Toxicity Of Primaquine Research Articles

Oxidative activity of hydroxylated primaquine analogs: Non-toxicity to glucose-6-phosphate dehydrogenase-deficient human red blood cells in vitro

The individual effects of two putative metabolites of primaquine (5,6-dihydroxyprimaquine and 5,6-dihydroxy-8-aminoquinoline) on the hexose monophosphate shunt (HMS) and on the ATP-dependent proteolytic system which rapidly degrades oxidized erythrocyte protein were measured in intact red blood cells in vitro from two blood donors. In red cells treated with nitrite (1–40 mM) or phenylhydrazine (0.01–10 mM), proteolytic activity was detected only with concentrations (7.5 mM NaNO 2 and 0.25mM phenylhydrazine) causing >15-fold elevation of HMS activity, and glucose-6-phosphate dehydrogenase (G6PD)-deficient (25% of normal activity) red cell suspensions thus treated showed approximatly 30% greater proteolysis. G6PD-normal and deficient red cells treated with the primaquine analogs, however, did not experience proteolysis with concentrations (0.25 mM) in excess of those causing 17-fold elevation of HMS activity. Stimulation of the HMS by the primaquine analogs thus appears unrelated to an erythrotoxic oxidative stress. Methylene blue is known to cause an elevation of HMS activity through direct and diaphorase II-dependent oxidation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) which is independent of injurious oxidative stress. It was found that the putative primaquine metabolites also caused direct and diaphorase II-dependent oxidation of NADPH in dilute hemolysate, thus suggesting that the putative primaquine metabolites have a methylene blue-like redox disposition in red blood cells. Results obtained in this study suggest that the hemolytic toxicity of primaquine may be unrelated to processes which lead to oxidative deterioration of red cell protein.

Selective toxicity of the antimalarial primaquine-evidence for both uncoupling and inhibitory effects of a metabolite on the energetics of mitochondria and its ATP synthase complex.

A methylene-linked dimeric metabolite of primaquine can exist as an oxidized form (PD(+)) or a reduced form (PDH). Using a rat liver mitochondrial preparation, low concentrations (E 50% = 12 µM) of PD(+) were found to act as a classical uncoupler of oxidative phosphorylation leading to a stimulation of mitochondrial respiration. At higher concentrations, PD(+) was found to inhibit a purified F1-ATPase preparation, while its effects on the complete ATP synthase complex (F0F1-ATPase) was bimodal. A working hypothesis relating F0F1-ATPase and glucose-6-phosphate dehydrogenase activity to the selective toxicity of primaquine on the malaria parasite and host is presented.

The disposition of free and liposomally encapsulated antimalarial primaquine in mice

Plasma clearance, urinary excretion and tissue distribution of radiolabeled free (FPQ)_and liposome-entrapped Primaquine (LPQ) in mice were monitored for 2 hr following intravenous administration. FPQ is eliminated very rapidly from the plasma and excreted predominantly in the urine, probably largely in a metabolized form. In decreasing order of magnitude, pronounced accumulation of label occurs in the lives, kidneys, lungs and skeletal muscle. Less than 1 per cent of the total initial dose is recovered in other tissues. Partial erythrocytic sequestration results in drug levels higher and more persistent in blood cells than in the plasma. Compared to the free drug form, Primaquine entrapped within negatively charged liposomes of the cholesterol-rich multilamellar type exhibits a prolonged plasmatic half-life and, within the observation period, excretion is 8-fold reduced. Liver accumulation of label is doubled, acconting for close to 50% of the injected dose; splenic uptake is tripled, while accumulation in the lungs, kidneys, heart and brain is drasticaly reduced. These differences in pharmacodynamic behaviour may explain why liposomal entrapment leads to diminished acute Primaquine toxicity.

Modifications of primaquine as antimalarials. 2. 5-Phenylthio and 5-anilino derivatives of primaquine

A number of 5-phenylthio and 5-anilino derivatives of primaquine have been prepared which are less toxic but less active than primaquine itself in murine and monkey antimalarial screens. It is apparent that the toxicity of primaquine can be diminished by introduction at position 5 of phenylthio, anilino, or phenoxy groups. However, the best hope for concomitant retention of high activity would seem to reside with the phenoxy moieties.

Causal Prophylactic Effect of Menoctone (A New Hydroxynaphthoquinone) against Sporozoite-Induced Plasmodium berghei Infection in Mice

Menoctone, a hydroxynaphthoquinone which was recently demonstrated to have suppressive effects against blood-induced rodent malarias, was tested against sporozoite-induced Plasmodium berghei infections in a susceptible white mouse strain. When menoctone was administered orally twice daily throughout the course of the preerythrocytic cycle, the protection afforded the mice was more than 21/ times as great on an equal weight basis as that of primaquine. Presumably because of its low solubility and a correspondingly slow absorption, subcutaneous administration of menoctone in single doses protected a high percentage of mice infected as long as 6 days following medication. Oral administration of menoctone in single doses was not as effective when given more than 24 hr before infection. However, menoctone was more effective than primaquine when administered 4 hr before infection and from 4 to 26 hr after infection. Moreover, acute oral toxicity tests in mice demonstrated that menoctone possessed 115 the toxicity of primaquine. When subeffective or minimally effective doses of 100 mg/kg of chloroquine or quinine were combined with menoctone, also at a subeffective level of 10 mg/kg, 60 to 70% of the infected mice were protected. The superiority of rodent malarias over avian malarias as models for screening and evaluation of suppressive and curative effects of antimalarials is now recognized (Peters, 1967; Bruce-Chwatt, 1967). Of the several species of rodent plasmodia now available, Plasmodium berghei is the species most commonly used. It has many similarities to human plasmodia in general and to P. falciparum in particular. Its sporogonic cycle under optimal temperature conditions lasts 11 to 13 days, more or less the same length of time the sporogonic cycles of human plasmodia require for completion in mosquitoes; and its tissue stages, indistinguishable morphologically from those of human and simian plasmodia, differ only in their rapid rhythm of development (Yoeli and Most, 1965). P. berghei resembles chloroquine-resistant strains of P. falciparum in its susceptibility to the action of sulfonamides, sulfones and pyrimethamine; and like P. falciparum, it fails to produce late exoerythrocytic schizonts (Yoeli et al., 1966). During the forties, Fieser et al. (1948) synthesized several series of 2-hydroxy-1,4naphthoquinone antimalarials. Two of these compounds possessed suppressive and curative effects against avian malarias but had no significant activity against P. vivax and P. falciparum infections of humans. Several hydroxynaphthoquinones synthesized later by Fieser and chemists at the Sterling-Winthrop Received for publication 19 July 1968. Research Institute (1967a, b) were tested against blood-induced and sporozoite-induced plasmodial infections of rodents. When tested against blood-induced P. berghei infection in Swiss mice, many hydroxynaphthoquinones were shown by Berberian and Slighter (1968) to have schizonticidal activity. However, all failed to prevent recrudescences unless medicated at near-toxic or toxic doses. When tested against preerythrocytic stages, several members of the various series of compounds possessed causal prophylactic activity. One member of the group of cyclohexylalkylhydroxynaphthoquinones bears the generic name menoctone. This paper will describe the chemoprophylactic and chemotherapeutic effects of menoctone and of menoctone combined with other antimalarials against preerythrocytic and erythrocytic forms of P. berghei. MATERIALS AND METHODS Menoctone Menoctone is a bright yellow substance consisting of needlelike crystals. It is sparingly soluble in water, but it is quite lipophilic and readily dissolves in sesame oil. Chemically, menoctone is 2hydroxy-3-( 8-cyclohexyloctyl)-1,4-naphthoquinone, and its structural formula is as follows: 0 II OH /CH2 2CH2 (C (CH2)8CH CH2

Studies of in vitro primaquine hemolysis: substrate requirement for erythrocyte membrane damage.

The hemolytic toxicity of primaquine has been recognized since its introduction as an antimalarial drug (2, 3). Both in vivo and in vitro primaquine hemolysis has been extensively characterized, but the actual mechanisms of red cell destruction are still unknown (4, 5). These two processes differ from one another in that much greater concentrations of primaquine are required for in vitro hemolysis (6). During this study of the mechanisms of primaquine hemolysis, we made the apparently paradoxical observation that red cells deficient in glucose 6-phosphate dehydrogenase (G-6-PD), although more sensitive than normal cells to primaquine hemolysis in vivo, are less sensitive to primaquine-induced changes in an in vitro system containing substrate. This led us to examine the relationship between erythrocyte metabolism and in vitro primaquine damage.

BIOCHEMICAL AND GENETIC ASPECTS OF PRIMAQUINE-SENSITIVE HEMOLYTIC ANEMIA

Excerpt Acute hemolysis, which may destroy half the red cells within a few days, occurs in approximately 10% of otherwise healthy American Negroes, very rarely in Caucasians,1, 2, 3when 30 mg. prim...

Toxicity of primaquine in Caucasians.

Primaquine, 8-(4-amino-1-methylbutylamino)-6-methoxyquinoline,1a new curative agent for vivax malaria, has recently been extensively tested in the Armed Forces. Since mid-December, 1951, veterans returning from Korea have received 15 mg. of primaquine base once daily for two weeks aboard Military Sea Transport ships after termination of weekly chloroquine (aralen®) suppression at the time of embarkation.2Chloroquine remains in the blood in effective concentration for several weeks; it suppresses clinical symptoms by eliminating the erythrocytic forms of the malaria parasite but does not prevent subsequent relapses. Relapses can be prevented, however, by the administration of primaquine, which acts primarily against the exoerythrocytic parasites. Thus, combined action of the two drugs has been exploited during the transpacific voyage to achieve radical cure of vivax infections before symptoms have developed. Primaquine, combined with chloroquine, has also been employed extensively in treating clinical attacks of vivax malaria in Army installations in the United