Effects of pyrimethamine versus proguanil in malarial chemoprophylaxis in children with sickle cell disease: a randomized, placebo-controlled, open-label study

Abstract

Background: Malarial chemoprophylaxis is essential for patients with homozygous sickle cell disease (SCD) who live in areas where malaria is endemic. Endemic regions include most sub-Saharan African countries and Southeast Asia.Objective: This study compared the efficacy and tolerability of pyrimethamine with that of proguanil and placebo in the prevention of malaria and the complications of Plasmodium falciparum infection (hepatomegaly, splenomegaly, bone pain crisis, hemolytic crisis) in children with SCD.Methods: In this single-center, open-label study conducted in Nigeria, children aged 1 to 16 years with SCD were randomly assigned to receive tablets of pyrimethamine (0.5 mg/kg·wk), proguanil (1.5 mg/kg·d), or placebo (vitamin C, 7 mg/kg·d) for 9 months as prophylaxis from February to December (which includes the rainy season), the period of greatest malarial transmission. The clinical and laboratory features of malaria (presence of parasitemia, parasite count and density, hepatomegaly and/or splenomegaly, symptomatic malarial infection [fever, rigors], bone pain crises, and hemolytic crises) were assessed.Results 9.5 [3.7] years; range, 3-16 years); and the placebo group, 29 patients (mean age, 5.9 years; range, 1-14 years). The male:female ratio was 1.1:1 in the pyrimethamine group, 1:1.7 in the proguanil group, and 1.6:1 in the placebo group. Parasitemia was noted in 7 patients (19.4%) in the pyrimethamine group, 6 (18.8%) in the proguanil group, and 7 (24.1%) in the placebo group at the start of the study. P falciparum was the only isolate.Accepted for publication August 6, 2003. doi:10.1016/S0011-393X(03)00161-9 Reproduction in whole or part is not permitted.0011-393X/03/$19.00 616Copyright ą 2003 Excerpta Medica, Inc. F.U. Eke and I. AnochieThe mean parasite density over the 9-month period was significantly lower with proguanil compared with pyrimethamine (P ϭ 0.045) and placebo (P Ͻ 0.05). The incidence of splenomegaly was least with pyrimethamine, but this group had the most patients clinically diagnosed with malaria. Hospitalizations and episodes of bone pain and hemolytic crisis occurred most frequently with placebo. One patient in the placebo group died of septicemia. Conclusions: Proguanil and pyrimethamine both reduced parasitemia; however, proguanil significantly decreased mean parasite density more effectively than pyrimethamine. Pyrimethamine and proguanil may protect children with SCD from the complications of P falciparum infection despite persistent parasitemia. Proguanil may be more useful than pyrimethamine in the prevention of bone pain crises among patients with SCD. (Curr Ther Res Clin Exp. 2003; 64:616-625)

Pharmacotherapeutical strategies in the prevention of acute, vaso-occlusive pain in sickle cell disease: a systematic review

“…58,59,61,65 Also, studies on the antiplatelet agent ticlopidine, the dietary supplement zinc, and antimalarial prophylaxis for patients in malaria-endemic regions provided encouraging results. 50,55,70 However, 23 of the 36 studies included in this review did not show any beneficial effect of the intervention under investigation. 38,40,43,[46][47][48][49][51][52][53][54]57,60,62,63,[66][67][68][69][71][72][73][74] The other studies were either too small or methodologically inadequate to draw strong conclusions.…”

“…Malaria infections are an important trigger for VOCs in SCD. In the open-label, placebo-controlled study by Eke et al, 70 a significantly lower proportion of patients with VOCs was observed in the proguanil arm, along with a lower proportion of patients with hospitalizations in the pyrimethamine arm as compared with placebo (Table 1). In the study by Diop et al, 69 monthly sulfadoxinepyrimethamine treatment as compared with placebo during hightransmission malaria season did not affect the frequency of VOCs or hospitalizations.…”

“…[56][57][58][59][60][61][62][63] Three studies did not use a placebo intervention for their control group. 43,54,56 A majority of studies were performed in North America (n 5 10), 33,46,47,51,61,62,[64][65][66][67][68] Africa (n 5 9), 38,42,52,55,56,59,[69][70][71] and Latin America (n 5 8). 40,44,48,49,53,54,57,72 Four studies were performed on multiple continents.…”

“…A majority of studies were limited to patients with the HbSS or HbSb 0 genotype (n 5 26). 37,38,42,44,45,[48][49][50][51][52][53][54][55][56][57][59][60][61]63,64,66,67,[69][70][71]74 A summary overview of the characteristics, risk of bias, and primary outcomes of the included studies is provided in Table 1. The complete results of our risk-of-bias assessment and a detailed overview of the primary and secondary outcomes of this review per study are provided in supplemental Tables 2 and 3, respectively.…”

“…[58][59][60]66,69,72,73 Fourteen studies scored a high risk of bias on at least 1 of the items of the quality assessment, in particular on incomplete outcome data (n 5 8) and blinding of participants (n 5 6) and personnel for intervention (n 5 6). 37,[43][44][45]48,49,51,54,56,63,64,70,71,74 Anticoagulation. A total of 7 studies assessed interventions targeting coagulation activation.…”