Korean Vivax Malaria

As, Alving; Dd, Hankey; Gr, Coatney; Wg, Coker; Pl, Garrison; Wn, Donovan

doi:10.4269/ajtmh.1953.2.970

Cited by 35 publications

(3 citation statements)

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“…5C). Nonetheless, when later applied against Korean strains of P. vivax (after essential correction for a relapse rate of 28%), just 27.5-mg daily dosing of plasmochin achieved a cure rate of 97% (164). As would later prove true with primaquine, P. vivax susceptibility to hypnozoitocidal therapies varies by the geographic origin of the strain, with the Chesson and Korean P. vivax strains representing strains with the known extremes of apparently naturally variable hypnozoite susceptibility to 8-aminoquinolines (165).…”

Section: Optimized Plasmochin Therapymentioning

confidence: 99%

“…Robert Coatney and colleagues at the U.S. National Institutes of Health conducted similar human trials from March 1944 to November 1946 at the United States Penitentiary at Atlanta, GA (174). Both groups would later experiment with an abundant supply of new research subjects after 1950: American soldiers infected by P. vivax on the Korean Peninsula at war, the findings for 3,531 of whom were described in just three consecutive 1953 reports, with the chloroquine treatment-only relapse rate being 44% (n ϭ 738) or 18% (n ϭ 331) (131,164,175,176). As the Germans had done at Elberfeld 2 decades earlier, the Americans assembled an essentially similar stepwise means of antimalarial drug discovery and development but employed a vastly larger and more complex web of partners (13).…”

Section: Preclinical Screening Of 8-aminoquinolinesmentioning

confidence: 99%

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8-Aminoquinoline Therapy for Latent Malaria

2019

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SUMMARYThe technical genesis and practice of 8-aminoquinoline therapy of latent malaria offer singular scientific, clinical, and public health insights. The 8-aminoquinolines brought revolutionary scientific discoveries, dogmatic practices, benign neglect, and, finally, enduring promise against endemic malaria. The clinical use of plasmochin—the first rationally synthesized blood schizontocide and the first gametocytocide, tissue schizontocide, and hypnozoitocide of any kind—commenced in 1926. Plasmochin became known to sometimes provoke fatal hemolytic crises. World War II delivered a newer 8-aminoquinoline, primaquine, and the discovery of glucose-6-phosphate dehydrogenase (G6PD) deficiency as the basis of its hemolytic toxicity came in 1956. Primaquine nonetheless became the sole therapeutic option against latent malaria. After 40 years of fitful development, in 2018 the U.S. Food and Drug Administration registered the 8-aminoquinoline called tafenoquine for the prevention of all malarias and the treatment of those that relapse. Tafenoquine also cannot be used in G6PD-unknown or -deficient patients. The hemolytic toxicity of the 8-aminoquinolines impedes their great potential, but this problem has not been a research priority. This review explores the complex technical dimensions of the history of 8-aminoquinolines. The therapeutic principles thus examined may be leveraged in improved practice and in understanding the bright prospect of discovery of newer drugs that cannot harm G6PD-deficient patients.

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Section: Optimized Plasmochin Therapymentioning

confidence: 99%

Section: Preclinical Screening Of 8-aminoquinolinesmentioning

confidence: 99%

8-Aminoquinoline Therapy for Latent Malaria

2019

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“…Artemisinin-based combination therapy (ACT) is emerging as the best option in this context, particularly in settings where there are concerns about chloroquine-resistant P. vivax [8]. ACT is effective against the blood stage of P. vivax [9], but must be co-administered with primaquine to eliminate P. vivax hypnozoites [8, 10]. Short-course primaquine regimens are preferable as they have been proven to have an efficacy not inferior to the standard 14 days’ regimens [11–14].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics/pharmacodynamics of chloroquine and artemisinin-based combination therapy with primaquine

Daher

Aljayyoussi

Pereira

et al. 2019

Malar J

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Background Activation of hypnozoites of vivax malaria causes multiple clinical relapses, which contribute to the Plasmodium vivax burden and continuing transmission. Artemisinin-based combination therapy (ACT) is effective against blood-stage P. vivax but requires co-administration with primaquine to achieve radical cure. The therapeutic efficacy of primaquine depends on the generation of a therapeutically active metabolite via cytochrome P450 2D6 (CYP2D6). Impaired CYP2D6 metabolism has been associated with primaquine treatment failure. This study investigated the association between impaired CYP2D6 genotypes, drug-exposure to the long-acting ACT component (schizonticidal drugs) and tolerance and efficacy. Methods Adult patients with acute vivax malaria were enrolled in a recently completed trial and treated with artesunate–mefloquine, chloroquine or artemether–lumefantrine. All received concomitant primaquine (0.5 mg/kg/day for 7–9 days). The association between efficacy and safety and drug exposure was explored using area-under-the-curve (AUC) and half-life (t1/2) estimates obtained by non-compartmental analysis of the long half-life drugs. Parasite recurrences by day 63 were categorized as related relapses or re-infections/unrelated hypnozoite activation by genotyping three microsatellite loci and two polymorphic loci of merozoite surface antigen-1. The CYP2D6 genotype was identified with Taqman assays by real-time PCR to 9 polymorphisms (8 SNPs and one deletion). Impaired CYP2D6 activity was inferred using the Activity Score System. Results Most recurrences in the ASMQ (67%), CQ (80%) and AL (85%) groups were considered related relapses. Eight of nine (88.9%) of the patients with impaired CYP2D6 activity relapsed with related parasite compared to 18/25 (72%) with normal activity (RR = 1.23, 0.88; 1.72, p = 0.40). There were no associations between the measured PK parameters and recurrence. Patients with longer chloroquine half-lives had more pruritus (RR = 1.09, 1.03; 1.14, p = 0.001). Higher CQ AUCs were associated with reduced falls in haemoglobin by day 14 (Coef − 0.02, − 0.005; − 0.03, p = 0.01). All regimens were well tolerated. Conclusion Genotyping of P. vivax showed that activation of related (homologous) hypnozoites was the most frequent cause of recurrence. The high proportion of the impaired CYP2D6 activity among patients with recurrent infections suggests that slow primaquine metabolism might influence related relapse rates in Brazil among patients receiving primaquine for radical cure, although confirmatory studies are needed. There was no association between drug exposure of the long-acting ACT component (schizonticidal drugs) and risk of related relapse. ACT was well tolerated. These results provide further re-assurance about the safety and efficacy of ACT when combined with short course primaquine to treat uncomplicated malaria vivax in Brazil. Trial registration RBR-79s56s (http://www.ensaiosclinicos.gov.br/rg/RBR-79s56s/)

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Malaria in American Soldiers

Martelo¹

1969

Arch Intern Med

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Korean Vivax Malaria

Cited by 35 publications

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8-Aminoquinoline Therapy for Latent Malaria

8-Aminoquinoline Therapy for Latent Malaria

Pharmacokinetics/pharmacodynamics of chloroquine and artemisinin-based combination therapy with primaquine

Malaria in American Soldiers

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