High-Performance Liquid Chromatographic-Ultraviolet Determination of Primaquine and Its Metabolites in Human Plasma and Urine

Parkhurst, George W.; Nora, M. V.; Thomas, Russel W.; Carson, Paul L.

doi:10.1002/jps.2600730943

Cited by 28 publications

(10 citation statements)

References 7 publications

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“…We used a high-pressure liquid chromatography assay with a lower limit of sensitivity of ca. 0.1 1xg/ml for primaquine and 0.5 ,ug/ml for carboxyprimaquine (22). Other workers have shown levels of primaquine in the blood to fall rapidly but levels in tissues to be higher and to fall more slowly.…”

Section: Discussionmentioning

confidence: 89%

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

Queener

Bartlett

Richardson

et al. 1988

Antimicrob Agents Chemother

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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 ,ug/ml reduced the numbers of organisms in cultures to less than 7% of control. Significant inhibition was observed down to 0.1 ,ug/ml. Clindamycin at 5 ,ug/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.Treatment or prophylaxis of pneumonia caused by Pneumocystis carinii in patients with acquired immune deficiency syndrome (AIDS) has been hampered by the lack of effective, nontoxic agents. Pentamidine causes a variety of side effects which may limit therapy, and relapses are frequent (29,34). Trimethoprim with sulfamethoxazole causes a surprisingly high incidence of side effects in AIDS patients, including severe hypersensitivity reactions that limit use for treatment (29,33,34). Other experimental agents have been tested with variable results. Difluoromethylornithine is effective in some patients, but thrombocytopenia may be a limiting toxicity (9, 34). Pyrimethamine with sulfadoxine (Fansidar) or dapsone with trimethoprim may be effective in individual patients, but significant adverse reactions still occur with both combinations (10, 21, 34). Trimetrexate, a lipid-soluble analog of methotrexate, is being investigated (1).In the course of screening antimicrobial agents for potential effectiveness against P. carinii, we have evaluated combinations as well as individual agents. One of the combinations we chose to test was clindamycin with primaquine. This selection was based on the observation by Schmidt (25) that the curative action of primaquine in malaria was enhanced by mirincamycin. Mirincamycin, like clindamycin, is a lincosamide but has not been exte...

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Section: Discussionmentioning

confidence: 89%

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

Queener

Bartlett

Richardson

et al. 1988

Antimicrob Agents Chemother

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“…Finally, the dried residue was reconstituted in 100 µl of methanol, and vortexed for 1 min. This solution was transferred to total recovery vial and 40 µl of solution was injected into HPLC for analysis [14]. …”

Section: Methodsmentioning

confidence: 99%

A pilot randomized controlled trial to compare the effectiveness of two 14-day primaquine regimens for the radical cure of vivax malaria in South India

Saravu

Tellapragada

Kulavalli

et al. 2018

Malar J

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BackgroundRadical cure of Plasmodium vivax malaria requires treatment with a blood schizonticide and a hypnozoitocide (primaquine) to eradicate the dormant liver stages. There has been uncertainty about the operational effectiveness and optimum dosing of the currently recommended 14-day primaquine (PQ) course.MethodsA two centre, randomized, open-label, two arm study was conducted in South India. Patients were randomized to receive either high dose (0.5 mg base/kg body weight) or conventional dose (0.25 mg/kg) PQ for 14 days. Plasma concentrations of PQ and carboxyprimaquine (CPQ) on the 7th day of treatment were measured by reverse phase high performance liquid chromatography. Study subjects were followed up for 6 months. Recurrent infections were genotyped using capillary fragment length polymorphism of two PCR-amplified microsatellite markers (MS07 and MS 10).ResultsFifty patients were enrolled. Baseline characteristics and laboratory features did not differ significantly between the groups. Mean age of the study population was 42 ± 16.0 years. Recurrences 80–105 days later occurred in 4 (8%) patients, two in each the groups. All recurrences had the same microsatellite genotype as that causing the index infection suggesting all were relapses. One relapse was associated with low CPQ concentrations suggesting poor adherence.ConclusionsThis small pilot trial supports the effectiveness of the currently recommended lower dose (0.25 mg/kg/day) 14 day PQ regimen for the radical cure of vivax malaria in South India.Trial registration Clinical Trials Registry-India, CTRI/2017/03/007999. Registered 3 March 2017, http://ctri.nic.in/Clinicaltrials/regtrial.php?modid=1&compid=19&EncHid=82755.86366.

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“…These events were considered as correlated and probably indicative of further metabolic conversion of 12. Proposed structures underlying observation of a PQ metabolite associated to m / z 497 (12), and its daughter ions, m / z 479 (13) and 305 (14); structures proposed for other PQ metabolites detected at m / z 516 (15) and 541 (16) are also shown. 4).…”

Section: Primaquine Metabolitesmentioning

confidence: 98%

“…Phase I first-pass metabolism mostly involves major redox and hydrolytic enzymes, as (i) oxidative enzymes: cytochrome P450/monooxygenases, flavincontaining monooxygenases, dehydrogenases, peroxidases, etc., (ii) reductive enzymes: NADPH-cytochrome P450 reductase, reduced (ferrous) cytochrome P450, etc., and (iii) hydrolytic enzymes: esterases, amidases or epoxide hydrolases, etc. Carboxyprimaquine (carboxyPQ) was first reported as a mammalian metabolite in rats [13], and it was subsequently found in monkeys [14] and humans [15][16][17][18]. Primaquine is primarily metabolised by monoamine oxidase (MAO) and cytochrome P450 to form carboxyprimaquine (2, Scheme 1) [11][12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Comparative Analysis of In Vitro Rat Liver Metabolism of the Antimalarial Primaquine and a Derived Imidazoquine

Vale

Fernandes²,

Moreira³

et al. 2012

DML

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The present study provides proof-of-concept regarding the expectedly high enzymatic stability of primaquinederived imidazolidin-4-ones, imidazoquines, formerly developed as alternatives to the parent antimalarial with potentially improved oral bioavailability [J. Med. Chem., 2009, 52, 7800-7807]. This study provides relevant experimental evidence on the remarkably low propensity of imidazoquines to undergo metabolic conversions mediated by rat liver enzymes. This, together with favourable key ADME parameters previously predicted for these compounds [Bioorg. Med. Chem. Lett. 2009, 19, 6914-6917], and proven lack of acute toxicity in mice, further reinforces the role of imidazoquines as reference leads for the development of novel primaquine surrogates. This is a particularly relevant issue in the present status of malaria chemotherapy worldwide, where primaquine remains the sole drug in clinical use able to block transmission between infected persons and the insect vector and to effectively act on liver-stage parasite forms, including hypnozoites.

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High-Performance Liquid Chromatographic-Ultraviolet Determination of Primaquine and Its Metabolites in Human Plasma and Urine

Cited by 28 publications

References 7 publications

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

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

A pilot randomized controlled trial to compare the effectiveness of two 14-day primaquine regimens for the radical cure of vivax malaria in South India

Comparative Analysis of In Vitro Rat Liver Metabolism of the Antimalarial Primaquine and a Derived Imidazoquine

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