Amodiaquine‐induced immune agranulocytosis

Rouveix, B; Coulombel, Laure; Aymard, J.P.; Chau, F.; Abel, Laurent

doi:10.1111/j.1365-2141.1989.tb06266.x

Cited by 34 publications

(24 citation statements)

References 10 publications

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“…Although it is still used in some countries, AQ was withdrawn from the market because of severe idiosyncratic drug reactions (IDR) that included hepatotoxicity (Larrey et al, 1986;Neftel et al, 1986), agranulocytosis (Rouveix et al, 1989), and aplastic anemia (Hatton et al, 1986). The mechanism of AQ-induced adverse reactions is currently not well understood, but AQ is metabolized to N-desethylamodiaquine (DEAQ) by CYP2C8 (Li et al, 2002), and both AQ or DEAQ can be oxidized to a reactive quinoneimine, which reacts with proteins to form covalent adducts (Maggs et al, 1987(Maggs et al, , 1988.…”

Section: Introductionmentioning

confidence: 99%

Development of a novel mouse model of amodiaquine-induced liver injury with a delayed onset

Metushi¹,

Cai

Dervovic

et al. 2014

Journal of Immunotoxicology

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Amodiaquine (AQ) treatment is associated with a high incidence of idiosyncratic drug-induced liver injury (IDILI) and agranulocytosis. Evidence suggests that AQ-induced IDILI is immune mediated. A significant impediment to mechanistic studies of IDILI is the lack of valid animal models. This study reports the first animal model of IDILI with characteristics similar to mild IDILI in humans. Treatment of female C57BL/6 mice with AQ led to liver injury with delayed onset, which resolved despite continued treatment. Covalent binding of AQ was detected in the liver, which was greater in female than in male mice, and higher in the liver than in other organs. Covalent binding in the liver was maximal by Day 3, which did not explain the delayed onset of alanine aminotransferase (ALT) elevation. However, coincident with the elevated serum ALT, infiltration of liver and splenic mononuclear cells and activation of CD8 T-cells within the liver were identified. By Week 7, when ALT levels had returned close to normal, down-regulation of several inflammatory cytokines and up-regulation of PD-1 on T-cells suggested induction of immune tolerance. Treatment of Rag1 À/À mice with AQ resulted in higher ALT activities than C57BL/6 mice, which suggested that the adaptive immune response was responsible for immune tolerance. In contrast, depletion of NK cells significantly attenuated the increase in ALT, which implied a role for NK cells in mild AQ-induced IDILI. This is the first example of a delayed-onset animal model of IDILI that appears to be immune-mediated.

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Section: Introductionmentioning

confidence: 99%

Development of a novel mouse model of amodiaquine-induced liver injury with a delayed onset

Metushi¹,

Cai

Dervovic

et al. 2014

Journal of Immunotoxicology

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“…This hypothesis requires further investigation. However, it is noteworthy that the metabolite has also been held responsible for the bone marrow toxicity of amodiaquine, either directly or via an immune-mediated mechanism (10,38). The relevance within the overall population of the interindividual variability in PMN sensitivity to monodesethyl amodiaquine observed here remains to be ascertained, although similar findings have been reported with other drugs (24).…”

Section: Discussionmentioning

confidence: 34%

“…The relevance within the overall population of the interindividual variability in PMN sensitivity to monodesethyl amodiaquine observed here remains to be ascertained, although similar findings have been reported with other drugs (24). Amodiaquine (8,26,37) and monodesethyl amodiaquine (10, 38) have both been reported to display granulocytotoxicity, and the prophylactic use of amodiaquine has been associated with sometimes fatal agranulocytosis (2,14,21,31,38). Given the large number of subjects who receive phophylaxis and the low overall incidence of reported agranulocytosis, it is possible that individual sensitivity combined with high doses of the drug may play a role in this phenomenom.…”

Section: Discussionmentioning

confidence: 75%

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Effect of monodesethyl amodiaquine on human polymorphonuclear neutrophil functions in vitro

Labro

Benna

1991

Antimicrob Agents Chemother

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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...

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“…The most commonly known drugs are areclonazapine, carbimazole, methimazole, ticlopidine and sulfasalazine. Less commonly involved drugs include ACE inhibitors, NSAIDS, antiarrhythmics and antimalarials [10][11][12].…”

Section: Discussionmentioning

confidence: 99%

Drug Induced Pure White Cell Aplasia: A Case Report and Review of Literature

Jamal¹,

Zaidi²,

Kazmi³

et al. 2017

Natl. j. health sci.

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Pure White Cell Aplasia (PWCA) is an extremely rare haematological entity. Various causes have been implicated in its pathogenesis. We are reporting here a case of a sixty seven years old female, referred to us with the concern of febrile neutropenia and extensive oral candidiasis. Workup for secondary causes of agranulocytosis was negative. Bone marrow findings were consistent with PWCA, and in the presence of convincing previous history of amodiaquine intake, she was diagnosed as drug (amodiaquine) induced PWCA.

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Amodiaquine‐induced immune agranulocytosis

Cited by 34 publications

References 10 publications

Development of a novel mouse model of amodiaquine-induced liver injury with a delayed onset

Development of a novel mouse model of amodiaquine-induced liver injury with a delayed onset

Effect of monodesethyl amodiaquine on human polymorphonuclear neutrophil functions in vitro

Drug Induced Pure White Cell Aplasia: A Case Report and Review of Literature

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