Drugs for treating urinary schistosomiasis.

BACKGROUND: Urinary schistosomiasis is caused by an intravascular infection with parasitic Schistosoma haematobium worms. The adult worms typically migrate to the venous plexus of the human bladder and excrete eggs which the infected person passes in their urine. Chronic infection can cause substantial morbidity and long-term complications as the eggs become trapped in human tissues causing inflammation and fibrosis. We summarised evidence of drugs active against the infection. This is new edition of a review first published in 1997. OBJECTIVES: To evaluate the efficacy and safety of drugs for treating urinary schistosomiasis. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, CENTRAL, EMBASE and LILACS and reference lists of articles up to 23 May 2014. SELECTION CRITERIA: Randomized controlled trials (RCTs) of antischistosomal drugs and drug combinations compared to placebo, no intervention, or each other. DATA COLLECTION AND ANALYSIS: Two researchers independently screened the records, extracted the data and assessed risk of bias. The primary efficacy outcomes were parasitological failure (defined as the continued presence of S. haematobium eggs in the urine at time points greater than one month after treatment), and percent reduction of egg counts from baseline. We presented dichotomous data as risk ratios (RR), and continuous data as mean difference (MD), alongside their 95% confidence intervals (CIs). Where appropriate we combined trials in meta analyses or tables. We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: We included 30 RCTs enrolling 8165 participants in this review. Twenty-four trials were conducted in children in sub-Saharan Africa, and 21 trials were over 20 years old. Many studies were assessed as being at unclear risk of bias due to inadequate descriptions of study methods. PraziquantelOn average, a single 40 mg/kg dose of praziquantel reduced the proportion of people still excreting eggs in their urine by around 60% compared to placebo at one to two months after treatment (treatment failure: RR 0.42, 95% CI 0.29 to 0.59, 864 participants, seven trials, high quality evidence). The proportion of people cured with praziquantel varied substantially between trials, from 22.5% to 83.3%, but was higher than 60% in five of the seven trials. At one to two months following praziquantel treatment at 40 mg/kg, the mean number of schistosome eggs in the urine was reduced by over 95% in five out of six trials (678 participants, six trials, high quality evidence).Splitting praziquantel 40 mg/kg into two doses over 12 hours probably has no benefits over a single dose, and in a single trial of 220 participants the split dose caused more vomiting (RR 0.5, 95% CI 0.29 to 0.86) and dizziness (RR 0.39, 95% CI 0.16 to 0.94). MetrifonateA single dose of metrifonate 10 mg/kg reduced egg excretion (210 participants, one trial, at eight months), but was only marginally better than placebo at achieving cure at one month (RR 0.83, 95% CI 0.74 to 0.94, 142 participants, one trial). In a single trial comparing one, two and three doses, the absolute number of participants cured improved from 47% after one dose to 81% after three doses (93 participants, one trial, low quality evidence).Two small trials compared 40 mg/kg single dose praziquantel with two or three doses of 10 mg/kg metrifonate and found no clear evidence of differences in cure (metrifonate 2 x 10 mg/kg at one month: RR 1.03, 95% CI 0.8 to 1.34, 72 participants, one trial; metrifonate 3 x 10 mg/kg at three months: RR 0.33, 95% CI 0.07 to 1.57, 100 participants, one trial. In one trial both drugs performed badly and in one trial both performed well. Other drugsThree trials have evaluated the antimalarial artesunate; with inconsistent results. Substantial antischistosomal effects were only seen in one of the three trials, which was at unclear risk of bias due to poor reporting of the trial methods. Similarly, another anti-malarial mefloquine has been evaluated in two small trials with inconsistent effects.Adverse events were described as mild for all evaluated drugs, but adverse event monitoring and reporting was generally of low quality. AUTHORS' CONCLUSIONS: Praziquantel 40 mg/kg is the most studied drug for treating urinary schistosomiasis, and has the strongest evidence base.Potential strategies to improve future treatments for schistosomiasis include the combination of praziquantel with metrifonate, or with antimalarial drugs with antischistosomal properties such as artesunate and mefloquine. Evaluation of these combinations requires rigorous, adequately powered trials using standardized outcome measures.

Corticosteroids for dengue infection.

BACKGROUND: Dengue is a common and important mosquito-borne viral infection. In many low- and middle-income countries it is endemic and is an important public health problem. Severe dengue is an important cause of death in children. There is no specific treatment for dengue, but observational studies suggest corticosteroids may have a benefit in dengue-related shock, and some people believe corticosteroids may prevent the progression to severe illness if given early in the course of the illness. OBJECTIVES: To compare treatment of dengue with and without use of corticosteroids or placebo in relation to preventing shock-related death and disease progression in children and adults. SEARCH METHODS: We searched the Cochrane Infectious Disease Group Centralized Register; CENTRAL; MEDLINE; EMBASE; and LILACS, up to 6 January 2014. We screened reference lists and contacted the relevant study authors for additional information where required. SELECTION CRITERIA: Randomized controlled trials or quasi-randomized controlled trials comparing corticosteroids with placebo or no corticosteroids in patients diagnosed with dengue-related shock, or patients in an early symptomatic state of dengue with positive serology. DATA COLLECTION AND ANALYSIS: Two researchers independently screened eligibility of records, extracted data and assessed quality of the studies. We presented findings in meta-analysis and summary of findings tables and evaluated the quality of evidence using GRADE. MAIN RESULTS: We included eight studies enrolling 948 participants in this review. Paitents with dengue-related shock Four studies enrolled children younger than 15 years with dengue-related shock at hospitals in Southeast Asia and evaluated intravenous corticosteroids. The trials did not detect an effect on death (four trials, 284 participants, very low quality evidence), the need for blood transfusion (two trials, 89 participants, very low quality evidence), pulmonary haemorrhage (one trial, 63 participants, very low quality evidence), convulsions (one trial, 63 participants, very low quality evidence), or duration of hospitalization (one trial, 63 participants, very low quality evidence). The body of evidence is too small to confidently prove or exclude clinically important effects. Furthermore, the trials are more than 20 years old with several methodological limitations. Patients with dengue at an early stage Four studies enrolled 664 children and adults with dengue at an early stage of infection (without shock) in Columbia, India, Sri Lanka and Vietnam. In these participants there were no evidence of effects of oral or intravenous corticosteroids on mortality (four trials, 664 participants, low quality evidence), or on the development of complications of severe dengue such as shock (two trials, 286 participants, very low quality evidence), severe bleeding (two trials, 425 participants, very low quality evidence), severe thrombocytopaenia (one trial, 225 participants, very low quality evidence), ascites (one trial, 178 participants, very low quality evidence) and intensive care unit (ICU) admissions (two trials, 286 participants, very low quality evidence). AUTHORS' CONCLUSIONS: The evidence from trials using corticosteroids in dengue is inconclusive and the quality of evidence is low to very low. This applies to both the use of corticosteroids in dengue-related shock and for dengue at an early stage. There is insufficient evidence to evaluate the effects of corticosteroids in the treatment of early stage dengue fever and dengue-related shock outside of the context of a randomized controlled trial.

Artesunate plus pyronaridine for treating uncomplicated Plasmodium falciparum malaria.

BACKGROUND: The World Health Organization (WHO) recommends that people with uncomplicated Plasmodium falciparum malaria are treated using Artemisinin-based Combination Therapy (ACT). ACT combines three-days of a short-acting artemisinin derivative with a longer-acting antimalarial which has a different mode of action. Pyronaridine has been reported as an effective antimalarial over two decades of use in parts of Asia, and is currently being evaluated as a partner drug for artesunate. OBJECTIVES: To evaluate the efficacy and safety of artesunate-pyronaridine compared to alternative ACTs for treating people with uncomplicated P. falciparum malaria. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; LILACS; ClinicalTrials.gov; the metaRegister of Controlled Trials (mRCT); and the WHO International Clinical Trials Search Portal up to 16 January 2014. We searched reference lists and conference abstracts, and contacted experts for information about ongoing and unpublished trials. SELECTION CRITERIA: Randomized controlled trials of artesunate-pyronaridine versus other ACTs in adults and children with uncomplicated P. falciparum malaria.For the safety analysis, we also included adverse events data from trials comparing any treatment regimen containing pyronaridine with regimens not containing pyronaridine. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility and risk of bias, and extracted data. We combined dichotomous data using risk ratios (RR) and continuous data using mean differences (MD), and presented all results with a 95% confidence interval (CI). We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: We included six randomized controlled trials enrolling 3718 children and adults. Artesunate-pyronaridine versus artemether-lumefantrineIn two multicentre trials, enrolling mainly older children and adults from west and south-central Africa, both artesunate-pyronaridine and artemether-lumefantrine had fewer than 5% PCR adjusted treatment failures during 42 days of follow-up, with no differences between groups (two trials, 1472 participants, low quality evidence). There were fewer new infections during the first 28 days in those given artesunate-pyronaridine (PCR-unadjusted treatment failure: RR 0.60, 95% CI 0.40 to 0.90, two trials, 1720 participants, moderate quality evidence), but no difference was detected over the whole 42 day follow-up (two trials, 1691 participants, moderate quality evidence). Artesunate-pyronaridine versus artesunate plus mefloquineIn one multicentre trial, enrolling mainly older children and adults from South East Asia, both artesunate-pyronaridine and artesunate plus mefloquine had fewer than 5% PCR adjusted treatment failures during 28 days follow-up (one trial, 1187 participants, moderate quality evidence). PCR-adjusted treatment failures were 6% by day 42 for these treated with artesunate-pyronaridine, and 4% for those with artesunate-mefloquine (RR 1.64, 95% CI 0.89 to 3.00, one trial, 1116 participants, low quality evidence). Again, there were fewer new infections during the first 28 days in those given artesunate-pyronaridine (PCR-unadjusted treatment failure: RR 0.35, 95% CI 0.17 to 0.73, one trial, 1720 participants, moderate quality evidence), but no differences were detected over the whole 42 days (one trial, 1146 participants, low quality evidence). Adverse effectsSerious adverse events were uncommon in these trials, with no difference detected between artesunate-pyronaridine and comparator ACTs. The analysis of liver function tests showed biochemical elevation were four times more frequent with artesunate-pyronaridine than with the other antimalarials (RR 4.17, 95% CI 1.38 to 12.62, four trials, 3523 participants, moderate quality evidence). AUTHORS' CONCLUSIONS: Artesunate-pyronaridine performed well in these trials compared to artemether-lumefantrine and artesunate plus mefloquine, with PCR-adjusted treatment failure at day 28 below the 5% standard set by the WHO. Further efficacy and safety studies in African and Asian children are required to clarify whether this combination is an option for first-line treatment.