The <i>in vitro</i> effect of amodiaquine on bone marrow granulocyte‐macrophage progenitor cells from normal subjects

Aymard, J.P.; Wioland, C.; Ferry, Robert J.; Netter, Patrick; Streiff, F

doi:10.1111/j.1472-8206.1992.tb00086.x

Cited by 6 publications

(5 citation statements)

References 10 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Parikh

Ouédraogo

et al. 2007

Clin Pharmacol Ther

158

128

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Metabolism of the antimalarial drug amodiaquine (AQ) into its primary metabolite, N-desethylamodiaquine, is mediated by CYP2C8. We studied the frequency of CYP2C8 variants in 275 malaria-infected patients in Burkina Faso, the metabolism of AQ by CYP2C8 variants, and the impact of other drugs on AQ metabolism. The allele frequencies of CYP2C8*2 and CYP2C8*3 were 0.155 and 0.003, respectively. No evidence was seen for influence of CYP2C8 genotype on AQ efficacy or toxicity, but sample size limited these assessments. The variant most common in Africans, CYP2C8(*)2, showed defective metabolism of AQ (threefold higher K(m) and sixfold lower intrinsic clearance), and CYP2C8(*)3 had markedly decreased activity. Considering drugs likely to be coadministered with AQ, the antiretroviral drugs efavirenz, saquinavir, lopinavir, and tipranavir were potent CYP2C8 inhibitors at clinically relevant concentrations. Variable CYP2C8 activity owing to genetic variation and drug interactions may have important clinical implications for the efficacy and toxicity of AQ.

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Section: Discussionmentioning

confidence: 99%

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

Parikh

Ouédraogo

et al. 2007

Clin Pharmacol Ther

158

128

View full text Add to dashboard Cite

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“…Hypersensitivity of progenitors from susceptible individuals to the toxicant or a toxic metabolite can be demonstrated with progenitor assays (161,(165)(166)(167)(168)(169)(170)(171). CFU-GM levels in patients with drug-induced agranulocytosis are depressed relative to controls (91,159-164), and inhibition of myeloid and erythroid progenitors is a likely mechanism for beta-lactam-induced agranulocytosis (158) and contributes to phenylhydrazine-induced anemia (10).…”

Section: Toxicity To the Progenitor Compartmentmentioning

confidence: 99%

“…CFU-GM levels in patients with drug-induced agranulocytosis are depressed relative to controls (91,159-164), and inhibition of myeloid and erythroid progenitors is a likely mechanism for beta-lactam-induced agranulocytosis (158) and contributes to phenylhydrazine-induced anemia (10). Unfortunately, in many cases when the immune system contributes to hematotoxicity, in vitro studies using marrow from normal donors are not informative and in fact are usually inconclusive (167,170,177). Hypersensitivity of progenitors from susceptible individuals to the toxicant or a toxic metabolite can be demonstrated with progenitor assays (161,(165)(166)(167)(168)(169)(170)(171).…”

Section: Toxicity To the Progenitor Compartmentmentioning

confidence: 99%

Alternative Testing Systems for Evaluating Noncarcinogenic, Hematologic Toxicity

Parchment¹

1998

Environmental Health Perspectives

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Hematopoietic tissues are the targets of numerous xenobiotics. Clinical hematotoxicity is either a decrease or an increase in peripheral blood cell counts in one or more cell lineages--a cytopenia or a cytosis, respectively--that carries a risk of an adverse clinical event. The purpose of in vitro hematotoxicology is the prediction of these adverse hematologic effects from the effects of the toxicants on human hematopoietic targets under controlled experimental conditions in the laboratory. Building on its important foundations in experimental hematology and the wealth of hematotoxicology data found in experimental oncology, this field of alternative toxicology has developed rapidly during the past decade. Although the colony-forming unit-granulocyte/monocyte neutrophil progenitor is most frequently evaluated, other defined progenitors and stem cells as well as cell types found in the marrow stroma can be evaluated in vitro. End points have been proposed for predicting toxicant exposure levels at the maximum tolerated dose and the no observable adverse effect level for the neutrophil lineage, and several clinical prediction models for neutropenia have developed to the point that they are ready for prospective evaluation and validation in both preclinical species and humans. Known predictive end points are the key to successful comparisons across species or across chemical structures when in vitro dose-response curves are nonparallel. Analytical chemistry support is critical for accurate interpretation of in vitro data and for relating the in vitro pharmacodynamics to the in vivo pharmacokinetics. In contrast to acute neutropenia, anemia and acute thrombocytopenia, as well as adverse effects from chronic toxicant exposure, are much more difficult to predict from in vitro data. Pharmacologic principles critical for clinical predictions from in vitro data very likely will apply to toxicities to other proliferative tissues, such as mucositis.

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“…In these cases the in vitro progenitor assays correctly identified the mechanism of myelosuppression. Hypersensitivity of progenitors from susceptible individuals to the toxicant or a toxic metabolite can be demonstrated with progenitor assays (161,(165)(166)(167)(168)(169)(170)(171) (168). Otherwise, the effects of inhibitory cytokines released by mature T cells and monocytes in response to toxicant may be measured instead, which would be a toxicity to the mature blood cell compartment rather than the progenitor compartment.…”

mentioning

confidence: 99%

“…Otherwise, the effects of inhibitory cytokines released by mature T cells and monocytes in response to toxicant may be measured instead, which would be a toxicity to the mature blood cell compartment rather than the progenitor compartment. Unfortunately, in many cases when the immune system contributes to hematotoxicity, in vitro studies using marrow from normal donors are not informative and in fact are usually inconclusive (167,170,177).…”

mentioning

confidence: 99%

Alternative testing systems for evaluating noncarcinogenic, hematologic toxicity.

Parchment

1998

Environ Health Perspect

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Hematopoietic tissues are the targets of numerous xenobiotics. Clinical hematotoxicity is either a decrease or an increase in peripheral blood cell counts in one or more cell lineages-a cytopenia or a cytosis, respectively-that carries a risk of an adverse clinical event. The purpose of in vitro hematotoxicology is the prediction of these adverse hematologic effects from the effects of the toxicants on human hematopoietic targets under controlled experimental conditions in the laboratory. Building on its important foundations in experimental hematology and the wealth of hematotoxicology data found in experimental oncology, this field of alternative toxicology has developed rapidly during the past decade. Although the colony-forming unit-granulocyte/monocyte neutrophil progenitor is most frequently evaluated, other defined progenitors and stem cells as well as cell types found in the marrow stroma can be evaluated in vitro. End points have been proposed for predicting toxicant exposure levels at the maximum tolerated dose and the no observable adverse effect level for the neutrophil lineage, and several clinical prediction models for neutropenia have developed to the point that they are ready for prospective evaluation and validation in both preclinical species and humans. Known predictive end points are the key to successful comparisons across species or across chemical structures when in vitro dose-response curves are nonparallel. Analytical chemistry support is critical for accurate interpretation of in vitro data and for relating the in vitro pharmacodynamics to the in vivo pharmacokinetics. In contrast to acute neutropenia, anemia and acute thrombocytopenia, as well as adverse effects from chronic toxicant exposure, are much more difficult to predict from in vitro data. Pharmacologic principles critical for clinical predictions from in vitro data very likely will apply to toxicities to other proliferative tissues, such as mucositis.Environ Health Perspect 106(Suppl 2):541-557 (1998). http://ehpnetl.niehs.nih.gov/docs/1998/Suppl-2/541-557parchment/abstract.html

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The in vitro effect of amodiaquine on bone marrow granulocyte‐macrophage progenitor cells from normal subjects

Cited by 6 publications

References 10 publications

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

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

Alternative Testing Systems for Evaluating Noncarcinogenic, Hematologic Toxicity

Alternative testing systems for evaluating noncarcinogenic, hematologic toxicity.

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