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At least 19 recordsLinked to original sources
PubMed1991

The conversion of primaquine into primaquine-aldehyde, primaquine-alcohol, and carboxyprimaquine, a major plasma metabolite.

Although efficacy and toxicity of primaquine (PQ) depend on bioconversion, the process is poorly understood, even for carboxyprimaquine (CPQ), the major plasma metabolite. Earlier work to clarify drug metabolism showed that PQ could be converted quantitatively into CPQ, in vitro, with human erythroleukemic K562 cells or nonleukemic bone marrow supplemented with calf serum. We have now found--using systems with serum only, as well as with K562, bone marrow, and adult or embryonic liver cells--that the bioconversion of the side chain of PQ involves a branched pathway with at least three separate enzymes and two derivatives other than CPQ. An oxidase activity in serum converted PQ first into a novel side chain aldehyde (Y). Aldehyde dehydrogenase transformed PQ-aldehyde into CPQ in cell-free systems and in K562, bone marrow, and adult liver cells. Embryonic hepatocytes or bone marrow treated with 1,3-bis(2-chloroethyl)-1-nitrosourea did not produce CPQ; instead, they made a metabolite (Xc) that we could synthetize via PQ-aldehyde and identify as PQ-alcohol. PQ-alcohol replaced CPQ as the final product whenever alcohol-dehydrogenase prevailed over aldehyde dehydrogenase. These enzymes operated in intact cells and controlled the biotransformation of PQ absolutely. Unless both dehydrogenase were absent, inhibited, or deprived of coenzyme, potentially cytotoxic PQ-aldehyde intermediate did not accumulate. Some of the unique tissues schizonticidal and gametocidal effects of PQ may depend on the distribution pattern and relative activities of PQ oxidase, aldehyde dehydrogenase, and alcohol dehydrogenase in human subjects and in parasites.

Alcohols↗
PubMed1990

In vitro effects of primaquine and primaquine metabolites on exoerythrocytic stages of Plasmodium berghei.

The antimalarial activities of primaquine and its metabolites against exoerythrocytic (EE) stages of Plasmodium berghei in vitro were compared with their abilities to spontaneously generate activated oxygen. A quantitative relationship between the number of sporozoites and the number of EE merozoites produced was established. The reduction in the number of merozoites was used as an assay of drug activity. The ED50 of primaquine, 3.7-3.9 x 10(-6) M, was the concentration of drug that reduced the number of merozoites to 50% of controls. Several of the primaquine metabolites were much more potent than primaquine, with ED50s as low as 2 x 10(-7) M. Metabolites containing the 4-amino-1-methylbutyl side chain were most effective in vitro. Superoxide generation was measured for the various metabolites. In general, superoxide generation did not correlate with antimalarial activity. However, for the 3 metabolites with 4-amino-1-methylbutyl side chains, there was a correlation between superoxide generation and antimalarial activity.

Animals↗
PubMed1987

Antimalarial activity and inhibition of monoamine oxidases A and B by exo-erythrocytic antimalarials. Optical isomers of primaquine, N-acylated congeners, primaquine metabolites and 5-phenoxy-substituted analogues.

When the terminal amino group in the side chain of primaquine was blocked with an ethoxyacetyl group shown in 2, or eliminated by oxidative deamination to carboxylic acid 3, the antimalarial effect was markedly reduced in a screening assay which measures tissue schizonticidal activity. The optical isomers 1A and 1B of primaquine had similar antimalarial potency to the racemic mixture but 1B appeared less toxic. The 5-phenoxy-substituted analogue 4, belonging to a new class of antimalarials, showed similar potency in the assays to either 1A or 1B but seemed less cytotoxic than (+/-)-primaquine. Compounds 1A and 1B were found to be competitive inhibitors of human monoamine oxidase (MAO) A and B (Ki range 103-225 microM), but 4 showed 10-30-fold greater competitive inhibition of MAO A (Ki = 6.8 microM) and 40-90-fold greater non-competitive inhibition of MAO B (Ki = 2.3 microM).

Animals↗
PubMed1992

High-performance liquid chromatographic determination of pamaquine, primaquine and carboxy primaquine in calf plasma using electrochemical detection.

A high-performance liquid chromatographic method with electrochemical detection is described for quantification of pamaquine, primaquine and carboxy primaquine in calf plasma. After the proteins had been precipitated with acetonitrile, the drugs were separated on a 5-microns C18-modified polymer gel column with an isocratic mobile phase. The detection limit was 0.01 microgram/ml in plasma for all three compounds. The applicability of the method in pharmacokinetic studies was demonstrated by determining the plasma concentrations of the three substances in calves administered a single dose of pamaquine or primaquine.

Aminoquinolines↗
PubMed1991

Susceptibility of glucose-6-phosphate dehydrogenase deficient red cells to primaquine, primaquine enantiomers, and its two putative metabolites. II. Effect on red blood cell membrane, lipid peroxidation, MC-540 staining, and scanning electron microscopic studies.

The effects of primaquine (PQ), its enantiomers [(+)PQ,(-)PQ] and hydroxy metabolites [5-hydroxyprimaquine (5HPQ) and 6-desmethyl-5-hydroxyprimaquine (6D5HPQ)] on cell membranes of glucose-6-phosphate dehydrogenase (G-6-PD) deficient red cells were studied in vitro. There was no significant effect of PQ on the malonyldialdehyde (MDA) content of normal and heterozygous red cells, but it caused a significant increase in MDA in G-6-PD deficient red cells (P less than 0.05). There was no noticeable difference between the effects of the two enantiomers on this variable (P greater than 0.05). Compared to PQ, the hydroxy metabolites produced a significantly greater increase in MDA in all the groups studied (P less than 0.001). Of the two hydroxy metabolites, 6D5HPQ was more toxic than 5HPQ. Staining with MC540 showed that exposure to PQ, its enantiomers and two putative metabolites produced significant fluorescence, indicating that the drug produces marked alterations in membrane fluidity. Although the fluorescence was seen both in normal and heterozygous cells, the effect was marked in hemizygous deficient red cells (P less than 0.001). Scanning electron microscopic (SEM) studies revealed that PQ enantiomers had a stomatocytic effect on red cells of normal, heterozygous and hemizygous G-6-PD deficient red cells, whereas the putative metabolites had an echinocytic effect. The effects were most pronounced in G-6-PD deficient red cells.

Erythrocyte Membrane↗
PubMed1987

Modifications of primaquine as antimalarials. 4. 5-Alkoxy derivatives of primaquine.

Thirty-two 5-alkoxyprimaquines have been synthesized and evaluated as blood schizonticides (Plasmodium berghei, mouse) and tissue schizonticides (Plasmodium cynomolgi, monkey). Several of these compounds were extremely active in both screens. Such a broad spectrum of antimalarial efficacy offers the possibility of a single drug that could cure the various relapsing and nonrelapsing malarias.

Animals↗
PubMed2025

14 days of high-dose versus low-dose primaquine treatment in patients with Plasmodium vivax infection in Cambodia: a randomised, single-centre, open-label efficacy study.

BACKGROUND: Most malaria-endemic countries, including Cambodia, use a total dose of 3&#xb7;5 mg/kg of primaquine to eliminate Plasmodium vivax hypnozoites and prevent relapses. There are, however, indications that the lower dose of 3&#xb7;5 mg/kg is insufficient for tropical P vivax isolates, particularly in southeast Asia, and WHO now recommends a total dose of 7&#xb7;0 mg/kg in most countries. We aimed to determine the most effective regimen to eliminate P vivax hypnozoites to support elimination efforts of this malaria parasite. METHODS: We conducted an open-label, randomised controlled trial in Kampong Speu province, western Cambodia. Patients infected with P vivax aged at least 15 years were offered to participate. Exclusion criteria were severe malaria or other diseases requiring treatment, low haemoglobin (<8&#xb7;0 g/dL), pregnancy or breastfeeding, sensitivity to study drugs, and use of antimalarials in the preceding month. Enrolled patients were treated with an artesunate regimen of 2 mg/kg per day for 7 days. Patients with normal glucose-6-phosphate dehydrogenase (G6PD) levels were randomly assigned (2:2:1) to receive 3&#xb7;5 mg/kg (low dose [0&#xb7;25 mg/kg per day]), 7&#xb7;0 mg/kg (high dose [0&#xb7;5 mg/kg per day]), or no primaquine for 14 days. Patients with deficient G6PD levels were assigned to the no primaquine comparator arm. Patients were relocated to the study site in Aoral town where no malaria transmission occurs to ensure that they were not reinfected during their 90-day follow-up. After 90 days of relocation, G6PD-normal patients in the no primaquine arm were provided 3&#xb7;5 mg/kg of primaquine for 14 days to be taken unsupervised. At day 90, relocation was terminated, and patients were followed up monthly for 3 months until day 180. The primary outcome was P vivax recurrence within 90 days of relocated follow-up, assessed in all patients who completed treatment and complied with relocation without interruption. All patients enrolled and assigned to an intervention arm were included in the safety analysis. The study is registered on ClinicalTrials.gov and recruitment is completed (NCT04706130). FINDINGS: Between Nov 10, 2021, and Feb 10, 2024, 160 patients were enrolled and 147 were included in the primary analysis-59 were assigned to the no primaquine arm (37 assigned as G6PD deficient [median age 22 years, IQR 18-28]; 22 randomly assigned [18, 17-25]), 45 to the low-dose primaquine arm (23, 19-30), and 43 to the high-dose primaquine arm (22, 18-25). Participants were mostly male (135 [92%] of 147) and all Cambodian. 48 (81% [95% CI 69&#xb7;6-89&#xb7;2]) participants in the no primaquine arm had at least one P vivax recurrence within 90 days, as did 11 (24%, 14&#xb7;2-38&#xb7;7) in the low-dose group and two (5%, 0&#xb7;8-15&#xb7;5) in the high-dose group (p=0&#xb7;0141 for high vs low). After imputation for missing data, low-dose primaquine remained associated with more recurrences than high-dose primaquine (hazard ratio 0&#xb7;17 [95% CI 0&#xb7;04-0&#xb7;79], p=0&#xb7;0229). Both primaquine regimens were well tolerated with no serious adverse events reported. INTERPRETATION: Not providing primaquine to patients led to a considerable rate of P vivax recurrence. The risk of P vivax recurrence was substantially lower for 7&#xb7;0 mg/kg primaquine treatment compared with 3&#xb7;5 mg/kg. Tolerability and safety of both primaquine regimens in G6PD normal individuals was comparable. FUNDING: US National Institutes of Health (R01AI146590).

Humans↗
PubMed1977

Comparison of the curative antimalarial activities and toxicities of primaquine and its d and l isomers.

This investigation was undertaken to determine whether either d-primaquine or l-primaquine has sufficient advantage over primaquine to warrant evaluation for curative activity in human volunteers infected with Plasmodium vivax. It was found: (i) that the capacities of the isomers and the racemate to cure infections with Plasmodium cynomolgi in rhesus monkeys were essentially identical; (ii) that the subacute toxicities of the isomers and racemate for this monkey were qualitatively the same, but that l-primaquine was three to five times as toxic as d-primaquine and at least twice as toxic as primaquine; and (iii) that the acute single-dose toxicities of the isomers for mice were not only qualitatively different, but that the d isomer was at least four times as toxic as l-primaquine. Since previous appraisals of curative activity and tolerability of 8-aminoquinolines in rhesus monkeys have correlated well with appraisals in human volunteers, attention was focused on results acquired with these test subjects. The relevant evaluations showed that d-primaquine had a therapeutic index at least twice that of primaquine. If this advantage carries over to man, problems that now complicate routine use of primaquine might be obviated. Therefore, a critical comparison of d-primaquine and primaquine in human volunteers seems indicated.

Animals↗
PubMed1988

Primaquine is lethal for intracellular but not extracellular Trypanosoma cruzi.

Primaquine has been used to treat Chagas' disease in humans and has been reported to be active against extracellular Trypanosoma cruzi. Experiments were designed to evaluate the relative activity of primaquine against extra- and intracellular T. cruzi and to determine if primaquine might be combined advantageously with ketoconazole. Primaquine at 0.5 micrograms/ml significantly inhibited T. cruzi replication in infected mouse peritoneal macrophages and also effectively treated infected L929 cells. To examine the effect of primaquine on extracellular organisms, tissue culture T. cruzi were incubated with primaquine for different periods of time and then used to infect macrophages. Incubation with 10 micrograms/ml for 14 hr but not 8 hr significantly inhibited but did not eradicate replication. Incubation of spleen amastigotes or blood trypomastigotes for 2 hr with 10 micrograms/ml did not inhibit replication. Incubation of extracellular tissue culture T. cruzi with primaquine for 2 hr did not potentiate the activity of ketoconazole against intracellular organisms. The combination of primaquine and ketoconazole administered to acutely infected mice significantly decreased parasitemias in comparison to treatment with primaquine or ketoconazole alone. Thus primaquine acts primarily on intracellular rather than extracellular T. cruzi. Primaquine and ketoconazole appear to have additive activity in vivo.

Animals↗
PubMed1982

Primaquine-mediated oxidative metabolism in the human red cell. Lack of dependence on oxyhemoglobin, H2O2 formation, or glutathione turnover.

Stimulation of the hexose monophosphate shunt by primaquine results from the oxidation of NADPH by primaquine. This conclusion was based on the observations that primaquine lowered cellular NADPH but not GSH and that, in red cells in which the GSH was unavailable for reaction, primaquine still stimulated the rate of the hexose monophosphate shunt. In a non-cellular system, primaquine interacted with NADPH, but not GSH, to produce H2O2. Stimulation of the hexose monophosphate shunt by primaquine does not primarily involve H2O2 accumulation since stimulation of the pathway by primaquine was also observed in red cells containing methemoglobin, a red cell preparation in which no H2O2 accumulates. Methemoglobin prevented the formation and/or accumulation of H2O2 in intact red cells incubated with primaquine as well as in a non-cellular system containing primaquine plus Fe2+-EDTA as an H2O2 source. Methemoglobin probably acts by scavenging reactive intermediates since oxyhemoglobin was formed from methemoglobin in the non-cellular experiments. In the red cell, primaquine stimulated glucose-dependent conversion of methemoglobin to oxyhemoglobin.

Blood Glucose↗
PubMed1988

Activity of clindamycin with primaquine against Pneumocystis carinii in vitro and in vivo.

The combination of primaquine with clindamycin is effective in both in vitro and in vivo models of Pneumocystis infection. Primaquine alone at concentrations from 10 to 300 micrograms/ml reduced the numbers of organisms in cultures to less than 7% of control. Significant inhibition was observed down to 0.1 microgram/ml. Clindamycin at 5 micrograms/ml was ineffective alone. Combinations of clindamycin and primaquine in culture at various concentrations were effective, but there was no evidence of true synergy. In rats with established Pneumocystis pneumonia, clindamycin alone at 5 or 225 mg/kg was ineffective. Primaquine alone at 0.5 or 2 mg/kg did not significantly affect the numbers of organisms remaining. The combination of 0.5 mg of primaquine per kg and 225 mg of clindamycin per kg was effective for therapy, lowering the numbers of organisms in the lungs by about 90%. The combination of 2 mg of primaquine per kg and 225 mg of clindamycin per kg was more effective, lowering the numbers of organisms by almost 98%. In the in vivo prophylaxis model, primaquine at 0.1 or 0.2 mg/kg did not prevent the development of Pneumocystis pneumonia in immune-suppressed rats. Clindamycin at 50 mg/kg had a modest effect alone, but at 5 mg/kg all animals became heavily infected. At 0.5 mg/kg, primaquine alone reduced the severity of infection, but seven of eight rats were still infected. In contrast, the combination of 5 mg of clindamycin per kg and 0.5 mg of primaquine per kg prevented infection in 8 of 10 rats; 2 rats had minimal infection. These studies suggest that the combination of clindamycin and primaquine should be tested in therapy or prophylaxis of Pneumocystis infections in humans.

Animals↗
PubMed1991

Low concentrations of primaquine inhibit degradation but not receptor-mediated endocytosis of asialoorosomucoid by HepG2 cells.

Asialoorosomucoid (ASOR) is internalized and degraded by HepG2 cells after binding to the asialoglycoprotein (ASGP) receptor, internalization through the coated pit/coated vesicle pathway, and trafficking to lysosomes. Primaquine, an 8-aminoquinoline antimalarial compound, inhibits ASOR degradation at concentrations greater than 0.2 mM by neutralizing intracellular acid compartments. This leads to alterations in surface receptor number, receptor-ligand dissociation, and receptor recycling. We have investigated the effects of primaquine on 125I-ASOR uptake and degradation as a function of primaquine concentration and duration of exposure. Concentrations below those required for neutralization of acidic compartments block 125I-ASOR degradation in HepG2 cells and lead to intracellular ligand accumulation. This effect is maximal at 80 microM primaquine. The intracellular 125I-ASOR is undegraded, dissociated from the ASGP receptor, and contained within vesicular compartments distinct from lysosomes, plasma membrane, or endosomes. In addition, the effect of 80 microM primaquine on 125I-ASOR degradation is very slowly reversible (greater than 6 h), in contrast to primaquine's rapidly reversible effect on receptor recycling and ligand uptake (10 min). Furthermore, the effect is ligand-specific. 125I-asialofetuin, another ASGP receptor ligand, is internalized and degraded in lysosomes at normal rates in HepG2 cells exposed to 80 microM primaquine. These findings indicate that primaquine has multiple effects on the uptake and degradation of ligand occurring in the endosome-lysosome pathway. These effects of primaquine differ in their concentration-dependence, site of action, reversibility, and ligand selectivity.

Asialoglycoprotein Receptor↗
PubMed1986

Effects of primaquine on hepatic microsomal haemoproteins and drug oxidation.

Administration of the antimalarial agent primaquine to male rats (50 mg/kg i.p. daily for 4 days) resulted in a 30% decrease in hepatic microsomal cytochrome P-450 (P-450) content; levels of other microsomal haemoproteins were unaltered. Kinetic analysis of 2 mixed-function oxidase activities (aminopyrine N-demethylase and aniline p-hydroxylase) in primaquine-pretreated rat liver microsomes revealed a significant and similar decrease in the maximal reaction velocities of these enzymes (Vmax), but the apparent Michaelis constants (Km) were not changed. The activity of mitochondrial delta-aminolaevulinic acid synthetase (the rate-limiting step in haem biosynthesis) was normal in primaquine-pretreated rat liver but haem oxygenase activity (the rate-limiting step in haem degradation) was elevated approximately 2-fold. Haem availability for haemoprotein assembly (determined as the haem-saturation ratio of the cytosolic haemoprotein tryptophan pyrrolase) was also normal although the absolute activity of tryptophan pyrrolase was decreased after primaquine pretreatment. In order to facilitate an analysis of the P-450 isozyme profile in control and primaquine-treated rat liver, total microsomal P-450 was isolated by hydrophobic affinity chromatography on n-octylamino-Sepharose 4B. Densitometry of stained polyacrylamide gels following electrophoresis of these partially-purified P-450 fractions indicated that primaquine exposure did not selectively decrease any of the 3 protein bands in the P-450 molecular weight region (48-56 kD). These observations, when considered together, suggest that primaquine may affect P-450 and mixed-function oxidase activity by inhibition of protein synthesis. The characteristic rapid turnover rates of P-450 isozymes may predispose these haemoproteins to the toxic effects of primaquine whereas those haemoproteins that turn over less rapidly, such as cytochrome b5, appear to be less susceptible. Microsomal haem oxygenase activity may be elevated after primaquine administration since lowered haemoprotein requirements for haem could result in excess haem levels within the hepatocyte.

Animals↗
PubMed1984

Pharmacokinetics of primaquine in man: identification of the carboxylic acid derivative as a major plasma metabolite.

A method is described for the simultaneous determination of the carboxylic acid and N-acetyl-derivatives of primaquine, in plasma and urine. After oral administration of 45 mg primaquine, to five healthy volunteers, absorption was rapid, with peak primaquine levels of 153.3 +/- 23.5 ng/ml at 3 +/- 1 h, followed by an elimination half-life of 7.1 +/- 1.6 h, systemic clearance of 21.1 +/- 7.1 l/h, volume of distribution of 205 +/- 371 and cumulative urinary excretion of 1.3 +/- 0.9% of the dose. Primaquine underwent rapid conversion to the carboxylic acid metabolite of primaquine, which achieved peak levels of 1427 +/- 307 ng/ml at 7 +/- 4 h. Levels of this metabolite were sustained in excess of 1000 ng/ml for the 24 h study period, and no carboxyprimaquine was recovered in urine. N-acetyl primaquine was not detected in plasma or urine. Following [14C]-primaquine administration to one subject, plasma radioactivity levels rapidly exceeded primaquine concentrations. Plasma radioactivity was accounted for mainly as carboxyprimaquine . Though 64% of the dose was recovered over 143 h, as [14C]-radioactivity in urine, only 3.6% was due to primaquine. As neither carboxyprimaquine nor N- acetylprimaquine were detected in urine, the remaining radioactivity was due to unidentified metabolites.

Adult↗