Amodiaquine-induced Agranulocytosis: Toxic Effect of Amodiaquine in Bone Marrow Cultures In Vitro

Abstract

1971; Slapak et al., 1971) and our own findings make it possible to construct a probable sequence of events in the hyperacute rejection process. The first change appears to be damage to the capillary endothelium presumably by an antibody antigen complex with subsequent binding of complement. This is followed by platelets adhering to the damaged endothelium and subsequent aggregation in the glomerular and peritubular capillaries. Substances released from these damaged platelets could result in the intense vasoconstriction, which together with the platelet plugs themselves could cause acute haemostasis and immediate rejection. Thrombosis is probably a later and secondary change.The action of heparin in prolonging graft survival is probably due to its direct effect on the platelets. This is consistent with our findings of a reduced fall in the platelet count in the heparintreated dogs. Linn et al. (1971) suggested that substances released by the breakdown of complement contribute to the vasoconstriction during acute rejection. For this reason we established that our heparin preparation was free from anticomplementary activity. Modification of the rejection process with aspirin or cyproheptadine hydrochloride (Periactin) could also be explained by their antagonism to platelet aggregation (O'Brien, 1968; Burrows et al., 1970).

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

“…The literature search revealed two postulated mechanisms by which amodiaquine can cause agranulocytosis:the first being dose dependent inhibitory effect on myeloid precursors [14] and second, an immune phenomenon attributed to anti IgG anti-neutrophil antibodies detected in the sera of the patients that were treated with amodiaquine and later developed agranulocytosis [15]. What really led to this extreme degree of agranulocytosis in our patient remains highly speculative.…”

The toxicity of amodiaquine and its principal metabolites towards mononuclear leucocytes and granulocyte/monocyte colony forming units.

“…The mechanism of agranulocytosis associated with the prophylactic use of AQ in man is unknown, though earlier investigations (Lind et al, 1973;Rhodes et al, 1986) suggested that an abnormal sensitivity of myeloid precursors to AQ might predispose individuals to this type of reaction. Inter-individual variation in drug disposition and drug-induced responses of the immune system might also play a role (Young & Vincent, 1980).…”

“…Cells from patients recovering from AQ-induced agranulocytosis, but not those obtained from healthy control subjects, displayed significant inhibition of colony formation with Correspondence: Dr J. W. Coleman, Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, L69 3BX AQ at 0.05-0.5 ,ug ml-' (approximately 0.1-1.0 ,umol 1-1). This suggested that patients had developed agranulocytosis as a result of abnormal sensitivity of their myeloid precursors to the drug, and that the myelosuppression was dosedependent and not idiosyncratic (Lind et al, 1973).…”

“…The effects of AQ on the proliferation of granulocyte-monocyte colony forming units (GM-CFU) obtained from patients with AQinduced agranulocytosis have been reported (Lind et al, 1973;Rhodes et al, 1986). The maximum concentration of AQ tested in these studies was 0.5 ,ug ml-' (approximately 1.0 ,umol 1-1).…”

Synthesis and Antimalarial Activity of New Isotebuquine Analogues

“…3 However, the clinical use of AQ has been severely restricted because of the hepatoxicity and agranulocytosis side effects associated with its long term use. 4,5 Recent reports indicate that AQ was metabolized by cytochrome P-450 oxidation to form reactive quinoneimine metabolite with subsequent conjugate addition of glutathione or cysteinyl function of the enzymes. 6,7 Lysosomal accumulation and bioactivation of reactive quinoneimine metabolite are implicated to be the cause of the observed AQ in vivo toxicity.…”