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Abnormal Red Cell Metabolism
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
This case is an example of acute hemolysis in a patient with G6PD deficiency following the administration of an oxidant antimalarial drug, pamaquine, resulting in severe anemia, hemoglobinuria, and renal damage. Pamaquine is useful in Plasmodium vivax infections, as it eradicates the exoerythrocytic cycle in the liver. Plasmodium falciparum does not colonize in liver, so it is unnecessary to use pamaquine in falciparum infections. After an episode of acute hemolysis, urine may be red due to the presence of hemoglobin. On standing, hemoglobin is oxidized to methemoglobin and urine becomes brown to black. Hemoglobin and methemoglobin give a positive occult blood test. Hemoglobinuria also damages the kidney and it is not uncommon to see albuminuria and granular casts in urine. The patient has moderate deficiency of G6PD, so all oxidant drugs (Table 1) should be avoided.
Humanized mouse models infected with human Plasmodium species for antimalarial drug discovery
Published in Expert Opinion on Drug Discovery, 2018
Alicia Moreno-Sabater, Jean Louis Pérignon, Dominique Mazier, Catherine Lavazec, Valerie Soulard
The value of the HmHPf-ES has been also explored as a platform for testing drugs against P. falciparum erythrocytic sexual forms, those responsible for malaria transmission [31]. As a proof of concept, the effect of primaquine, which is currently the only licensed drug that has demonstrated efficacy to eliminate P. falciparum gametocytes in humans, was evaluated. After primaquine treatment, gametocytes were eliminated from peripheral blood and from sequestration sites, proving that the HmHPf-ES can be used for testing drugs against gametocytes. Primaquine can also eradicate the LS of P. vivax and P. ovale. Its activity against different stages and different Plasmodium spp. makes primaquine an important antimalarial drug, but the risk of inducing hemolytic anemia in G6PD-deficient persons has reduced its utilization. Evaluation of drugs safer than primaquine in vivo is hampered by the fact that treatment with drugs known to cause hemolytic anemia in humans does not cause damage to mouse RBCs. To overcome this limitation, NSG mice have been humanized with G6PD-deficient HRBCs. In this new model, oral administration of primaquine induces a dose-dependent hemolytic response [75,76] and treatment with drugs known to cause hemolytic toxicity (pamaquine, sitamaquine, tafenoquine, and dapsone) resulted in loss of G6PD-deficient HRBCs comparable to primaquine. In contrast, results obtained in this model show that (−)-(R)-primaquine may have a better safety margin than the racemate in human [77].
Tafenoquine: a toxicity overview
Published in Expert Opinion on Drug Safety, 2021
The 8-aminoquinoline group of drugs is known to have several toxicities that limit their use. The most serious adverse effect is a dose-dependent drug-induced hemolysis in G6PD deficient populations [12–14]; this includes tafenoquine [7]. The prevalence of G6PD deficiency is approximately 8% in malaria-endemic countries reaching 30% in some localities [15]. Mild to moderate elevations in methemoglobin levels are nearly universal after primaquine treatment, while severe, life-threatening methemoglobinemia is rare [16] only occurring in individuals with nicotinamide adenine dinucleotide phosphate (NADPH) methemoglobin reductase deficiency [17]. Abdominal pain is a dose-related adverse effect which is improved if the drug is taken after food [18]. Elevations in liver function test results are uncommon, and hepatotoxicity is rare. Early synthetic 8-aminoquinoline analogs such as pamaquine and pentaquine had significant adverse effects as noted above [19]. The subsequent development of primaquine resulted in a drug that was better tolerated and more efficacious [20]; however, low access to reliable G6PD testing and risk of drug-induced hemolysis in G6PD deficient individuals have limited the widespread use of primaquine in many P. vivax endemic areas. In addition, the prolonged treatment course (7 to 14 days) required for the radical cure of P. vivax has limited adherence [21]. Nevertheless, over 150 million doses of primaquine have been prescribed during mass drug administration programs for P. vivax elimination without significant numbers of passively reported severe adverse events, including hemolysis [22–26].