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European Journal of Medicinal Chemistry Nov 2019Numerous modifications of the well-known antimalarial drug primaquine, both at the quinoline ring and at the primary amino group, have been reported, mostly to obtain... (Review)
Review
Numerous modifications of the well-known antimalarial drug primaquine, both at the quinoline ring and at the primary amino group, have been reported, mostly to obtain antimalarial agents with improved bioavailability, reduced toxicity and/or prolonged activity. Modifications of the terminal amino group were made with the main idea to prevent the metabolic pathway leading to inactive and toxic carboxyprimaquine (follow-on strategy), but also to get compounds with different activity (repurposing strategy). The modifications undertaken until 2009 were included in a review published in the same year. The present review covers various classes of primaquine N-derivatives with diverse biological profiles, prepared in the last decade by our research group as well as the others. We have summarized the synthetic procedures applied for their preparation and discussed the main biological results. Several hits for the development of novel antiplasmodial, anticancer, antimycobacterial and antibiofilm agents were identified.
Topics: Animals; Anti-Bacterial Agents; Antimalarials; Antineoplastic Agents; Biofilms; Dose-Response Relationship, Drug; Humans; Molecular Structure; Primaquine; Structure-Activity Relationship
PubMed: 31472472
DOI: 10.1016/j.ejmech.2019.111640 -
Malaria Journal Nov 2014Primaquine is the only generally available anti-malarial that prevents relapse in vivax and ovale malaria, and the only potent gametocytocide in falciparum malaria.... (Review)
Review
Primaquine is the only generally available anti-malarial that prevents relapse in vivax and ovale malaria, and the only potent gametocytocide in falciparum malaria. Primaquine becomes increasingly important as malaria-endemic countries move towards elimination, and although it is widely recommended, it is commonly not given to malaria patients because of haemolytic toxicity in subjects who are glucose-6-phosphate dehydrogenase (G6PD) deficient (gene frequency typically 3-30% in malaria endemic areas; >180 different genetic variants). In six decades of primaquine use in approximately 200 million people, 14 deaths have been reported. Confining the estimate to reports with known denominators gives an estimated mortality of one in 621,428 (upper 95% CI: one in 407,807). All but one death followed multiple dosing to prevent vivax malaria relapse. Review of dose-response relationships and clinical trials of primaquine in G6PD deficiency suggests that the currently recommended WHO single low dose (0.25 mg base/kg) to block falciparum malaria transmission confers a very low risk of haemolytic toxicity.
Topics: Antimalarials; Glucosephosphate Dehydrogenase Deficiency; Hemolysis; Humans; Malaria, Falciparum; Primaquine
PubMed: 25363455
DOI: 10.1186/1475-2875-13-418 -
Clinical Infectious Diseases : An... Nov 2004Primaquine is the only available drug for preventing relapse of malaria, and confusion surrounds its use. This review examines the wide range of clinical applications of... (Review)
Review
Primaquine is the only available drug for preventing relapse of malaria, and confusion surrounds its use. This review examines the wide range of clinical applications of primaquine described in the medical literature between 1946 and 2004. The risk of relapse of Plasmodium vivax malaria without primaquine therapy ranged from 5% to 80% or more, depending largely upon geographic location. Supervision of therapy profoundly impacts the risk of relapse, and almost all reports of malaria resistant to primaquine are associated with lack of such supervision. We nonetheless suspect that there is widespread resistance to the standard course of primaquine therapy, which is 15 mg primaquine base daily for 14 days. Clinical evidence confirms that a course of 15 mg daily for just 5 days, a regimen widely used in areas where malaria is endemic, has no discernible efficacy. This review supports a recommendation for a regimen of 0.5 mg/kg primaquine daily for 14 days, on the basis of superior efficacy and good tolerability and safety in nonpregnant persons without glucose-6-phosphate dehydrogenase deficiency.
Topics: Animals; Antimalarials; Drug Resistance; Humans; Malaria; Plasmodium; Primaquine
PubMed: 15494911
DOI: 10.1086/424663 -
Pharmacology & Therapeutics May 2016Primaquine is the only antimalarial drug available to clinicians for the treatment of relapsing forms of malaria. Primaquine development and usage dates back to the... (Review)
Review
Primaquine is the only antimalarial drug available to clinicians for the treatment of relapsing forms of malaria. Primaquine development and usage dates back to the 1940s and has been administered to millions of individuals to treat and eliminate malaria infections. Primaquine therapy is not without disadvantages, however, as it can cause life threatening hemolysis in humans with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In addition, the efficacy of primaquine against relapsing malaria was recently linked to CYP 2D6 mediated activation to an active metabolite, the structure of which has escaped definitive identification for over 75years. CYP 2D6 is highly polymorphic among various human populations adding further complexity to a comprehensive understanding of primaquine pharmacology. This review aims to discuss primaquine pharmacology in the context of state of the art understanding of CYP 2D6 mediated 8-aminoquinoline metabolic activation, and shed light on the current knowledge gaps of 8-aminoquinoline mechanistic understanding against relapsing malaria.
Topics: Animals; Antimalarials; Cytochrome P-450 CYP2D6; Drug Interactions; Humans; Metabolomics; Polymorphism, Genetic; Primaquine; Prodrugs
PubMed: 27016470
DOI: 10.1016/j.pharmthera.2016.03.011 -
European Journal of Medicinal Chemistry Mar 2009Primaquine was firstly synthesized in 1946 in the USA, and is the most representative member of the anti-malarial 8-aminoquinolines. Six decades have passed and... (Review)
Review
Primaquine was firstly synthesized in 1946 in the USA, and is the most representative member of the anti-malarial 8-aminoquinolines. Six decades have passed and primaquine is still the only transmission-blocking anti-malarial clinically available, displaying a marked activity against gametocytes of all species of human malaria, including multi-resistant Plasmodium falciparum strains. Primaquine is also effective against all exoerythrocytic forms of the parasite and is used in conjunction with other anti-malarials for the treatment of vivax and ovale malaria. However, primaquine is often associated with serious adverse effects, in consequence of its toxic metabolites. 5-Hydroxyprimaquine or 6-methoxy-8-aminoquinoline has been considered to be directly responsible for complications such as hemolytic anemia. Primaquine toxicity is aggravated in people deficient of 6-glucose phosphate dehydrogenase or glutathione synthetase. Adverse effects are further amplified by the fact that primaquine must be repeatedly administered at high doses, due to its limited oral bioavailability. Over the last two decades, Medicinal Chemists have battled against primaquine's disadvantages, while keeping or even improving its unequalled performance as an anti-malarial. The present text revisits primaquine and its properties on the occasion of its 60th anniversary and aims to give a general overview of what has been the path towards the development of effective and safe primaquine-based anti-malarials. Presently, aablaquine and tafenoquine the two most promising primaquine analogues are already in the final stages of clinical trials against Plasmodium vivax and P. falciparum. Both compounds are a new hope against malaria and other primaquine-sensitive illnesses, such as Pneumocystis Pneumonia or the Chagas disease.
Topics: Animals; Antimalarials; Humans; Plasmodium falciparum; Primaquine
PubMed: 18930565
DOI: 10.1016/j.ejmech.2008.08.011 -
Malaria Journal Dec 2011Primaquine was officially licensed as an anti-malarial drug by the FDA in 1952. It has remained the only FDA licensed drug capable of clearing the intra-hepatic... (Review)
Review
Primaquine was officially licensed as an anti-malarial drug by the FDA in 1952. It has remained the only FDA licensed drug capable of clearing the intra-hepatic schizonts and hypnozoites of Plasmodium vivax. This update and review focuses on five major aspects of primaquine use in treatment of vivax malaria, namely: a) evidence of efficacy of primaquine for its current indications; b) potential hazards of its widespread use, c) critical analysis of reported resistance against primaquine containing regimens; d) evidence for combining primaquine with artemisinins in areas of chloroquine resistance; and e) the potential for replacement of primaquine with newer drugs.
Topics: Aminoquinolines; Antimalarials; Artemisinins; Chloroquine; Clinical Trials as Topic; Drug Resistance; Glycogen Storage Disease Type I; Hemolysis; Humans; Malaria, Vivax; Plasmodium vivax; Primaquine
PubMed: 22152065
DOI: 10.1186/1475-2875-10-351 -
Malaria Journal Aug 2012Primaquine has been the only widely available hypnozoitocidal anti-malarial drug for half a century. Despite this its clinical efficacy is poorly characterized resulting... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Primaquine has been the only widely available hypnozoitocidal anti-malarial drug for half a century. Despite this its clinical efficacy is poorly characterized resulting in a lack of consensus over the optimal regimen for the radical cure of Plasmodium vivax.
METHODS
Published studies since 1950 of the use of primaquine regimens for preventing P. vivax relapse were reviewed. Data were extracted systematically from available papers. Primaquine regimens were categorized according to the total dose administered: very low (≤2.5 mg/kg), low (>2.5 mg/kg- < 5.0 mg/kg) and high (≥ 5.0 mg/kg). The risk of recurrent infection were summarized across geographical regions and the odds ratios between treatment regimens calculated after stratifying by total treatment dose and duration of study follow up.
RESULTS
Data could be retrieved from 87 clinical trials presenting data in 59,735 patients enrolled into 156 treatment arms, conducted in 20 countries. There was marked heterogeneity in study design, particularly primaquine dosing and duration of follow up. The median rate of recurrence following very low dose of primaquine (n = 44) was 25% (range 0-90%) at 4-6 months, compared to 6.7 % (range 0-59%) following low dose primaquine (n = 82). High dose primaquine regimens were assessed in 28 treatment arms, and were associated with a median recurrence rate of 0% (Range: 0-15%) at one month. In 18 studies with control arms, the effectiveness of a very low dose primaquine regimen was no different from patients who did not receive primaquine (OR = 0.60, 95%CI 0.33-1.09, p = 0.09), whereas for the low dose regimens a significant difference was reported in 50% (6/12) of studies (overall OR = 0.14, 95%CI: 0.06-0.35, p < 0.001). Two studies enrolling 171 patients demonstrated high effectiveness of high dose primaquine compared to a control arm (OR = 0.03 (95%CI: 0.01-0.13); p < 0.0001).
CONCLUSIONS
Low dose regimens retain adequate efficacy in some areas, but this is not uniform. The efficacy and safety of pragmatic high dose primaquine regimens needs to be assessed in a range of endemic and geographical locations. Such studies will require a prolonged period of follow up and comparison with control arms to account for confounding factors.
Topics: Antimalarials; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Humans; Malaria, Vivax; Primaquine; Treatment Outcome
PubMed: 22900786
DOI: 10.1186/1475-2875-11-280 -
Acta Tropica Aug 2016Primaquine has been the drug of choice for the prevention of Plasmodium vivax relapse for more than 60 years. Primaquine tolerant strain of P. vivax was identified in... (Review)
Review
Primaquine has been the drug of choice for the prevention of Plasmodium vivax relapse for more than 60 years. Primaquine tolerant strain of P. vivax was identified in 1944. Significant mortality and disease burden of P. vivax calls for the need of new drugs. Primaquine resistance is a complex issue, as the mechanism of resistance is not clear. Direct evidence of resistance to primaquine by hypnozoites has not yet been shown. There are some reports detailing risk of primaquine resistance in specific regions, but the overall distribution of primaquine resistance in P. vivax-infected people is largely unknown. Confounding factors contribute to treatment failures; such as inadequate doses, inappropriate dosing intervals, risk of reinfection, combinations with blood schizontocidals, and compliance. Therefore, primaquine resistance needs to be addressed along with additional important confounding factors. Tafenoquine is the most studied drug in replacing primaquine for the radical cure of P. vivax malaria. It has comparable efficacy with primaquine. The potential advantage of tafenoquine is better compliance with a single dose regimen. Rational use of primaquine can secure its effectiveness, but it is essential in the future to have better or similar alternatives to treat P. vivax.
Topics: Antimalarials; Humans; Malaria, Vivax; Plasmodium vivax; Primaquine; Treatment Failure
PubMed: 27109040
DOI: 10.1016/j.actatropica.2016.04.009 -
International Journal For Parasitology.... Apr 2021Plasmodium vivax radical cure requires the administration of a blood schizonticide for killing blood-stage parasites and the addition of a drug able to kill hypnozoites,...
Plasmodium vivax radical cure requires the administration of a blood schizonticide for killing blood-stage parasites and the addition of a drug able to kill hypnozoites, the dormant parasite stages residing in the liver of infected patients. All drugs used clinically for killing hypnozoites are 8-aminoquinolines and among them, primaquine has been at the forefront of P. vivax case management for decades. We discuss here the possible factors that could lead to the emergence and selection of P. vivax primaquine resistant parasites and emphasize on how a better understanding of the mechanisms underlying primaquine treatment and hypnozoite biology is needed to prevent this catastrophic scenario from happening.
Topics: Animals; Antimalarials; Humans; Liver; Malaria, Vivax; Parasites; Plasmodium vivax; Primaquine
PubMed: 33529838
DOI: 10.1016/j.ijpddr.2020.12.004 -
Trends in Parasitology Nov 2022Flannery et al. and Luiza-Batista et al. recently reported on liver and blood stages of Plasmodium vivax in humanized mice. The biology of P. vivax can be investigated...
Flannery et al. and Luiza-Batista et al. recently reported on liver and blood stages of Plasmodium vivax in humanized mice. The biology of P. vivax can be investigated using the mouse models, which will also facilitate drug research. This could lead to better treatment and control of P. vivax malaria.
Topics: Animals; Antimalarials; Malaria, Vivax; Mice; Plasmodium vivax; Primaquine; Recurrence
PubMed: 36180306
DOI: 10.1016/j.pt.2022.09.006