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Methemoglobinemia and Adverse Events in Plasmodium vivax Malaria Patients Associated with High Doses of Primaquine Treatment
Abstract
Primaquine (PQ) is recommended to prevent relapses in patients with Plasmodium vivax malaria infection. However, treatment with PQ causes methemoglobinemia. In this study, we measured the methemoglobin (MetHB) levels in three groups of subjects who received PQ treatment at 0.58, 0.83, or 1.17 mg/kg/d. A total of 112 subjects were studied. MetHB levels were detected at > or = 4% in 46-50% 1 day after PQ treatment in all three groups and 4-9% of subjects had MetHB levels > or = 4% 15 days after treatment. Only subjects receiving the highest doses of PQ had mild and brief adverse events, and 17% of them were associated with treatment. We conclude that when PQ is administered under certain conditions (i.e., normal glucose-6-phosphate dehydrogenase activity, in non-pregnant subjects and with a light meal), daily doses as high as 1.17 mg/kg do not represent a serious risk of high MetHB levels to patients.
... 7,24 Las dosis diarias altas de primaquina (1, no se asociaron con eventos adversos más graves que las dosis medias (0,50-7), lo que corrobora informes anteriores. 30 La metahemoglobinemia no fue un problema importante en los niños de ninguno de los dos grupos (1,17-3 y 0,50-7), tal como sucedió en adultos. 30 Por eso afirmamos que es seguro administrar PQ en un lapso menor de 14 días, por ejemplo, en 7 días, si se satisfacen completamente algunas condiciones críticas: actividad normal de la G6PD, no estar en embarazo y tomarla con alguna comida (inclusive liviana). ...
... 30 La metahemoglobinemia no fue un problema importante en los niños de ninguno de los dos grupos (1,17-3 y 0,50-7), tal como sucedió en adultos. 30 Por eso afirmamos que es seguro administrar PQ en un lapso menor de 14 días, por ejemplo, en 7 días, si se satisfacen completamente algunas condiciones críticas: actividad normal de la G6PD, no estar en embarazo y tomarla con alguna comida (inclusive liviana). 30 Una reciente revisión Cochrane sobre el uso de primaquina para prevenir las recurrencias de P. vivax señaló que "los eventos adversos fueron escasamente informados, con tres estudios que informaron sobre brote cutáneo, vértigo, cefalea, dolor abdominal o náusea, y otros dos que reportaron que la primaquina fue bien tolerada". ...
... 30 Por eso afirmamos que es seguro administrar PQ en un lapso menor de 14 días, por ejemplo, en 7 días, si se satisfacen completamente algunas condiciones críticas: actividad normal de la G6PD, no estar en embarazo y tomarla con alguna comida (inclusive liviana). 30 Una reciente revisión Cochrane sobre el uso de primaquina para prevenir las recurrencias de P. vivax señaló que "los eventos adversos fueron escasamente informados, con tres estudios que informaron sobre brote cutáneo, vértigo, cefalea, dolor abdominal o náusea, y otros dos que reportaron que la primaquina fue bien tolerada". 31 Esto sugiere que los eventos adversos asociados a la primaquina pueden no ser graves pero que es necesario evaluarlos más estricta y sistemáticamente para obtener conclusiones más claras y sólidas. ...
Introduction: Worldwide, the efficacy of cloroquine-primaquine for treating acute Plasmodium vivax malarious attacks has not been thoroughly evaluated. In Latin America such studies are scarce, and in Colombia, almost nonexisting. Objective: To assess the efficacy of two regimens for administration of primaquine in children aged less than 18 years. Methodology: A clinical, controlled, unmasked study was carried out, with randomized administration of two primaquine regimens, namely: 0.50 mg/kg/day for 7 days (0.50-7) vs. 1.17 mg/kg/day for 3 days (1.17-3). Results: A. Healing of the acute attack: efficacy was 100% in both groups. B. Prevention of recurrences during 120 days: recurrences occurred in 68.4% of children treated with the 1.17-3 regimen, and in 34.2% of those receiving the 0.5-7 one. Conclusions: 1. Proportion of recurrences during the 120 days follow-up was significantly lower (34.2%) in children receiving the 0.50-7 regimen than in those treated with the 1.17-3 one (68.4%). The length of administration of the same total dose of primaquine influenced its efficacy against recurrences: shorter periods of administration were associated with lesser efficacy.
... Methemoglobin has been reported to mediate toxicity toward macrophages, which might lead to a weakened immune response during malaria 44 . In patients with malaria, increased methemoglobin levels have been observed after treatment with antimalarial drugs like primaquine [45][46][47] . However, in patients with normal glucose-6-phosphate dehydrogenase (G-6-PD) activity and in nonpregnant women, high doses of primaquine were not associated with elevated methemoglobin levels 45,46 . ...
... In patients with malaria, increased methemoglobin levels have been observed after treatment with antimalarial drugs like primaquine [45][46][47] . However, in patients with normal glucose-6-phosphate dehydrogenase (G-6-PD) activity and in nonpregnant women, high doses of primaquine were not associated with elevated methemoglobin levels 45,46 . A decline in methemoglobin levels after treatment following the clearance of parasites was due to the partial restoration of the redox balance inside red blood cells and the consequent reduction of the methemoglobin level 45 . ...
Reports indicate that Plasmodium infections influence methemoglobin levels. However, findings have been inconclusive or have varied across different geographic and demographic contexts. This systematic review and meta-analysis aimed to consolidate existing data regarding the association between Plasmodium infections and alterations in methemoglobin levels related to the severity of the infection. A comprehensive literature search of several databases, including Ovid, ProQuest, Embase, Scopus, MEDLINE, and PubMed, was conducted to identify relevant studies that examined methemoglobin levels in patients with malaria. Qualitative synthesis and meta-analysis of the pooled standardized mean difference were conducted to synthesize the differences in methemoglobin levels between: (1) patients with malaria and those without malaria and (2) patients with severe malaria and those with uncomplicated malaria based on various themes including publication year, study design, study area, Plasmodium species, age group, symptomatic status, severity status, and method of malaria detection. Of the 1846 studies that were initially identified from the main databases and additional searches on Google Scholar, 10 studies met the eligibility criteria and were selected for this review. The systematic review distinctly highlighted an association between malaria and elevated methemoglobin levels, an observation consistent across diverse geographical regions and various Plasmodium species. Furthermore, the meta-analysis confirmed this by demonstrating increased methemoglobin levels in patients with malaria compared to those without malaria (P < 0.001, Hedges’ g 2.32, 95% CI 1.36–3.29, I² 97.27, 8 studies). Moreover, the meta-analysis found elevated methemoglobin levels in patients with severe malaria compared to those with uncomplicated malaria (P < 0.001, Hedges’ g 2.20, 95% CI 0.82–3.58, I² 96.20, 5 studies). This systematic review and meta-analysis revealed increased methemoglobin levels in patients with P. falciparum and P. vivax infections, with a notable association between elevated methemoglobin levels and severe malaria. Future research should focus on elucidating the specific mechanisms by which changes in methemoglobin levels are related to infections by P. falciparum and P. vivax, particularly in terms of severity, and how these alterations could potentially impact patient management and treatment outcomes.
... Methemoglobinemia is one of the hallmark effects of PQ with multiple days dosing. However, methemoglobinemia, per se, is rarely of serious clinical significance with PQ administration (Carmona-Fonseca et al., 2009). A rise in MetHgB was observed in most of our subjects, and there was no difference between the two enantiomers. ...
... All other subjects exhibited minimal to modest responses with a gradual rise in MetHgB to an average of 4%-5% of HgB. Our findings are thus consistent with earlier reports that methemoglobinemia is generally not a limiting concern with PQ administration, in that many subjects experience mild increases, with no obvious impact on hemolysis (Carmona-Fonseca et al., 2009). This study was not designed to address gender differences-nor was it sufficiently powered for such. ...
Primaquine (PQ) is an 8-aminoquinoline antimalarial, active against dormant Plasmodium vivax hypnozoites and P. falciparum mature gametocytes. PQ is currently used for P. vivax radical cure and prevention of malaria transmission. PQ is a racemic drug and since the metabolism and pharmacology of PQ’s enantiomers have been shown to be divergent, the objectives of this study were to evaluate the comparative tolerability and metabolism of PQ with respect to its two enantiomers in human volunteers in a 7 days’ treatment schedule. Fifteen subjects with normal glucose-6-phosphate dehydrogenase (G6PDn) completed four arms, receiving each of the treatments, once daily for 7 days, in a crossover fashion, with a 7–14 days washout period in between: R-(−) enantiomer (RPQ) 22.5 mg; S-(+) enantiomer (SPQ) 22.5 mg; racemic PQ (RSPQ) 45 mg, and placebo. Volunteers were monitored for any adverse events (AEs) during the study period. PQ and metabolites were quantified in plasma and red blood cells (RBCs) by UHPLC-UV-MS/MS. Plasma PQ was significantly higher in SPQ treatment group than for RPQ. Carboxy-primaquine, a major plasma metabolite, was much higher in the RPQ treated group than SPQ; primaquine carbamoyl glucuronide, another major plasma metabolite, was derived only from SPQ. The ortho-quinone metabolites were also detected and showed differences for the two enantiomers in a similar pattern to the parent drugs. Both enantiomers and racemic PQ were well tolerated in G6PDn subjects with the 7 days regimen; three subjects showed mild AEs which did not require any intervention or discontinuation of the drug. The most consistent changes in G6PDn subjects were a gradual increase in methemoglobin and bilirubin, but these were not clinically important. However, the bilirubin increase suggests mild progressive damage to a small fraction of red cells. PQ enantiomers were also individually administered to two G6PD deficient (G6PDd) subjects, one heterozygous female and one hemizygous male. These G6PDd subjects showed similar results with the two enantiomers, but the responses in the hemizygous male were more pronounced. These studies suggest that although the metabolism profiles of individual PQ enantiomers are markedly different, they did not show significant differences in the safety and tolerability in G6PDn subjects.
... With treatment after 7 days the Met-Hb concentration decreased. It supports the reports that showed decreasing Met-Hb concentration with time after administration of antimalarial suggests decreasing level of ROS due to the killing of parasites 16 . The highest mean level of Met-Hb observed in this study is 14.5 ±3.6% which is found among the patients who died. ...
... Clinical findings in patients with excessive Met-Hb correlate to blood levels and Met-Hb < 20% provokes no signs and symptoms. When it exceeds 20% it causes dyspnea with a characteristic bluish-brown muddy color resembling cyanosis and levels > 50-60% is fatal 16 . ...
... Overall, it is autolimited, does not require interruption of the therapy, and returns to normal range within 28 days after commencement of the treatment. [9][10][11] There are considerable evidences that the hydroxylated metabolites formed by the cytochrome P450 (CYP)dependent pathway, such as 5-hydroxyprimaquine, rather than the parent drug, are responsible for MetHB formation and other adverse reactions, as well as, the hypnozoiticidal action. [12][13][14] The significant interethnic differences in CYP2D6 allele found in studies across many countries may influence the metabolism of the parent drug and, consequently, the MetHB formation in the course of treatment with primaquine, once the genetic polymorphism of CYP2D6 was associated with both the efficacy and the toxicity of primaquine. ...
... 7,8 Moreover, the levels of MetHB found in the study are in line to reports from other endemic areas, which suggests the probable absence of interracial difference in MetHB formation in the course of treatment with primaquine. [9][10][11] There was no significant correlation between the plasma primaquine concentrations and the MetHB levels, suggesting that other compounds were responsible for the increase in the MetHB levels. This finding is corroborated by the nonsignificant correlation between the total dose of primaquine and the MetHB levels, suggesting that the compounds responsible for the increase in MetHB levels have a short half-life and do not show significant accumulation in tissue, which is in accordance with the reports on the profiles of the hydroxylated metabolites of the primaquine. ...
Primaquine is the only licensed drug available for the elimination of Plasmodium vivax hypnozoites. Methemoglobinemia is currently reported in the course of treatment. There is evidence that metabolites of primaquine formed by the cytochrome pathway are responsible for methemoglobin formation; a genetic polymorphism of cytochrome isoforms; and a potential influence of gender in the activities of these enzymes requiring the establishment of dose × response curves profiles in different population groups. Concentrations of primaquine in plasma and methemoglobin levels were investigated in 54 patients with malaria due to P. vivax during the course of the standard regimen of chloroquine with primaquine (0.25 mg/kg/day for 14 days). All study subjects lived in an endemic area of the Brazilian Amazon Basin. The blood samples were collected before initiation of treatment and 3 hours (range 2-4 hours) after the administration of antimalarial drugs on days 2, 7, and 14. Plasma primaquine concentrations were similar in both genders (males: range = 164-191 ng/mL, females: range = 193-212 ng/mL). Methemoglobin levels ranged from 3.3% to 5.9% in males and from 3.1% to 6.5% in females. There were no significant correlations between the plasma primaquine concentrations or total dose and methemoglobin levels, suggesting that unidentified metabolites rather than parent drug were likely responsible for changes in methemoglobin levels. There was no significant influence of gender on primaquine concentrations in plasma or methemoglobin levels.
... MetHb levels of 30% are commonly associated with dyspnea, nausea and tachycardia; up to 55% are associated with lethargy and stupor; over 55% MetHb results in cardiac arrhythmia and CNS depression. Levels of MetHb >70% are generally considered fatal [6]. Hb is very sensitive to oxidative stress, and a G6PD deficit increases this sensitivity, resulting in more pronounced methemoglobinemia when such patients are given primaquine. ...
... It is feasible to administer primaquine whenever required, but only after previous fulfillment of three simple criteria: normal G6PD activity, in white, non-pregnant subjects and with a light meal. Under these conditions, the major adverse effect after administration of this drug, serious methemoglobinemia is rare, but adverse events at even the highest daily dose are short-lived, mild and without long-term side effects [6]. ...
We report the case of a 12-year-old child who was admitted to our Department, with 7 days' history of high fever and splenomegaly. His father had similar symptoms starting on the same day. A rapid test and microscopy for malaria yielded a positive result for Plasmodium vivax Antimalarial therapy was initiated. He developed methemoglobinemia treated with ascorbic acid and had uneventful recovery.
... The monkey model of relapsing malaria (P. cynomolgi in rhesus monkeys developed by Schmidt and co-workers (47)) showed that the ratio of the maximum tolerated dose to the curative dose in 90% of animals was seven times better for primaquine than pamaquine. In clinical studies primaquine was three times more active than pamaquine against preerythrocytic stages, four to six times better for radical cure of vivax malaria and half as toxic. ...
... In clinical studies primaquine was three times more active than pamaquine against preerythrocytic stages, four to six times better for radical cure of vivax malaria and half as toxic. Primaquine is a racemic mixture, and studies in mice and rhesus monkeys have shown that the D and L isoforms have different biological activities (47) and different efficacy and toxicity (reviewed in references 48 and 49). Nevertheless, racemic primaquine is the only form available. ...
Primaquine is an antimalarial drug of the 8-aminoquinoline class. It has prophylactic activity, relatively weak schizontocidal activity and radical curative activity in Plasmodium vivax and P. ovale malaria and is a potent gametocytocide in P. falciparum infections. In this review, we focus on primaquine but also discuss pamaquine (plasmoquine), the more toxic forerunner of primaquine, which prompted drug screening for addi- tional antimalarial agents that would be less toxic. We also describe other 8-aminoquinolines (quinocide, pentaquine, bulaquine (elubaquine) and tafenoquine). Studies of the efficacy and safety of pamaquine and primaquine, and especially their toxicity when used as antimalarial agents, are reviewed. As the main severe adverse event reported after 8-aminoquinoline use is haemolytic anaemia in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals, G6PD deficiency and G6PD deficiency tests for use in the field are discussed in detail, as are anaemia and haemoglobi- nuria in relation to malaria and primaquine use. Chlorproguanil–dapsone (Lapdap®) is included as an example of a commercially developed oxidant antimalarial drug that had to be withdrawn from the market because of the adverse haemolytic effects in G6PD-deficient individuals.
Additional sections of the review cover the use of primaquine in malaria prophylaxis and treatment, radical cure of vivax malaria and as a P. falci- parum gametocytocide. Studies in various settings of the efficacy of the different primaquine regimens used for these purposes, with various total and daily doses and intervals of administration, are presented. Primaquine has proved to be effective in curing and preventing relapse from vivax malaria, although parasite strains in certain regions (notably East Asia and Oceania) required higher dose regimens. Shortening the standard 14-day regimen to 5 days to improve adherence substantially reduced its radical curative efficacy. Primaquine was also shown to be an effective gametocytocidal drug for falciparum malaria when given as a single dose with other antimalarial agents. We found no studies in which primaquine was given to pregnant women or infants, except one study of mass drug administration which included some African children > 6 months of age (1). When older children were included, the age ranges and numbers (when provided by the authors) are indicated. The dose of drug used in the studies in this review is reported as the adult dose in milligrams of base equivalent, unless otherwise specified; in every study in which children were included, they received proportionally lower doses. This review spans nearly a century, during which research methodology has changed substantially and knowledge in biology and pharmacology has made great advances. The data reported are heterogeneous and not readily amenable to pooling (or weighting) as in standard meta-analyses. We therefore present the information chronologically.
... Most of the antimalarials cause methemoglobinemia by oxidizing the ferrous iron (fe2þ) to ferric (fe3þ) state. Methemoglobinemia due to usual doses of chloroquine has previously been reported only in adults [3, 4]. In a case series published by CASE REPORT Cohen et al. [3] , 6 adult soldiers developed methemoglobinemia-related symptoms following administration of chloroquine chemoprophylaxis. ...
... The possibility of such deficiency state cannot therefore be ruled out in this child. The other study a randomized, nonblinded, controlled clinical trial by Carmona Fonsesca et al. [4] on 112 adult subjects with P. vivax infection showed that MetHb levels were elevated in majority of the subjects receiving varying doses of Primaquine. In this study a combination of chloroquine and primaquine was used hence one cannot be sure about which of the two agents was responsible for the elevated MetHb levels in these patients. ...
A 16-year-old girl working in a paint and dye-casting factory of aniline dyes presented to the emergency with cyanosis, fever
and altered sensorium. She had been diagnosed as a case of malaria and treated with chloroquine elsewhere. At admission, her
saturation was 79%, which did not improve despite mechanical ventilation with 100% oxygen. Her PaO2 levels, however, remained
high-140 mmHg. The observed difference in PaO2 and SpO2 prompted us to investigate her for methemoglobinemia, which was confirmatory.
Despite symptomatic and specific treatment, she succumbed to her illness possibly due to late presentation and prolonged cerebral
anoxia. Though the girl's raised methemoglobin levels may be explained by her history of exposure to aniline dyes, the temporal
association of her methemoglobinemia related symptoms with chloroquine administration cannot be ignored. We believe that this
rare complication of chloroquine therapy should be kept in mind before prescribing it to any child with malaria.
... However, this is still controversial because several studies have yielded contradictory results with some claiming that the protective effects of G6PD deficiency were observed in male hemizygotes only, in female heterozygotes only, or in both [6][7][8][9]. The major clinical concern associated with G6PD deficiency is haemolysis upon exposure to oxidant drugs, including antimalarials such as 8-aminoquinolines (primaquine and tafenoquine) [10][11][12][13]. Primaquine and tafenoquine are the only medications capable of killing Plasmodium vivax and Plasmodium ovale at the dormant liver stage (hypnozoite). ...
Background
Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common enzymopathy in humans, is prevalent in tropical and subtropical areas where malaria is endemic. Anti-malarial drugs, such as primaquine and tafenoquine, can cause haemolysis in G6PD-deficient individuals. Hence, G6PD testing is recommended before radical treatment against vivax malaria. Phenotypic assays have been widely used for screening G6PD deficiency, but in heterozygous females, the random lyonization causes difficulty in interpreting the results. Over 200 G6PD variants have been identified, which form genotypes associated with differences in the degree of G6PD deficiency and vulnerability to haemolysis. This study aimed to assess the frequency of G6PD mutations using a newly developed molecular genotyping test.
Methods
A multiplexed high-resolution melting (HRM) assay was developed to detect eight G6PD mutations, in which four mutations can be tested simultaneously. Validation of the method was performed using 70 G6PD-deficient samples. The test was then applied to screen 725 blood samples from people living along the Thai–Myanmar border. The enzyme activity of these samples was also determined using water-soluble tetrazolium salts (WST-8) assay. Then, the correlation between genotype and enzyme activity was analysed.
Results
The sensitivity of the multiplexed HRM assay for detecting G6PD mutations was 100 % [95 % confidence interval (CI): 94.87–100 %] with specificity of 100 % (95 % CI: 87.66–100 %). The overall prevalence of G6PD deficiency in the studied population as revealed by phenotypic WST-8 assay was 20.55 % (149/725). In contrast, by the multiplexed HRM assay, 27.17 % (197/725) of subjects were shown to have G6PD mutations. The mutations detected in this study included four single variants, G6PD Mahidol (187/197), G6PD Canton (4/197), G6PD Viangchan (3/197) and G6PD Chinese-5 (1/197), and two double mutations, G6PD Mahidol + Canton (1/197) and G6PD Chinese-4 + Viangchan (1/197). A broad range of G6PD enzyme activities were observed in individuals carrying G6PD Mahidol, especially in females.
Conclusions
The multiplexed HRM-based assay is sensitive and reliable for detecting G6PD mutations. This genotyping assay can facilitate the detection of heterozygotes, which could be useful as a supplementary approach for high-throughput screening of G6PD deficiency in malaria endemic areas before the administration of primaquine and tafenoquine.
... Cases of drug-induced methemoglobinemia are more frequently related to use of local anesthetic agents and dapsone [5][6][7][8][9][10]. Medications that have been associated with acquired methemoglobinemia are listed in Table 1 [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Nevertheless, phenazopyridine is a commonly used over-the-counter medication for symptoms of urinary tract infection that can cause significant methemoglobinemia. ...
Background
Phenazopyridine-induced methemoglobinemia is relatively rare with fewer than ten cases reported over the past 35 years. We describe a case of phenazopyridine-induced methemoglobinemia that is unique in the way the patient presented and how initial workup was completed.
Case presentation
The patient presented with lethargy, diarrhea, light-headedness, and headaches, with past medical history of breast cancer, seizures, and recent dysuria for which she had been taking phenazopyridine. She was noted to have a persistent hypoxemia despite supplemental oxygen delivery and a shunting process was considered, with pulmonary embolus and methemoglobinemia due to phenazopyridine use being of chief concern. She was stabilized, and confirmation of original diagnosis was made at the main ED and treatment successfully rendered with good effect.
Conclusions
Methemoglobinemia, while rare, can be associated with use of over-the-counter medicines and should be considered as part of a broad differential. This case serves to emphasize the importance of a thorough history and physical—tools especially helpful when at a satellite facility with relatively limited resources.
... Inhibition of cytochrome b 5 reduction may result in deficiencies in processes dependent on this cofactor including fatty acid and cholesterol synthesis , methemoglobin and cytoglobin reduction, and xenobiotic oxidation (Amdahl, et al., 2017;Galeeva, et al., 2013;Guengerich, 2005;Hudspeth, et al., 2010;Nagai, et al., 1993;Xu, et al., 2011). Interestingly, high doses of primaquine, a quinone used to treat malaria, have been shown to induce methemoglobinemia in humans (Carmona-Fonseca et al., 2009;Kantor, 1992;Sin and Shafran, 1996) and this may be due to redox cycling. However, the extent to which redox cycling affects different metabolic pathways mediated by cytochrome b 5 reductase/cytochrome b 5 remains to be determined. ...
NADH cytochrome b5 reductase mediates electron transfer from NADH to cytochrome b5 utilizing flavin adenine dinucleotide as a redox cofactor. Reduced cytochrome b5 is an important cofactor in many metabolic reactions including cytochrome P450-mediated xenobiotic metabolism, steroid biosynthesis and fatty acid metabolism, hemoglobin reduction, and methionine and plasmalogen synthesis. Using recombinant human enzyme, we discovered that cytochrome b5 reductase mediates redox cycling of a variety of quinones generating superoxide anion, hydrogen peroxide, and, in the presence of transition metals, hydroxyl radicals. Redox cycling activity was oxygen-dependent and preferentially utilized NADH as a co-substrate; NADH was 5-10 times more active than NADPH in supporting redox cycling. Redox cycling activity was greatest for 9,10-phenanthrenequinone and 1,2-naphthoquinone, followed by 1,4-naphthoquinone and 2-methyl-1,4-naphthoquinone (menadione), nitrofurantoin and 2-hydroxyestradiol. Using menadione as the substrate, quinone redox cycling was found to inhibit reduction of cytochrome b5 by cytochrome b5 reductase, as measured by heme spectral changes in cytochrome b5. Under anaerobic conditions where redox cycling is inhibited, menadione had no effect on the reduction of cytochrome b5. Chemical redox cycling by cytochrome b5 reductase may be important in generating cytotoxic reactive oxygen species in target tissues. This activity, together with the inhibition of cytochrome b5 reduction by redox-active chemicals and consequent deficiencies in available cellular cytochrome b5, are likely to contribute to tissue injury following exposure to quinones and related redox active chemicals.
... primaquine (PQ) is the only approved compound active against all stages of Plasmodium development: liver stages, including hypnozoites, and blood stages, including gametocytes, thereby also blocking parasite transmission to mosquitoes. However, PQ causes haemolytic anaemia in moderate to severely glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals [7]. Moreover, recent studies show that PQ is ineffective in people with low metabolizing cytochrome P450 2D6 genotypes [8]. ...
Background:
In the context of malaria elimination/eradication, drugs that are effective against the different developmental stages of the parasite are highly desirable. The oldest synthetic anti-malarial drug, the thiazine dye methylene blue (MB), is known for its activity against Plasmodium blood stages, including gametocytes. The aim of the present study was to investigate a possible effect of MB against malaria parasite liver stages.
Methods:
MB activity was investigated using both in vitro and in vivo models. In vitro assays consisted of testing MB activity on Plasmodium falciparum, Plasmodium cynomolgi and Plasmodium yoelii parasites in human, simian or murine primary hepatocytes, respectively. MB in vivo activity was evaluated using intravital imaging in BALB/c mice infected with a transgenic bioluminescent P. yoelii parasite line. The transmission-blocking activity of MB was also addressed using mosquitoes fed on MB-treated mice.
Results:
MB shows no activity on Plasmodium liver stages, including hypnozoites, in vitro in primary hepatocytes. In BALB/c mice, MB has moderate effect on P. yoelii hepatic development but is highly effective against blood stage growth. MB is active against gametocytes and abrogates parasite transmission from mice to mosquitoes.
Conclusion:
While confirming activity of MB against both sexual and asexual blood stages, the results indicate that MB has only little activity on the development of the hepatic stages of malaria parasites.
... Both 8-aminoquinolines, primaquine and tafenoquine, cause hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals [19,20]. Both agents also cause usually mild increases methemoglobin levels [14,21]. In a phase III prophylaxis trial in Australian soldiers, possible eye and renal safety findings were noted with tafenoquine [22]. ...
Background
Tafenoquine is an investigational 8-aminoquinoline for the prevention of Plasmodium vivax relapse. Tafenoquine has a long half-life and the potential for more convenient dosing, compared with the currently recommended 14-day primaquine regimen.
Methods
This randomized, active-control, double-blind trial was conducted in Bangkok, Thailand. Seventy patients with microscopically confirmed P. vivax were randomized (2:1) to tafenoquine 400 mg once daily for 3 days or 2500 mg total dose chloroquine phosphate (1500 mg chloroquine base) given over 3 days plus primaquine 15 mg daily for 14 days. Patients were followed to day 120.
Results
Day 28 adequate clinical response rate in the per-protocol population was 93% (40/43) (90%CI 83–98%) with tafenoquine, and 100% (22/22) (90%CI 87–100%) with chloroquine/primaquine. Day 120 relapse prevention was 100% (35/35) with tafenoquine (90%CI 92–100%), and 95% (19/20) (90%CI 78–100%) with chloroquine/primaquine. Mean (SD) parasite, gametocyte and fever clearance times with tafenoquine were 82.5 h (32.3), 49.1 h (33.0), and 41.1 h (31.4) versus 40.0 h (15.7), 22.7 h (16.4), and 24.7 h (17.7) with chloroquine/primaquine, respectively. Peak methemoglobin was 1.4–25.6% (median 7.4%, mean 9.1%) in the tafenoquine arm, and 0.5–5.9% (median 1.5%, mean 1.9%) in the chloroquine/primaquine arm. There were no clinical symptoms of methemoglobinemia in any patient.
Discussion
Although there was no difference in efficacy in this study, the slow rate of parasite, gametocyte and fever clearance indicates that tafenoquine should not be used as monotherapy for radical cure of P. vivax malaria. Also, monotherapy increases the potential risk of resistance developing to this long-acting agent. Clinical trials of single-dose tafenoquine 300 mg combined with standard 3-day chloroquine or artemisinin-based combination therapy are ongoing.
Trial registration
Clinicaltrials.gov NCT01290601
... deficiency [5]. Other common side effects of the drug are gastrointestinal disorders, headache, cardiac arrhythmia, leucopenia, hypertension and methemoglobinemia [6][7][8][9]. ...
A gold nanourchins modified glassy carbon electrode (AuNu/GCE) was developed for the determination of antimalarial drug, primaquine (PQ). The surface of AuNu/GCE was characterized by electrochemical impedance spectroscopy (EIS), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and cyclic voltammetry (CV). EIS results indicated that the electron transfer process at AuNu/GCE was faster as compared to the bare electrode. The SEM and TEM image confirmed the presence and uniform dispersion of gold nanourchins on the GCE surface. Upon investigating the electrochemical behavior of PQ at AuNu/GCE, the developed sensor was found to exhibit high electrocatalytic activity towards the oxidation of PQ. Under optimal experimental conditions, the sensor showed fast and sensitive current response to PQ over a linear concentration range of 0.01–1 μM and 0.001–1 μM with a detection limit of 3.5 nM and 0.9 nM using differential pulse voltammetry (DPV) and square wave voltammetry (SWV), respectively. The AuNu/GCE showed good selectivity, reproducibility and stability. Further, the developed sensor was successfully applied to determine the drug in human urine samples and pharmaceutical formulations demonstrating its analytical applicability in clinical analysis as well as quality control. The proposed method thus provides a promising alternative in routine sensing of PQ as well as promotes the application of gold nanourchins in electrochemical sensors.
... deficiency [5]. Other common side effects of the drug are gastrointestinal disorders, headache, cardiac arrhythmia, leucopenia, hypertension and methemoglobinemia [6][7][8][9]. ...
A gold nanourchins modified glassy carbon electrode (AuNu/GCE) was developed for the determination of antimalarial drug, primaquine (PQ). The surface of AuNu/GCE was characterized by electrochemical impedance spectroscopy (EIS), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and cyclic voltammetry (CV). EIS results indicated that the electron transfer process at AuNu/GCE was faster as compared to the bare electrode. The SEM and TEM image confirmed the presence and uniform dispersion of gold nanourchins on the GCE surface. Upon investigating the electrochemical behavior of PQ at AuNu/GCE, the developed sensor was found to exhibit high electrocatalytic activity towards the oxidation of PQ. Under optimal experimental conditions, the sensor showed fast and sensitive current response to PQ over a linear concentration range of 0.01–1 μM and 0.001–1 μM with a detection limit of 3.5 nM and 0.9 nM using differential pulse voltammetry (DPV) and square wave voltammetry (SWV), respectively. The AuNu/GCE showed good selectivity, reproducibility and stability. Further, the developed sensor was successfully applied to determine the drug in human urine samples and pharmaceutical formulations demonstrating its analytical applicability in clinical analysis as well as quality control. The proposed method thus provides a promising alternative in routine sensing of PQ as well as promotes the application of gold nanourchins in electrochemical sensors.
... Therefore, the most recent malaria treatment guidelines recommend pretreatment G6PD testing to exclude patients at the highest risk for hemolysis (2). Additionally, 8-aminoquinolines are known to increase methemoglobin levels when given at high doses, although clinical signs of methemoglobinemia are rare (8,9). ...
Tafenoquine is in development as a single-dose treatment for relapse prevention in Plasmodium vivax malaria. Tafenoquine must be co-administered with a blood schizonticide; either chloroquine or artemisinin-based combination therapy (ACT). This open-label, randomized, parallel-group study evaluated potential drug interactions between tafenoquine and two ACTs: dihydroartemisinin-piperaquine or artemether-lumefantrine. Healthy volunteers of either sex, aged 18–65 years, without glucose-6-phosphate dehydrogenase deficiency, were randomized into five cohorts (n=24 per cohort) to receive tafenoquine on day 1 (300 mg) plus: once daily dihydroartemisinin-piperaquine on days 1, 2 and 3 (120:960 mg for 36–<75 kg bodyweight; 160:1280 mg for ≥75–100 kg bodyweight); or artemether-lumefantrine (80:480 mg) two doses 8 h apart on day 1, then twice daily on days 2 and 3; or each drug given alone. The pharmacokinetic parameters of tafenoquine, piperaquine, lumefantrine, artemether, and dihydroartemisinin were determined using non-compartmental methods. Point estimates and 90% confidence intervals were calculated for AUC and Cmax comparisons of tafenoquine plus ACT versus tafenoquine or ACT. All subjects receiving dihydroartemisinin-piperaquine experienced QTc prolongation (a known risk for this drug), but tafenoquine co-administration had no clinically relevant additional effect. Tafenoquine co-administration had no clinically relevant effects on dihydroartemisinin, piperaquine, artemether or lumefantrine pharmacokinetics. Dihydroartemisinin-piperaquine co-administration increased tafenoquine Cmax by 38% (90% confidence interval: 25 to 52%), AUC0–∞ by 12% (1 to 26%) and t1/2 by 29% (19 to 40%); with no effect on AUC0–last. Artemether-lumefantrine co-administration had no effect on tafenoquine pharmacokinetics. Tafenoquine can be co-administered with dihydroartemisinin-piperaquine or artemether-lumefantrine without dose adjustment for any of these compounds. (This clinical trial is registered at ClinicalTrials.gov with the study identifier NCT02184637).
... In this case, PQ blocks transmission and prevents late relapse (7). However, prolonged use of PQ requires medical supervision, because this drug may cause gastrointestinal problems and severe hemolytic anemia in patients who lack the glucose-6phosphate dehydrogenase (G6PD) enzyme (8,9). ...
Most antimalarial drugs target asexual parasites without reducing gametocyte formation or development. Drugs with a dual role, i.e., those that can target both asexual parasites and gametocytes, would improve malaria control. In the current study, MEFAS, a hybrid drug derived from mefloquine and artesunate that has been shown to be an active blood schizonticidal drug, was assessed to determine its ability to block the infectivity of
Plasmodium falciparum
gametocytes. MEFAS was 280 and 15 times more effective than mefloquine alone and artesunate alone, respectively.
... Implicated agents include phenacetin, lignocaine, notably nitrate and nitrite containing compounds [2][3][4][5]. It has also been documented in P. vivax malaria patients associated with high doses of primaquin treatment [6,7]. In malaria infections, modification of haemoglobin molecules lead to acquired methaemoglobinemia. ...
To estimate the concentration of methemoglobin (MetHb) in malaria patients and correlate with severity of malaria infection. This prospective study included 30 untreated cases of malaria confirmed by Quantitative Buffy Coat (QBC) test and 30 age sex matched non-malarial cases taken as controls. All the patients underwent thorough clinical examination and routine biochemical investigation. Methemoglobin levels were estimated by spectrophotometric (co-oxymeter) method on day 1 and day 10 of diagnosis of all study group patients and correlated with clinical profile and severity. Out of 30 malaria patients 22 were males and eight were females. The clinical presentations in complicated malaria group (n = 21) were fever 21 (100 %), anemia 17 (80.95 %), renal failure 12 (52.38 %) and coma/convulsion 5 (23.8 %). The mean age of the study group was 41.66 years. Mean MetHb in complicated malaria on day 1 was 2.55 ± 1.75 % and day 10 was 10.69 ± 8.19 % (statistically significant). The overall mortality was 13 (43.33 %) among study group while 5 (16.66 %) was found among control group. Mean MetHb who died (n = 13) on day 1 was 3.144 ± 1.829 % and (n = 8) on day 10 it was 19.982 ± 8.406 %. Increase in level of methaemoglobin is detrimental to the body and is associated with increase in mortality. Routine MetHb estimation may be used as a prognostic indicator in the management of malaria patients. It is suggested that addition of drugs which reduce MetHb may be tried along with antimalarial drugs to decrease morbidity and mortality in malaria.
... A recent in vitro study revealed that while there was evidence of red cell oxidative stress in the presence of primaquine alone, hepatic metabolism was required to generate significant dose-dependent methemoglobinemia and this effect was similar in both normal and G6PD-deficient erythrocytes (21). It is well established that the hematological toxicity of PQ in individuals with normal G6PD is minimal, despite a commonly observed rise in MetHgb (22)(23)(24). ...
Primaquine (PQ) remains the sole available drug to prevent relapse of P. vivax malaria after more than 60 years. While administered as a racemic mixture, prior studies suggested a pharmacodynamic advantage based on differential anti-relapse activity and/or toxicities of its enantiomers. Oral primaquine enantiomers prepared using a novel easily scalable method were given for 7 days to healthy Rhesus macaques in dose-rising fashion to evaluate effects on the blood, liver and kidneys. The enantiomers were then administered to Plasmodium cynomolgi infected Rhesus at doses of 1.3 and 0.6 mg/kg/day in combination with chloroquine. The (-) PQ primaquine enantiomer had higher clearance and apparent volume of distribution compared to (+) PQ, and was more extensively converted to the carboxy metabolite. There evidence for differential oxidative stress with a concentration-dependent rise in methemoglobin with increasing doses of (+) PQ greater than that seen for (-) PQ. There was a marked, reversible hepatotoxicity in 2 of 3 animals dosed with (-) PQ at 4.5 mg/kg. (-) PQ, in combination with chloroquine was successful in preventing P. cynomolgi relapse at doses of 0.6 and 1.3 mg/kg, while 1 of 2 animals receiving (+) PQ at 0.6 mg/kg/d relapsed. While (-) PQ was also associated with hepatotoxicity at higher doses as seen previously, this has not been identified as clinical concern in humans over 60+ years of use. Limited evidence for increased MetHgb generation with the (+) form in the Rhesus model suggests it may be possible to improve the therapeutic window for hematologic toxicity in the clinic by separating primaquine into its enantiomers.
... LA literature is contradictory in the presentation of adverse events after treatment with PQ. Despite one Colombian study reporting that two and five-fold higher PQ dosages caused only shortterm mild-to-moderate side effects (Carmona-Fonseca et al. 2009), another study from this same country reported severe gastrointestinal distress in a small proportion of non-immune male soldiers (Soto et al. 1999). ...
Plasmodium vivax radical cure requires the use of primaquine (PQ), a drug that induces haemolysis in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals, which further hampers malaria control efforts. The aim of this work was to study the G6PDd prevalence and variants in Latin America (LA) and the Caribbean region. A systematic search of the published literature was undertaken in August 2013. Bibliographies of manuscripts were also searched and additional references were identified. Low prevalence rates of G6PDd were documented in Argentina, Bolivia, Mexico, Peru and Uruguay, but studies from Curacao, Ecuador, Jamaica, Saint Lucia, Suriname and Trinidad, as well as some surveys carried out in areas of Brazil, Colombia and Cuba, have shown a high prevalence (> 10%) of G6PDd. The G6PD A-202A mutation was the variant most broadly distributed across LA and was identified in 81.1% of the deficient individuals surveyed. G6PDd is a frequent phenomenon in LA, although certain Amerindian populations may not be affected, suggesting that PQ could be safely used in these specific populations. Population-wide use of PQ as part of malaria elimination strategies in LA cannot be supported unless a rapid, accurate and field-deployable G6PDd diagnostic test is made available.
... toxins [5,6,7]. The level of methemoglobin in malaria patients and in the malaria culture supernatant varies from 0-54 mM [30,45,46]. As per the estimate, approximately 200 mM haemozoin is found in P.falciparum infected patients [47] where as the level of haemozin at the brain site may be upto 100 mM [48]. ...
Apoptosis in macrophages is responsible for immune-depression and pathological effects during malaria. Phagocytosis of PRBC causes induction of apoptosis in macrophages through release of cytosolic factors from infected cells. Heme polymer or β-hematin causes dose-dependent death of macrophages with LC50 of 132 µg/ml and 182 µg/ml respectively. The toxicity of hemin or heme polymer was amplified several folds in the presence of non-toxic concentration of methemoglobin. β-hematin uptake in macrophage through phagocytosis is crucial for enhanced toxicological effects in the presence of methemoglobin. Higher accumulation of β-hematin is observed in macrophages treated with β-hematin along with methemoglobin. Light and scanning electron microscopic observations further confirm accumulation of β-hematin with cellular toxicity. Toxicological potentiation of pro-oxidant molecules toward macrophages depends on generation of H2O2 and independent to release of free iron from pro-oxidant molecules. Methemoglobin oxidizes β-hematin to form oxidized β-hematin (βH*) through single electron transfer mechanism. Pre-treatment of reaction mixture with spin-trap Phenyl-N-t-butyl-nitrone dose-dependently reverses the β-hematin toxicity, indicates crucial role of βH* generation with the toxicological potentiation. Acridine orange/ethidium bromide staining and DNA fragmentation analysis indicate that macrophage follows an oxidative stress dependent apoptotic pathway to cause death. In summary, current work highlights mutual co-operation between methemoglobin and different pro-oxidant molecules to enhance toxicity towards macrophages. Hence, methemoglobin peroxidase activity can be probed for subduing cellular toxicity of pro-oxidant molecules and it may in-turn make up for host immune response against the malaria parasite.
... Primaquine is used as a tissue schizontocide in the treatment and prophylaxis of vivax and ovale malaria. However, primaquine administration often results in methemoglobinemia [1,9]. Antioxidants like glutathione and ascorbic acid together with antioxidant enzymes like NADH-cytochrome b 5 reductase, glutathione reductase and glucose 6-phosphate dehydrogenase play a role in protecting Hb from oxidative denaturation [10]. ...
... Poor-quality primaquine, as identified in abundance in this study, may compromise the global strategy to contain the spread of artemisinin-resistant P. falciparum and efforts of eliminating P. vivax. At the same time, under-dosing of primaquine may provide false reassurance as to the incidence and severity of major drug-related adverse effects such as haemolytic anaemia in G6PD deficient patients, and methaemoglobinaemia [45,46]. The evidence of the wide-spread availability of poor-quality primaquine found in this study alongside results from investigations in other locations [6,47,48] is therefore a concern for all countries in which primaquine should have a major role in malaria control, including settings in which the drug is already frequently used [48,49]. ...
Background:
Poor-quality life-saving medicines are a major public health threat, particularly in settings with a weak regulatory environment. Insufficient amounts of active pharmaceutical ingredients (API) endanger patient safety and may contribute to the development of drug resistance. In the case of malaria, concerns relate to implications for the efficacy of artemisinin-based combination therapies (ACT). In Papua New Guinea (PNG), Plasmodium falciparum and P. vivax are both endemic and health facilities are the main source of treatment. ACT has been introduced as first-line treatment but other drugs, such as primaquine for the treatment of P. vivax hypnozoites, are widely available. This study investigated the quality of antimalarial drugs and selected antibiotics at all levels of the health facility supply chain in PNG.
Methods and findings:
Medicines were obtained from randomly sampled health facilities and selected warehouses and hospitals across PNG and analysed for API content using validated high performance liquid chromatography (HPLC). Of 360 tablet/capsule samples from 60 providers, 9.7% (95% CI 6.9, 13.3) contained less, and 0.6% more, API than pharmacopoeial reference ranges, including 29/37 (78.4%) primaquine, 3/70 (4.3%) amodiaquine, and one sample each of quinine, artemether, sulphadoxine-pyrimethamine and amoxicillin. According to the package label, 86.5% of poor-quality samples originated from India. Poor-quality medicines were found in 48.3% of providers at all levels of the supply chain. Drug quality was unrelated to storage conditions.
Conclusions:
This study documents the presence of poor-quality medicines, particularly primaquine, throughout PNG. Primaquine is the only available transmission-blocking antimalarial, likely to become important to prevent the spread of artemisinin-resistant P. falciparum and eliminating P. vivax hypnozoites. The availability of poor-quality medicines reflects the lack of adequate quality control and regulatory mechanisms. Measures to stop the availability of poor-quality medicines should include limiting procurement to WHO prequalified products and implementing routine quality testing.
... The oxidative challenge must be very insubstantial and fleeting compared with, for example, nitrite poisoning. Although a mild methaemoglobinaemia typically occurs with normal primaquine dosing (Carmona-Fonseca et al., 2009), it does not appear linked to depletion of GSH via a generalised oxidative attack of RBC proteins. The damage being done, whatever it may be, seems irreversible during the intervals between dosing. ...
Glucose-6-phosphate dehydrogenase (G6PD) is a potentially pathogenic inherited enzyme abnormality and, similar to other human red blood cell polymorphisms, is particularly prevalent in historically malaria endemic countries. The spatial extent of Plasmodium vivax malaria overlaps widely with that of G6PD deficiency; unfortunately the only drug licensed for the radical cure and relapse prevention of P. vivax, primaquine, can trigger severe haemolytic anaemia in G6PD deficient individuals. This chapter reviews the past and current data on this unique pharmacogenetic association, which is becoming increasingly important as several nations now consider strategies to eliminate malaria transmission rather than control its clinical burden. G6PD deficiency is a highly variable disorder, in terms of spatial heterogeneity in prevalence and molecular variants, as well as its interactions with P. vivax and primaquine. Consideration of factors including aspects of basic physiology, diagnosis, and clinical triggers of primaquine-induced haemolysis is required to assess the risks and benefits of applying primaquine in various geographic and demographic settings. Given that haemolytically toxic antirelapse drugs will likely be the only therapeutic options for the coming decade, it is clear that we need to understand in depth G6PD deficiency and primaquine-induced haemolysis to determine safe and effective therapeutic strategies to overcome this hurdle and achieve malaria elimination.
... Level of methemoglobin reported in the previous studies varies from 1-3.5 mg/ml and it depends on factors such as different parasite strain, level of parasitemia, host age (young/old, child or pregnant women etc.), sex [35,36]. Therefore a wide range of methemoglobin (0.2-1 mg/ml) is used in an in vitro RBC aggregation assay to explore the role of exogenous metHb in RBC aggregation. ...
Toxic byproducts from infected RBC cause rheological alteration and RBC aggregation. Malaria culture supernatant has the ability to exhibit RBC aggregation. Ammonium sulfate fractionation and immunodepletion of methemoglobin from culture supernatant confirms methemoglobin as a major aggregant. In vitro treatment of RBC with methemoglobin induces irreversible high order RBC aggregates, resistant to shear stress and physical forces. Methemoglobin-mediated ROS generation in the external micro-environment to develop oxidative stress close to RBC membrane seems to be responsible for initiating and forming high order RBC aggregates through phosphatidyl-serine externalization. Removal of oxidative stress through antioxidant treatment abolishes high order RBC aggregate formation. In conclusion, we discovered a novel pathway of methemoglobin-mediated RBC aggregation and its potential role in patho-physiological effects during malaria.
... An extensive study might help to unravel the role of other factors present in the parasite culture supernatant and their relative contribution. Level of methemoglobin reported in the previous studies varies from 1–3.5 mg/ml and it depends on factors such as different parasite strain, level of parasitemia, host age (young/old, child or pregnant women etc.), sex [35,36]. Therefore a wide range of methemoglobin (0.2–1 mg/ml) is used in an in vitro RBC aggregation assay to explore the role of exogenous metHb in RBC aggregation . ...
... 1. Post and distribute copies of the research article and the journal club discussion questions to interested persons 2. Set up a convenient meeting time and location (e.g., monthly) 3. Identify a facilitator for the meeting (initially, this could be a clinical educator, clinical nurse specialist, nurse practitioner, nurse manager, or senior staff member, with journal club members then taking turns to lead subsequent journal club sessions) 4. Hold the journal club (encourage active participation of those attending by using the discussion questions) 5. Evaluate the journal club (e.g., at the end of the session, gather feedback from participants). ...
In the current era of evidence-based healthcare, online learning resources provide accessible and affordable training and teaching resources to stimulate the next generation of medical professionals. In the first of a series of qualitative case studies on the Cochrane student’s journal club, the authors evaluate and portray the outcomes in each of its patient-focused, evidence-based learning activities. This study illustrates an exercise centered on the hypothetical case of a patient treated for Plasmodium vivax presenting with a suspected relapse.
... PQ also targets the primary liver exo-erythrocytic forms (EEFs), iRBCs and gametocytes; for example, PQ is used to block malarial transmission in Brazil (WHO 2010b) (Table III). However, PQ metabolites cause severe haemolytic anaemia and methemoglobinaemia in patients who are genetically deficient in glucose-6-phosphate dehydrogenase (G6PD) (Carmona-Fonseca et al. 2009). This side effect imposes a pre-screening requirement for G6PD deficiency in P. vivax malaria patients and limits PQ use. ...
Malaria remains a major world health problem following the emergence and spread of Plasmodium falciparum that is resistant to the majority of antimalarial drugs. This problem has since been aggravated by a decreased sensitivity of Plasmodium vivax to chloroquine. This review discusses strategies for evaluating the antimalarial activity of new compounds in vitro and in animal models ranging from conventional tests to the latest high-throughput screening technologies. Antimalarial discovery approaches include the following: the discovery of antimalarials from natural sources, chemical modifications of existing antimalarials, the development of hybrid compounds, testing of commercially available drugs that have been approved for human use for other diseases and molecular modelling using virtual screening technology and docking. Using these approaches, thousands of new drugs with known molecular specificity and active against P. falciparum have been selected. The inhibition of haemozoin formation in vitro, an indirect test that does not require P. falciparum cultures, has been described and this test is believed to improve antimalarial drug discovery. Clinical trials conducted with new funds from international agencies and the participation of several industries committed to the eradication of malaria should accelerate the discovery of drugs that are as effective as artemisinin derivatives, thus providing new hope for the control of malaria.
... Primaquine administration in pregnancy should remain contraindicated as the G6PD state of the foetus cannot be determined. Methaemoglobinaemia is another consequence of primaquine administration which is commonly identified with therapeutic doses of primaquine; however, clinical effects are not usually seen (except possibly in individuals with gas diffusion defects in lungs and those with congenital NADH methaemoglobin reductase deficiency) [1,47]. Methaemoglobinaemia is defined as a level of more than 1% of the haemoglobin level [1] . ...
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.
... Tal discrepância de resultados pode estar associada tanto ao elevado número de indivíduos participantes do referido estudo, quando comparado a este, quanto à possibilidade de isoformas com atividade diferente da referida enzima, pela diversidade étnica dos grupos estudados. A ausência de correlação entre o teor de metemoglobina e a expressão enzimática corrobora estudo realizado na Colômbia, no qual foi demonstrada ausência de significância estatística na correlação entre a metmeoglobinemia e a atividade qualitativa desta enzima, corroborando achados que demonstraram que apesar da metemoglobinemia ser um importante marcador de toxicidade sanguínea, pode não se correlacionar à resposta hemolítica nos pacientes enzimopênicos 11,15 . ...
Primaquine can produce adverse reactions as toxicity to blood when used in the treatment of vivax malaria. This work aimed to determine methemoglobinemia in patients with vivax malaria receiving oral therapy with primaquine.
Spectrophotometric quantification of methemoglobinemia and qualitative assay for glucose-6-phosphate dehydrogenase.
Methemoglobinemia ranged from 2.85 to 5.45% in male patients and 3.77 to 7.34% in female patients.
A statistically significant increase in methemoglobinemia was observed following oral therapy with primaquine, with no clinical manifestations, and independent of sex and the qualitative expression of glucose-6-phosphate dehydrogenase.
Les combinaisons thérapeutiques à base d'artémisinine (CTA) sont depuis vingt ans les médicaments de référence pour le traitement du paludisme causé par Plasmodium falciparum. Les CTA se composent de deux molécules antipaludiques : un dérivé d'artémisinine à action rapide et brève, et une molécule partenaire à action plus lente mais prolongée. Leur mise en place globale a contribué à la diminution drastique de la mortalité liée au paludisme. La mondialisation des CTA a permis à de nombreux pays endémiques de tendre vers l'élimination du paludisme.L'accomplissement de cet objectif se heurte cependant à l'émergence de résistances à l'artémisinine et aux composés partenaires. Cette problématique est particulièrement présente au Cambodge, et s'étend maintenant à une grande partie de l'Asie du Sud-Est. La perte de l'efficacité des CTA en Afrique aurait de lourdes conséquences en termes de santé publique, c'est pourquoi des stratégies de surveillance des résistances doivent être mises en place pour pallier à ce risque. De précédentes études ont permis de mettre en place de nouveaux tests phénotypiques participant à la découverte de marqueurs moléculaires de résistance aujourd'hui utilisés pour la surveillance de l'efficacité des traitements. La première partie de ce travail a visé à mieux définir, en utilisant ces outils, l'épidémiologie de la résistance de Plasmodium falciparum aux CTA en Asie et en Afrique. Nos recherches se sont concentrées sur deux pays stratégiques : le Cambodge, pays à faible transmission mais qui est l'épicentre de l'émergence des résistances aux composés antipaludiques, et le Cameroun, pays à forte transmission d'Afrique centrale, dont la résistance aux CTA n'a pas encore été rapportée. Dans une deuxième partie, de nouvelles options thérapeutiques ont été testées cliniquement et/ou in vitro sur des parasites multi-résistants isolés au Cambodge. Enfin, une troisième partie a étudié les mécanismes de résistance à l'artémisinine additionnels aux polymorphismes du gène Kelch13, en associant culture in vitro à long terme et séquençage ARN de cellules individuelles. L'ensemble des travaux présentés s'inscrit dans une stratégie de surveillance de la résistance aux antipaludiques au Cambodge et au Cameroun. Les études épidémiologiques des résistances décrites dans cette thèse permettront de mieux adapter les traitements antipaludiques pour limiter la sélection de parasites résistants dans ces deux pays. De nouvelles données concernant les mécanismes cellulaires impliqués dans la résistance à l'artémisinine ont aussi été apportées. Parmi les nouvelles options thérapeutiques testées, certaines étaient efficaces sur les parasites multi-résistants, et pourraient remplacer les traitements de première ligne actuels en cas d'augmentation du nombre d'échecs thérapeutiques au Cambodge.
Antimalarial medications carry a risk of rare, but serious side effects. Primaquine in particular is known to cause methemoglobinemia and hemolytic anemia. In patients with underlying glucose-6-phosphate dehydrogenase (G6PD) deficiency, these side effects become amplified and can be life-threatening. This can complicate treatment plans as the recommended first-line management of severe methemoglobinemia, methylene blue, may cause or worsen hemolytic anemia in G6PD deficient patients. We present a case of a toddler with an accidental primaquine overdose who had undiagnosed G6PD deficiency. Over the 2 days following his ingestion he developed severe methemoglobinemia and hemolytic anemia toxicity. He was initially treated with a dose of methylene blue prior to learning of his G6PD deficiency. He was subsequently given additional doses of ascorbic acid and a blood transfusion. His condition gradually improved and he was ultimately discharged in good condition. To our knowledge, this case represents a unique presentation of mixed methemoglobinemia and hemolytic toxicity due to an accidental primaquine overdose in a G6PD deficient pediatric patient. Though cases remain relatively rare, pediatric patients represent the vast majority of known primaquine overdoses. Their diagnosis and treatment require maintaining a high index of suspicion and a good working knowledge of antimalarial toxicities and management options.
Malaria is a disease that requires new drugs not only to fight Plasmodium but also to reduce symptoms of infection such as fever and inflammation. A series of 21 hybrid compounds were designed from chloroquine (CQ) and primaquine (PQ) linked to the pharmacophoric group present in phenylacetic anti-inflammatory drugs. These compounds were designed to have dual activity: namely, to be capable of killing Plasmodium and still act on the inflammatory process caused by malaria infection. The compounds were assayed with nine different biological methods. The carbonylated CQ derivative 6 (n = 3; R1 = Cl) was more potent than CQ in vitro, and 8 (n = 4; R1 = H) reduced P. berghei parasitemia up to 37% on day 7. The carbonylated PQ derivative 17 (R = Br) was slightly less potent than PQ. The gem-difluoro PQ derivative 20 (R = Cl) exhibited high transmission blockade of the malaria sporogonic cycle in mosquitoes. Compounds 6 and 20 dose-dependently reduced nitric oxide (NO) production and inhibited TNFα production by LPS-stimulated J774A.1 macrophages. Our results indicate a viable and interesting approach in planning new chemical entities that act as transmission-blocking drugs for treating malaria caused by P. falciparum and P. vivax and the anti-inflammatory process related to this disease.
Background:
Plasmodium vivax malaria has a persistent liver stage that causes relapse of the disease and continued P vivax transmission. Primaquine (PQ) is used to clear the liver stage of the parasite, but treatment is required for 14 days. Primaquine also causes haemolysis in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Tafenoquine (TQ) is a new alternative to PQ with a longer half-life and can be used as a single-dose treatment.
Objectives:
To assess the effects of tafenoquine 300 mg (single dose) on preventing P vivax relapse.
Search methods:
We searched the following up to 3 June 2020: the Cochrane Infectious Diseases Group Specialized Register; CENTRAL; MEDLINE; Embase; and three other databases. We also searched the WHO International Clinical Trial Registry Platform and the metaRegister of Controlled Trials for ongoing trials using "tafenoquine" and "malaria" as search terms up to 3 June 2020.
Selection criteria:
Randomized controlled trials (RCTs) that gave TQ to prevent relapse in people with P vivax malaria. We planned to include trials irrespective of whether participants had been screened for G6PD enzyme deficiency.
Data collection and analysis:
All review authors independently extracted data and assessed risk of bias. As true relapse and reinfection are difficult to differentiate in people living in endemic areas, studies report "recurrences" of infection as a proxy for relapse. We carried out meta-analysis where appropriate, and gave estimates as risk ratios (RR) with 95% confidence intervals (CI). We assessed the certainty of the evidence using the GRADE approach.
Main results:
Three individually randomized RCTs met our inclusion criteria, all in endemic areas, and thus reporting recurrence. Trials compared TQ with PQ or placebo, and all participants received chloroquine (CQ) to treat the asexual infection). In all trials, pregnant and G6PD-deficient people were excluded. Tafenoquine 300 mg single dose versus no treatment for relapse prevention Two trials assessed this comparison. TQ 300 mg single dose reduces P vivax recurrences compared to no antihypnozoite treatment during a six-month follow-up, but there is moderate uncertainty around effect size (RR 0.32, 95% CI 0.12 to 0.88; 2 trials, 504 participants; moderate-certainty evidence). In people with normal G6PD status, there is probably little or no difference in any type of adverse events (2 trials, 504 participants; moderate-certainty evidence). However, we are uncertain if TQ causes more serious adverse events (2 trials, 504 participants; very low-certainty evidence). Both RCTs reported a total of 23 serious adverse events in TQ groups (One RCT reported 21 events) and a majority (15 events) were a drop in haemoglobin level by > 3g/dl (or >30% reduction from baseline). Tafenoquine 300 mg single dose versus primaquine 15 mg/day for 14 days for relapse prevention Three trials assessed this comparison. There is probably little or no difference between TQ and PQ in preventing recurrences (proxy measure for relapse) up to six months of follow-up (RR 1.04, 95% CI 0.8 to 1.34; 3 trials, 747 participants; moderate-certainty evidence). In people with normal G6PD status, there is probably little or no difference in any type of adverse events (3 trials, 747 participants; moderate-certainty evidence). We are uncertain if TQ can cause more serious adverse events compared to PQ (3 trials, 747 participants; very low-certainty evidence). Two trials had higher point estimates against TQ while the other showed the reverse. Most commonly reported serious adverse event in TQ group was a decline in haemoglobin level (19 out of 29 events). Some other serious adverse events, though observed in the TQ group, are unlikely to be caused by it (Hepatitis E infection, limb abscess, pneumonia, menorrhagia).
Authors' conclusions:
TQ 300 mg single dose prevents relapses after clinically parasitologically confirmed P vivax malaria compared to no antihypnozoite treatment, and with no difference detected in studies comparing it to PQ to date. However, the inability to differentiate a true relapse from a recurrence in the available studies may affect these estimates. The drug is untested in children and in people with G6PD deficiency. Single-dose treatment is an important practical advantage compared to using PQ for the same purpose without an overall increase in adverse events in non-pregnant, non-G6PD-deficient adults.
Objective:
To determine the efficacy of chloroquine monotherapy in Colombian pregnant women with acute uncomplicated malaria vivax (GMV).
Methods:
Prospective cohort study in pregnant women who presented of their own accord between February 1, 2015 and December 31, 2017 to malaria or prenatal care centers in two Colombian towns and in whom the diagnosis of Plasmodium vivax was confirmed by means of blood spot test and and quantitative polymerase chain reaction (qPCR). Measured variables included sociodemographics, therapeutic failure (TF) and serious adverse events at 28 days and frequency of recurrence-relap (RR) over a follow-up period of 120 days. The WHO protocol was applied for the assessment of monotherapy with cloroquine (m-CQ) efficacy.
Results:
Overall, 47 pregnant women were identified. During the 28-day follow-up period there were no losses, and there were two cases of TP (4.2%=2/47). Of the 45 women followed between 29 and 120 days, 11 were lost (24.4%=11/45) and there were 13 cases of RR, with an RR frequency ranging between 29 and 53 % depending on the type of analysis.
Conclusions:
Chloroquine is still highly effective as a cure of acute malaria vivax attack in GM in Colombia, and continues to be a good option for the treatment of acute phase GM. The RR frequency is high. Studies are required that evaluate therapeutic alternatives in MG. There is a pressing need for medications and/or procedures that can help reduce this very high risk.
The endothelial cell barrier is tightly regulated, and disruption or the leaky behavior of the barrier leads to pathology. Disturbance of blood‐brain barrier is observed during viral infection, cerebral malaria, and acute hemorrhagic encephalitis. Red blood cells (RBCs) bind to the endothelial cells (ECs) and their affinity towards ECs enhances in the presence of Plasmodium falciparum infection. ECs stimulated with methemoglobin (MetHb; 20 µM) for 1 hour exhibit high levels of cyto‐adherence receptors CD36 and ICAM‐1 on their cell surface compared with unstimulated cells. These ECs have acquired affinity towards uninfected RBCs in flow at arterial shear stress. SEM analysis indicates that EC–RBC cyto‐adherence involved multiple attachment points. Initially, ECs bind single layer of RBCs and the number of RBCs increases over time to give high‐order cyto‐adherence with more than 30 RBCs adhered to each endothelial cell. The cyto‐adherence complexes are stable to high shear stress and can withstand shear stress up to 450 dyne/cm ². MetHb‐treated ECs exhibited high reactive oxygen species level, and preincubation of ECs with antioxidant (NAC or mannitol) abolished the formation of EC–RBC cyto‐adherence complexes. In addition, gallic acid (present in red wine) and green tea extract has inhibited the formation of EC–RBC cyto‐adherence complex. A better understanding of gallic acid and tea polyphenol targeting pathological cyto‐adherence may allow us to develop a better adjuvant therapy for cerebral malaria and other noninfectious diseases.
Background
Primaquine is an anti-malarial used to prevent Plasmodium vivax relapses and malaria transmission. However, PQ metabolites cause haemolysis in patients deficient in the enzyme glucose-6-phosphate dehydrogenase (G6PD). Fifteen PQ-thiazolidinone derivatives, synthesized through one-post reactions from primaquine, arenealdehydes and mercaptoacetic acid, were evaluated in parallel in several biological assays, including ability to block malaria transmission to mosquitoes. ResultsAll primaquine derivatives (PQ-TZs) exhibited lower cell toxicity than primaquine; none caused haemolysis to normal or G6PD-deficient human erythrocytes in vitro. Sera from mice pretreated with the test compounds thus assumed to have drug metabolites, caused no in vitro haemolysis of human erythrocytes, whereas sera from mice pretreated with primaquine did cause haemolysis. The ability of the PQ-TZs to block malaria transmission was evaluated based on the oocyst production and percentage of mosquitoes infected after a blood meal in drug pre-treated animals with experimental malaria caused by either Plasmodium gallinaceum or Plasmodium berghei; four and five PQ-TZs significantly inhibited sporogony in avian and in rodent malaria, respectively. Selected PQ-TZs were tested for their inhibitory activity on P. berghei liver stage development, in mice and in vitro, one compound (4m) caused a 3-day delay in the malaria pre-patent period. Conclusions
The compound 4m was the most promising, blocking malaria transmissions and reducing the number of exoerythrocytic forms of P. berghei (EEFs) in hepatoma cells in vitro and in mice in vivo. The same compound also caused a 3-day delay in the malaria pre-patent period.
This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effectiveness of primaquine and tafenoquine for primary prophylaxis againstPlasmodium vivax andPlasmodium falciparum infections. To assess the effectiveness of tafenoquine for terminal prophylaxis of vivax malaria. To compare the safety profile and compliance rates of tafenoquine and primaquine when used for primary (P. vivax and P. falciparum infections) and terminal (P. vivax infections) prophylaxis.
This is the protocol for a review and there is no abstract. The objectives are as follows: To assess effects of tafenoquine in relation to cure and prophylaxis of P. vivax malaria To compare the side effects and adverse events of tafenoquine versus placebo or other antimalarial drugs.
Background:
Plasmodium vivax malaria is widespread, and the persistent liver stage causes relapse of the disease which contributes to continued P. vivax transmission. Primaquine is currently the only drug that cures the parasite liver stage, but requires 14 days to be effective and can cause haemolysis in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In addition, there is some evidence of parasite resistance to the drug. Tafenoquine is a new alternative with a longer half-life.
Objectives:
To assess the effects of tafenoquine in people with P. vivax infection.
Search methods:
We searched the following databases up to 13 April 2015: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; CINAHL; SCOPUS; and LILACS. We also searched the World Health Organization (WHO) International Clinical Trial Registry Platform and the metaRegister of Controlled Trials (mRCT) for ongoing trials using "tafenoquine" and "malaria" as search terms up to 13 April 2015.
Selection criteria:
Randomized controlled trials (RCTs) in people with P. vivax malaria. Adverse effects of tafenoquine are assessed in populations where people with G6PD deficiency have been excluded, and in populations without screening for G6PD deficiency.
Data collection and analysis:
All review authors independently extracted data and assessed trial quality. Meta-analysis was carried out where appropriate, and estimates given as relative risk with 95% confidence intervals. We assessed the quality of the evidence using the GRADE approach.
Main results:
Three RCTs met our inclusion criteria, with the asexual infection in both the tafenoquine and comparator arm treated with chloroquine, and in all trials G6PD deficiency patients were excluded. Tafenoquine dose comparisonsThree of the included trials compared eight different dosing regimens. Tafenoquine doses of 300 mg and above resulted in fewer relapses than no hypnozoite treatment over six months follow-up in adults (300 mg single dose: RR 0.19, 95% CI 0.08 to 0.41, one trial, 110 participants, moderate quality evidence; 500 to 600 mg single dose: RR 0.14, 95%CI 0.06 to 0.34, two trials, 122 participants, moderate quality evidence; 1800 mg to 3000 mg in divided doses: RR 0.05, 95% CI 0.01 to 0.23, two trials, 63 participants, low quality evidence).In people with normal G6PD status, there may be little or no difference in serious adverse events (three trials, 358 participants, low quality evidence); or any adverse event (one trial, 272 participants, low quality evidence). Tafenoquine versus primaquine Two of the included trials compared four different dosing regimens of tafenoquine against the standard primaquine regimen of 15 mg/day for 14 days. A single tafenoquine dose of 600 mg may be more effective than primaquine in relation to relapses at six months follow-up (RR 0.29, 95% CI 0.10 to 0.84, two trials, 98 participants, low quality evidence)In people with normal G6PD status, there may be little or no difference for serious adverse events (two trials, 323 participants, low quality evidence) or any adverse event (two trials, 323 participants, low quality evidence) between tafenoquine and primaquine.
Authors' conclusions:
Tafenoquine prevents relapses after clinically and parasitologically confirmed P. vivax malaria. The drug is untested in pregnancy, children and in G6PD-deficient people. The shorter treatment course is an important practical advantage in people who do not have G6PD deficiency, but the longer half-life may have more substantive consequences if given inadvertently to people with G6PD deficiency.
Primaquine (PQ) is used against relapses of vivax malaria (RVM) but several aspects about dosage are unknown, as the total effective dose (TD) in a number of days.
To compare PQ regimens against RVM in randomized or non randomized controlled clinical trials (CCTs).
Meta analysis. Information was sought until 31 December, 2012 in Lilacs, SciELO, PubMed (Medline), Cochrane Library, Cochrane Infectious Diseases Group, Embase. Experimental studies or CCT were used, always with concurrent control group. No matter whether or not the design was randomized, close label, supervised. It is not required that the study established difference between relapse and reinfection by molecular evidence. Inclusion and exclusion criteria for articles were applied and meet the inclusion criteria constituted adequate quality to be left in the meta analysis.
23 ECC with or without random allocation of treatment met the selection criteria. Include four schemes of TD (TD mg number of days): 210 14 = 210 mg in 14 days; 210 7 = 210 mg in 7 days, 45 to 150 mg in 3 to 10 days, 0 (not PQ). If PQ is absent, recurrences occurr 34.48% versus 19.66% with PQ 210 14 (significant difference), 210 14 showed effectiveness equal to that of 210 7. Treatments 210 7 and 210 14 were statistically better than 45 to 150 effectiveness.
The use of PQ is necessary to reduce recurrences and TD 210 mg given at 7 or 14 days is which is more effective but more studies are required to treatment 210 7.
Recently, a dose of 30 mg (base) primaquine daily for 14 days is increasingly recommended for radical cure of Plasmodium vivax malaria. However, total primaquine doses, or those per body weight, are also recognized as important. In Japan, primaquine is not a licensed medicine, but has been used through the Research Group on Chemotherapy of Tropical Diseases for >3 decades.
Based on clinical records submitted to the Research Group, patients with P. vivax and Plasmodium ovale malaria treated with primaquine were analyzed to determine the efficacy and safety of the antimalarial drug.
Seventy-five P. vivax cases, including 3 in children, and 19 P. ovale cases were enrolled. Five of the P. vivax cases demonstrated at least one relapse despite primaquine therapy. Total primaquine doses per body weight were obtained in 4 of the 5 relapsed patients, presenting 9 malaria episodes totally, and most of the primaquine failures were caused with a total dose ≤3.5 mg/kg. Liver function disturbance was reported in 2 cases.
In order to optimize radical cure of P. vivax, the total primaquine dose per body weight should be considered, at least 3.5 mg/kg or even more if contracted in countries with significant drug resistance. Possibility of primaquine hepatotoxicity in chronic liver disease patients remains to be elucidated.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Plasmodium vivax infections are an important contributor to the malaria burden worldwide. The World Health Organization recommends a 14-day course of primaquine (0.25 mg/kg/day, giving an adult dose of 15 mg/day) to eradicate the liver stage of the parasite and prevent relapse of the disease. Many people find a 14-day primaquine regimen difficult to complete, and there is a potential risk of haemolytic anaemia in people with glucose-6-phosphate-dehydrogenase enzyme (G6PD) deficiency. This review evaluates primaquine in P. vivax, particularly alternatives to the standard 14-day course.
To compare alternative primaquine regimens to the recommended 14-day regimen for preventing relapses (radical cure) in people with P. vivax malaria treated for blood stage infection with chloroquine. We also summarize trials comparing primaquine to no primaquine that led to the recommendation for the 14-day regimen.
We searched the Cochrane Infectious Diseases Group's Specialized Register, CENTRAL (The Cochrane Library), MEDLINE, EMBASE and LILACS up to 8 October 2013. We checked conference proceedings, trial registries and reference lists and contacted researchers and pharmaceutical companies for eligible studies.
Randomized controlled trials (RCTs) and quasi-RCTs comparing various primaquine dosing regimens with the standard primaquine regimen (15 mg/day for 14 days), or with no primaquine, in people with vivax malaria treated for blood stage infection with chloroquine.
We independently assessed trial eligibility, trial quality, and extracted data. We calculated risk ratios (RR) with 95% confidence intervals (CI) for dichotomous data, and used the random-effects model in meta-analyses if there was significant heterogeneity. We assessed the overall quality of the evidence using the GRADE approach.
We included 15 trials (two cluster-RCTs) of 4377 adult and child participants. Most trials excluded people with G6PD deficiency. Trials compared various regimens of primaquine with the standard primaquine regimen, or with placebo or no treatment. All trials treated blood stage infection with chloroquine. Alternative primaquine regimens compared to 14-day primaquineRelapse rates were higher over six months with the five-day primaquine regimen than the standard 14-day regimen (RR 10.05, 95% CI 2.82 to 35.86; two trials, 186 participants, moderate quality evidence). Similarly, relapse over six months was higher with three days of primaquine than the standard 14-day regimen (RR 3.18, 95% CI 2.1 to 4.81; two trials, 262 participants, moderate quality evidence; six months follow-up); and with primaquine for seven days followed up over two months, compared to 14-day primaquine (RR 2.24, 95% CI 1.24 to 4.03; one trial, 126 participants, low quality evidence).Relapse with once-weekly supervised primaquine for eight weeks was little different over nine months follow-up compared to 14-day self-administered primaquine in one small study (RR 2.97, 95% CI 0.34 to 25.87; one trial, 129 participants, very low quality evidence). Primaquine regimens compared to no primaquineThe number of people that relapsed was similar between people given five days of primaquine or given placebo or no primaquine (four trials, 2213 participants, high quality evidence; follow-up six to 15 months); but lower with 14 days of primaquine (RR 0.6; 95% CI 0.48 to 0.75; ten trials, 1740 participants, high quality evidence; follow-up seven weeks to 15 months).No serious adverse events were reported. Treatment-limiting adverse events were rare and non-serious adverse events were mild and transient. Trial authors reported that people tolerated the drugs.We did not find trials comparing higher dose primaquine regimens (0.5 mg/kg/day or more) for five days or more with the 14-day regimen.
The analysis confirms the current World Health Organization recommendation for 14-day primaquine (15 mg/day) to prevent relapse of vivax malaria. Shorter primaquine regimens at the same daily dose are associated with higher relapse rates. The comparative effects with weekly primaquine are promising, but require further trials to establish equivalence or non-inferiority compared to the 14-day regimen in high malaria transmission settings.
FMetHb 0 10 20 30 40 50 60 70 80 90 100 Saturación (%) 5 6 7 8 9 Figura 1 Saturación de las distintas fracciones de hemoglo-bina en función de la evolución de la paciente, a partir del primer día de exposición a primaquina. FMetHb: fracción de metahemoglobina; FO 2 Hb: fracción de hemoglobina oxidada por oxígeno; StHb: saturación total de hemoglobina. ingesta regular de un fármaco) pueden haberse adaptado progresivamente a tasas altas de MHB sin presentar sinto-matología severa. Sin embargo, pacientes con enfermedades cardiorrespiratorias o hematológicas subyacentes, tolerarán peor la MHB 5. Con posterioridad se realizó el algoritmo de Karch-Lasagna modificado 6 y el de Naranjo 7 obteniendo por ambos métodos la categoría de relación causa-efecto probable. La metahemoglobinemia por primaquina es una reacción adversa descrita ya en la bibliografía. Su lenta instauración es de esperar por el mecanismo de la reacción y las dosis de primaquina administradas. La paciente comenzó a mejorar tras la retirada de primaquina y con la administración de vitamina C. Además no existe causa alternativa que pueda explicar la transformación de hemoglobina en MHB. En conclusión, nos encontramos ante un problema rela-cionado con la medicación que pertenece a la categoría de seguridad. En el caso que nos ocupa la cianosis de piel y mucosas fue tan llamativa que permitió detectar el pro-blema en las primeras horas e intervenir rápidamente en consecuencia. La metahemoglobinemia es una reacción adversa inhe-rente a primaquina y no comporta ningún fallo del sistema asociado sobre el que se pueda actuar. Sin embargo, la gravedad de las posibles consecuencias que pueden desen-cadenarse justifican una estrecha vigilancia del paciente mientras sea administrado dicho tratamiento.
Inflammation or vascular occlusion by parasitized red blood cell contributes to the pathogenesis of cerebral malaria. The current study aimed to characterize the role of major pro-oxidant factor methemoglobin present in the malaria culture supernatant contributing in inflammation during malaria. Heme and heme polymer stimulate macrophage to secrete large amount of reactive oxygen species into the external micro-environment. The addition of methemoglobin along with heme or heme polymer amplifies production of ROS from macrophages several folds. Methemoglobin mediated stimulatory effect is not due to release of iron, enhanced production of H2O2 or mutual interaction of reaction components. Spectroscopic studies show that methemoglobin accepts heme as a substrate and oxidizes it through a single electron transfer mechanism. Heme oxidation product is a heme polymer with similar chemical and structural properties to synthetic β-hematin. Phenyl N-t-butylnitrone inhibits heme polymerization (IC50=30 nM) and indicates the absolute necessity of heme oxidation and heme free radical generation for heme polymerization. Methemoglobin produced heme polymer is a potent pro-inflammatory factor to release ROS into external microenvironment. Interestingly, methemoglobin not only produces pro-inflammatory heme polymer, but it also amplifies the potential of heme or preformed heme polymer (haemozoin or β-hematin) to produce several folds high ROS production from macrophages. This study illustrates the pro-inflammatory effect of methemoglobin, the underlying novel mechanism by which this occurs and a possible clinical intervention. Based on the results, we recommend methemoglobin directed peroxidase inhibitors as an adjuvant therapy during malaria.
Background:
Primaquine (Pq) metabolic products are responsible for drug-associated hemotoxicity and limit primaquine usage.
Methods:
Methemoglobin (MetHb)-Pq molecular modeling was used to identify the Pq binding pocket. UPLC, mass spectrometry, and other indirect analytical methods were used to predict the metabolite. MetHb generation, development of oxidative stress, inhibition of antioxidant enzymes, and scanning electron microscope (SEM) were used to characterize the hemotoxic potentials of oxidized Pq (Pqox).
Results:
MetHb binded Pq at the heme site with KD =6.4 μM as evidenced by a difference spectroscopy study. MetHb oxidized Pq through a single e-transfer mechanism to form Pqox. The analysis of Pq from MetHb-H2O2 peroxidase reaction mixture gave peaks at m/z 300.53 and m/z 243.42, corresponding to the hydroxyl and desamino derivative of Pq, respectively. Similar peaks were absent in Pq or Pq incubated with H2O2 in the same buffer system. A robust increase in MetHb formation, reactive oxygen species generation, and inhibition of antioxidant enzymes were found in red blood cells (RBCs) exposed to Pqox compared with a parent drug molecule. The RBC membrane exhibited visible damages to plasma membrane (holes) as evidenced by SEM analysis of Pqox-exposed RBCs.
Conclusions:
The MetHb-H2O2 system transforms quiescent parent drug molecule to a highly reactive oxidative form to exhibit severe hemolysis. MetHb-H2O2-mediated Pq hemolytic potentiation that is sensitive to spin trap indicates the role of Pq* radical or other single e-species in the process. The result suggests that MetHb incites the molecular property of the Pq and peroxidase inhibitors can be explored to control drug-associated toxicity.
primaquine (PQ) is the only drug available in the market to prevent Plasmodium vivax malaria recurrence, but several aspects are still unknown.
To compare PQ regimens to prevent recurrence of vivax malaria.
systematic review and meta-analysis of data.
1. According to descriptive studies, is PQ effective in preventing recurrence of vivax malaria? Yes. The comparison of studies that did not use PQ to others that did, using any regimen, showed that if PQ is not used, recurrence is highly likely. 2. Are equal daily doses effective (mg/kg) but total doses different? The total dose of 75 mg is equally or more effective than 210 mg. 3. Does the efficacy depend on where the infection happens? Yes. There is variation by country and region. 4. Does the recurrence rate depend on the post-treatment time follow-up? The answer is not uniform everywhere.
Although not 100%, PQ is effective in preventing recurrence. Total doses of 210 and 75 mg are equally effective, but 75 mg alone has been evaluated in India, where P. vivax seems to respond better to PQ than elsewhere. The effect of place in the proportion of recurrences seems evident, even using the same total dose. The role of follow-up time is not clear. Although the standard regimen has an average effectiveness of 90% or more, alternative regimens should be assessed.
A 25 year old man was rushed to the emergency department when he was found unconscious in his room after taking two chloroquine tablets (600 mg base) for fever prescribed by local practitioner. On examination, the patient was unconscious and deep cyanosis was present on lips, tongue, oral cavity, nail beds and finger tips. Subsequent laboratory investigation revealed methaemoglobin level of 54%. Diagnosis of chloroquine-induced methaemoglobinaemia was made and methylene blue (1 mg/kg) was administered. The patient improved dramatically and was discharged following day.
Genetic diversity of Plasmodium populations has been more extensively documented in Colombia for Plasmodium falciparum than for Plasmodium vivax. Recently, highly variable microsatellite markers have been described and used in population-level studies of genetic variation of P. vivax throughout the world. We applied this approach to understand the genetic structure of P. vivax populations and to identify recurrence-associated haplotypes. In this, three microsatellite markers of P. vivax were amplified and the combined size of the fragments was used to establish genotypes. Patients from an ongoing treatment efficacy trial who were kept either in endemic or non-endemic regions in the northwest of Colombia were included in the study. In total 58 paired clinical isolates, were amplified. A total of 54 haplotypes were observed among the two regions. Some haplotypes were exclusive to the endemic region where the highest degree of polymorphism was detected. In addition, we confirmed the different genotypes of recurrent-relapsing and primary infection isolates suggesting the activation of heterologous hypnozoite populations. We conclude that analysis of the three microsatellites is a valuable tool to establish the genetic characteristics of P. vivax populations in Colombia.
Methaemoglobin is haemoglobin with the iron oxidised to the ferric (Fe ) state from the normal (or reduced) ferrous (Fe++) state. Methaemoglobinaemia refers to the presence of greater than the normal physiological concentration of 1 to 2% methaemoglobin in erythrocytes. Methaemoglobin is incapable of transporting oxygen. It has an intense dark blue colour; thus, clinical cyanosis becomes apparent at a concentration of about 15%. The symptoms are manifestations of hypoxaemia with increasing concentrations of methaemoglobin. Concentrations in excess of 70% are rare, but are associated with a high incidence of mortality. Methaemoglobinaemia may be congenital but is most often acquired. Congenital methaemoglobinaemia is of two types. The first is haemoglobin M disease (several variants) which is due to the presence of amino acid substitutions in either the alpha or beta chains. The second type is due to a deficiency of the NADH-dependent methaemoglobin reductase enzyme. This deficiency has an autosomal dominant transmission, and both homozygous and heterozygous forms have been reported. The heterozygous form is not normally associated with clinical cyanosis, but such individuals are more susceptible to form methaemoglobin when exposed to inducing agents. A wide variety of chemicals including several drugs, e.g. the antimalarials chloroquine and primaquine, local anaesthetics such as lignocaine, benzocaine and prilocaine, glyceryl trinitrate, sulphonamides and phenacetin, have been reported to induce methaemoglobinaemia. An intense 'chocolate brown' coloured blood and central cyanosis unresponsive to the administration of 100% oxygen suggests the diagnosis. A simple bedside test using a drop of the patient's blood on filter paper helps to confirm the clinical suspicion. Methaemoglobin can be quantitated rapidly by a spectrophotometric method.(ABSTRACT TRUNCATED AT 250 WORDS)
Methaemoglobin is haemoglobin with the iron oxidised to the ferric (Fe+++) state from the normal (or reduced) ferrous (Fe++) state. Methaemoglobinaemia refers to the presence of greater than the normal physiological concentration of 1 to 2% methaemoglobin in erythrocytes.
Methaemoglobin is incapable of transporting oxygen. It has an intense dark blue colour; thus, clinical cyanosis becomes apparent at a concentration of about 15%. The symptoms are manifestations of hypoxaemia with increasing concentrations of methaemoglobin. Concentrations in excess of 70% are rare, but are associated with a high incidence of mortality.
Methaemoglobinaemia may be congenital but is most often acquired. Congenital methaemoglobinaemia is of two types. The first is haemoglobin M disease (several variants) which is due to the presence of amino acid substitutions in either the a or β chains. The second type is due to a deficiency of the NADH-dependent methaemoglobin reductase enzyme. This deficiency has an autosomal dominant transmission, and both homozygous and heterozygous forms have been reported. The heterozygous form is not normally associated with clinical cyanosis, but such individuals are more susceptible to form methaemoglobin when exposed to inducing agents.
A wide variety of chemicals including several drugs, e.g. the antimalarials chloroquine and primaquine, local anaesthetics such as lignocaine, benzocaine and prilocaine, glyceryl trinitrate, sulphonamides and phenacetin, have been reported to induce methaemoglobinaemia.
An intense ‘chocolate brown’coloured blood and central cyanosis unresponsive to the administration of 100% oxygen suggests the diagnosis. A simple bedside test using a drop of the patient’s blood on filter paper helps to confirm the clinical suspicion. Methaemoglobin can be quantitated rapidly by a spectrophotometric method.
The intravenous administration of methylene blue (tetramethylthionine chloride) is a specific treatment for acquired methaemoglobinaemia, but may be ineffective in chlorate poisoning. Chlorate poisoning and severe cases of methaemoglobinaemia require exchange transfusion. Hyperbaric oxygen can sustain life during preparations for exchange transfusion.
Antecedentes y Problema: en 1998-2002 se investigó en Antioquia (Turbo, Zaragoza y El Bagre), la eficacia terapéutica de medicamentos y combinaciones antimaláricos. La interpretación de la respuesta terapéutica (adecuada, fallas precoz y tardía) requiere información adicional para una mejor comprensión. Objetivo: definir un marco de referencia para interpretar los resultados de las evaluaciones de respuesta terapéutica antimalárica, constituido por información sobre el comportamiento de los programas antimaláricos en Colombia y por información demográfica, epidemiológica, climatológica y socioeconómica sobre el departamento de Antioquia, las regiones de Urabá y Bajo Cauca y los municipios de Turbo y El Bagre. Metodología: se usó información oficial secundaria y en menor cantidad, información primaria. Con los datos recogidos se construyeron cuadros y gráficos, y se hicieron cálculos sobre otras variables. Resultados: se describe la malaria (paludismo) en Colombia en 1960-2002. En 2002, de los 43,707 millones de habitantes, 22,403 millones (51,17%) están expuestos (41,88% con bajo riesgo). El P. vivax es la especie predominante (66% de los casos), excepto en la región del Pacífico, donde el P. falciparum causa el 75% de los casos. Hay brotes de malaria cada 2 a 7 años; la más intensa epidemia en la historia conocida ocurrió en 1998. La mortalidad ha pasado de 25 por cien mil en 1983 a 3 por cien mil en 2000. El índice parasitario anual (IPA) ha estado alrededor de 8 por mil expuestos después de 1990, valor que es el cuádruple del existente en 1960-1970. La ineficacia del programa ha sido evidente casi desde su inicio en 1958 y la tendencia de la enfermedad siempre ha sido creciente. El fracaso de los programas gubernamentales antimalaria no tiene origen en fenómenos principalmente biológicos (resistencias del plasmodio a los medicamentos y del anofeles a los insecticidas), ni tampoco en las “condiciones de orden público”. Las principales responsables de la situación malárica en Colombia han sido fallas de origen social: a) las deficiencias financieras de origen gubernamental, b) querer aplicar insecticidas residuales en las viviendas humanas en un país donde ellas, en las zonas palúdicas, con alta frecuencia carecen de paredes y donde los anofelinos tienen hábitos extradomiciliarios, c) se supone que han influido la automedicación inadecuada y la ausencia de diagnóstico oportuno, d) el desinterés de muchos gobernantes y funcionarios y e) después de 1993, con la ley 100 de ese año, la situación ha llegado a su peor nivel. En 1959-2003, se describe la malaria en Antioquia, donde la población expuesta es menos del 20%. El paludismo ha estado siempre presente (IPA ajustado para 1959-2002: mínimo 8, máximo 140,7 y mediana 23,8 por mil expuestos) y desde comienzos del decenio de 1980 hasta ahora su frecuencia se ha incrementado, en 2000-2002 es el doble de la existente hace 30 ó 40 años. Según el IPA bruto máximo (2,66 por mil), Antioquia sería una región de riesgo medio, pero según la mediana del IPA ajustado sería de muy alto riesgo. En 1985-1999, la razón vivax/falciparum osciló entre 1,6 y 4,7 (promedio: 2,5). La mortalidad y letalidad por malaria han disminuido en forma casi constante desde 1946; en 1985-1989 ocurrieron 154 decesos, de los cuales el 86% fueron por P. falciparum.
A sensitive and specific assay for primaquine in plasma and urine using gas chromatography/mass spectrometry has been developed and used to study the plasma kinetics of primaquine. Preliminary studies on the effects of single and multiple oral doses have been carried out. In both cases the drug was completely, or almost completely, removed from the plasma in 24 h. The concentration of primaquine in the plasma usually reached a peak 1-2 hours after oral administration. The plasma elimination half-life was about 4 h. Less than 1% of the dose was detected in the urine collected over a 24-h period following drug ingestion. When Caucasian volunteers were given primaquine and chloroquine concurrently, some of them developed significant methaemoglobinaemia. Primaquine was not detectable in the plasma of any of the volunteers, 24 h after each daily dose.
To improve upon the efficacy of primaquine prophylaxis for malaria (94%, Plasmodium falciparum malaria; 85%, Plasmodium vivax malaria), we administered chloroquine (300 mg weekly) in combination with primaquine (30 mg daily) to nonimmune Colombian
soldiers during 16 weeks of patrol in a region of endemicity and for a further 1 week in base camp. The occurrence of symptomatic
parasitemia was determined during those 17 weeks and during a further 3 weeks in base camp. The protective efficacy for the
chloroquine/primaquine treatment group of 100 subjects, compared with that for the placebo treatment group of 51 subjects,
was 88% (95% confidence interval [CI], 76–94) against all types of malaria, 89% (95% CI, 61–97) against P. falciparum malaria, and 88% (95% CI, 58–93) against P. vivax malaria. Two chloroquine/primaquine recipients had severe gastrointestinal distress. Comparison of these data with data from
a previous study indicates that the addition of chloroquine did not increase the prophylactic efficacy of primaquine.
Relapse of Plasmodium vivax malaria following standard primaquine dosing has been reported from many areas, and more recently from sub-Saharan Africa. In this report we describe eight episodes (in five patients) of treatment failure in non-immune Israeli travelers returning from Ethiopia. Retrospective calculation of the primaquine dose per kilogram of body weight for 23 treatment courses showed a lower total dose per kilogram in heavier patients. The mean calculated dose (95% CI) in the eight failed treatments was 2.5 +/- 0.3 mg/kg compared with 4.4 +/- 0.5 mg/kg in the 15 successful treatment courses. Weight-adjusted dosing regimens may prevent inadvertent subtherapeutic drug failure, and thus apparent primaquine failure. In these cases, no relapses were observed in those who received > 3.5 mg/kg. Consideration should be given to adjusting the dose of primaquine according to body weight. For those infected by strains from Ethiopia a dose > 3.5 mg/kg is preferable.
Plasmodium vivax malaria is an important cause of morbidity in Central and South America. In Colombia, this is the most prevalent malaria infection, representing 75% of the reported cases. To define the efficacy of the chloroquine and primaquine regimen to eliminate hypnozoites and prevent relapses, we conducted a random controlled clinical trial of three primaquine regimens in an open-label study. We evaluated the anti-relapse efficacy of total primaquine doses of 45, 105, and 210 mg administered at a dosage of 15 mg/day in 210 adults with P. vivax infection from the northwestern region of Colombia. Cure rates for blood-stage P. vivax malaria by day 28 of follow-up were 100% in all groups. Post-treatment reappearance of parasitemia during the six months of follow-up was 45%, 36.6% and 17.6%, respectively, for each group. When compared with other groups, administration of 210 mg was a significant protection factor for reappearance of parasitemia in a malaria-endemic area.
This study had the aim of investigating occurrences of methemoglobinemia among individuals with glucose-6-phosphate dehydrogenase deficiency during treatment for malaria infection using primaquine. Patients with a diagnosis of malaria caused by Plasmodium vivax or the V+F mixture (Plasmodium vivax + Plasmodium falciparum) were selected. Group 1 consisted of 74 individuals with a clinical diagnosis of methemoglobinemia and Group 2 consisted of 161 individuals without a clinical diagnosis of methemoglobinemia. The glucose-6-phosphate dehydrogenase deficiency rates (numbers of enzymopenic individuals) in Groups 1 and 2 were 51.3% (38) and 8.7% (14) respectively. These data demonstrated a statistically significant association with methemoglobinemia only among the individuals in Group 1 (p<0.05). Investigation of the relationship between methemoglobinemia and glucose-6-phosphate dehydrogenase deficiency showed that there was a possible association such that enzymopenic individuals may develop methemoglobinemia more frequently.
Antecedentes y Problema: en 1998-2002 se investigó en Antioquia (Turbo, Zaragoza y El Bagre) la eficacia terapéutica de medicamentos y combinaciones antimaláricos. La interpretación de la respuesta terapéutica (adecuada, fallas precoz y tardía) requiere información adicional para una mejor comprensión. Objetivo: definir un marco de referencia para interpretar los resultados de las evaluaciones de respuesta terapéutica antimalárica, constituido por información sobre el comportamiento de los programas antimaláricos en Colombia y por información demográfica, epidemiológica, climatológica y socioeconómica sobre el departamento de Antioquia, las regiones de Urabá y Bajo Cauca y los municipios de Turbo y El Bagre. Metodología: se usó información oficial secundaria y, menos, información primaria. Con los datos recogidos se construyeron cuadros y gráficos y se hicieron cálculos sobre otras variables. Resultados: la malaria en Antioquia es la malaria de Urabá y Bajo Cauca: aportan el 90% de los casos. En esas zonas hay falla terapéutica in vivo y resistencia in vitro a varios medicamentos antimaláricos por parte de P. falciparum. En 2002, el 8,38% de la población de Antioquia residía en Urabá y el 3,98% en Bajo Cauca, mientras Turbo poseía el 25,62% de la población urabaense y El Bagre reunía el 27,2% de la población bajocaucana. El 100% de la población de estas regiones está expuesto a la malaria. En 1973-1982, la incidencia mediana malárica en Urabá fue de 2.997,3 casos por cien mil expuestos y en el Bajo Cauca fue de 4.463,7 por cien mil expuestos. En 1996-2000, el promedio aritmético del índice parasitario anual fue 40‰ en Turbo y 156‰ en el conjunto de El Bagre y Zaragoza. En 2000-septiembre 2003, la relación vivax: falciparum fue de 2:1 y los casos en pacientes masculinos representaron el 61%. En las dos regiones, la malaria no complicada tiene el mismo cuadro clínico con ambas especies (P. vivax, P. falciparum). Los hallazgos, entre 1998 y 2002, de falla terapéutica en la malaria por Plasmodium falciparum indican: a) Cloroquina (CQ): ha crecido en Zaragoza-El Bagre y en Turbo y en ambos lugares supera el 80%; no debe usarse más ni como monoterapia ni combinada con otros medicamentos. b) Sulfadoxina-pirimetamina (S-P) en monoterapia: la falla ha crecido y no debe usarse más como monoterapia, aunque combinada con amodiaquina se comportó en forma adecuada y así debe usarse. c) Combinación CQ-sulfadoxina-pirimetamina (CQS- P): tuvo falla del 12 al 22%, según el lugar; debe suspenderse el empleo de esta triple combinación. d) Amodiaquina (AQ): en 1998, la falla fue del 3 al 7%; ahora, la respuesta en Turbo fue adecuada en el 100%. Si la AQ regresa al mercado, debe retomarse en vez de la mefloquina, pero combinada son S-P. e) Combinación AQ-S-P: la falla fue del 2% en cada municipio; esta combinación es la primera opción terapéutica. f) Mefloquina (MQ): como monoterapia, hubo 2 al 6% de falla; no se ha usado, ni debe emplearse, como monoterapia. Frente al P. vivax, la CQ mostró, en dos evaluaciones que cubrieron ambos municipios, una eficacia del 100% y sigue como opción terapéutica de primera línea.
Glucose-6-phosphate dehydrogenase-normal adult volunteers infected with mosquito-bone Chesson strain vivax malaria were treated with chloroquine and primaquine during the initial attack. Administration of 60 mg (base) of primaquine daily for 7 days was as effective in preventing relapse as is the regimen customarily used for the radical cure of infections produced by this strain, namely, 30 mg daily for 14 days. However, it is stressed that because of the risk of primaquine-induced hemolysis in individuals having genetically-transmitted erythrocyte abnormalities this high dosage should not be used routinely.
Primaquine was tested as a prophylactic drug against Plasmodium falciparum in a region in western Kenya in which malaria is holoendemic. Children 9–14 years old were randomized to receive regimens
of daily primaquine, daily doxycycline, daily proguanil plus weekly chloroquine, daily vitamin plus weekly mefloquine, or
daily vitamin alone. Primaquine, doxycycline, and mefloquine were equally effective in preventing both symptomatic and asymptomatic
malarial infections. Chloroquine plus proguanil was the least effective regimen. There was no toxicity from daily primaquine
during the 11 weeks of the study. Findings show that primaquine can be successfully used as a causal prophylactic regimen
against falciparum malaria in western Kenya; chloroquine plus proguanil was not as efficacious as the three other preventive
regimens; most Kenyan children receiving standard doses of mefloquine and doxycycline had lower than expected serum trough
drug levels; and some volunteers with adequate mefloquine or doxycycline levels at trough developed asymptomatic parasitemias
and clinical malaria.
Reports have appeared calling attention to what has been termed primaquine resistance in Plasmodium vivax in several geographic areas. The possibility exists that primaquine tolerant strains (often referred to as the tropical zone type from the South Pacific and Southeast Asian regions characterized by early and frequent relapses) may have become widely disseminated to areas where they had not previously existed through the widespread population mobility that has characterized the last 50 years. The appearance in the relatively recent past of strains of P. vivax, particularly from the South Pacific area, that are resistant to the 4-aminoquinolines has added a new dimension to the resistance problem. While there seems to be little evidence to date of the existence of acquired primaquine resistance in P. vivax, the possibility of its emergence in the future can certainly not be ruled out, and its timely detection and confirmation will be most important, albeit quite difficult because of the relatively covert sites of drug effect. The occurrence of relapses in P. vivax after primaquine therapy would be assumed to be the most reliable indication of resistance. Reports of the sporontocidal or gametocytocidal activity of primaquine when used alone (i.e., without concomitant administration of an effective suppressive) against a P. vivax infection have been few and inconclusive. The establishment of baselines of this activity in P. vivax might be useful in detecting and evaluating primaquine resistance in this species.
Plasmodium vivax infections caused by strains with low sensitivity to primaquine are widespread in the Western Pacific and Southeast Asia, and have been recently reported from Central America as well. We report a case of primaquine failure in a P. vivax infection acquired in Guatemala. A 28-year-old Italian woman developed two months after returning from Guatemala a vivax malaria attack that was treated with a standard chloroquine course (1,500 mg over three days) combined with primaquine (15 mg/day for 14 days). Two months later, she had a relapse that was again treated with chloroquine and primaquine at the same doses. After two more months, a second relapse occurred: this time primaquine (30 mg/day for 14 days was administered; the patient remained well during a follow-up period of six months and all parasitologic examination results were negative. Doses of primaquine as high as 6 mg/kg total dose may be indicated in the treatment of vivax malaria cases from Central America.
8 patients with paludism diagnosis due to Plasmodium vivax and deficiency of glucose-6-phosphate dehydrogenase that should receive antipaludism radical treatment with primaquine were studied. It was determined that 87.5% of the patients presented hemolysis but its relation with the enzymatic activity was not significant (p > 0.05). 50% of the patients could not finish their treatment because of the appearance of important hemolysis. It is concluded that primaquine should not be used indiscriminately among those patients with deficit of glucose 6 phosphate dehydrogenase.
Primaquine had a prophylactic efficacy of 90% to 95% against infection with Plasmodium falciparum and P. vivax in Indonesian settlers.
To evaluate the efficacy of primaquine prophylaxis for protecting nonimmune persons from malaria.
Randomized, double-blind, placebo-controlled field study.
A malaria-endemic area in Colombia.
176 healthy, young, nonimmune adult male soldiers.
Primaquine, 30 mg/d, or matching placebo during 15 weeks of patrol in the endemic area and 1 week afterward.
Symptomatic parasitemia was determined over the 16-week intervention period and for 3 weeks in base camp.
Protective efficacy in the primaquine group (122 participants) was 89% (95% CI, 75% to 96%) against all types of malaria, 94% (CI, 78% to 99%) against P. falciparum malaria, and 85% (CI, 57% to 95%) against P. vivax malaria. Six primaquine recipients had mild to moderate gastrointestinal distress, and three had severe distress.
For prophylaxis against P. falciparum malaria, primaquine has an efficacy and toxicity competitive with those of standard agents. A potential advantage of primaquine is that prophylaxis may be discontinued 1 week after the recipient has left the endemic area.
To define the current efficacy of Fansidar (F. Hoffmann-La Roche Ltd., Basel Switzerland) (pyrimethamine and sulfadoxine), primaquine in a high dose, and artesunate for treating acute Plasmodium vivax malaria, we conducted a comparative clinical trial of these 3 drugs in an open-label study. Patients (15-65 years old) were assigned to 1 of 4 treatments regimens in a serial order. Ninety percent of the patients were infected at Thailand-Myanmar border. Patients in group I (n = 23) received Fansidar (3 tablets, 75 mg of pyrimethamine and 1,500 mg of sulfadoxine, a single dose on the first day), group II (n = 23) received Fansidar (3 tablets, 75 mg of pyrimethamine and 1,500 mg of sulfadoxine, a single dose on the first day) and then received primaquine (30 mg a day for 14 days), group III (n = 23) received primaquine (30 mg a day for 14 days), and group IV (n = 23) received artesunate (200 mg once a day for 3 days) and then primaquine (30 mg a day for 14 days). Cure rates on day 28 of follow-up were 40%, 100%, 100%, and 100% in groups I, II, II, and IV, respectively. There were 4 and 5 patients in group I showing post-treatment reappearance of parasitemia at < or = 16 days and between 17 and 28 days, respectively. Patients in the other 3 groups showed negative parasitemias within 7 days after treatment. Artesunate plus primaquine (group IV) cleared parasitemia faster than the other 3 regimens. There is a high proportion of ineffectiveness of Fansidar for treatment of P. vivax malaria and it should be no longer used for treatment of P. vivax malaria acquired at the Thailand-Myanmar border. A high dose of primaquine is safe and effective in the treatment of P. vivax malaria during the 28-day follow-up period.
• 1.After 36 sequential subinoculations with suboptimal treatment of a single strain of vivax malaria, it has been possible to show a significant increase in trophozoite resistance to primaquine. In fact this resistance reached the point where maximum tolerated doses of primaquine had no action on parasitaemia and fever. This constitutes the maximum resistance that can be achieved in human volunteers.
• 2.During this programme gametocytes were observed to form and were transmitted through mosquitoes to the stage of mature and apparently viable sporozoites. These failed to infect man.
• 3.This induced resistance to primaquine should be one additional reason for always using primaquine in conjunction with a good blood schizontocide.
Methaemoglobin is formed by oxidation of ferrous (FeII) haem to the ferric (FeIII) state and the mechanisms by which this occurs are complex. Most cases are due to one of three processes. Firstly, direct oxidation of ferrohaemoglobin, which involves the transfer of electrons from ferrous haem to the oxidising compound. This mechanism proceeds most readily in the absence of oxygen. Secondly, indirect oxidation, a process of co-oxidation which requires haemoglobin-bound oxygen and is involved, for example, in nitrite-induced methaemoglobinaemia. Thirdly, biotransformation of a chemical to an active intermediate that initiates methaemoglobin formation by a variety of mechanisms. This is the means by which most aromatic compounds, such as amino- and nitro-derivatives of benzene, produce methaemoglobin. Methaemoglobinaemia is an uncommon occupational occurrence. Aromatic compounds are responsible for most cases, their lipophilic nature and volatility facilitating absorption during dermal and inhalational exposure, the principal routes implicated in the workplace. Methaemoglobinaemia presents clinically with symptoms and signs of tissue hypoxia. Concentrations around 80% are life-threatening. Features of toxicity may develop over hours or even days when exposure, whether by inhalation or repeated skin contact, is to relatively low concentrations of inducing chemical(s). Not all features observed in patients with methaemoglobinaemia are due to methaemoglobin formation. For example, the intravascular haemolysis caused by oxidising chemicals such as chlorates poses more risk to life than the methaemoglobinaemia that such chemicals induce. If an occupational history is taken, the diagnosis of methaemoglobinaemia should be relatively straightforward. In addition, two clinical observations may help: firstly, the victim is often less unwell than one would expect from the severity of 'cyanosis' and, secondly, the 'cyanosis' is unresponsive to oxygen therapy. Pulse oximetry is unreliable in the presence of methaemoglobinaemia. Arterial blood gas analysis is mandatory in severe poisoning and reveals normal partial pressures of oxygen (pO2) and carbon dioxide (pCO2,), a normal 'calculated' haemoglobin oxygen saturation, an increased methaemoglobin concentration and possibly a metabolic acidosis. Following decontamination, high-flow oxygen should be given to maximise oxygen carriage by remaining ferrous haem. No controlled trial of the efficacy of methylene blue has been performed but clinical experience suggests that methylene blue can increase the rate of methaemoglobin conversion to haemoglobin some 6-fold. Patients with features and/or methaemoglobin concentrations of 30-50%, should be administered methylene blue 1-2 mg/kg/bodyweight intravenously (the dose depending on the severity of the features), whereas those with methaemoglobin concentrations exceeding 50% should be given methylene blue 2 mg/kg intravenously. Symptomatic improvement usually occurs within 30 minutes and a second dose of methylene blue will be required in only very severe cases or if there is evidence of ongoing methaemoglobin formation. Methylene blue is less effective or ineffective in the presence of glucose-6-phosphate dehydrogenase deficiency since its antidotal action is dependent on nicotinamide-adenine dinucleotide phosphate (NADP+). In addition, methylene blue is most effective in intact erythrocytes; efficacy is reduced in the presence of haemolysis. Moreover, in the presence of haemolysis, high dose methylene blue (20-30 mg/kg) can itself initiate methaemoglobin formation. Supplemental antioxidants such as ascorbic acid (vitamin C), N-acetylcysteine and tocopherol (vitamin E) have been used as adjuvants or alternatives to methylene blue with no confirmed benefit. Exchange transfusion may have a role in the management of severe haemolysis or in G-6-P-D deficiency associated with life-threatening methaemoglobinaemia where methylene blue is relatively contraindicated.
Glucose-6-phosphate dehydrogenase deficiency, the most common enzyme deficiency worldwide, causes a spectrum of disease including neonatal hyperbilirubinemia, acute hemolysis, and chronic hemolysis. Persons with this condition also may be asymptomatic. This X-linked inherited disorder most commonly affects persons of African, Asian, Mediterranean, or Middle-Eastern descent. Approximately 400 million people are affected worldwide. Homozygotes and heterozygotes can be symptomatic, although the disease typically is more severe in persons who are homozygous for the deficiency. The conversion of nicotinamide adenine dinucleotide phosphate to its reduced form in erythrocytes is the basis of diagnostic testing for the deficiency. This usually is done by fluorescent spot test. Different gene mutations cause different levels of enzyme deficiency, with classes assigned to various degrees of deficiency and disease manifestation. Because acute hemolysis is caused by exposure to an oxidative stressor in the form of an infection, oxidative drug, or fava beans, treatment is geared toward avoidance of these and other stressors. Acute hemolysis is self-limited, but in rare instances it can be severe enough to warrant a blood transfusion. Neonatal hyperbilirubinemia may require treatment with phototherapy or exchange transfusion to prevent kernicterus. The variant that causes chronic hemolysis is uncommon because it is related to sporadic gene mutation rather than the more common inherited gene mutation.
