Effect of paracetamol on parasite clearance time in Plasmodium falciparum malaria. Antipyretic, parasitologic, and immunologic effects of combining sulfadoxine/pyrimethamine with chloroquine or paracetamol for treating uncomplicated Plasmodium falciparum malaria. A randomized trial to monitor the efficacy and effectiveness by QT-NASBA of artemether-lumefantrine versus dihydroartemisinin-piperaquine for treatment and transmission control of uncomplicated Plasmodium falciparum malaria in western Kenya. Evaluation of the relative efficacy of various antimalarial drugs in Nigerian children under five years of age suffering from acute uncomplicated falciparum malaria. A comparative clinical trial of sequential treatments of severe malaria with artesunate suppository followed by mefloquine in Thailand. Effect of antipyretic drugs in children with malaria. Impact of repeated four-monthly anthelmintic treatment on Plasmodium infection in preschool children: a double-blind placebo-controlled randomized trial. A randomized trial comparing a pentavalent antimonial drug and recombinant interferon-gamma in the local treatment of cutaneous leishmaniasis. A randomized, placebo-controlled, double-blind trial on sulfadoxine-pyrimethamine alone or combined with artesunate or amodiaquine in uncomplicated malaria.
Routine antipyretic therapy in children with infectious diseases has long been the source of controversy. Each year, in addition to antimalarial medication, millions of children with Plasmodium falciparum malaria receive paracetamol to reduce fever. However, the usefulness of this practice has not been proven.
                In a randomised trial in Lambaréné, Gabon, 50 children with P falciparum malaria were treated with intravenous quinine, and received either mechanical antipyresis alone, or in combination with paracetamol. Rectal body temperature and parasitaemia were recorded every 6 h for 4 days. Plasma concentrations and inducible concentrations of tumour necrosis factor (TNF) and interleukin-6 were measured every 24 h. In addition, production of oxygen radicals was measured in both groups.
                The mean fever clearance time was 32 h for children treated with paracetamol and 43 h for those who received mechanical antipyresis alone; however, this 11 h difference was not significant (95% CI -2 to 24 h; p = 0.176). Parasite clearance time was significantly prolonged in patients who received paracetamol with a difference of 16 h (8-24 h; p = 0.004). Plasma concentrations of TNF and interleukin-6 were similar in both groups during the study. However, the induced concentrations of TNF, and the production of oxygen radicals, were significantly lower in children treated with paracetamol than those who received mechanical antipyresis alone.
                These data suggest that paracetamol has no antipyretic benefits over mechanical antipyresis alone in P falciparum malaria. Moreover, paracetamol prolongs parasite clearance time, possibly by decreased production of TNF and oxygen radicals. Sulfadoxine/pyrimethamine (SP) is increasingly used against malaria in sub-Saharan Africa because of chloroquine resistance. However, chloroquine may have a beneficial antipyretic effect. We therefore compared the combination of SP plus chloroquine, chloroquine alone, SP alone, and SP plus paracetamol in the treatment of uncomplicated Plasmodium falciparum malaria in 175 Tanzanian children (1-4 years old) in a randomized trial. Outcome variables were axillary temperatures every six hours, daily parasitemias, and serum levels of IgG antibodies to P. falciparum. Lower mean temperatures (6-48 hours) were achieved with SP plus chloroquine or paracetamol than with SP alone (P < 0.001) or chloroquine alone (P < 0.05). All three SP-treated groups showed high and similar parasite reduction (0-48 hours), whereas treatment with chloroquine alone was much less effective. Levels of IgG antibodies to P. falciparum increased significantly (P < 0.001) and similarly in the four treatment groups between days 0, 2, and 3. Thus, the addition of chloroquine or paracetamol to SP improved the clinical outcome, but did not affect the parasitologic response or antibody production. Many countries have implemented artemisinin-based combination therapy (ACT) for the first-line treatment of malaria. Although many studies have been performed on efficacy and tolerability of the combination arthemeter-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP), less is known of the effect of these drugs on gametocyte development, which is an important issue in malaria control.
                In this two-arm randomized controlled trial, 146 children were treated with either AL or DP. Both groups received directly observed therapy and were followed for 28 days after treatment. Blood samples were analysed with microscopy and NASBA. In comparison with microscopy NASBA detected much more gametocyte positive individuals. Moreover, NASBA showed a significant difference in gametocyte clearance in favour of AL compared to DP. The decline of parasitaemia was slower and persistence or development of gametocytes was significantly higher and longer at day 3, 7 and 14 in the DP group but after 28 days no difference could be observed between both treatment arms.
                Although practical considerations could favour the use of one drug over another, the effect on gametocytogenesis should also be taken into account and studied further using molecular tools like NASBA. This also applies when a new drug is introduced.
                Current controlled trials ISRCTN36463274. A parallel group-randomized comparison of the therapeutic efficacy of chloroquine (CQ), amodiaquine (AM), quinine (QN), sulphadoxine-pyrimethamine (S-P), mefloquine 15 mg kg-1 (M15) and mefloquine 25 mg kg-1 (M25) in acute symptomatic uncomplicated falciparum malaria was carried out in 325 children under the age of five years in Ibadan, southwestern Nigeria, using the 28-day in vivo test. The parasitological cure rate, assessed only up to day 14, was 85% in the CQ group and 100% in the other groups. The mean parasite and fever clearance times were, respectively, 2.64 and 1.20 days in the CQ-sensitive subgroup, 2.32 and 1.13 days in the AM group, 2.27 and 1.17 days in the QN group, 2.23 and 1.76 days in the S-P group, 2.13 and 1.10 days in the M15 group, and 2.07 and 1.09 days in the M25 group. The CQ-treatment failures (seven of 46 patients) were successfully treated with 25 mg kg-1 mefloquine, with parasite and fever clearance times of 1.73 and 1.0 days respectively. The study shows that, in Nigeria, CQ is now less effective than AM, S-P, QN and M in acute falciparum malaria in the group most vulnerable to the infection (the under-five-year-olds).(ABSTRACT TRUNCATED AT 250 WORDS) Sixty-three patients with severe falciparum malaria were randomly administered one of the two regimens of a sequential combination of artesunate suppository followed by an oral mefloquine tablet. Thirty-two patients received artesunate suppositories (200 mg/capsule) given rectally at 0, 4, 8, 12, 24, 36, 48, and 60 hr (total = 1,600 mg: Group I). Thirty-one patients received the same artesunate suppositories given rectally at 0, 12, 24, 36, 48, and 60 hr (total = 1,200 mg: Group II). Both regimens were followed by two doses of oral mefloquine, 750 mg given at 72 hr and 500 mg at 84 hr. Patient baseline characteristics were comparable in the two groups. All patients were admitted for 28 days to the Bangkok Hospital for Tropical Diseases to assess efficacy, tolerability, and delayed neuropsychiatric effects. The mean [SD] parasite clearance time was significantly shorter in Group I than Group II (47.3 [12.4] hr versus 55.3 [17.4] hr; P = 0.05) and the rate of parasite reduction was significantly faster in Group I (P = 0.05, by log-rank test). Mean [SD] fever clearance times were similar in the two Groups (71.1 [41.2] hr and 76.9 [47.9] hr, respectively). Twenty-two patients with unrousable coma on admission (median Glasgow Coma Score = 9) regained consciousness after 1-4 days. No deaths occurred. Sixty of sixty-three patients were parasitologically and clinically cured within 3-4 days of treatment. Three patients (5%) with deteriorating conditions required rescue treatment (one patient in Group I was administered intravenous artesunate, and two patients in Group II required two extra doses of suppository). No patients had major adverse drug effects. The cure rates at 28 days of follow-up in Group I were 96% (26 of 27 patients) and 89% (24 of 27 patients) in Group II. Artesunate suppository followed by mefloquine was well tolerated and effective. In severe malaria, the sequential treatment is a suitable alternative treatment to parenteral drugs. Further studies in a larger number of patients under field conditions are required. A comparison of different antipyretics in children with malaria showed a small effect of naproxen, but not of metamizol, on the reduction of fever peaks. Antipyretic treatment had no effect on fever clearance and therefore should be used cautiously in the treatment of malaria. Helminth infections can alter susceptibility to malaria. Studies need to determine whether or not deworming programs can impact on Plasmodium infections in preschool children.
                A double-blind placebo-controlled randomised trial was conducted to investigate the impact of anthelmintic treatment on Plasmodium infection in children aged 12-59 months. Children were randomly assigned to receive either albendazole or placebo every four months for 12 months with a follow-up at 14 months.
                320 Children (out of 1228, 26.1%) complied with all the follow-up assessments. Plasmodium prevalence and mean Plasmodium parasite density was significantly higher in the treatment group (44.9% and 2319 ± SE 511) compared to the placebo group (33.3% and 1471 ± 341) at baseline. The odds of having Plasmodium infection increased over time for children in both the placebo and treatment groups, however this increase was significantly slower for children in the treatment group (P = 0.002). By month 14, mean Plasmodium density had increased by 156% in the placebo group and 98% in the treatment group but the rate of change in Plasmodium density was not significantly different between the groups. The change from baseline in haemoglobin had a steeper increase among children in the treatment group when compared to the placebo group but this was not statistically significant.
                Repeated four-monthly anthelminthic treatments for 14 months resulted in a significantly lower increase in the prevalence of Plasmodium infection in preschool children which coincided with a reduction in both the prevalence and intensity of A. lumbricoides infections.
                Current controlled trials ISRCTN44215995. In a randomized prospective trial N-methyl-glucamine antimoniate (Glucantime) and human recombinant interferon-gamma were infiltrated around lesions of cutaneous leishmaniasis caused by Leishmania tropica in Syria. A previous trial had shown that intradermal application of interferon-gamma promoted the healing of similar lesions in the study area. Twenty patients with 38 lesions received 1-3 ml Glucantime and 20 patients with 37 lesions received 25 micrograms of interferon-gamma intradermally once weekly for 5 consecutive weeks. While all lesions treated with Glucantime were free of parasites after the third injection, only 69% of those treated with interferon-gamma were parasitologically cured by week 10. Within 10 weeks, lesions treated with Glucantime healed completely in 29/38, and partially in 9/38, cases, whereas 1/37 and 13/37 lesions treated with interferon-gamma healed completely and partially, respectively. Perilesional application of Glucantime was highly effective and superior to interferon-gamma for treatment of cutaneous leishmaniasis caused by L. tropica. The therapeutic efficacy of sulfadoxine-pyrimethamine (SP) alone, SP plus amodiaquine (AQ), and SP plus artesunate (AS) was assessed in a randomized, placebo-controlled, and double-blind trial among 438 children with uncomplicated Plasmodium falciparum malaria in northern Ghana. Clinical and parasitological responses were monitored for 28 days following treatment; 86%, 98% and 97% of SP-, SP + AQ-, and SP + AS-treated patients achieved adequate clinical and parasitological response (ACPR) within 2 weeks, respectively. Parasite clearance was better with SP + AS than with SP or SP + AQ treatment but re-infections were more common. Polymerase chain reaction (PCR)-corrected rates of ACPR at day 28 were 72.2% for SP, 94.1% for SP + AQ (P < 0.0001), and 94.5% for SP + AS (P < 0.0001). Gametocyte prevalence and density 1 week after treatment were highest in children treated with SP, and lowest in patients receiving SP + AS. No severe adverse events attributable to study medication were observed. In northern Ghana, more than one of four children suffered SP treatment failure within 4 weeks. Both SP + AQ and SP + AS are efficacious alternative therapeutic options in this region. Although SP + AS and SP + AQ treatments have virtually identical cure rates, rapid parasite clearance and pronounced gametocidal effects are the advantages of the former, whereas cost and a lower rate of late re-infections are those of the latter.
We do not know whether antipyretics alter parasite clearance time. Whether further trials are worthwhile to investigate this or not would require a judgement of whether this was an important question to resolve using interventional trials.