Primaquine

Comparative mutagenic and genotoxic effects of three antimalarial drugs, chloroquine, primaquine and amodiaquine, were assessed in the Ames mutagenicity assay (in strains TA97a, TA100, TA102 and TA104) and in vivo sister chromatid exchange (SCE) and chromosome aberration (CA) assays in bone marrow cells of mice. These are the most commonly used antimalarial drugs available at present throughout the world. The results of the bacterial mutagenicity assays showed a very weak mutagenic effect of all three drugs in Salmonella strains TA97a and TA100 both with and without S9 mix and in TA104 only with S9 mix. The results of the in vivo SCE and CA assays indicate that these three drugs are genotoxic in bone marrow cells of mice.

AimsTo evaluate the effects of gender, food and grapefruit juice on the pharmacokinetics of primaquine in healthy subjects.To evaluate the effects of gender, food and grapefruit juice on the pharmacokinetics of primaquine in healthy subjects.MethodsIn a randomized, two-phase cross-over study, 10 male and 10 female healthy Vietnamese subjects were administered 30 mg primaquine in the fasting state or with food, followed by administration of primaquine with grapefruit juice.In a randomized, two-phase cross-over study, 10 male and 10 female healthy Vietnamese subjects were administered 30 mg primaquine in the fasting state or with food, followed by administration of primaquine with grapefruit juice.ResultsThe pharmacokinetics of primaquine were comparable between male and female subjects, with geometric mean ratios of Cmax = 0.89 [95% confidence interval (CI) 0.65, 1.22] and AUC = 0.80 (95% CI 0.56, 1.15). The mean CL/F of primaquine was slightly higher in males than in females [0.52 l h−1 kg−1vs. 0.43 l h−1 kg−1, mean difference of 0.09 (95% CI –0.10, 0.28), P = 0.32]. When compared with fasting state values, food increased the geometric mean Cmax of primaquine by 26% (95% CI 12, 40) and the AUC by 14% (95% CI 3, 27). Similarly, grapefruit juice increased the geometric mean Cmax by 23% (95% CI 4, 45) and the AUC by 19% (95% CI 4, 37).The pharmacokinetics of primaquine were comparable between male and female subjects, with geometric mean ratios of Cmax = 0.89 [95% confidence interval (CI) 0.65, 1.22] and AUC = 0.80 (95% CI 0.56, 1.15). The mean CL/F of primaquine was slightly higher in males than in females [0.52 l h−1 kg−1vs. 0.43 l h−1 kg−1, mean difference of 0.09 (95% CI –0.10, 0.28), P = 0.32]. When compared with fasting state values, food increased the geometric mean Cmax of primaquine by 26% (95% CI 12, 40) and the AUC by 14% (95% CI 3, 27). Similarly, grapefruit juice increased the geometric mean Cmax by 23% (95% CI 4, 45) and the AUC by 19% (95% CI 4, 37).ConclusionsThe disposition of primaquine was comparable between genders, suggesting no need to modify the dose of primaquine for malaria treatment or prophylaxis. Food increased the oral bioavailability of primaquine, which may lead to higher antimalarial efficacy. Grapefruit juice increased the bioavailability of primaquine, with marked interindividual differences suggesting that people should not take primaquine with grapefruit juice.The disposition of primaquine was comparable between genders, suggesting no need to modify the dose of primaquine for malaria treatment or prophylaxis. Food increased the oral bioavailability of primaquine, which may lead to higher antimalarial efficacy. Grapefruit juice increased the bioavailability of primaquine, with marked interindividual differences suggesting that people should not take primaquine with grapefruit juice.

Afghanistan's national guidelines recommend primaquine (PQ) for radical treatment of Plasmodium vivax malaria, but this is rarely implemented because of concerns over potential hemolysis in patients who have G6PD deficiency. Between August 2009 and February 2014, we conducted an open-label, randomized controlled trial of chloroquine (CQ) alone versus chloroquine plus primaquine (0.25 mg base/kg/day for 14 days) (CQ+PQ) in patients aged 6 months and older with microscopy confirmed P. vivax infection. In the CQ+PQ group, G6PD deficiency was excluded by fluorescent spot testing. The primary outcome was P. vivax recurrence assessed by survival analysis over one year follow-up. Of 593 patients enrolled, 570 attended at or after 14 days of follow-up. Plasmodium vivax recurrences occurred in 37 (13.1%) of 282 patients in the CQ+PQ arm versus 86 (29.9%) of 288 in the CQ arm (Cox proportional hazard ratio [HR] 0.37, 95% confidence interval [CI] 0.25-0.54) (intention-to-treat analysis). P...

BACKGROUND: Primaquine is a key drug for malaria elimination. In addition to being the only drug active against the dormant relapsing forms of Plasmodium vivax, primaquine is the sole effective treatment of infectious P. falciparum gametocytes, and may interrupt transmission and help contain the spread of artemisinin resistance. However, primaquine can trigger haemolysis in patients with a deficiency in glucose-6-phosphate dehydrogenase (G6PDd). Poor information is available about the distribution of individuals at risk of primaquine-induced haemolysis. We present a continuous evidence-based prevalence map of G6PDd and estimates of affected populations, together with a national index of relative haemolytic risk. METHODS AND FINDINGS: Representative community surveys of phenotypic G6PDd prevalence were identified for 1,734 spatially unique sites. These surveys formed the evidence-base for a Bayesian geostatistical model adapted to the gene's X-linked inheritance, which predicted ...

Primaquine is a traditional antimalarial drug with low parasitic resistance and generally good acceptance at higher doses, which has been used for over 60 years in malaria treatment. However, several limitations related to its hematotoxicity have been reported. It is believed that this toxicity comes from the hydroxylation of the C-5 and C-6 positions of its 8-aminoquinoline ring before binding to the molecular target: the quinone reductase II (NQO2) human protein. In this study we propose primaquine derivatives, with substitution at position C-6 of the 8-aminoquinoline ring, planned to have better binding to NQO2, compared to primaquine, but with a reduced toxicity related to the C-5 position being possible to be oxidized. On this sense the proposed analogues were suggested in order to reduce or inhibit hydroxylation and further oxidation to hemotoxic metabolites. Five C-6 substituted primaquine analogues were selected by de novo design and further submitted to docking and molecula...

Mechanisms affecting patterns of vector distribution among host individuals may influence the population and evolutionary dynamics of vectors, hosts and the parasites transmitted. We studied the role of different factors affecting the species composition and abundance of Culicoides found in nests of the blue tit (Cyanistes caeruleus). We identified 1531 females and 2 males of 7 different Culicoides species in nests, with C. simulator being the most abundant species, followed by C. kibunensis, C. festivipennis, C. segnis, C. truncorum, C. pictipennis and C. circumscriptus. We conducted a medi-cationrfumigation experiment randomly assigning bird's nests to different treatments, thereby generating groups of medicated and control pairs breeding in fumigated and control nests. Medicated pairs were injected with the anti-malarial drug Primaquine diluted in saline solution while control pairs were injected with saline solution. The fumigation treatment was carried out using insecticide solution or water for fumigated and control nests respectively. Brood size was the main factor associated with the abundance of biting midges probably because more nestlings may produce higher quantities of vector attractants. In addition, birds medicated against haemoparasites breeding in non-fumigated nests supported a higher abundance of C. festivipennis than the rest of the groups. Also, we found that the fumigation treatment reduced the abundance of engorged Culicoides in both medicated and control nests, thus indicating a reduction of feeding success produced by the insecticide. These results represent the first evidence for the role of different factors in affecting the Culicoides infracommunity in wild avian nests.

Plasmodium vivax parasites are the predominant cause of malaria infections in the Brazilian Amazon. Infected individuals are treated with primaquine, which can induce haemolytic anaemia in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals and may lead to severe and fatal complications. This X-linked disorder is distributed globally and is caused by allelic variants with a geographical distribution that closely reflects populations exposed historically to endemic malaria. In Brazil, few studies have reported the frequency of G6PD deficiency (G6PDd) present in malaria-endemic areas. This is particularly important, as G6PDd screening is not currently performed before primaquine treatment. The aim of this study was to determine the prevalence of G6PDd in the region of Alto do Juruá, in the Western Brazilian Amazon, an area characterized by a high prevalence of P. vivax infection. Five-hundred and sixteen male volunteers were screened for G6PDd using the fluorescence spot te...

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common human genetic abnormalities, and it has a significant prevalence in the male population (X chromosome linked). The purpose of this study was to estimate the frequency of impaired fasting glucose and diabetes among G6PD-deficient persons in Manaus, Brazil, an area in the Western Brazilian Amazon to which malaria is endemic. Glucose-6-phosphate dehydrogenase-deficient males had more impaired fasting glucose and diabetes. This feature could be used as a screening tool for G6PD-deficient persons who are unable to use primaquine for the radical cure of Plasmodium vivax malaria.

An enantioselective capillary electrophoresis method for the simultaneous determination of primaquine (PQ) and carboxyprimaquine (CPQ) in rat liver mitochondrial fraction, suitable for in vitro metabolism studies is presented. The drug and metabolite were extracted by liquid-liquid extraction using ethyl ether. The enantiomers were resolved in a fused-silica capillary, 50 microm inside diameter (ID) and 24 cm of effective length, using an electrolyte solution consisting of a 20 mmol/L sodium phosphate solution, pH 3.0, and 10% w/v maltodextrin. Hydrodynamic sample injection was used with a 10 s injection time at 50 mbar pressure. The applied voltage was 22 kV and the capillary temperature was controlled at 20 degrees C. Detection was carried out at 264 nm. Under these conditions, the enantiomeric fractions of the drug and of its metabolite were analyzed within 6 min. The extraction procedure was efficient in removing endogenous interferents and low values (<10%) for the coefficients of variation and deviation from theoretical values were demonstrated for both within-day and between-day assays. The method described allows the determination of PQ and CPQ enantiomers as low as 100 and 40 ng/mL, respectively. After validation, the method was used for an in vitro metabolism study of PQ. The results showed that the enantiomer (-)-PQ was preferentially metabolized to (-)-CPQ.

Background The objective of mass antimalarial drug administration (MDA) is to eliminate malaria rapidly by eliminating the asymptomatic malaria parasite reservoirs and interrupting transmission. In the Greater Mekong Subregion, where artemisinin-resistant Plasmodium falciparum is now widespread, MDA has been proposed as an elimination accelerator, but the contribution of asymptomatic infections to malaria transmission has been questioned. The impact of MDA on entomological indices has not been characterized previously. Methods MDA was conducted in 4 villages in Kayin State (Myanmar). Malaria mosquito vectors were captured 3 months before, during, and 3 months after MDA, and their Plasmodium infections were detected by polymerase chain reaction (PCR) analysis. The relationship between the entomological inoculation rate, the malaria prevalence in humans determined by ultrasensitive PCR, and MDA was characterized by generalized estimating equation regression. Results Asymptomatic P. fa...

Single low doses of primaquine, when added to artemisinin-based combination therapy, might prevent transmission of Plasmodium falciparum malaria to mosquitoes. We aimed to establish the activity and safety of four low doses of primaquine combined with dihydroartemisinin-piperaquine in male patients in Mali. In this phase 2, single-blind, dose-ranging, adaptive randomised trial, we enrolled boys and men with uncomplicated P falciparum malaria at the Malaria Research and Training Centre (MRTC) field site in Ouelessebougou, Mali. All participants were confirmed positive carriers of gametocytes through microscopy and had normal function of glucose-6-phosphate dehydrogenase (G6PD) on colorimetric quantification. In the first phase, participants were randomly assigned (1:1:1) to one of three primaquine doses: 0 mg/kg (control), 0·125 mg/kg, and 0·5 mg/kg. Randomisation was done with a computer-generated randomisation list (in block sizes of six) and concealed with sealed, opaque envelopes...