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Primaquine Therapy for Malaria
Abstract
Primaquine is the only available drug for preventing relapse of malaria, and confusion surrounds its use. This review examines
the wide range of clinical applications of primaquine described in the medical literature between 1946 and 2004. The risk
of relapse of Plasmodium vivax malaria without primaquine therapy ranged from 5% to 80% or more, depending largely upon geographic location. Supervision
of therapy profoundly impacts the risk of relapse, and almost all reports of malaria resistant to primaquine are associated
with lack of such supervision. We nonetheless suspect that there is widespread resistance to the standard course of primaquine
therapy, which is 15 mg primaquine base daily for 14 days. Clinical evidence confirms that a course of 15 mg daily for just
5 days, a regimen widely used in areas where malaria is endemic, has no discernible efficacy. This review supports a recommendation
for a regimen of 0.5 mg/kg primaquine daily for 14 days, on the basis of superior efficacy and good tolerability and safety
in nonpregnant persons without glucose-6-phosphate dehydrogenase deficiency.
... The pitfall in this TES is CQ blood level wasn't measured to investigate the presence of CQ resistant vivax malaria in the recurrent samples. PQ failure and P. vivax relapse is a major global public health concern [25,43]. Resistance or tolerance to PQ by P. vivax has been documented in Somalia and South East Asia [43][44][45]. ...
... PQ failure and P. vivax relapse is a major global public health concern [25,43]. Resistance or tolerance to PQ by P. vivax has been documented in Somalia and South East Asia [43][44][45]. True treatment failure with PQ is difficult to define due to the presence of confounding factors [24,25]. Potential risk factors for the occurrences of relapse after PQ treatment could be age and baseline anti-malarial immunity and quality of PQ drug being used [25], dose of treatment [46,47], duration of therapy [48], individual variations in CYP2D6 [49,50], adherence to treatment [24,25] and re-infection [51]. ...
... Though, it was reported that in Ethiopia about 29% of the population is known to carry active CYP2D6 gene duplications and multiplications associated with increased enzyme activity [53], and there is no report on the effect of CYP2D6 activity for PQ metabolism in Ethiopia. Though there are other factors impact the risk of relapse after PQ therapy, it was suggested that almost all reports of malaria resistant to PQ are associated with lack of such supervision [43]. Regarding adherence to treatment, in this s study for the first four days (day 0 to day 3) treatment with CQ and PQ were directly observed and from day 4 up to 13 PQ was given to the patients to be taken at home and adherence was assessed by tablet review at the subsequent visit. ...
Background
Ethiopia rolled out primaquine nationwide in 2018 for radical cure along with chloroquine for the treatment of uncomplicated Plasmodium vivax malaria in its bid for malaria elimination by 2030. The emergence of anti-malarial drug resistance would challenge the elimination goal. There is limited evidence on the emergence of chloroquine drug resistance. The clinical and parasitological outcomes of treatment of P. vivax with chloroquine plus radical cure using low dose 14 days primaquine were assessed in an endemic area of Ethiopia.
Methods
A semi-directly observed 42-days follow up in-vivo therapeutic efficacy study was conducted from October 2019 to February 2020. Plasmodium vivax mono-species infected patients (n = 102) treated with a 14 days low dose (0.25 mg/kg body weight per day) primaquine plus chloroquine (a total dose of 25 mg base/kg for 3 days) were followed for 42 days to examine clinical and parasitological outcomes. Samples collected at recruitment and days of recurrence were examined by 18 S based nested polymerase chain reaction (nPCR) and Pvmsp3α nPCR-restriction fragment length polymorphism. Asexual parasitaemia and the presence of gametocytes were assessed on the scheduled days using microscopy. Clinical symptoms, haemoglobin levels, and Hillmen urine test were also assessed.
Results
Of the 102 patients followed in this study, no early clinical and parasitological failure was observed. All patients had adequate clinical and parasitological responses within the 28 days of follow up. Late clinical (n = 3) and parasitological (n = 6) failures were observed only after day 28. The cumulative incidence of failure was 10.9% (95% confidence interval, 5.8–19.9%) on day 42. Among the paired recurrent samples, identical clones were detected only in two samples on day 0 and day of recurrences (day 30 and 42) using Pvmsp3α genotyping. No adverse effect was detected related to the low dose 14 days primaquine administrations.
Conclusion
Co-administration of CQ with PQ in the study area is well tolerated and there was no recurrence of P. vivax before 28 days of follow up. Interpretation of CQ plus PQ efficacy should be done with caution especially when the recurrent parasitaemia occurs after day 28. Therapeutic efficacy studies with appropriate design might be informative to rule out chloroquine or primaquine drug resistance and/or metabolism in the study area.
... Primaquine is an 8-aminoquinoline pro-drug indicated for radical cure of Plasmodium vivax and Plasmodium ovale infection [12][13][14]. It is also the only readily available drug potent against mature P. falciparum gametocytes, a parasite stage responsible for onward transmission of the infection [12,15,16]. ...
... Primaquine is an 8-aminoquinoline pro-drug indicated for radical cure of Plasmodium vivax and Plasmodium ovale infection [12][13][14]. It is also the only readily available drug potent against mature P. falciparum gametocytes, a parasite stage responsible for onward transmission of the infection [12,15,16]. The World Health Organization (WHO) recommends the addition of 0.25 mg/kg singledose primaquine to ACT for the elimination of malaria in low transmission settings and containment in areas threatened by artemisinin resistance [4,17]. ...
... Primaquine is the only approved anti-malarial drug potent against mature P. falciparum gametocytes [12,16,59,60]. The drug is, however, metabolized by the CYP2D6 enzyme to its active metabolite, and previous studies have indicated the safety and efficacy of primaquine for reducing transmission of P. falciparum gametocytes, to probably be influenced by the polymorphic nature of the gene encoding this enzyme [26,28,29,36,61]. ...
Background
Primaquine is a pro-drug and its active metabolite is potent against mature Plasmodium falciparum gametocytes. Primaquine is metabolized by a highly polymorphic cytochrome P450 2D6 (CYP2D6) enzyme. Mutations in the gene encoding this enzyme may lead to impaired primaquine activity. This study assessed if 0.25 mg/kg single-dose primaquine is safe and sufficient to reduce transmission of gametocytes in individuals with no, reduced, or increased CYP2D6 enzyme activity.
Methods
Between June 2019 and January 2020 children aged 1–10 years, attending at Yombo dispensary, Bagamoyo district, with confirmed microcopy-determined uncomplicated P. falciparum malaria were enrolled in the study. The enrolled patients were treated with a standard artemether-lumefantrine regimen plus 0.25 mg/kg single-dose primaquine and followed up for 28 days for clinical and laboratory assessment. Primaquine was administered with the first dose of artemether-lumefantrine. Safety assessment involved direct questioning and recording of the nature and incidence of clinical signs and symptoms, and measurement of haemoglobin (Hb) concentration. Blood samples collected from 100 patients were used for assessment of post-treatment infectiousness on day 7 using mosquito membrane feeding assays. Molecular methods were used to determine CYP2D6 and glucose-6-phosphate dehydrogenase (G6PD) status. The primary outcome was the safety of 0.25 mg/kg single-dose primaquine based on CYP2D6 status.
Results
In total, 157 children [median age 6.4 (Interquartile range 4.0–8.2) years] were recruited, of whom 21.0% (33/157) and 12.7% (20/157) had reduced CYP2D6 and deficient G6PD activity, respectively. Day 3 mean absolute Hb concentration reduction was 1.50 g/dL [95% confidence interval (CI) 1.10–1.90] and 1.51 g/dL (95% CI 1.31–1.71) in reduced and normal CYP2D6 patients, respectively ( t = 0.012, p = 0.990). The day 3 mean absolute Hb concentration reduction in G6PD deficient, G6PD normal and heterozygous female was 1.82 g/dL (95% CI 1.32–2.32), 1.48 g/dL (95% CI 1.30–1.67) and 1.47 g/dL (95% CI 0.76–2.18), respectively ( F = 0.838, p = 0.435). Sixteen percent (16/98) of the patients each infected at least one mosquito on day 7, and of these, 10.0% (2/20) and 17.9% (14/78) had reduced and normal CYP2D6 enzyme activity, respectively ( x 2 = 0.736, p = 0.513).
Conclusion
Single-dose 0.25 mg/kg primaquine was safe and sufficient for reducing transmission of P. falciparum gametocytes regardless of CYP2D6 or G6PD status.
Trial registration Study registration number: NCT03352843.
... It has activity against intra-hepatic schizonts and hypnozoites of P. vivax and P. ovale [45]; thus it is indicated for a radical cure of P. vivax and P. ovale infection, for causal prophylaxis, and terminal prophylaxis [18,19,44,45]. Primaquine is also potent against mature P. falciparum gametocytes, a parasite stage responsible for the transmission of the infection from human to female Anopheles mosquito [19,45,46]. Whereas it is given daily for 14 days for radical cure of vivax and ovale malaria, when used as P. falciparum gametocytocidal primaquine it is given as a single dose [43]. ...
... Primaquine however induces a dose-dependent hemolysis of the red blood cells (RBCs) in individuals with G6PD deficiency leading to acute hemolytic anemia (AHA) [18,43,46,47,[49][50][51][52], an adverse effect that has led to limited use of the drug especially in SSA where the condition is more prevalent [44]. The AHA can be lifethreatening since massive intravascular hemolysis with hemoglobinuria may precipitate acute renal failure especially in adults [43,45]. ...
... Primaquine is the only approved antimalarial drug that can sterilize and kill mature P. falciparum gametocytes, and therefore, reduce the transmission of the parasite [19,45,46]. However, administered at higher doses of 0.5-0.75 ...
Primaquine is a gametocytocidal drug known to significantly reduce malaria transmission. However, primaquine induces a dose-dependent acute hemolytic anemia (AHA) in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency that has led to a limited use of the drug especially in Africa where the condition is common. The World Health Organization (WHO) now recommends a single low dose (SLD) of primaquine (0.25 mg/kg) as P. falciparum gametocytocidal without the need for prior screening of G6PD status. Adoption and implementation of SLD primaquine in Africa may probably reduce malaria transmission, a pre-requisite for malaria elimination. This review therefore, focused on the safety of primaquine for control of malaria in Africa. The literature search was performed using online database Google Scholar, PubMed, HINARI, and Science Direct. Search terms used were “malaria”, “primaquine”, “safety”, “G6PD deficiency”, “large scale” or “mass administration”. Clinical trials in many African countries have shown SLD primaquine to be safe especially in a milder African G6PD A- variant. Likewise, large-scale primaquine administrations outside Africa involving hundreds of thousands to tenths of millions of participants and with severe variants of G6PD deficiency have also shown primaquine to be safe and well-tolerated. Fourteen deaths associated with primaquine have been reported globally over the past 6 decades, but none occurred following the administration of SLD primaquine. Available evidence shows that the WHO-recommended SLD primaquine dose added to effective schizonticides is safe and well-tolerated even in individuals with G6PD deficiency, and therefore, it can be safely used in the African population with the mildest G6PD A- variant.
... [4][5][6] Relapse is the main cause of vivax illness in endemic areas. 6,7 Primaquine, an 8-aminoquinoline, is the only widely available drug that kills hypnozoites and prevents relapses, 8 but its use is limited by the risk of acute haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. When supervised, a 14-day regimen of primaquine effectively prevents P vivax relapses. ...
... 16,17 The primary determinant of the radical curative efficacy of primaquine is the total dose administered. 8 Shorter courses with higher daily doses might improve adherence, and thus effectiveness, without reducing efficacy, 18,19 but concerns over safety in patients with unknown G6PD status have made policy makers reluctant to adopt this strategy. The primary objective of this study was to evaluate the tolerability, safety, and efficacy of a 7-day high-dose (1 mg/kg per day) primaquine regimen for the radical cure of vivax malaria in patients screened as G6PD normal. ...
... The median time to haemoglobin nadir was 3 days (IQR 3-7) in the placebo group and 3 days (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) in both primaquine groups. The mean absolute decreases in haemoglobin at day 3 were 0·52 g/dL (SD 1·19) in the 7-day primaquine group, 0·62 g/dL (1·09) in the 14-day group, and 0·72 g/dL (1·12) in the placebo group. ...
Background
Primaquine is the only widely used drug that prevents Plasmodium vivax malaria relapses, but adherence to the standard 14-day regimen is poor. We aimed to assess the efficacy of a shorter course (7 days) of primaquine for radical cure of vivax malaria.
Methods
We did a randomised, double-blind, placebo-controlled, non-inferiority trial in eight health-care clinics (two each in Afghanistan, Ethiopia, Indonesia, and Vietnam). Patients (aged ≥6 months) with normal glucose-6-phosphate dehydrogenase (G6PD) and presenting with uncomplicated vivax malaria were enrolled. Patients were given standard blood schizontocidal treatment and randomly assigned (2:2:1) to receive 7 days of supervised primaquine (1·0 mg/kg per day), 14 days of supervised primaquine (0·5 mg/kg per day), or placebo. The primary endpoint was the incidence rate of symptomatic P vivax parasitaemia during the 12-month follow-up period, assessed in the intention-to-treat population. A margin of 0·07 recurrences per person-year was used to establish non-inferiority of the 7-day regimen compared with the 14-day regimen. This trial is registered at ClinicalTrials.gov (NCT01814683).
Findings
Between July 20, 2014, and Nov 25, 2017, 2336 patients were enrolled. The incidence rate of symptomatic recurrent P vivax malaria was 0·18 (95% CI 0·15 to 0·21) recurrences per person-year for 935 patients in the 7-day primaquine group and 0·16 (0·13 to 0·18) for 937 patients in the 14-day primaquine group, a difference of 0·02 (−0·02 to 0·05, p=0·3405). The incidence rate for 464 patients in the placebo group was 0·96 (95% CI 0·83 to 1·08) recurrences per person-year. Potentially drug-related serious adverse events within 42 days of starting treatment were reported in nine (1·0%) of 935 patients in the 7-day group, one (0·1%) of 937 in the 14-day group and none of 464 in the control arm. Four of the serious adverse events were significant haemolysis (three in the 7-day group and one in the 14-day group).
Interpretation
In patients with normal G6PD, 7-day primaquine was well tolerated and non-inferior to 14-day primaquine. The short-course regimen might improve adherence and therefore the effectiveness of primaquine for radical cure of P vivax malaria
... Although PQ-based treatment is generally successful in curing P. vivax malaria, there have been reports of obese individuals exhibiting relapse after the completion of the recommended treatment regimen [7][8][9]. As the anti-parasitic effects of PQ depend on the patient's exposure to the drug, the most likely cause of this treatment failure is insufficient PQ exposure [7][8][9]. ...
... Although PQ-based treatment is generally successful in curing P. vivax malaria, there have been reports of obese individuals exhibiting relapse after the completion of the recommended treatment regimen [7][8][9]. As the anti-parasitic effects of PQ depend on the patient's exposure to the drug, the most likely cause of this treatment failure is insufficient PQ exposure [7][8][9]. In this respect, it has been suggested that the dose should be adjusted in obese patients [10], however, there have been limited reports of dose adjustment in such patients. ...
... BW was found to be in our study a significant covariate to ensure an adequate exposure level of PQ, which was consitent with a previous result [7,12,28,29]. However, there is a lack of study regarding the influence of obesity on the PK of PQ, and the plausible mechanism for this is currently unknown. ...
While primaquine has long been used for malaria treatment, treatment failure is common. This study aims to develop a population pharmacokinetic model of primaquine and its metabolite, carboxyprimaquine, and examine factors influencing pharmacokinetic variability. The data was obtained from a clinical study in 24 Korean subjects randomly assigned to normal and obese groups. The participants received primaquine 15 mg daily for 4 days and blood samples were collected at day 4. Pharmacokinetic modeling was performed with NONMEM and using simulations; the influences of doses and covariates on drug exposure were examined. A minimal physiology-based pharmacokinetic model connected with a liver compartment comprehensively described the data, with CYP450 mediated clearance being positively correlated with the body weight and CYP2D6 activity score (p < 0.05). In the simulation, while the weight-normalized area under drug concentration for primaquine in the obese group decreased by 29% at the current recommended dose of 15 mg, it became similar to the normal weight group at a weight-normalized dose of 3.5 mg/kg. This study has demonstrated that the body weight and CYP2D6 activity score significantly influence the pharmacokinetics of primaquine. The developed model is expected to be used as a basis for optimal malaria treatment in Korean patients.
... Primaquine is, however, contraindicated in pregnant women, infants, and persons with the deficiency of glucose-6-phosphate dehydrogenase (G6PD) (78)(79)(80). Because of the risk of foetalhaemolysis, it is strongly not recommended for pregnant women (79). ...
... It is also concerning that the new ACT medication has a lower impact on P. vivax than on P. falciparum (93). Dihydroartemisininpiperaquine or Artemether-lumefantrine combinations are generally used, where a high level of resistance of P. vivax to chloroquine is detected (78). Therefore, there is an urgent need for revised P. vivax treatment guidelines to control and eliminate P. vivax malaria. ...
Plasmodium vivax is geographically the most widely dispersed human malaria parasite species. It has shown resilience and a great deal of adaptability. Genomic studies suggest that P. vivax originated from Asia or Africa and moved to the rest of the world. Although P. vivax is evolutionarily an older species than Plasmodium falciparum, its biology, transmission, pathology, and control still require better elucidation. P. vivax poses problems for malaria elimination because of the ability of a single primary infection to produce multiple relapses over months and years. P. vivax malaria elimination program needs early diagnosis, and prompt and complete radical treatment, which is challenging, to simultaneously exterminate the circulating parasites and dormant hypnozoites lodged in the hepatocytes of the host liver. As prompt surveillance and effective treatments are rolled out, preventing primaquine toxicity in the patients having glucose-6-phosphate dehydrogenase (G6PD) deficiency should be a priority for the vivax elimination program. This review sheds light on the burden of P. vivax, changing epidemiological patterns, the hurdles in elimination efforts, and the essential tools needed not just in India but globally. These tools encompass innovative treatments for eliminating dormant parasites, coping with evolving drug resistance, and the development of potential vaccines against the parasite.
... Whether or not to use primaquine in this group of patients must be considered on a case-by-case basis. [57] In pregnant women, primaquine is contraindicated because of the risk of fetal hemolysis. [58] Treatment with primaquine should be delayed until after delivery. ...
Malaria is referred to as imported malaria in countries outside malaria-endemic areas such as Morocco. The aim of our study was to highlight the importance of epidemiological data for the diagnosis of imported malaria. A 29-year-old moroccan female, presenting with a 3-month history of headache unresolved with usual analgesics, for which she was put on antidepressants and neuroleptics. She then presented to the emergency department with nausea, vomiting, abdominal pain, and fever. History and clinical examination revealed only mild abdominal pain with fever. Blood count showed anemia at 10.4 g/dl, MCHC at 34, MCH at 32, MCV at 90 fl and reticulocytes at 157920.Symptomatic treatment was given and the patient was referred to the haematology department for etiological diagnosis of her regenerative normocytic normochromic anaemia.Patient was then referred to Internal Medicine, the patient reported having visited Pakistan 1 year previously.In view of this situation, and taking into account the fact that she had travelled to a malaria-endemic area, a thin blood smear (TBS) and a thick blood smear stained with MGG were carried out urgently. A diagnosis of P. vivax malaria was established. Results were communicated immediately to the attending physician, and treatment was administered in an outpatient setting.
... Primaquine therapy, known as radical cure, is a World Health Organization (WHO)-recommended regimen for eradicating the liver stage of P. vivax malaria. However, there is a risk of potentially fatal haemolysis (acute haemolytic anaemia, or AHA) among G6PD deficient individuals, limiting the proportion of the population that can safely receive radical cure treatment with primaquine [5][6][7]. Therefore, WHO guidelines in 2016 recommend a 14-day primaquine regimen with 0.25 to 0.5 mg base per kilogram for patients without G6PD deficiency ("G6PD normal"), and an 8-week primaquine regimen with 0.75 mg base per kilogram for G6PD deficient patients when administered under medical supervision [8]. Additionally, the WHO recommends that patients' G6PD status should be tested before prescribing primaquine [9]. ...
Background
Cambodia aims to eliminate all forms of malaria by 2025. In 2020, 90% of all malaria cases were Plasmodium vivax. Thus, preventing P. vivax and relapse malaria is a top priority for elimination. 14-day primaquine, a World Health Organization-recommended radical cure treatment regimen, specifically targets dormant hypnozoites in the liver to prevent relapse. Cambodia introduced P. vivax radical cure with primaquine after glucose-6-phosphate dehydrogenase (G6PD) qualitative testing in 2019. This paper presents Cambodia’s radical cure Phase I implementation results and assesses the safety, effectiveness, and feasibility of the programme prior to nationwide scale up.
Methods
Phase I implementation was carried out in 88 select health facilities (HFs) across four provinces. Males over 20kgs with confirmed P. vivax or mixed (P. vivax and Plasmodium falciparum) infections were enrolled. A descriptive analysis evaluated the following: successful referral to health facilities, G6PD testing results, and self-reported 14-day treatment adherence. P. vivax incidence was compared before and after radical cure rollout and a controlled interrupted time series analysis compared the estimated relapse rate between implementation and non-implementation provinces before and after radical cure.
Results
In the 4 provinces from November 2019 to December 2020, 3,239 P. vivax/mixed infections were reported, 1,282 patients underwent G6PD deficiency testing, and 959 patients received radical cure, achieving 29.6% radical cure coverage among all P. vivax/mixed cases and 98.8% coverage among G6PD normal patients. Among those who initiated radical cure, 747 patients (78%) completed treatment. Six patients reported side effects. In implementation provinces, an average 31.8 relapse cases per month were estimated signaling a 90% (286 cases) reduction in relapse compared to what would be expected if radical cure was not implemented.
Conclusions
Plasmodium vivax radical cure is a crucial tool for malaria elimination in Cambodia. The high coverage of radical cure initiation and adherence among G6PD normal patients demonstrated the high feasibility of providing radical cure at point of care in Cambodia. Incomplete referral from community to HFs and limited capacity of HF staff to conduct G6PD testing in high burden areas led to lower coverage of G6PD testing. Phase I implementation informed approaches to improve referral completion and patient adherence during the nationwide expansion of radical cure in 2021.
... • The rosette stage: the nuclei are divided at the maximum (16)(17)(18)(19)(20)(21)(22)(23)(24). Sometimes we can also see the division of the protoplasm surrounding each nucleus, resulting in merozoites of 40-80μm diameter. ...
GUIDE OF MAIN PARASITIC DISEASES TRANSMITTED FROM NON-HUMAN ANIMALS TO HUMANS
... Therefore, it is imperative to persist in developing new anticancer medications [5]. Quinoline is a nitrogen containing pharmacophore occur in several natural compounds and synthetic derivatives used in numerous medications, such as chloroquine [6], amodiaquine [7], mefloquine [8], piperaquine [9] and primaquine [10] used as antimalarial agents, pitavastatin is used for lowering the cholesterol [11], lenvatinib [12], carbozatinib [13] and bosutinib [14] are used as anticancer agents, saquinavir [15] used as antiretroviral agent and lophocerine as antibiotic [16] are well known in literature. ...
Regioselective synthesis of a series of 1-aryl 1,2,3-triazoles-4-methoxy methyl-3-quinoline-2-morpholine employing click reaction is presented. Highly selective and efficient copper(I)-catalyzed 1,3-dipolar cycloaddition between 2-morpholinoquinoline-3-methyl propargyl ether and various aryl azides 5a-j yielded the title compounds 6a-j in 71% to 85%. The structure of all the novel 1,2,3-triazoles was characterized by 1H NMR, 13C NMR, IR and mass spectral analysis. The analogues were evaluated for their in vitro anticancer activity against MDA-MB-231 cell line. All the synthesized compounds were proven to have anticancer activity in comparison to reference drug doxorubicin. Especially, chloro and fluoro substituent compounds demonstrated potent activity with IC50 values of 17.20 ± 0.09 µM and 23.56 ± 0.09 µM, which proved their efficacy and could be further studied for the development of novel chemotherapeutics.
... G6PD testing is recommended by the World Health Organization (WHO) before giving 8-aminoquinolones for radical cure of P. vivax but this has only been rolled out to health centres and hospitals in Cambodia. Administering 8-aminoquinolones in G6PD-deficient patients can cause haemolysis [27][28][29][30]. Although there are various options for G6PD enzyme assessment, point-ofcare tests are seen as the most promising and are being implemented [31][32][33][34][35][36]. ...
In Southeast Asia malaria elimination is targeted by 2030. Cambodia aims to achieve this by 2025, driven in large part by the urgent need to control the spread of artemisinin-resistant falciparum malaria infections. Rapid elimination depends on sustaining early access to diagnosis and effective treatment. In much of Cambodia, rapid elimination will rely on a village malaria worker (VMW) network. Yet as malaria declines and is no longer a common cause of febrile illness, VMWs may become less popular with febrile patients, as VMWs do not diagnose or treat other conditions at present. There is a risk that VMWs become inactive and malaria rebounds before the complete interruption of transmission is achieved.
During 2021–23 a large-scale operational research study was conducted in western Cambodia to explore how a VMW network could be sustained by including health activities that cover non-malarial illnesses to encourage febrile patients to continue to attend. 105 VMWs received new rapid diagnostic tests (including dengue antigen–antibody and combined malaria/C-reactive protein tests), were trained in electronic data collection, and attended health education packages on hygiene and sanitation, disease surveillance and first aid, management of mild illness, and vaccination and antenatal care.
In August 2023 the National Malaria Control Programme of Cambodia convened a stakeholder meeting in Battambang, Cambodia. Findings from the study were reviewed in the context of current malaria elimination strategies. The discussions informed policy options to sustain the relevance of the VMW network in Cambodia, and the potential for its integration with other health worker networks. This expansion could ensure VMWs remain active and relevant until malaria elimination is accomplished.
... Recommended anti-malarial regimens for P. vivax include a three-day course of schizontocidal drugs such as chloroquine or artemisinin-based combination therapy, plus a 7-to 14-day course of primaquine for hypnozoitocidal treatment [50]. Adherence to the blood schizontocidal therapy tends to be better when patients are clinically unwell with malaria, however, subsequent adherence to primaquine then decreases as patients begin to feel better [16,51]. In turn, poor adherence and supervision have been associated with reduced effectiveness of primaquine radical cure regimens [7,52]. ...
Background:
Imperfect adherence is a major barrier to effective primaquine radical cure of Plasmodium vivax. This study investigated the effect of reduced adherence on the risk of P. vivax recurrence.
Methods:
Efficacy studies of patients with uncomplicated P. vivax malaria, including a treatment arm with daily primaquine, published between January 1999 and March 2020 were identified. Individual patient data from eligible studies were pooled using standardized methodology. Adherence to primaquine was inferred from i) the percentage of supervised doses and ii) the total mg/kg dose received compared to the target total mg/kg dose per protocol. The effect of adherence to primaquine on the incidence of P. vivax recurrence between days 7 and 90 was investigated by Cox regression analysis.
Results:
Of 82 eligible studies, 32 were available including 6917 patients from 18 countries. For adherence assessed by percentage of supervised primaquine, 2790 patients (40.3%) had poor adherence (≤ 50%) and 4127 (59.7%) had complete adherence. The risk of recurrence by day 90 was 14.0% [95% confidence interval: 12.1-16.1] in patients with poor adherence compared to 5.8% [5.0-6.7] following full adherence; p = 0.014. After controlling for age, sex, baseline parasitaemia, and total primaquine dose per protocol, the rate of the first recurrence was higher following poor adherence compared to patients with full adherence (adjusted hazard ratio (AHR) = 2.3 [1.8-2.9]). When adherence was quantified by total mg/kg dose received among 3706 patients, 347 (9.4%) had poor adherence, 88 (2.4%) had moderate adherence, and 3271 (88.2%) had complete adherence to treatment. The risks of recurrence by day 90 were 8.2% [4.3-15.2] in patients with poor adherence and 4.9% [4.1-5.8] in patients with full adherence; p < 0.001.
Conclusion:
Reduced adherence, including less supervision, increases the risk of vivax recurrence.
... For P. falciparum treatment, artemisinin derivates prevent gametocyte development, while primaquine is the only drug known to act on mature gametocytes [1]. Primaquine has been used for radical cure of P. vivax [38] and also kills the asexual blood stages of P. vivax in therapeutic doses [37], as well as neutralizes the infectivity of mature P. vivax gametocytes to mosquitoes [39]. Klein et al. [40] showed that, when combined, chloroquine and primaquine required at least 5 h to affect transmissibility, and these data agree with the data reported in the present study. ...
Malaria is caused by parasite of the genus Plasmodium and is still one of the most important infectious diseases in the world. Several biological characteristics of P. vivax contribute to the resilience of this species, including early gametocyte production, both of which lead to efficient malaria transmission to mosquitoes. This study evaluated the impact of currently used drugs on the transmission of P. vivax. Participants received one of the following treatments for malaria: i) chloroquine [10 mg/kg on day 1 and 7.5 mg/kg on day 2 and 3] co-administered with Primaquine [0.5 mg/kg/day for 7 days]; ii) Chloroquine [10 mg/kg on day 1 and 7.5 mg/kg on day 2 and 3] co-administered with one-dose of Tafenoquine [300 mg on day 1]; and iii) Artesunate and Mefloquine [100 mg and 200 mg on day 1, 2 and 3] co-administered with Primaquine [0.5 mg/kg/day for 14 days]. Patient blood was collected before treatment and 4 h, 24 h, 48 h and 72 h after treatment. The blood was used to perform a direct membrane feeding assay (DMFA) using Anopheles darlingi mosquitoes. The results showed 100% inhibition of the mosquito infection after 4 h using ASMQ+PQ, after 24 h for the combination of CQ+PQ and 48 h using CQ+TQ. The density of gametocytes declined over time in all treatment groups, although the decline was more rapid in the ASMQ+PQ group. In conclusion, it was possible to demonstrate the transmission-blocking efficacy of the malaria vivax treatment and that ASMQ+PQ acts faster than the two other treatments.
... The mechanism is unclear. It interferes with the mitochondrial ETS pathway and destroys mitochondria Mitochondria [32] 15 Proguanil Proguanil inhibits dihydrofolate reductase of the Plasmodium, which blocks the purine and pyrimidine biosynthesis. This inhibition leads to nuclear division failure at schizont formation in the liver and erythrocytes Inhibition of DNA synthesis RBC, liver malaria: the past and the present [33] 16 Pyrimethamine Pyrimethamine inhibits dihydro-folate reductase (DHFR). ...
Malaria is a vector-borne parasitic disease caused by the apicomplexan protozoan parasite Plasmodium. Malaria is a significant health problem and the leading cause of socioeconomic losses in developing countries. WHO approved several antimalarials in the last 2 decades, but the growing resistance against the available drugs has worsened the scenario. Drug resistance and diversity among Plasmodium strains hinder the path of eradicating malaria leading to the use of new technologies and strategies to develop effective vaccines and drugs. A timely and accurate diagnosis is crucial for any disease, including malaria. The available diagnostic methods for malaria include microscopy, RDT, PCR, and non-invasive diagnosis. Recently, there have been several developments in detecting malaria, with improvements leading to achieving an accurate, quick, cost-effective, and non-invasive diagnostic tool for malaria. Several vaccine candidates with new methods and antigens are under investigation and moving forward to be considered for clinical trials. This article concisely reviews basic malaria biology, the parasite's life cycle, approved drugs, vaccine candidates, and available diagnostic approaches. It emphasizes new avenues of therapeutics for malaria.
Graphical Abstract
... Doxycycline is avoided during pregnancy because other tetracyclines have been associated with transient suppression of bone growth and with staining of developing teeth, but available data do not show teratogenic effects from doxycycline. Pregnancy is a contraindication for primaquine therapy since it is not possible to assess G6PD status of a fetus in utero (Baird and Hoffman, 2004). Primaquine and the tetracyclines should be avoided while breastfeeding (White, 1996). ...
... Quinoline is a key pharmacophore with diverse biological profile in many drugs such as chloroquine [8], amodiaquine [9], mefloquine [10], piperaquine [11], and primaquine [12] used as antimalarial agents, pitavastatin is used for lowering the cholesterol [13], lenvatinib [14,15], carbozatinib [16], and bosutinib [17] are anticancer agents, saquinavir [18] used as antiretroviral agent, bedaquiline [19] is an antituberculosis medicine and lophocereine as antibiotic [20] are well known in literature. Besides, 1,2,3-triazole has vital role in medicinal field by showing antimicrobial [21][22][23][24] anticancer [25,26] anti-HIV [27,28] antimalarial [29] antiinflammatory [30,31] anti-tubercular [32,33] activities. ...
A novel series of quinoline-based 1,2,3-triazole hybrids were developed by copper-catalyzed 1,3-dipolar cycloaddition reactions of terminal alkyne appended to quinoline and aromatic/aliphatic azides individually. Structure of all the newly synthesized molecules was analyzed and confirmed based on 1H-NMR, 13C-NMR and HRMS data. Cytotoxicity of all molecules was evaluated against MCF-7 cell line by MTT assay in various µM concentrations. The activity of a few compounds of this series is comparable to that of marketed drug Cisplatin. All the molecules showed good to moderate activity. The 2-chloro (7a) and 4-chloro (7b) substituted analogs showed excellent activity with IC50 values of 7.46 and 6.45 μM, respectively, and the t-butyloxycarbonyl containing azetidine and pyperizine-substituted analogs showed moderate activity compared to Cisplatin. The Molecular docking performed against human estrogen receptor alpha ligand-binding domain and in-silico evaluation of pharmacokinetics are in favor to the experimental data.Graphical abstract
... NPC1161B (Fig. 13) is an enantiomerically pure compound of the 8-aminoquinoline class, which was derived from primaquine by medicinal chemistry efforts to identify compounds with better safety and efficacy profiles. Prior to the identification of this compound and its related analogue, tafenoquine and primaquine (Fig. 13) had been the only drugs of choice for the radical cure of the relapsing form of malaria due to P. vivax infections [122]. However, to clear P. vivax parasites from the body, primaquine therapy requires administration for fourteen days and is contraindicated in patients with G6PD (glucose 6-phosphate dehydrogenase) deficiency as they are predisposed to an increased risk of haemolysis [123]. ...
Background
The downward trend in malaria cases and deaths is steadily reversed – 627,000 deaths in 2020 compared to 405,000 deaths in 2018. Drug resistance has compromised the effectiveness of currently available treatment options, with some reports documenting molecular markers of resistance to artemisinins in African countries in addition to the Greater Mekong subregion, which was initially associated with this kind of resistance. Therefore, the development of novel drugs is crucial to replenishing the antimalarial drug arsenal toward malaria eradication. In this review, we summarize the progress made in antimalarial drug discovery in the period 2000 – 2022, focusing on drug candidates which have made it to advanced preclinical trials (drugs tested in rodent species and at least one higher species such as dog or monkey) and beyond.
Method
We searched Google Scholar and selected studies meeting these defined criteria. We highlight the medicinal chemistry optimization of these compounds; the preclinical/clinical evaluation and the mechanisms of action.
Results and conclusion
Although the pipeline seems promising, the prospect of having an antimalarial medicine that meets the current target product profiles (TPPs) towards the malaria eradication agenda is far from reality. Some of the key TPP attributes required include multistage activity, resistance-proof; ability to achieve a single dose cure and safety across a wide range of patient populations. Clinical trials are ongoing for some promising molecules, inspiring optimism toward identifying better drugs that meet these defined TPPs. Until then, concerted research efforts should continue to be mounted to populate the antimalarial drug discovery and development pipeline.
... 27 In endemic countries like India, these relapses are main cause of malaria than primary infection itself. 28,29 Primaquine is only drug that most effectively targets P.vivax hypnozoites. 30 However, Primaquine is known to cause hemolysis in G-6-P-D deficient individuals. ...
Background: In India, severe Malaria as well as malnutrition is quite prevalent in children. Till now, relationship between malnutrition and malaria remains inconclusive. Therefore, this study was carried out as an attempt to find relationship between severe malaria and malnutrition in pediatric age group. Materials and methods: Study design was observational and was conducted in a tertiary care center in Uttar Pradesh. In age group of 6 month-18 years, total of 200 children suffering of severe malaria were included in study. Patients were classified into severe malaria as per WHO guidelines. Diagnosis and grading of malnutrition was done as per WHO guidelines for malnutrition. Results: In age group of 0.5-5 years, comprising of 64 children with severe malaria, 56(87.5%) were malnour-ished while 8(12.5%) were well nourished. In age group of 5-18 years comprising of 136 cases of severe malaria, 103 (75.7%) were malnourished while 33 (24.3%) were well nourished. In 0.5-5 years of age group, all three species of malaria were found to be affecting malnourished children in higher percentage as compared to well nourished children.. However, in 5-18 years of age group, cases of P.vivax severe malaria were significantly higher in malnourished children. Conclusion: This study showed higher percentage of malnourished children as compared to healthy children in cases of severe malaria and P.vivax cases with undernutrition to be significantly higher than other malarial parasites with undernutrition in 5-18 years age group. Therefore, malaria control strategies and nutritional intervention programmes should be consolidated together.
... Primaquineis the only FDA licensed therapy to treat relapsing strains of malaria. These strains include Plasmodium vivax and Plasmodium ovale and relapses are assumed to be caused by the reactivation of dormant liver forms of the parasites called hypnozoites [6,7]. Primaquine, introduced in 1950, for preventing relapse and sterilizes infectious sexual plasmodia, and among the several widely used regimens, none has been adequately evaluated [8]. ...
Background: Malaria is a major public health problem throughout human history, particularly in the tropical and subtropical countries. Primaquine, introduced in 1950, for preventing relapse and sterilizes infectious sexual plasmodia. Methods: A retrospective study was performed for 610 patients (250 were male and 360 were female), (all ages) to study the efficacy of Primaquine in the treatment of falciparum malaria after receiving this drug for five days. Results: Five hundred and ninety three patients (97.2 %) were completely recovered from malaria within 3 to 5 days after receiving Primaquine tablets. Conclusion: In our opinion Primaquine should become the first line as antimalarial drug soon later for uncomplicated malaria, because of its high efficiency against infections with Plasmodiumfalciparum and P.vivax active stages.
... Hypnozoites lie dormant for weeks to months after the primary infection until they develop into mature liver-stage schizonts containing thousands of merozoites. Eventually, the schizonts burst and release merozoites into the bloodstream to infect red blood cells (RBCs), resulting in the relapse of malaria (2,3). ...
Primaquine (PQ), an 8-aminoquinoline antimalarial drug, has been widely used for the eradication of hypnozoites from the liver and, therefore, recognized as the radical cure of malaria. However, the clinical applications of PQ are restricted to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to severe dose-related hemolytic side effects. Nanoparticle carriers have shown great potential in achieving higher PQ concentrations in the target site, thereby reducing dose-related systemic toxicity caused by non-specific exposure. This work aims to develop, compare, and evaluate three PQ-loaded lipid-based drug carriers including solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), and nano-emulsions (NE). The optimized PQ-SLN, PQ-NLC, and PQ-NE had a particle size of 250 nm, a PDI range of 0.1 to 0.3, a zeta potential of − 30 mV, and entrapment efficiency of ~ 90%. All lipid formulations showed sustained release in both simulated gastric and intestinal fluids over 6 h. Four empirical models — including zero-order, Higuchi, Korsmeyer-Peppas, and Hixson-Crowell models — were tested to understand the drug release mechanisms of PQ-SLN, PQ-NLC, and PQ-NE. The model fitness was found to be the highest in the Korsmeyer-Peppas model for all the PQ-loaded lipid formulations (R2: 0.88–0.94). No significant changes were observed in the entrapment efficiency, particle size, and PDI of lipid formulations throughout 1 month of storage at 4 °C and 25 °C. PQ-SLN and PQ-NLC can be further lyophilized with cryoprotectants to improve long-term stability. Finally, the treatment of erythrocytes with PQ-SLN, PQ-NLC, and PQ-NE reduced erythrocyte hemolysis by approximately 4.5-fold compared to the free drug solution.Graphical abstract
... In striving to mitigate risk of harm to G6PD-unknown patients, we have consistently applied doses at the margin of good efficacy. This has been true of primaquine (Baird and Hoffman, 2004), and remains true of tafenoquine (Hanboonkunupakarn and White, 2020). Intrinsically variable susceptibility to 8aminoquinolines among strains of P. vivax has long been recognized (Collins and Jeffery, 1996) and authoritative guidance to apply universally more effective higher dosing regimens (Hill et al., 2006) are not broadly accepted and implemented (Recht et al., 2018). ...
The emerging understanding of Plasmodium vivax as an infection seated in extravascular spaces of its human host carries fundamentally important implications for its management as a complex clinical and public health problem. This progress begins to reverse decades of neglected research borne of the false dogma of P. vivax as an intrinsically benign and inconsequential parasite. This Review provides real world context for the on-going laboratory explorations of the molecular and cellular events in the life of this parasite. Chemotherapies against the latent reservoir impose extraordinarily complex and difficult problems of science and medicine, but great strides in studies of the biology of hepatic P. vivax promise solutions. Fundamental assumptions regarding the interpretation of parasitaemia in epidemiology, clinical medicine, and public health are being revisited and reassessed in light of new studies of P. vivax cellular/molecular biology and pathogenesis. By examining these long overlooked complexities of P. vivax malaria, we open multiple new avenues to vaccination, chemoprevention, countermeasures against transmission, epidemiology, diagnosis, chemotherapy, and clinical management. This Review expresses how clarity of vision of biology and pathogenesis may rationally and radically transform the multiple means by which we may combat this insidiously harmful infection.
... For example, P. vivax has high predisposition for immature red blood cells-RBCs (reticulocytes) which is not readily available [5]. Another drawback as regards vivax control is the use of primaquine (PQ ) to achieve hypnozoites clearance, which causes haemolytic anaemia in glucose 6 phosphate dehydrogenase (G6PD) deficient individuals [6,7]. In sSA with very limited resources for ascertaining the G6PD status of individuals, this presents a practical challenge as individuals are either treated without their G6PD status known or remain untreated. ...
Plasmodium vivax being the most geographically spread Plasmodium species is considered sparsely distributed in sub-Saharan Africa (sSA) while P. falciparum is the most prevalent species in this region. Thus, control strategies in sSA have been disproportionately targeted towards falciparum malaria. Nevertheless, with the use of more sensitive malaria diagnostic platforms, there are more reports of P. vivax and other non-falciparum malaria in sSA. In addition, P. vivax is presumed benign, however there are new findings of severe cases recorded from P. vivax single or mixed infection with other Plasmodium species. Besides, the extended dormant period (lasting for weeks or months) is a challenge for achieving effective cure for vivax infections. Although, chloroquine has been proscribed for treatment P. falciparum, it still remains the drug of choice for P. vivax in most Asian countries where it is predominant. In sSA, artemisinin combination-based therapies (ACTs) are used for treatment of falciparum malaria and, it is probable that the use of ACT could be enhancing adaptive selection for P. vivax in the face of its increasing prevalence in the population. Hence, understanding epidemiological and biological factors, and data that could be contributing to the observed steady increase in P. vivax prevalence in sSA is important. In this chapter, we discuss the mechanisms for invasion of red blood cells, trends in increasing prevalence of vivax malaria, diagnostic tools, and the public health implications of P. vivax and P. falciparum co-endemicity in Africa.
... Any therapeutic failures of PQ in P. vivax radical cure could plausibly result from reasons other than PQ resistance. For example, treatment may fail because of improper PQ dose, short duration of treatment, or poor adherence to the treatment regimen [80,161,162]. Further, with the current genotyping strategy, it is not possible to reliably determine whether a recurrent infection after day 28 is due to relapse or reinfection. In endemic areas, patients can harbor multiple genotypically different hypnozoites and a relapse infection may be from reactivation of a heterologous hypnozoite clone [163,164]. ...
Malaria is one of the most important tropical diseases in the history of the world. This vector-borne disease has been a significant cause of morbidity and mortality in tropical countries of Africa, Asia, and Latin America. As such, this book provides updated information on epidemiological and public health research of malaria conducted in the last decade. Over four sections, chapters discuss such topics as diagnosis, epidemiology and surveillance, policy and prevention, and vector control and vaccines.
... P. ovale is mainly found in Islands in western pacific and Sub-Saharan Africa [45,47]. But the parasite also exists in Thailand [48], Vietnam [49] Guinea [50], Bangladesh [51], Cambodia [52] India, [53] and Myanmar [54]. The incubation period of P. ovale ranges from 12 to 20 days. ...
Malaria is a leading public health problem in tropical and subtropical countries of the world. In 2019, there were an estimated 229 million malaria cases and 409, 000 deaths due malaria in the world. The objective of this chapter is to discuss about the different Plasmodium parasites that cause human malaria. In addition, the chapter discusses about antimalarial drugs resistance. Human malaria is caused by five Plasmodium species, namely P. falciparum, P. malariae, P. vivax, P. ovale and P. knowlesi. In addition to these parasites, malaria in humans may also arise from zoonotic malaria parasites, which includes P. i n u i and P. cynomolgi. The plasmodium life cycle involves vertebrate host and a mosquito vector. The malaria parasites differ in their epidemiology, virulence and drug resistance pattern. P. falciparum is the deadliest malaria parasite that causes human malaria. P. falciparum accounted for nearly all malarial deaths in 2018. One of the major challenges to control malaria is the emergence and spread of antimalarial drug-resistant Plasmodium parasites. The P. vivax and P. falciparum have already developed resistance against convectional antimalarial drugs such as chloroquine, sulfadoxine-pyrimethamine, and atova-quone. Chloroquine-resistance is connected with mutations in pfcr. Resistance to Sulfadoxine and pyrimethamine is associated with multiple mutations in pfdhps and pfdhfr genes. In response to the evolution of drug resistance Plasmodium parasites, artemisinin-based combination therapies (ACTs) have been used for the treatment of uncomplicated falciparum malaria since the beginning of 21th century. However, artemisinin resistant P. falciparum strains have been recently observed in different parts of the world, which indicates the possibility of the spread of arte-misinin resistance to all over the world. Therefore, novel antimalarial drugs have to be searched so as to replace the ACTs if Plasmodium parasites develop resistance to ACTs in the future.
... Since parasite arising from relapse may be genetically heterologous [11-13], distinguishing these events using molecular technologies is not yet possible, and this imposes limitations in estimating primaquine efficacy against relapse or resistance. Our inability to detect the presence of hypnozoite lead us to the assumption that every acute attack of P. vivax shall also harbour hypnozoites in the liver cell and this is supported by the fact that without prescription of antirelapse, almost all acute attack will experience relapse within a year [14,15]. Recent studies have tried to identify any protein (s) that are released by hypnozoites during its dormancy and some progress have been achieved in this endeavour. ...
Resistance to antimalarial drugs is a threat to global efforts to eliminate malaria by 2030. Currently, treatment for vivax malaria uses chloroquine or ACT for uncomplicated P. vivax whereas primaquine is given to eliminate latent liver stage infections (a method known as radical cure). Studies on P. vivax resistance to antimalarials and the molecular basis of resistance lags far behind the P. falciparum as in vitro cultivation of the P. vivax has not yet been established. Therefore, data on the P. vivax resistance to any antimalarial drugs are generated through in vivo studies or through monitoring of antimalarial treatments in mixed species infection. Indirect evidence through drug selective pressure on the parasites genome, as evidenced by the presence of the molecular marker(s) for drug resistance in areas where P. falciparum and P. vivax are distributed in sympatry may reflect, although require validation, the status of P. vivax resistance. This review focuses on the currently available data that may represent the state-of-the art of the P. vivax resistance status to antimalarial to anticipate the challenge for malaria elimination by 2030.
... One of the oldest medicines used for the treatment malaria is primaquine and belongs to quinine family, which is effective against both P. vivax and P. ovale strains. It causes disruption of the mitochondrial membrane and is the most commonly used drug against malarial infection (Baird & Hoffman, 2004). Singh & Vingkar (2008) developed a stable primaquine-loaded NE with a particle size of 96.5 nm. ...
Cancer is the second leading cause of death worldwide, with approximately one in six deaths attributed to this disease. Due to its complex requirements in treatment and management, cancer remains a global social challenge, driving extensive scientific efforts into the development of new technological advances and materials, to provide novel cancer therapies with enhanced efficacy and safety. Monotherapy or the administration of a sole anticancer drug is still a clinical standard in cancer therapy; however, these treatment options are often deemed less effective than combinational therapy. Over the past few years, research efforts into the use of mesoporous silica nanoparticles (MSNs) as delivery vehicles for drug combinations have increased significantly. Owing to their distinctly ordered porous structures, MSNs provide high loading capacities for various types of guest materials. In this chapter, we will touch upon the origin and synthesis of these versatile nanoparticles, as well as the many parameters by which MSNs can be tuned to effectively deliver drug combinations to tumors. We will also review various studies in which MSNs have been employed as nanocarriers for combinational therapies in cancer treatment. Finally, the obstacles associated with the use of MSNs and the future outlook of these multifaceted nanovehicles will be discussed.
Parasites, such as the malaria parasite P. falciparum , are critically dependent on host nutrients. Interference with nutrient uptake can lead to parasite death and, therefore, serve as a successful treatment strategy. P. falciparum parasites cannot synthesise cholesterol, and instead source this lipid from the host. Here, we tested whether cholesterol uptake pathways could be ‘hijacked’ for optimal drug delivery to the intracellular parasite. We found that fluorescent cholesterol analogues were delivered from the extracellular environment to the intracellular parasite. We investigated the uptake and inhibitory effects of conjugate compounds, where proven antimalarial drugs (primaquine and artesunate) were attached to steroids that mimic the structure of cholesterol. These conjugated antimalarial drugs improved the inhibitory effects against multiple parasite lifecycle stages, multiple parasite species, and drug-resistant parasites, whilst also lowering the toxicity to human host cells. Steroids with introduced peroxides also displayed antimalarial activity. These results provide a proof-of-concept that cholesterol mimics can be developed as a drug delivery system against apicomplexan parasites with the potential to improve drug efficacy, increase therapeutic index, and defeat drug resistance.
This review discusses the potential of liposomes as drug delivery systems for antimalarial therapies. Malaria continues to be a significant cause of mortality and morbidity, particularly among children and pregnant women. Drug resistance due to patient non-compliance and troublesome side effects remains a significant challenge in antimalarial treatment. Liposomes, as targeted and efficient drug carriers, have garnered attention owing to their ability to address these issues. Liposomes encapsulate hydrophilic and/or hydrophobic drugs, thus providing comprehensive and suitable therapeutic drug delivery.
Moreover, the potential of passive and active drug delivery enables drug concentration in specific target tissues while reducing adverse effects. However, successful liposome formulation is influenced by various factors, including drug physicochemical characteristics and physiological barriers encountered during drug delivery. To overcome these challenges, researchers have explored modifications in liposome nanocarriers to achieve efficient drug loading, controlled release, and system stability. Computational approaches have also been adopted to predict liposome system stability, membrane integrity, and drug-liposome interactions, improving formulation development efficiency. By leveraging computational methods, optimizing liposomal drug delivery systems holds promise for enhancing treatment efficacy and minimizing side effects in malaria therapy. This review consolidates the current understanding and highlights the potential of liposome strategies against malaria.
Antimalarial drug resistance is persistently posing a major risk for eradicating malaria and is the key challenge for radically curing malaria. Multipronged approach is utmost needed for eliminating malaria. It is promising that several novel strategies to antimalarial drug discovery are presently under assessment, including plant-based drugs. Safety and efficacy aspects of novel drug candidates also require specific focus and are a matter of prime concern for the discovery of antimalarial drugs. The challenge of drug resistance and other limitations yet needs to be overcome and more potent drugs including phyto-products and their synthetic analogs are needed to be further investigated that can plausibly be proved to be potent enough for inhibiting the parasitic transmission at the erythrocytic phase.
Introduction:
Chloroquine (CQ) is the drug of choice for treating uncomplicated Plasmodium vivax (P. vivax) malaria in India. The knowledge about the exact burden of CQ resistance in P. vivax in India is scarce. Therefore, this systematic review aimed to assess the prevalence of CQ resistance in reported P. vivax cases from India.
Methods:
PubMed, EMBASE, and Web of Science, were searched using the search string: 'Malaria AND vivax AND chloroquine AND (resistance OR resistant) AND India'. We systematically reviewed in-vivo and in-vitro drug efficacy studies that investigated the CQ efficacy of P. vivax malaria between January 1995 and December 2022. Those studies where patients were followed up for at least 28 days after initiation of treatment were included.
Results:
We identified 12 eligible CQ therapeutic efficacy studies involving 2470 patients, Of these 2329 patients were assessed by in-vivo therapeutic efficacy methods and the remaining 141 were assessed by in-vitro methods. CQ resistance was found in 25/1787 (1.39%) patients from in-vivo and in 11/141 (7.8%) patients from in-vitro drug efficacy studies.
Conclusion:
Based on the available studies, the prevalence of CQ resistance in P. vivax was found to be relatively lower in India. However, continued surveillance and monitoring are crucial to identify the emergence of CQ resistance.
Objectives:
To assess the pharmacokinetics, safety, and tolerability of two high-dose short-course PQ regimens compared to standard care in children with Plasmodium vivax infections.
Methods:
We performed an open-label paediatric dose-escalation study in Madang, Papua New Guinea (Clinicaltrials.gov NCT02364583). Children aged 5-10 years with confirmed blood-stage vivax malaria and normal G6PD activity were allocated to one of three PQ treatment regimens in a stepwise design (Group A: 0·5 mg/kg once daily for 14-days, Group B: 1 mg/kg once daily for 7-days, and Group C: 1 mg/kg twice daily for 3·5-days). Study assessments were completed at each treatment time-point, and fortnightly for 2-months after PQ administration.
Results:
Between August 2013 and May 2018, 707 children were screened and 73 met eligibility criteria (15, 40 and 16 allocated to Groups A, B and C, respectively). All children completed study procedures. The three regimens were safe and generally well tolerated. Pharmacokinetic analysis indicated that additional weight adjustment of conventionally recommended mg/kg PQ doses is not necessary to ensure therapeutic plasma concentrations in paediatric patients.
Conclusions:
A novel ultra-short 3·5-day PQ regimen has potential benefits for improving treatment outcomes in children with vivax malaria that warrants further investigation in large-scale clinical trial.
A new series of 6,9-dihydrofuro[3,2-f]quinoline-8-carbonitrile derivatives were prepared, via one-pot reaction of ethyl 5-aminobenzofuran-2-carboxylate, aromatic aldehydes and 3-oxo-3-phenylpropanenitrile in ethanol as a solvent at reflux. The advantages of this protocol include mild reaction conditions, easy purification, high yields, and catalyst-free approach. IR, ¹H NMR, ¹³C NMR and HRMS spectras were used to identify the structures of all the synthesized compounds.
Plasmodium vivax is a malaria-causing pathogen that establishes a dormant form in the liver (the hypnozoite), which can activate weeks, months or years after the primary infection to cause a relapse, characterized by secondary blood stage infection. These asymptomatic and undetectable latent liver infections present a significant obstacle to the goal of global malaria eradication. We use a human liver-chimeric mouse model (FRG huHep) to study P. vivax hypnozoite latency and activation in an in vivo model system. Functional activation of hypnozoites and formation of secondary schizonts is demonstrated by first eliminating primary liver schizonts using a schizont-specific antimalarial tool compound, and then measuring recurrence of secondary liver schizonts in the tissue and an increase in parasite RNA within the liver. We also reveal that while primaquine does not immediately eliminate hypnozoites from the liver, it arrests developing schizonts and prevents activation of hypnozoites, consistent with its clinical activity in humans. Our findings demonstrate that the FRG huHep model can be used to study the biology of P. vivax infection and latency and assess the activity of anti-relapse drugs.
Plasmodium vivax and P. falciparum are the most important human malaria species. P. fal-ciparum is considered the most virulent and widespread species in sub-Saharan Africa. Hence, control effort s have f ocused on reducing the morbidity and mortality associated with falciparum malaria. However, with improved malaria diagnostics, there is more evidence of high vivax burden in Africa. As P. vivax is capable of dormancy in the liver, it is suspected that artemisinin-based combination treatment widely use across Africa to combat falciparum malaria may be favouring adaptive selection for P. vivax. Additionally, a better understanding of the mechanism of erythrocytes invasion in Duffy-negative individuals who were previously believed to be protected against P. vivax is needed. Therefore, this review discusses the epidemiological implications of P. vivax and P. falciparum co-endemicity in Africa. We also examine available tools for diagnosis of vivax malaria. We conclude by recommending specific interventions against P. vivax that can impact current malaria elimination strategies.
Background
Tafenoquine was recently approved as a prophylaxis and radical cure for Plasmodium vivax infection, but its Plasmodium falciparum transmission-blocking efficacy is unclear. We aimed to establish the efficacy and safety of three single low doses of tafenoquine in combination with dihydroartemisinin–piperaquine for reducing gametocyte density and transmission to mosquitoes.
Methods
In this four-arm, single-blind, phase 2, randomised controlled trial, participants were recruited at the Clinical Research Unit of the Malaria Research and Training Centre of the University of Bamako in Mali. Eligible participants were aged 12–50 years, with asymptomatic P falciparum microscopy-detected gametocyte carriage, had a bodyweight of 80 kg or less, and had no clinical signs of malaria defined by fever. Participants were randomly assigned (1:1:1:1) to standard treatment with dihydroartemisinin–piperaquine, or dihydroartemisinin–piperaquine plus a single dose of tafenoquine (in solution) at a final dosage of 0·42 mg/kg, 0·83 mg/kg, or 1·66 mg/kg. Randomisation was done with a computer-generated randomisation list and concealed with sealed, opaque envelopes. Dihydroartemisinin–piperaquine was administered as oral tablets over 3 days (day 0, 1, and 2), as per manufacturer instructions. A single dose of tafenoquine was administered as oral solution on day 0 in parallel with the first dose of dihydroartemisinin–piperaquine. Tafenoquine dosing was based on bodyweight to standardise efficacy and risk variance. The primary endpoint, assessed in the per-protocol population, was median percentage change in mosquito infection rate 7 days after treatment compared with baseline. Safety endpoints included frequency and incidence of adverse events. The final follow-up visit was on Dec 23, 2021; the trial is registered with ClinicalTrials.gov, NCT04609098.
Findings
From Oct 29 to Nov 25, 2020, 1091 individuals were screened for eligibility, 80 of whom were enrolled and randomly assigned (20 per treatment group). Before treatment, 53 (66%) individuals were infectious to mosquitoes, infecting median 12·50% of mosquitoes (IQR 3·64–35·00). Within-group reduction in mosquito infection rate on day 7 was 79·95% (IQR 57·15–100; p=0·0005 for difference from baseline) following dihydroartemisinin–piperaquine only, 100% (98·36–100; p=0·0005) following dihydroartemisinin–piperaquine plus tafenoquine 0·42 mg/kg, 100% (100–100; p=0·0001) following dihydroartemisinin–piperaquine plus tafenoquine 0·83 mg/kg, and 100% (100–100; p=0·0001) following dihydroartemisinin–piperaquine plus tafenoquine 1·66 mg/kg. 55 (69%) of 80 participants had a total of 94 adverse events over the course of the trial; 86 (92%) adverse events were categorised as mild, seven (7%) as moderate, and one (1%) as severe. The most common treatment-related adverse event was mild or moderate headache, which occurred in 15 (19%) participants (dihydroartemisinin–piperaquine n=2; dihydroartemisinin–piperaquine plus tafenoquine 0·42 mg/kg n=6; dihydroartemisinin–piperaquine plus tafenoquine 0·83 mg/kg n=3; and dihydroartemisinin–piperaquine plus tafenoquine 1·66 mg/kg n=4). No serious adverse events occurred. No significant differences in the incidence of all adverse events (p=0·73) or treatment-related adverse events (p=0·62) were observed between treatment groups.
Interpretation
Tafenoquine was well tolerated at all doses and accelerated P falciparum gametocyte clearance. All tafenoquine doses showed improved transmission reduction at day 7 compared with dihydroartemisinin–piperaquine alone. These data support the case for further research on tafenoquine as a transmission-blocking supplement to standard antimalarials.
Funding
Bill & Melinda Gates Foundation.
Translations
For the French, Portuguese, Spanish and Swahili translations of the abstract see Supplementary Materials section.
Nanotechnology is a pioneering field among the diverse fields of science, including insect pest management. Mosquito-borne diseases have an important public health issues in morbidity and mortality worldwide. They include malaria, yellow fever, Japanese encephalitis, filariasis and dengue fever. The development of insecticide-resistant mosquito species is becoming a challenging risk factor. To resolve this, nanoparticles provide a new direction to control vector and vector borne diseases. Nanoparticles have an effective similar to that of chemical insecticides against the larva and mosquitoes. Due to this biogenic nature as well as the eco-friendly approach and host specificity actions, the use of nanomaterials becomes effective. Recently, many innovative techniques have been introduced in nanobiotechnology, including green nanotechnology, the development of tissue-specific nanopores and nanobiosensor. Thus, they have opened the door to a safe and environmentally friendly clinical approach. According to this chapter focus was on the different nanoparticle synthesis and their target basic mechanisms of malarial parasite and arbovirus control. Nanoparticles coated with drug are used for control release, biocompatibility and stability. Beside these, different types of nanoparticles have shown a potent ability to control mosquito-borne infectious diseases.
Acanthamoeba is free living amoeba and can cause Acanthamoeba keratitis, a serious disease which affects the cornea. It is widely existing in fresh water and soil. Acanthamoeba has three phases during the life cycle; trophozoite and a resistant double walled cyst and protocysts. The pathogenesis starts when the trophozoites bind to the surface of cornea by expressing mannose-binding protein which can bind to mannose glycoproteins on the corneal surface. The contaminated contact lenses can increase the infection by increasing the binding ability of the trophozoites. This project aimed to study the cytopathic effect of different stages Acanthamoeba keratitis. Study strains of Acanthamoeba castellani (ATCC 50370) was cultured and seeded in Hep2 cell lines. E. coli (strain M12) was used to isolate the trophozoites. The third stage, protocysts was made using Neff’s medium. The cytopathic effect was checked trophozoites invasion to monolayer cells cultured in a small flask and in 24 well tissue culture plate. The time of destroying Hep2 cells by the trophozoites is less than that of other Acanthamoeba stages. The double ring-shaped cell wall of the cysts may increase the time-kill of Hep2 due to their resistant which was very slow to hatch. Reactivating the trophozoites from cysts then seeding in Hep2 destroyed the cells at less time compared fresh trophozoites as the virulence of the reactivated trophozoites being higher. The result could suggest that the infection of corneas with reactivated trophozoites may be more complex. Finally, the study found that the number of the trophozoites can limit the cytopathic effect of Acanthamoeba.
Fe3O4@SiO2/Schiff base/Pd(II) is reported as a magnetically recoverable heterogeneous catalyst for the chemoselective reduction of aromatic nitro compounds to the corresponding amines through catalytic transfer hydrogenation (CTH). In this regard, a small amount of the nanocatalyst (0.52 mol% Pd) and hydrazine hydrate, showing safe characteristics and perfect ability as the hydrogen donor, were added to the nitro substrates. The experiments described the successful reduction of aromatic nitro compounds with good to excellent yields and short reaction times. The catalyst, due to its magnetic property, could be simply separated from the reaction mixture by a permanent magnet and reused in seven consecutive reactions without considerable loss in its activity. Moreover, the leaching of Pd was only 3.6% after the seventh run. Thus, the most striking feature of this method is to use a small amount of the magnetic nanocatalyst along with a cheap and safe hydrogen source to produce the important amine substances selectively, which makes the method economical, cheap, environmentally friendly, and simple.
Background:
The effect of primaquine in preventing P. vivax relapses from dormant stages is well established. For P. ovale, the relapse characteristics and the use primaquine is not as well studied. We set to evaluate the relapsing properties of these two species, in relation to primaquine use among imported malaria cases in a non-endemic setting.
Methods:
We performed a nationwide retrospective study of malaria diagnosed in Sweden 1995-2019, by reviewing medical records of 3254 cases. All episodes of P. vivax (n=972) and P. ovale (n=251) were selected for analysis.
Results:
First time relapses were reported in 80/857 (9.3%) P. vivax and 9/220 (4.1%) P. ovale episodes, respectively (p<0.01). Without primaquine, the risk for relapse was higher in P. vivax, 20/60 (33.3%), compared to 3/30 (10.0%) in P. ovale (HR 3.5, 95% CI 1.0-12.0). In P. vivax, patients prescribed primaquine had a reduced risk of relapse compared to episodes without relapse preventing treatment, 7.1% vs 33.3%, (HR 0.2, 95%CI 0.1-0.3). In P. ovale, the effect of primaquine on the risk of relapse did not reach statistical significance, with relapses seen in 2.8% of the episodes compared to 10.0% in patients not receiving relapse preventing treatment (HR 0.3, 95% CI 0.1-1.1).
Conclusion:
The risk of relapse was considerably lower in P. ovale than in P. vivax infections indicating different relapsing features between the two species. Primaquine was effective in preventing P. vivax relapse. In P. ovale, relapse episodes were few and the supportive evidence for primaquine remains limited.
Malaria is the most common parasitic disease around the world, especially in tropical and sub-tropical regions. This parasitic disease can have a rapid and severe evolution. It is transmitted by female anopheline mosquitoes. There is no reliable vaccine or diagnostic test against malaria; instead, Artesunate is used for the treatment of severe malaria and Artemisinin is used for uncomplicated falciparum malaria. However, these treatments are not efficient against severe malaria and improvements are needed. Primaquine (PQ) is one of the most widely used antimalarial drugs. It is the only available drug to date for combating the relapsing form of malaria. Nevertheless, it has severe side effects. Particle drug-delivery systems present the ability to enhance the therapeutic properties of drugs and decrease their side effects. Here, we report the development of Polymeric Primaquine Microparticles (PPM) labeled with 99mTc for therapeutic strategy against malaria infection. The amount of primaquine encapsulated into the PPM was 79.54%. PPM presented a mean size of 929.47 ± 37.72 nm, with a PDI of 0.228 ± 0.05 showing a homogeneous size for the microparticles and a monodispersive behavior. Furthermore, the biodistribution test showed that primaquine microparticles have a high liver accumulation. In vivo experiments using mice show that the PPM treatments resulted in partial efficacy and protection against the development of the parasite compared to free Primaquine. These results suggest that microparticles drug delivery systems of primaquine could be a possible approach for malaria prevention and treatment.
The liver acts as an important filter for the body and is thus exposed to a wide range of pathogens. In order to study a hepatotropic pathogen’s intricate life cycle as well as associated disease and pathogenesis, authentic culture systems are vital. As such, human induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells have recently been proposed as an attractive alternative to conventionally used primary human hepatocytes and hepatoma cell lines.
Here, we summarize current knowledge on the biology of major liver pathogens, including hepatotropic viruses A–E as well as the malaria parasite Plasmodium. We discuss the available systems used to study them, remaining questions in the field, and how iPSC technology may help to solve them. We also summarize limitations of available iPSC-derived hepatic systems and recent efforts to overcome them. With their ability to provide a universally susceptible system for personalized, complex, and at the same time isogenic infection models, we believe that iPSCs have the potential to transform the future of hepatotropic infectious disease medicine.
Infectious diseases are spreading at a very fast pace in the world, and around one-fifth of the population is affected every year. Though antibiotics are the first choice of drugs for the treatment of these diseases, but their use is limited because of the rapid increase in development of antibiotic resistance. This becomes a major challenge in the management of infections. New antibiotics that can combat the problem of resistance and provide effective treatment for curing the infectious diseases are the need of the day; however, the number of new antibiotics getting approvals is declining over the years. To overcome these problems, one of the strategies is the use of phytotherapeutics. Owing to their multimode of actions and various properties such as antibacterial, antioxidant, and antiinflammatory, phytocompounds, especially in combinations, offer an alternative over antibiotics. This chapter discusses the activity of phytocompounds, their synergistic behavior, mechanism of action with other drugs, and their nanocarrier-based formulations.
Malaria is an infectious disease caused by Plasmodium parasites that are mainly transmitted through the bites of infected female Anopheles mosquitoes. The average annual number of malaria cases was less than ten in Taiwan in the last five years. Most of the cases were caused by Plasmodium vivax and Plasmodium falciparum, and were primarily diagnosed in travelers who returned from Southeast Asia and Africa. Here, we report the first case of Plasmodium ovale infection within five years that was confirmed by peripheral blood smear examination and molecular identification in a 25-year-old Asian female patient who returned from Uganda.
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)
Em virtude da existência de poucas informações, devidamente registradas, sobre freqüência e épocas de recaídas de malária por Plasmodium vivax, contraída no Brasil, foi analisada casuística observada em região não endêmica e constituída por pacientes corretamente tratados. O índice de recaídas documentadas em São Paulo, foi alto (24,5%), com desenvolvimento precoce na maioria das oportunidades, ou seja, em tempo inferior a três meses.Very few well-established information is available about the frequency and timeliness of relapses in cases of Plasmodium vivax malaria acquired in Brazil. So, we analysed a series of correctly treated patients observed out of endemic areas. The rate of relapses seen in São Paulo, which may represent that of the parasitosis in the whole country, was high, ranging from 7.5% to 24.5%, and early in most cases, i.e. appearing by three months, what anticipates a high endemicity.
Five patients with asexual and sexual parasites of Plasmodium vivax were treated orally with 600 mg chloroquine diphosphate (hour 0) followed with 300 mg at 8, 24 and 48 h later. Primaquine phosphate, 15 mg, was administered concurrently at h 0 and at 24 h intervals for 14 days. Anopheles darlingi were fed before the first dose (h -0.5) and 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48, 60 and 72 h later. Mosquitoes were examined for oocysts on day 8 and for sporozoites on day 15 after infection. Four of the five patients studied were still infective to mosquitoes from 1-5 h after the first dose of chloroquine plus primaquine. One of these and one other patient, who vomited 15 min after the first dose, became infective again at hours 10 and 12, respectively. Once produced, oocysts in mosquitoes fed on patients before, during and after chloroquine plus primaquine treatment appeared normal and produced sporozoite infected salivary glands. In view of these data, it is concluded that primaquine demonstrated rapid gametocytocidal activity and should be administered concurrently with chloroquine to reduce vivax malaria transmission.
Very few well-established information is available about the frequency and timeliness of relapses in cases of Plasmodium vivax malaria acquired in Brazil. So, we analysed a series of correctly treated patients observed out of endemic areas. The rate of relapses seen in São Paulo, which may represent that of the parasitosis in the whole country, was high, ranging from 7.5% to 24.5%, and early in most cases, i.e. appearing by three months, what anticipates a high endemicity.
Patients with asexual and sexual parasites of Plasmodium vivax were treated orally with 600 mg of chloroquine diphosphate at hour zero, followed by 300 mg at 8, 24 and 48 hr. Anopheles darlingi were fed before the first dose (-0.5 hr) and at 0.5, 1, 2, 4, 6, 8, 9, 10, 11, 12, 20, 24, 36, 48, 60, and 72 hr later. Mosquitoes were examined for oocysts on day 8 and sporozoites on day 15 after infection. The frequency of infected mosquitoes and the mean number of oocysts were lower in mosquitoes that fed on patients 2-4 hr after the initial dose of chloroquine than in mosquitoes fed before treatment and at 0.5 and 1 hr. This sporontocidal effect was temporary, since the frequency of infected mosquitoes and the mean number of oocysts increased in mosquitoes fed 4-8 hr after the first dose. Nearly all mosquitoes fed on patients after the third dose of chloroquine, at 24 hr, were negative for P. vivax oocysts. Oocysts in mosquitoes fed on patients before, during, and after chloroquine treatment appeared normal and produced sporozoites. We conclude that chloroquine affects either the gametocytes, fertilization, zygotes, and/or ookinetes of P. vivax, but not subsequent stages of development.
Two soldiers continued weekly prophylaxis with 300 mg chloroquine base on their return to Australia from Papua New Guinea but were not protected against Plasmodium vivax malaria. Both had symptoms and parasitaemia although plasma concentrations of chloroquine were considerably higher than those regarded as adequate for suppression of vivax malaria. Parasitaemia did not clear after one of the patients was treated with 600 mg chloroquine base. The results suggest the emergence of strains of P vivax with a reduced susceptibility to chloroquine.
In an investigation of relapse patterns, 5541 cases of Plasmodium vivax malaria, from four major industrial complexes, each received at least one, 5-day course of primaquine (at 15 mg/day). Any subject relapsing was retreated with the same course. Overall, 511 (9.2%) of the P. vivax cases relapsed after the first course and 99 (1.78%), 25 (0.45) and three (0.05%) cases relapsed two, three and four times, respectively. Most cases of relapse occurred within 1 year of treatment. Clearly, a 5-day primaquine regimen is inadequate to control relapses among P. vivax cases and there is therefore an urgent need to review the treatment strategy. It may now be appropriate to implement the 14-day regimen recommended by the World Health Organization, although this is much less feasible under field conditions.
Seventy-nine adults with Plasmodium vivax malaria, from the Porto Velho area of Rondônia (western Amazon region, Brazil), gave informed consent to participate in a blind, clinical study of two regimens of treatment with chloroquine (CQ) and primaquine. The effectiveness of the ‘classical’ regimen (CQ for 3 days, followed by primaquine for 14 days) was compared with that of a ‘short’ regimen in which the two drugs were given simultaneously for 5 days. There were no cases of recrudescence indicative of CQ resistance (i.e. within 30 days of the first treatment dose) among the 73 patients who each completed a full, supervised course of treatment. However, 10 cases of apparent relapse were observed (all > 60 days after first treatment dose), representing 6.5% (2/31) of the patients who completed 60 days of follow-up after the classical treatment and 26.7% (8/30) of the short-regimen patients who completed the same period of follow-up. PCR-based comparison of parasitic DNA collected pre- and post-treatment was successful for eight of the 10 cases of apparent relapse and indicated that two such cases, both given the short regimen of treatment, were, in fact, probable cases of re-infection rather than of relapse.
The results indicate that the classical schedule of treatment with chloroquine and primaquine was more effective at preventing relapses than the short regimen. However, since prolonged treatment with primaquine often produces side-effects that are severe enough to reduce compliance, the short schedule could be a useful alternative for malaria control in endemic areas of the Amazon region.
Vivax malaria accounts for 80% of malaria cases in Mumbai (Bombay) and has high morbidity. In India, the standard treatment to prevent relapses of vivax malaria is a 5-day regimen of primaquine. However, between 1977 and 1997, the efficacy of this treatment declined from approximately 99% to 87%. The efficacy of the 5-day regimen was therefore compared with that of the 14-day regimen currently recommended by the World Health Organization, in Mumbai. The relapse rates observed, over a 6-month period of follow-up, were 0% with the 14-day regimen, 26.7% with the 5-day, and 11.7% when no primaquine treatment was given.
The expenditure incurred on the door-to-door dispensing of the 5-day regimen appears to be without benefit. There is an urgent need to review the present strategy for controlling relapses in vivax malaria, at least for the city of Mumbai, and similar studies need to be carried out in other parts of India, to make all anti-relapse strategies more appropriate.
In the city of Mumbai (formerly Bombay), chloroquine (CQ) continues to be recommended as the drug of first choice for the treatment of Plasmodium vivax and P. falciparum infections, even though > 50% of local isolates of P. falciparum are resistant to it. Primaquine, an 8-aminoquinoline is also given to patients with falciparum malaria, in a single, 45-mg dose, to kill the gametocytes and so reduce transmission. The gametocytocidal activity of supervised primaquine (45 mg given on day 8) was investigated in 90 patients who had been treated with CQ. Of these, 15 were found to be CQ-sensitive patients, 61 were resistant (49, eight and four considered RI, RII and RIII, respectively) and 14 were lost before completion of the follow-up. The mean (S.D.) baseline gametocytaemias in the CQ-sensitive and RI-resistant cases were 665.1 (411.3) and 1537.4 (1045.5)/µl, respectively. Despite supervised primaquine treatment, four of the 15 CQ-sensitive patients and 32 of the 49 patients found to be RI-resistant had gametocytes on day 29. There therefore appears to be a need to review the current, gametocytocidal, primaquine-dosage schedule and to re-treat patients who remain gametocytaemic with higher doses of primaquine, as an important, transmission-blocking strategy.
Completion of the Panama Canal in 1914 marked the beginning of an era of vector control that achieved conspicuous success against malaria. In 1955 the World Health Organization (WHO) adopted the controversial Global Eradication Campaign emphasising DDT (dichlorodiphenyltrichloroethane) spraying in homes. The incidence of malaria fell sharply where the programme was implemented, but the strategy was not applied in holoendemic Africa. This, along with the failure to achieve eradication in larger tropical regions, contributed to disillusionment with the policy. The World Health Assembly abandoned the eradication strategy in 1969. Aresurgence of malaria began at about that time and today reaches into areas where eradication or control had been achieved. A global malaria crisis looms. In 1993 the WHO adopted a Global Malaria Control Strategy that placed priority in control of disease rather than infection. This formalises a policy that emphasises diagnosis and treatment in a primary healthcare setting, while de-emphasising spraying of residual insecticides. The new policy explicitly stresses malaria in Africa, but expresses the intent to bring control programmes around the world into line with the strategy.
This review raises the argument that a global control strategy conceived to address the extraordinary malaria situation in Africa may not be suitable elsewhere. The basis of argument lies in the accomplishments of the Global Eradication Campaign viewed in an historical and geographical context. Resurgent malaria accompanying declining vector control activities in Asia and the Americas suggests that the abandonment of residual spraying may be premature given the tools now at hand. The inadequacy of vector control as the primary instrument of malaria control in holoendemic Africa does not preclude its utility in Asia and the Americas.
A study of malaria occurring in 176 soldiers returning from Vietnam was undertaken to determine the type, clinical course, complications, prognosis, and most effective treatment. In contrast to other studies, malaria in 93% of our patients was due to Plasmodium vivax and only 3% to P falciparum. Anemia was found in 15% of our patients, and hemolysis was the most frequent cause. Leukopenia and thrombocytopenia were relatively frequent. A significant number had intestinal parasites. Outstanding complications in these patients were spontaneous rupture of spleen and malarial hepatitis. Patients with P vivax malaria frequently were not cured with the modes of therapy presently used and had up to four recurrences. Recurrent malaria will be seen frequently by physicians in civilian practice.
Primaquine, 8-(4-amino-1-methylbutylamino)-6-methoxyquinoline,1 a new curative agent for vivax malaria, has recently been extensively tested in the Armed Forces. Since mid-December, 1951, veterans returning from Korea have received 15 mg. of primaquine base once daily for two weeks aboard Military Sea Transport ships after termination of weekly chloroquine (aralen®) suppression at the time of embarkation.2 Chloroquine remains in the blood in effective concentration for several weeks; it suppresses clinical symptoms by eliminating the erythrocytic forms of the malaria parasite but does not prevent subsequent relapses. Relapses can be prevented, however, by the administration of primaquine, which acts primarily against the exoerythrocytic parasites. Thus, combined action of the two drugs has been exploited during the transpacific voyage to achieve radical cure of vivax infections before symptoms have developed. Primaquine, combined with chloroquine, has also been employed extensively in treating clinical attacks of vivax malaria in Army installations in the United
Using serum or infected blood from Danish volunteers and Plasmodium falciparum-infected Mozambican patients, respectively, the impact of curative doses of chloroquine and pyrimethamine/sulfadoxine upon infectivity of P. falciparum to Anopheles arabiensis and An. gambiae or of P. berghei to An. stephensi was studied. Both treatments cleared circulating P. falciparum gametocytes within 28 days. Before this clearance, chloroquine enhanced infectivity to An. arabiensis, whereas pyrimethamine/sulfadoxine decreased infectivity. Patients harboring chloroquine-resistant parasites as opposed to -sensitive ones were 4.4 times more likely to have gametocytes following treatment. In contrast, pyrimethamine/sulfadoxine-resistant parasites were 1.9 times less likely to produce gametocytes. In laboratory infections using replicated P. berghei or P. falciparum preparations, serum from chloroquine-treated, uninfected, nonimmune volunteers enhanced gametocyte infectivity with increasing efficiency for 21 days following treatment, whereas pyrimethamine/sulfadoxine significantly suppressed infectivity. The observed enhancement in infectivity induced by the use of chloroquine combined with increased gametocytemias in chloroquine-resistant strains may in part explain the rapid spread of chloroquine resistance in endemic populations.
During the recent war an intensive search for new antimalarial drugs was conducted in the course of which thousands of chemical substances were investigated under the auspices of the Office of Scientific Research and Development. Studies were designed to find drugs which might have one or more of the following properties: (a) true causal prophylaxis, (b) ability to effect complete cure following treatment, (c) greater efficacy than quinacrine and quinine in suppression and (d) greater efficacy than quinine and quinacrine in the treatment of acute clinical attacks.
The present report is concerned with chloroquine (SN 7618): 7-chloro-4-(4-diethylamino-1-methylbutylamino) quinoline, which is one of a series of new active antimalarial agents. Detailed studies of the antimalarial properties, pharmacology and toxicity of this drug have been carried out by numerous investigators, and undoubtedly the results of these studies will be generally available in the near future.¹ This paper is concerned principally with
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.
A total of 26 patients infected with Solomon Islands strains of Plasmodium vivax was treated with one of three regimens of cloroquine-primaquine, in an attempt to determine the relapse patterns and the response to treatment of the local strains of parasite. The results suggest that the standard course of chloroquine-primaquine provides a radical cure for the strains of Plasmodium vivax from the Solomon Islands, provided that strict supervision of drug administration is enforced.
Two regimens of primaquine in combination with amodiaquine have been compared with amodiaquine alone in known cases of Plasmodium vivax in an endemic area of El Salvador, C.A. A 5-day regimen of primaquine, with dosages based on an adult dose of 15 mg per day, produced a substantial reduction in the numbers of patients experiencing renewed parasite activity and in the number of parasitemias experienced by the group during 9 mo of posttreatment observation, when compared with patients treated only with amodiaquine. A single dose regimen, based on an adult dose of 45 mg, similarly reduced the number of patients with renewed parasite activity and the number of parasitemias in the group. Those patients who experienced malaria attacks subsequent to treatment with either primaquine regimen experienced fewer such attacks than did those receiving amodiaquine alone. It is concluded that such primaquine regimens, which are more practicable for field use than the full 14-days curative regimen, are of value to both the patient and the community through the reduction of parasite episodes and the reduction of the source of mosquito infection for continuation of transmission.
A series of studies on rhesus monkeys infected with sporozoites of the M and B strains of Plasmodium cynomolgi have shown: 1) at the same total course doses (with quinine as a companion blood schizonticidal drug) 7-day and 14-day dosage regimens of pamaquine, pentaquine, or isopentaquine are essentially equally effective in producing radical cure of infections with the M strain; 2) at the same total course dose (with chloroquine as a companion drug) a 7-day dosage regimen of primaquine is at least as effective as a 14-day dosage regimen in inducing radical cure of infections with the B strain, and may be slightly more effective; 3) at the same total course doses (with chloroquine as a companion drug), single dose, 3-day, and 7-day dosage regimens of primaquine or 4-methyl primaquine are essentially equally effective in producing radical cure of infections with the B strain. These observations have led to the conclusion that the total dose of 8-aminoquinoline administered is the primary determinant of radical curative activity, rather than the duration of drug treatment. This total dose concept derives support from currently available observations on the capacity of primaquine to cure naturally acquired and induced infections with P. vivax and underpins the current search for 8-aminoquinoline derivatives which will cure such infections when administered in single dose or three daily dose treatment regimens.
Patients were followed for 2 yr after an attack of peptic ulcer. Intake of an antacid regimen was monitored objectively. Quantitative data were obtained on errors in statements about intake (i.e., 'compliance') made by 116 patients and errors in estimates of 'compliance' made by 3 physicians. Although patients said their intake of antacid averaged 89% of the amount prescribed, their actual intake averaged only 47%. For patients who claimed they took 100%, intake varied from 2% to 130% with a mean of 59%. Patients who admitted missing only an occasional dose actually missed substantially more doses than those who claimed 100% compliance. Estimates of intake made by the 3 physicians were more accurate than patients' statements but averaged 50% higher than actual intakes. In patients with low intakes (median 13%), the median estimate by physicians was 55% - an overestimate of 400%. The correlation between actual intakes and physicians' estimates was +0.48, indicating that physicians' judgements were significantly better than chance but nevertheless low in accuracy. Physicians' accuracy did not improve as they gained familiarity with the patient. Demographic data were of limited value in estimating intake. These observations, along with others cited in the literature, indicate the importance of series of objective and quantitative measures of medicine intake. A single measurement, even though accurate, may be grossly misleading because monthly antacid intake for a given patient could vary from 80% above his mean (2SD) to 80% below, and daily fluctuation could be even larger.
Evidence of emerging resistance to chloroquine by Plasmodium vivax is described from Irian Jaya (Indonesian New Guinea). Sixteen of 24 residents in the village of Arso PIR II taking supervised weekly chloroquine prophylaxis (5 mg base/kg) had asexual parasitemia with P. vivax at least once during eight weeks of surveillance. An American working in the same village developed symptomatic P. vivax parasitemia despite chloroquine prophylaxis. Five days after therapy with 600 mg chloroquine base, the asexual parasitemia in the American increased 40-fold, but cleared after treatment with 1,500 mg chloroquine base. Serum samples were not available from many of the cases, but six local residents and the American had serum levels of chloroquine in excess of the ordinarily suppressive 15 ng/ml at the time of their asexual parasitemias (16-70 ng/ml). The weekly 300 mg base tablet of chloroquine, which has been the standard for prophylaxis against malaria for more than 40 years, was not effective against P. vivax in Arso PIR, Irian Jaya.
In an endemic area relapse and reinfection in Plasmodium vivax cases poses serious problems for the malaria control program. We have studied the relapse/reinfection patterns of P. vivax infection in 26 villages of District Shahjahanpur, a malaria endemic area of UP, India for a period of four years (May, 1986 to October, 1988). All the P. vivax cases were given a complete course of radical treatment and were followed-up for relapse/reinfection. There were 8,914, 2,484, 1,439 and 883 P. vivax cases in 1986, 1987 and 1989 respectively, our of which 2,066, 141, 58 and 18 cases in the respective years showed relapse/reinfection. The maximum number of relapse/reinfection was recorded from a 47 year old male patient, who suffered from P. vivax infection eight times. The percentage occurrence of relapse/reinfection was much higher (70.2%) in males compared with females (29.8%). Relapses were more common among 16-30 years old patients. In conclusion it was felt that in 1986 relapse/reinfection in vivax cases was higher due to improper treatment of these cases. This situation may have occurred due to lack of awareness among the public, poor surveillance by the National Malaria Program or higher density of the vector mosquitos in the area.
We report 34 infections by Plasmodium ovale found among 15,806 blood film examinations taken between 1973 and 1989 from several sites in Indonesia. Twenty five of the P. ovale infections occurred in a single sample of 514 people living in Owi, Irian Jaya. We detected five additional infections at 3 other sites in Irian Jaya. Other infections by P. ovale occurred at two sites in West Flores. Another infection has already been reported from East Timor. Despite relatively frequent sampling of populations on Sumatra, Kalimantan, Java and Sulawesi, P. ovale has not been found on those islands. It appears that this parasite occurs only on the easternmost islands of the Indonesian archipelago where it is nonetheless a rare finding.
We have analyzed the clinical data of 189 patients with malaria to establish antimalarial regimens in Japan. The causative parasite species were Plasmodium falciparum in 56 cases (30%), P. vivax in 132 (70%) and P. malariae in 1 (1%). The outcomes f malaria cases are as follows: Cure rats in falciparum and vivax malaria are 86% and 91%, respectively. Two patients died of falciparum malaria and recurrence occurred in 6 cases (11%) of falciparum malaria. Relapse was seen in 12 (9%) of vivax malaria. Chloroquine was most frequently used among antimalarial agents (in 123 cases, 65% of the total) for suppressing acute attacks. The efficacy of chloroquine was evaluated by classifying each case into three groups: chloroquine alone in group one, chloroquine in combination with other antimalarials in group two and other antimalarials except chloroquine in group three. The cure rate among each group is about 80% and there is no difference among them. However, it is noticeable that recurrence occurred when patients were treated with a combination of chloroquine and quinine. We have found a similar result as this in another old report in Japan. Primaquine is effective for eliminating hepatic tissue schizonts but in this study, relapse occurred in 12 cases of vivax, although primaquine had been used in 10 out of 12 cases. In primaquine group, relapse occurred at a similar rate between chloroquine and Fansidar cases. Further studies are needed to decide whether a larger dose of primaquine is appropriate for treatment of vivax malaria. Recovery periods from fever and parasitemia were compared between chloroquine and Fansidar cases.(ABSTRACT TRUNCATED AT 250 WORDS)
A study on relapse pattern of P. vivax in Kheda district of Gujarat revealed that the relapse rate in P. vivax within 8 months of primary attack was around 40% in untreated cases. It was 2.6% within one year in patients treated with 5-day course of primaquine. Relapses occurred more frequently from April to October and 82% relapses occurred within one year of the primary attack. Relapses occurred up to 4 years after primary attack but they were less frequent in 3rd and 4th year.
This report describes 11 cases of Plasmodium vivax infection of Colombian origin that relapsed 49-166 days following treatment with chloroquine or amodiquine (1.5 g in 3 days) plus primaquine (15 mg daily for 14 days) a regimen widely used to effect radical cure of infections with this parasite. Relapses occurred under conditions that precluded reinfection. The fact that most of the relapses occurred within the last two years suggest that P. vivax drug resistance may be developing in Colombia and possibly other regions of South America.
Studies on 725 P. vivax infected patients at the Bharat Heavy Electricals Ltd. produced 6.9 per cent relapse rate after administration of radical treatment of primaquine / 15 mg daily for 5 days as followed under the National Malaria Eradication Programme. Maximum relapses were recorded in a female patient in spite of repeated radical treatment.
The effect of primaquine as a gametocytocidal drug was investigated in 218 P. falciparum (Pf) malaria cases detected during passive case detection (PCD) from August to December 1985 in two coastal villages of North Sumatra, where chloroquine-resistant and Fansidar-sensitive Pf was prevalent. Sulfonamide + pyrimethamine (SP) in combination with primaquine (Pr) was administered in Kuala Tanjung village and SP alone in Nana Siam village. Parasitologically confirmed Pf cases were followed up to observe the fluctuation of gametocytemia after the treatment. In 87 cases treated with SP alone, no significant change was observed in gametocyte positivity rate (GPR) and density on day 2 and day 7. In 131 cases treated with SP and Pr, no significant change was found on day 2 but significant reduction was observed in GPR and density on day 7. The gametocyte positive cases on day 7 were followed up weekly until gametocytes disappeared. SP alone did not reduce GPR from day 0 to week 2, then afterward GPR began to decline but was still 11.5% at week 5. On the other hand, SP with Pr reduced GPR from 77% on day 0 to 30% on day 7, after which GPR declined further to 7% at week 3. Reduction of parasite rate was observed in Kuala Tanjung after the PCD activities, reflecting a reduction in Pf prevalence rate from 18.6% in August 1985 to 2.9% in January 1986. These data indicate that a single dose of Pr 45 mg with SP was partially effective in reducing gametocytes and reducing malaria prevalence rate when administered through PCD activities.
An American physician-traveler to East Africa presented with manifestations of cerebral malaria and was treated with intravenous quinidine for chloroquine-resistant falciparum malaria. He later relapsed with Plasmodium ovale infection, despite previous primaquine therapy. Treatment of chloroquine-resistant malaria is discussed. The difficulty in diagnosing P. ovale infections and the predominance of this malaria species over P. vivax in East Africa are reviewed.
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Seven relapses of Plasmodium vivax or Plasmodium ovale despite standard treatment with primaquine (3.0 mg Kg-1) daily for fourteen days are presented. The majority of patients came from areas outside the countries where resistance to primaquine is well known. The various possibilities of reasons for relapses are discussed.