Poor gametocytocidal activity of 45 mg primaquine in chloroquine-treated patients with acute, uncomplicated, Plasmodium falciparum malaria in Mumbai (Bombay): an issue of public-health importance

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)/microliter, 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.     

A randomized, parallel study of the safety and efficacy of 45 mg primaquine versus 75 mg bulaquine as gametocytocidal agents in adults with blood schizonticide-responsive uncomplicated falciparum malaria [ISCRTN50134587]

Background  

The WHO recommends that adults with uncomplicated P. falciparum successfully treated with a blood schizonticide receive a single dose of primaquine (PQ) 45 mg as a gametocytocidal agent. An earlier pilot study suggested that 75 mg of bulaquine (BQ), of which PQ is a major metabolite, may be a useful alternate to PQ.     

HLA associations in P. falciparum malaria patients from Mumbai, western India

In the present study, HLA associations among the cohort of 171 severe P. falciparum malaria patients were compared with that of 101 normal sex, age and ethnically matched control samples. All these individuals lived in Mumbai in an area of low and seasonal P. falciparum transmission. HLA A, B, DRB1 and DQB1 antigens were serologically (A and B) and molecularly (DRB and DQB) determined using isolated lymphocytes and genomic DNA following the microlymphocytotoxicity assay and PCR-SSP techniques. Significant differences were observed between patients with malaria and controls in the following groups of alleles: A3, B27, B49, DRB1*04, and DRB1*0809 were increased, while A19, A34, B18, B37, and DQB1*0203 were decreased. HLA B49 and DRB1*0809 were found to be positively associated with the complicated severe malaria patients (OR = 13.88; p < 0.0001). HLA A19, B5 and B13 were protective in patients with high parasite index (> 2%). These observations revealed the importance of ethnic background, which has to be taken into consideration while developing an ideal malaria vaccine. Further, when compared to HLA associations of other world populations the present study indicates the relative importance of different HLA alleles that may vary in different populations.     

Randomized, prospective, three-arm study to confirm the auditory safety and efficacy of artemether-lumefantrine in Colombian patients with uncomplicated Plasmodium falciparum malaria

The safety of artemether-lumefantrine in patients with acute, uncomplicated Plasmodium falciparum malaria was investigated prospectively using the auditory brainstem response (ABR) and pure-tone thresholds. Secondary outcomes included polymerase chain reaction-corrected cure rates. Patients were randomly assigned in a 3:1:1 ratio to either artemether-lumefantrine (N = 159), atovaquone-proguanil (N = 53), or artesunate-mefloquine (N = 53). The null hypothesis (primary outcome), claiming that the percentage of patients with a baseline to Day-7 ABR Wave III latency increase of > 0.30 msec is ≥ 15% after administration of artemether-lumefantrine, was rejected; 2.6% of patients (95% confidence interval: 0.7-6.6) exceeded 0.30 msec, i.e., significantly below 15% (P < 0.0001). A model-based analysis found no apparent relationship between drug exposure and ABR change. In all three groups, average improvements (2-4 dB) in pure-tone thresholds were observed, and polymerase chain reaction-corrected cure rates were > 95% to Day 42. The results support the continued safe and efficacious use of artemether-lumefantrine in uncomplicated falciparum malaria.     

A longitudinal investigation of Plasmodium falciparum malaria in children in northern India

A group comprising 27 young children (1-4 y of age) suffering from uncomplicated falciparum malaria were studied to characterize the isolates and to measure humoral immune responses during acute infection and after recovery. Finger prick blood from each individual was collected on d 1. After treatment with chloroquine, a further blood sample was collected from each child on d 7, 30, 90 and 180 for assay of antibody responses to P. falciparum antigens. Isolates from individual patients were incubated in vitro for demonstration of rosette formation, assay of plasmodial growth rate and analysis of Pfcrt gene polymorphism. Out of 27 isolates of P. falciparum, 20 showed formation of rosettes in vitro. The growth rate at 96 h varied widely among the isolates. In Pfcrt gene analysis at 76-codon site, 14 showed wild-type Lys 76, 7 showed mutant type Thr 76 and 6 had mixed type. 14 children, all with anaemia on d 7, showed a positive direct antiglobulin test (DAT). Sera positive by ELISA IgG on d 90 also showed parasite growth inhibitory activity in vitro. Significant levels of IgG, IgG1 and IgG3 subclass antibodies against MSP1 were detected in 14 sera collected on d 90. On d 180, there was a decline in IgG and its subtypes. These findings suggest that a variability in isolates may occur in one and the same seasonal area, making children prone to infection. As a consequence, they develop antibodies during recovery phase from an acute attack, which remain in circulation for a period of 4-5 months. After that, a decline in antibody level may again make them susceptible to the disease. Prevalence of different serotypes in a small area may suggest the complexity of malaria transmission.     

Thrombocytopenia in Plasmodium falciparum,Plasmodium vivax and mixed infection malaria: A study from Bikaner (Northwestern India)

The occurrence, relation and magnitude of thrombocytopenia in different species of malaria are not clearly defined. This study included 1,064 patients admitted with malaria to study thrombocytopenia (platelet count <150,000 /cumm) in Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) mono infection and mixed infection (Pf?+?Pv). The species diagnosis was done by peripheral blood film (PBF) and rapid diagnostic test (RDT). Validation by polymerase chain reaction (PCR) was done only in patients with severe thrombocytopenia (platelet count <20,000 /cumm). The breakup of patients was 525 (49.34%) Pf, 460 (43.23%) Pv and 79 (7.42%) mixed malaria (Pf?+?Pv). Thrombocytopenia was observed in 24.6% (262/1064) patients. The risk was greatest in the mixed infections in comparison to monoinfection individually (43.04% [34/79]; mixed vs Pv monoinfection: Odds Ratio [OR]?=?1.675 [95% Confidence Interval (CI) 1.029–2.726], p?<?0.0366; mixed vs Pf monoinfection: OR=3.911 [95% CI 2.367–6.463], p?<?0.0001). Pv monoinfection (31.09% [143/460]) had greater risk compared to Pf monoinfection (16.19% [85/525]; OR?=?2.335 [95% CI 1.722–3.167], p?<?0.0001). The occurrence of severe thrombocytopenia was also higher in Pv monoinfection (18.18% [26/143]) in comparison to either Pf monoinfection (10.59% [9/85], OR?=?1.877 (95% CI 0.834–4.223)) or mixed infection (11.76% [4/34]; OR?=?1.667 (95% CI 0.540–5.142) but this association was statistically not significant. Six patients (3 Pv, 2?Pf and 1 mixed) developed severe epistaxis requiring platelet transfusion. There was no relation between parasite density and platelet count as many patients with severe thrombocytopenia had parasite density similar to patients without thrombocytopenia. We found that the association of thrombocytopenia was statistically more significant with P. vivax monoinfection as compared to P. falciparum.     

Thrombocytopenia in Plasmodium falciparum, Plasmodium vivax and mixed infection malaria: a study from Bikaner (Northwestern India)

The occurrence, relation and magnitude of thrombocytopenia in different species of malaria are not clearly defined. This study included 1,064 patients admitted with malaria to study thrombocytopenia (platelet count <150,000 /cumm) in Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) mono infection and mixed infection (Pf?+?Pv). The species diagnosis was done by peripheral blood film (PBF) and rapid diagnostic test (RDT). Validation by polymerase chain reaction (PCR) was done only in patients with severe thrombocytopenia (platelet count <20,000 /cumm). The breakup of patients was 525 (49.34%) Pf, 460 (43.23%) Pv and 79 (7.42%) mixed malaria (Pf?+?Pv). Thrombocytopenia was observed in 24.6% (262/1064) patients. The risk was greatest in the mixed infections in comparison to monoinfection individually (43.04% [34/79]; mixed vs Pv monoinfection: Odds Ratio [OR]?=?1.675 [95% Confidence Interval (CI) 1.029-2.726], p?相似文献   

A randomized, parallel-group study in Mumbai (Bombay), comparing chloroquine with chloroquine plus sulfadoxine-pyrimethamine in the treatment of adults with acute, uncomplicated, Plasmodium falciparum malaria

A major problem in the control of malaria is the development of resistance, of the parasites to the existing drugs and of the vectors to insecticides. With few new drugs in the pipeline, in an era of declining resources, it is imperative to make judicious use of the existing antimalarials. In the city of Mumbai, resistance exists to chloroquine (CQ) and to sulfadoxine-pyrimethamine (SP). Use of a combination of CQ with SP would theoretically slow down the development of resistance to each of the drugs and increase their useful lives. The effectiveness of this combination in the treatment of adults from Mumbai, who had acute, uncomplicated Plasmodium falciparum malaria, was compared with that of CQ alone. The combination was found to be significantly more effective, in terms of 28- or 42-day cure rates, and to be more cost-effective.     

Short report: therapeutic efficacy of chloroquine combined with primaquine against Plasmodium falciparum in northeastern Papua,Indonesia

Chloroquine combined with primaquine was evaluated for therapy of uncomplicated malaria caused by Plasmodium falciparum in nonimmune Javanese migrants to northeastern Papua, Indonesia. Subjects were randomized to treatment with standard chloroquine therapy (25 mg/kg in 3 doses over the course of 48 hours) with 30 mg primaquine administered daily for 28 days (n = 25) or a placebo of primaquine (n = 28). The 14-day cumulative incidence of therapeutic failure was 56% with primaquine and 79% with placebo (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.1-1.3; P = 0.08). Primaquine administered daily created a marginally significant improvement in therapeutic efficacy at day 14, but not at day 7 (20% versus 36%; OR, 0.2; 95% CI, 0.1-1.8; P = 0.2) or day 28 (82% versus 93%; OR, 0.31; 95% Cl, 0.04-2.1; P = 0.23). This report corroborates studies suggesting that therapeutic doses of primaquine exert no discernible effect on parasitemia by P. falciparum.     

A multicenter study of azithromycin, alone and in combination with chloroquine, for the treatment of acute uncomplicated Plasmodium falciparum malaria in India

BACKGROUND: Azithromycin has demonstrated in vitro and in vivo activity against Plasmodium falciparum, but small treatment studies have given mixed results. METHODS: Participants with fever and with both a blood smear and a rapid diagnostic test positive for falciparum malaria were randomly assigned to groups that were treated with either azithromycin or chloroquine or to matched groups receiving a placebo. After an interim analysis, open-label combination therapy with both drugs was initiated. RESULTS: At day 28, 5 (33%) of 15 participants in the azithromycin-treated group had remained free of fever, compared with 4 (27%) of 15 in the chloroquine-treated group. All subsequently enrolled participants then received combination therapy with azithromycin and chloroquine. In 61 (97%) of 67 participants, resolution of fever and parasitemia had occurred by day 7, and, through day 28, no clinical or parasitologic relapse had occurred in them. CONCLUSIONS: Resolution of parasitemia was inadequate with monotherapy with either azithromycin or chloroquine, but combination therapy provided substantially improved clinical and parasitologic outcomes. The combination of azithromycin and chloroquine may be an effective alternative treatment for falciparum malaria and deserves further study.     

Age as a risk factor for severe Plasmodium falciparum malaria in nonimmune patients.

In this nationwide, cross-sectional study, we evaluated the influence of age and other factors that affect clinical outcome of Plasmodium falciparum malaria in nonimmune patients. Of 135 patients with P. falciparum malaria, 84 (62%) were < 40 years old, and only 5% of the patients in this age group developed severe malaria, compared with 18% of the subjects who were > or =40 years of age (odds ratio, 4.29); moreover, all deaths occurred in the latter group. Male subjects did not differ from female subjects with regard to severity of disease.     

Procalcitonin as a parameter of disease severity and risk of mortality in patients with Plasmodium falciparum malaria

The serum levels of procalcitonin (PCT) in Plasmodium falciparum malaria were evaluated for clinical significance in 66 nonimmune and semi-immune patients. Of the 66 patients, 36 had uncomplicated malaria, 24 had severe and complicated malaria, and 6 had fatal malaria (5 from previous studies). Pretreatment PCT concentrations were closely correlated with parasitemia. Concentrations were lowest in semi-immune patients with uncomplicated malaria, compared with those in nonimmune patients (geometric mean concentrations [GMCs], 1.07 and 2.37 ng/mL, respectively), and were highest in severe and complicated cases (GMC, 10.67 ng/mL; P<.001 among all subgroups). Six of 7 patients with PCT concentrations >25 ng/mL died. PCT concentrations decreased on day 2 of treatment in survivors but not in patients with fatal outcome. Thus, repeated PCT measurements may provide useful prognostic information, especially in medical centers that are not experienced in parasite density determination.     

In-vivo efficacy of amodiaquine-artesunate in children with uncomplicated Plasmodium falciparum malaria in western Kenya

Objectives  To assess the efficacy of amodiaquine-artesunate in an area with high chloroquine resistance in western Kenya.
Methods  Twenty-eight day in-vivo efficacy trial of amodiaquine-artesunate in 103 children aged 6–59 months in western Kenya with smear-confirmed uncomplicated Plasmodium falciparum malaria.
Results  The 28-day uncorrected adequate clinical and parasitological response (ACPR) was 69.0%, with 15.5% Late Clinical Failure and 15.5% Late Parasitologic Failure rates. The PCR-corrected 28-day ACPR was 90.2%. Clinical risk factors for recurrent infection (recrudescences and reinfections) were lower axillary temperature at enrolment and low weight-for-age Z-score. The presence of single nucleotide polymorphisms pfcrt 76T and pfmdr1 86Y at baseline was associated with increased risk of recurrent infections, both reinfections and recrudescences.
Conclusion  Although artemether-lumefantrine (Coartem^®) is the first line ACT in Kenya, amodiaquine-artesunate is registered as an option for treatment of uncomplicated P. falciparum and remains an effective alternative to Coartem^® in western Kenya. Continued amodiaquine monotherapy in the private sector may jeopardise the future use of amodiaquine-artesunate as an alternative artemisinin-based combination therapy.     

Regional differences in the response of Plasmodium vivax malaria to primaquine as anti-relapse therapy

We used logistic regression to assess effectiveness of primaquine as Plasmodium vivax anti-relapse therapy using data extracted from studies of P. vivax relapses in Brazil, India, and Thailand. The risk of relapse in Thailand was 10 times that in India and twice that in Brazil. In comparison with no primaquine treatment, the risk of relapse decreased by approximately 80% for a total adult primaquine regimen of 210 mg and by > or =95% for regimens of 315 mg and 420 mg. In addition, we used logistic regression to estimate the risk of P. vivax relapse according to weight-based primaquine dose using data from case studies. There was a three-fold increase in the likelihood of successful treatment of each additional milligram of primaquine per kilogram of body weight. Tailoring primaquine therapy to a region requires consideration of factors including body weight, natural relapse rates, and local response to primaquine.