane disturbances, specific binding to inositol biphosphate resulting in inhibition of PLC, and inhibition of PKC.…”

“…Chloramphenicol impairs bacterial protein biosynthesis by acting on the 50S ribosomal subunit. Controversial data exist on the potential drug-induced reduction in phagocyte functions (197). It seems unlikely that this drug displays any significant direct interference with phagocyte activities at therapeutic concentrations.…”

Interference of Antibacterial Agents with Phagocyte Functions: Immunomodulation or “Immuno-Fairy Tales”?

“…Although the immunomodulatory profile of any drug encompasses its effect on specific and nonspecific immune mediators, owing to the key role of the phagocyte in innate and adaptive defenses and homeostasis, this cell is a major target for immunomodulation. The relevant literature has been periodically reviewed (16,25,113,140,197,199,202,203,205,208,236,330,386,417), reflecting a gradual change from basic, fundamental, and sometimes controversial observations (considered epiphenomena of antibacterial activity) to serious, well-founded tests of the effects of some antibacterial agents in noninfectious diseases.…”