8-Aminoquinoline Therapy for Latent Malaria

Abstract

The 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.

Keywords: 8-aminoquinolines; CYP2D6; G6PD deficiency; Plasmodium vivax; hemolytic toxicity; latency; plasmochin; primaquine; tafenoquine; therapy.

FIG 1

Contemporary schematic representing the biology of Plasmodium vivax primary attack and relapses according to the polymorphic intrinsic latency period hypothesis proposed by Lysenko et al. in 1977 (31). Tachysporozoites launch immediate hepatic schizogony and then a single primary attack. Bradysporozoites develop to latent hypnozoites that later awaken to hepatic schizogony and patent relapses according to intrinsic latency period phenotypes.

FIG 2

Antimalarial drug classes (red lettering), preventive strategies (bold black), and the life cycle of the plasmodia.

FIG 3

(A) The discoverers of aniline dyes and methylene blue therapy of malaria: on the left, audacious teenager William Henry Perkin (a self-portrait in 1852, aged just 14 years, 4 years before he discovers mauvine in coal tars), and on the right, physician-scientist Paul Ehrlich (in Berlin, 1910; by Alfred Krauth, courtesy of the Wellcome Collection), who cured acute vivax malaria in two patients in 1891. (B) Werner Schulemann (top left, in 1924) and his colleagues August Wingler (top right, in 1934) and Fritz Schoenhoefer (bottom left, in 1939) at Bayer’s Elberfeld facility synthesized plasmochin in 1925. (Bottom right) The Bayer company logo in ca. 1925. Photos courtesy of Bayer AG, Corporate History & Archives, with permission. (C) (Top) Wilhelm Roehl and an unidentified colleague at the Bayer Elberfeld laboratory dosing Javanese rice finches infected by Plasmodium relictum with experimental antimalarial compounds in 1926. Roehl identified plasmochin to be 60 times more effective than quinine against that asexual blood-stage infection. (Bottom left) Portrait of Wilhelm Roehl in the same year. These photos courtesy of Bayer AG, Corporate History & Archives, with permission. (Bottom right) John A. Sinton (in ca. 1938), the prodigious British military malariologist who defined radical cure of Plasmodium vivax in British soldiers in India with optimized therapy with plasmochin combined with quinine and, later, atabrine (photo courtesy of the Wellcome Collection, London, United Kingdom, with permission).

FIG 4

Methylene blue as the progenitor of modern synthetic 4- and 8-aminoquinoline antimalarial drugs beginning in 1921 at the Bayer laboratory at Elberfeld near Dusseldorf, Germany, and continuing up to the present day (with tafenoquine). Mefloquine (bottom right) is not a 4-aminoquinoline but a quinoline methanol structurally related to halofantrine and lumefantrine.

FIG 5

Studies of plasmochin monotherapy versus plasmochin combined with quinine. (A) Complex dosing regimens of 100 mg plasmochin (orange boxes) or 100 mg plasmochin with 1.25 g coformulated quinine (orange and blue boxes), as recommended by the manufacturer, with days of rest (white boxes) or on consecutive days without rest (right), listing therapeutic outcomes among 63 patients thus treated and followed for at least 2 months after the initiation of therapy (based on data from Sinton and Bird [136]). (B) Based on data from Craige et al. (139), the impact of 15 to 63 mg daily plasmochin (for 14 days) on delayed attacks when administered separately or concurrently with quinine (2 g daily for 8 days) in a total of 38 subjects challenged with the Chesson strain of P. vivax and followed for about 1 year. (C) Based on data from Berliner et al. (140), therapeutic outcomes when plasmochin (90 mg daily for 14 days) was administered before or during quinine therapy (2 g daily for 8 days).

FIG 6

Studies of primaquine monotherapy against delayed attacks of vivax malaria. (A) Relapse findings (right) after daily dosing of primaquine and quinine, each administered alone or concurrently, as reported by Edgcomb et al. (61). (B) Relapse findings after daily dosing of primaquine and quinine consecutively (top) or currently (middle) or of primaquine with 1 g chloroquine administered over 24 h (bottom), as reported by Alving et al. (143).

FIG 7

Effects of quinine (QN) and methylene blue (MB) coadministered with increasing daily doses of primaquine (PQ) on methemoglobinemia in Caucasian subjects, showing the average value for the last 5 days of dosing. The figure is based on data from Clayman et al. (59).

FIG 8

Key figures in the development of primaquine from 1943 to 1952 included wartime antimalarial development project leader James A. Shannon (top left, ca. 1968, from the U.S. NIH Almanac); chemist Robert C. Elderfield (top right; in about 1970, with permission of The National Academies Press), who first synthesized primaquine in 1945; physician Alf Alving (bottom left, in about 1968; photo by L. J. Bruce-Chwatt, courtesy of the Wellcome Collection), who oversaw clinical trials of many 8-aminoquinolines for the University of Chicago at Stateville Penitentiary, Joliet, IL; and biologist Clay Huff (bottom right; in 1967, with permission of Elsevier [341]), who experimentally challenged those human subjects at the Stateville Penitentiary facilities with P. vivax-infected Anopheles stephensi mosquitoes.

FIG 9

Experimental 8-aminoquinolines advanced to human trials in the late 1940s.

FIG 10

The most active and least toxic 8-aminoquinolines: plasmochin, primaquine, pentaquine, isopentaquine, and SN-3883.

FIG 11

The 8-aminoquinolines exhibiting >4-fold greater therapeutic activity relative to primaquine against relapse of P. cynomolgi in macaques up to 1981, where WR225448 emerged as the most active, being 4.8-fold more active than the other 5-phenoxy derivatives. WR225448 would later compete with WR242511 (10-fold more active) and WR238605 (tafenoquine, 7-fold more active) for selection as the sole candidate for clinical development.

FIG 12

The photomicrograph illustrates Heinz bodies (the dark blue bodies) within red blood cells stained with crystal violet. The thin smear slide derived from a suspension of red blood cells prepared from a sample of venous blood taken from a G6PD-deficient Karen woman living in Thailand incubated for 1 h with acetyl-phenylhydrazine. Germana Bancone at the Shoklo Malaria Research Unit at Mae Sot, Thailand, provided the image, and it is published here with her permission.

FIG 13

The acute hemolytic anemias induced by closely related 8-aminoquinolines in a single healthy volunteer having the African A− variant of G6PD deficiency exhibiting different degrees of hemolytic toxicity. From Alving et al. (246), reproduced with permission of the Bulletin of the World Health Organization.

FIG 14

Hypothesized metabolism of 8-aminoquinolines, as represented by primaquine, to 5-hydroxylated species. In a G6PD-normal individual, who therefore has a reducing redox equilibrium in the cytosol (larger green arrows, above), the presumably harmless 5-hydroxyprimaquine metabolite dominates. In a G6PD-deficient individual, who therefore has an oxidizing redox equilibrium in the cytosol, the highly reactive primaquine quinonimine species dominates and forms irreversible hemochromes that precipitate as Heinz bodies, causing acute hemolytic anemia. Hb, hemoglobin; MetHb, methemoglobin; GS⁻, oxidized glutathione.

FIG 15

Primaquine-induced hemolytic crises expressed as percent of hematocrit in patients having the African A− or Mediterranean variant of G6PD deficiency, based on data from Alving et al. (246) (top) and Pannacciulli et al. (271) (bottom). In the patient with the African A− variant, there is tolerance to continued primaquine exposure as the vulnerable older red blood cells destroyed by drug are replaced by more G6PD-robust and drug-tolerant reticulocytes and younger normocytes and dosing is extended to 120 days without a hemolytic event. In the patient with the Mediterranean variant, hemolysis deepens with each primaquine exposure, and after the 7th dose, dosing must cease due to danger to the patient (red X). The resumption of dosing 2 weeks later renews the hemolytic crisis, again with the clinical necessity of cessation of therapy. There is no acquired tolerance to primaquine exposure in the patient with the Mediterranean variant.

FIG 16

Data illustrating the centrifugal gradient separation of erythrocytes by age (C.D.F. is the cumulative distribution function) among G6PD-normal, African A− variant, and Mediterranean variant donors (A, B, and C, respectively). The extent to which G6PD activity declines with the age of the red blood cells in the same gradient and from the same donors is also shown (G, H, and I, respectively). G6PD activity in normal donors (G) decreases slightly with age, whereas in African A− variant donors (H), young red cells exhibit almost normal G6PD activity, but it declines more sharply with age. Mediterranean variant donor red blood cells (I) have very low levels of activity among the youngest reticulocytes and undetectable activity among older cells. Reproduced from Piomelli et al. (263) with permission of the Journal of Clinical Investigation.