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Drugs for treating urinary schistosomiasis

  1. Anthony Danso-Appiah1,*,
  2. Jürg Utzinger2,
  3. Jianping Liu3,
  4. Piero Olliaro4

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 16 JUL 2008

Assessed as up-to-date: 15 OCT 2007

DOI: 10.1002/14651858.CD000053.pub2


How to Cite

Danso-Appiah A, Utzinger J, Liu J, Olliaro P. Drugs for treating urinary schistosomiasis. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD000053. DOI: 10.1002/14651858.CD000053.pub2.

Author Information

  1. 1

    Liverpool School of Tropical Medicine, International Health Group, Liverpool, UK

  2. 2

    Swiss Tropical Institute, Department of Public Health and Epidemiology, Basel, Switzerland

  3. 3

    Beijing University of Chinese Medicine, Centre for Evidence-Based Chinese Medicine , Beijing, China

  4. 4

    World Health Organization, Special Programme for Research and Training in Tropical Diseases (TDR), Geneva, Switzerland

*Anthony Danso-Appiah, International Health Group, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK. tdappiah@yahoo.co.uk.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 16 JUL 2008

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This is not the most recent version of the article. View current version (06 AUG 2014)

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Urinary schistosomiasis is caused by the blood fluke, Schistosoma haematobium. The disease, which causes chronic ill-health, is endemic in most African and Eastern Mediterranean countries (Chitsulo 2000; Engels 2002; Steinmann 2006). It is especially important in poor, rural areas where attempts to alleviate poverty also promote water resources development that may increase transmission and hence exacerbate the disease burden (Danso-Appiah 2004; Fenwick 2006b; Steinmann 2006). In some areas of sub-Saharan Africa there is an overlap in distribution with S. mansoni resulting in mixed infections (WHO 2002). The two parasites infect about 131 million people (Davis 2003) and are associated with considerable morbidity and even mortality (van der Werf 2003). A recent meta-analysis suggested that the burden due to schistosomiasis has been significantly underestimated, since disability weights might be two to 15 times higher than previously estimated (King 2005). The social and economic burden of schistosomiasis is thought to be even greater (WHO 2002).

 

Mode of infection

The infection is acquired through contact with freshwater infested with the infective cercariae shed from the intermediate host snail (Bulinus spp.). Once cercariae have penetrated the human skin, the parasites develop into the adult worm within, on average, 63 to 65 days (Smith 1976; Ghandour 1978), and the worms usually migrate to the blood vessels draining the bladder where they reside and produce large numbers of eggs. On average, adult worm pairs live for three to five years, but some can live up to 30 years with the reproduction potential of one schistosome pair estimated to be up to 600 billion schistosomes (Gryseels 2006). The eggs of S. haematobium have a terminal spine and must traverse the bladder tissues towards the lumen of the bladder and urinary tract for elimination via urine. In the process, a considerable number become trapped in the bladder walls and surrounding tissues to initiate immune-induced inflammatory reactions, which subsequently lead to morbidity. It is important to note that eggs trapped in the tissues cause disease rather than the worms themselves.

 

Symptoms and effects

The disease can present as chronic, which is most common, or acute. Haematuria (blood in urine) and dysuria (painful urination) are the main early symptoms of the disease. For most people who are regularly exposed, the severity of disease depends upon the intensity of infection. Mostly individuals with few schistosome worms, and especially adults, remain asymptomatic, although about 80% of infected children show early symptoms and signs of disease (Mott 1983; Olds 2000). Late-stage complications are insidious and include calcification of the bladder wall, bladder stones, and secondary bacterial infection (Jordan 1993). Tissue damage caused by trapped eggs can lead to diffuse or localized wall thickening of the bladder and the distal ureter hydronephrosis or hydroureter, which may eventually lead to kidney failure (Kardorff 2001; WHO 2002; van der Werf 2003).

Elevated urine albumin levels and reported pain upon micturition by children have a strong correlation with S. haematobium infection (Rollinson 2005). An important long-term consequence of infection is squamous cell carcinoma of the bladder (Jordan 1993; King 2005; Shiff 2006). A recent review points out that bladder carcinoma is the seventh most common cancer worldwide in men and that the highest incidence rate among men is found in Egypt (37.1 per 100,000 person-years) (Murta-Nascimento 2007), which might be related to S. haematobium infection and morbidity (Jordan 2000). Eggs produced in venous blood vessels elsewhere such as the vertebral column, and resulting in granuloma formation, may cause spinal cord compression and neurological complications. Severe chronic disease occurs later in life following the infection, and many deaths are rarely acknowledged to be due to schistosomiasis because there is hardly any recognition of the link between infection in early life and later development of severe disease.

Sustained heavy infection leads to iron deficiency anaemia and other nutritional deficiencies, especially in children (Awasthi 2003; King 2005). The disease often results in retarded growth, reduced physical activity, and impaired cognitive function in children (Stephenson 1993; Nokes 1999; PCD 1999; Jukes 2002; WHO 2002).

Diagnosis
Parasitological diagnosis by microscopy of urine for parasite eggs is the most practical and widely used method for identifying infected individuals (Hassan 1994). Egg output in urinary schistosomiasis can be influenced by several factors, such as time of collection of urine (peak egg excretion occurs around noon), day-to-day variations, seasonal variations, and environmental conditions (Braun-Munzinger 1992). Therefore negative results following microscopic examination of a single urine specimen, as with a single stool for intestinal schistosomiasis, are not reliable, particularly in areas characterized by low intensities of infection (de Vlas 1992). Indeed, measurement of prevalence and intensities of infection by egg count has shortcomings (Gryseels 1996; de Vlas 1997; Utzinger 2001b). Egg count is quantified using a nucleopore membrane by urine filtration of a standard 10 mL volume of urine. Reagent strips for detecting blood in the urine (haematuria), and recently, monoclonal antibody-based dipstick tests for detecting schistosome-specific by-products are used to diagnose the disease (Bosompem 1997; Bosompem 2004). Clinically, the disease is diagnosed by reported terminal blood after urination or by inspecting urine for haematuria. Diagnosis on the basis of presence of blood in urine is less reliable in adults (RUSG 1995; Ansell 1997). This is because blood in the urine of an adult may be due to causes other than urinary schistosomiasis. Ultrasound was introduced in the 1970s to detect schistosomal pathology first in the hospital and then in field studies (Hatz 2001). It is a safe, rapid, non-invasive, and relatively inexpensive technique for assessing bladder or urinary tract pathology both in the hospital and in community surveys (Hatz 1990).

 

Disease control strategies

There is no effective antischistosomal vaccine (Gryseels 2000; Fenwick 2006a), although significant progress has been made in recent years (McManus 2008). Therefore, schistosomiasis control programmes have the primary objective of reducing the burden of disease. Four main control strategies have been employed with varying success.

  • Health education to promote good hygiene and sanitation, especially among school-aged children and caregivers. It discourages practices such as bathing in streams and indiscriminate disposal of refuse that tend to increase risk of the infection. The ultimate goal is to decrease the number of eggs reaching and contaminating the environment, particularly freshwater bodies. However, the long-term impact of health education on the transmission of schistosomiasis in rural traditional communities is questionable (Kloos 1995; Sow 2003).

  • Water supply and sanitation to reduce frequency of water contact for most domestic activities such as fetching water for drinking, washing clothing, or bathing in streams and ponds; and access to adequate sanitation to avoid environmental contamination with parasite eggs.

  • Control of the intermediate host snail by environmental management such as removal of vegetation around banks of streams and lining irrigation canals with concrete slabs (Steinmann 2006); and treating infested water bodies with molluscicide to destroy the intermediate host snail. The important role environmental management as part of an integrated control approach has played in conquering S. japonicum in China has been emphasized (Utzinger 2005).

  • Morbidity control by chemotherapy of the human population aims to reduce disease burden and thereby transmission. Past control measures focused largely on reducing or interrupting transmission, but such measures have not been sustainable due to high cost and operational difficulties (WHO 2002). The advent of safe, efficacious, and inexpensive drugs shifted the emphasis to morbidity control in areas of high disease burden, endorsed by the World Health Organization (WHO) in the mid-1980s (WHO 1993; WHO 2002), while in low-burden areas the emphasis is to interrupt transmission of the infection. Although chemotherapy has emerged as the most cost-effective control strategy because of availability of inexpensive drugs, it has been suggested that in most endemic areas addition of preventive measures focusing on clean water, adequate sanitation, and health education to complement chemotherapy is necessary to achieve long-term sustainable schistosomiasis control (Utzinger 2001a; Singer 2007).

 

Chemotherapy

Chemotherapy is targeted especially at school-aged children (Magnussen 2001; WHO 2002; Savioli 2004). The assumption is that reducing the worm burden in childhood, when infection intensity is highest, will prevent most long-term complications occurring later in adulthood.

Several drugs have been used or tried for the treatment of urinary schistosomiasis and later abandoned because of poor effect or adverse events: antimonials, niridazole, lucanthone, hycanthone, oltipraz, cyclosporin A, levamisole, and oxamniquine; see Cioli 1995 for a comprehensive review.

Current treatment options are limited to praziquantel and metrifonate.

  • Praziquantel. Praziquantel is the only drug on the WHO Model List of Essential Medicines for treating S. haematobium. This broad-spectrum antischistosomal drug is effective against all Schistosoma species, although it is refractory against immature parasites (Sabah 1986). Praziquantel is administered orally at a standard dose of 40 mg/kg body weight. The most common adverse effects are gastrointestinal, including abdominal pain, nausea, vomiting and diarrhoea, and are usually mild and last less than 24 hours.

  • Metrifonate. Metrifonate was introduced as a drug for humans in the 1960s (Snellen 1981) and has been used extensively to treat urinary schistosomiasis. The standard dose of 7.5 to 10 mg/kg given three times at 14-day intervals has been used extensively and is mostly well tolerated (Forsyth 1967; Davis 1969; Rugemalila 1981; Feldmeier 1987). Adverse effects are mainly as a result of cholinergic stimulation and include fatigue, muscular weakness, tremor, sweating, salivation, fainting, abdominal colic, diarrhoea, nausea, vomiting, and bronchospasm. Its use has been limited after a suggestion that it was inferior clinically, economically, and operationally to praziquantel (Feldmeier 1999). Subsequently, metrifonate was withdrawn from the WHO Model List of Essential Medicines (Cioli 2000; Utzinger 2004).

Other drugs have potential as treatment options for urinary schistosomiasis, such as artemisinin derivatives, albendazole, and amoscanate. Albendazole is often administered together with praziquantel for simultaneous control of schistosomiasis and soil-transmitted helminthiasis.

  • Artemisinins. The antischistosomal activity of the artemisinins, such as artesunate and artemether, was discovered in the early 1980s (Le 1982; Le 1983). The artemisinins are active against the liver stages (immature) worms, while the invasive stages and adult worms are less susceptible to the drugs. Adverse effects are minor and last for less than 24 hours. Artemisinin monotherapy may not be beneficial due to stage-specific activity, but combination with existing drugs effective against other stages (eg praziquantel) may improve therapeutic efficacy.

  • Albendazole. Albendazole is indicated for the treatment of a variety of worm infestations. In recent years it has often been co-administered with praziquantel with the goal of simultaneously controlling schistosomiasis and soil-transmitted helminthiasis (Friis 2003; Zhang 2007). Albendazole is administered orally (usually as single 400 mg dose), and reported adverse effects include gastrointestinal upsets, headaches, and dizziness, while rash, fever, elevated liver enzymes, and hair loss occur less frequently. There have been reports of elevated liver enzymes, headaches, loss of hair, low levels of white blood cells (neutropenia), fever, and itching if taken at higher doses and/or for a long period of time.

  • Amoscanate. Amoscanate is a broad-spectrum anthelminthic drug that exhibits activity against all major human schistosome parasites (Striebel 1976), other systemic parasites (eg filariae), and gastrointestinal nematodes (eg hookworms). It has been tested extensively in China using the locally produced equivalent called 'nithiocyaminum' (Bueding 1976; Striebel 1976). Toxicity in experimental animals was quite low, and mutagenicity tests in bacteria gave negative results; however, mutagenic metabolites were detected in urine of mammals given amoscanate (Batzinger 1977). It was abandoned because of concerns over liver toxicity and availability of better drugs, such as praziquantel (Cioli 1995). It is possible that amoscanate may represent a unique, broad-spectrum schistosomicide with the appropriate structural modifications to decrease liver toxicity (Cioli 1995).

Combinations of antischistosomal drugs have also been tested with the aim of improving therapeutic efficacy.

  • Artemisinin derivatives (artesunate or artemether) plus praziquantel. This combination is suggested because artesunate and artemether are effective against immature worms, and artemether has shown in mouse models to prevent infection. Combining artesunate or artemether with praziquantel, which is effective against adult worms, may improve therapeutic efficacy.
  • Metrifonate plus praziquantel. The rationale for this combination is that both drugs are independently effective against S. haematobium and that their targets of action in the parasite are not linked. Combination may improve therapeutic efficacy by offering mutual protection to each drug, and it may also slow or prevent the development of resistance.
  • Albendazole plus praziquantel. Albendazole has broad activity, and it has been suggested that combining with praziquantel may help improve therapeutic efficacy. This combination has not been tested widely.

Praziquantel is virtually the only drug currently available for clinical management and control of urinary schistosomiasis. The sharp reduction in price of praziquantel has stalled advancement of other potential control options, such as vaccines, new drugs, and diagnostics (Utzinger 2007). It is noteworthy that pressure on praziquantel is growing, following the policy adopted at the 54th World Health Assembly to increase distribution of the drug and treat at least 75% of school-aged children and other high-risk groups living in areas with high burden of the disease by 2010 (Colley 2001; WHO 2002; Hagan 2004), and new efforts made by the Schistosomiasis Control Initiative to treat millions of school-aged children in selected African countries (Fenwick 2006a). It is therefore timely to assess other antischistosomal compounds as potential alternatives should resistance to praziquantel develop, compare metrifonate with praziquantel as a potentially useful second-line drug, and assess the potential of combination treatments.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

To evaluate antischistosomal drugs, used alone or in combination, for treating urinary schistosomiasis. Specifically:

  • Praziquantel, metrifonate, and artemisinin derivatives versus placebo; and to assess the appropriate dose for each from randomized comparisons by dose.
  • Praziquantel versus metrifonate.
  • Praziquantel plus other drugs (eg metrifonate, albendazole, or artemisinins) versus praziquantel alone.

Other relevant drugs or comparisons will be included in the future if they help address relevant safety, efficacy, or policy questions.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomized and quasi-randomized controlled trials.

 

Types of participants

Individuals infected with S. haematobium diagnosed either microscopically for the presence of S. haematobium eggs in a standard filtrate of 10 mL of urine or by haematuria in endemic areas.

 

Types of interventions

Praziquantel, metrifonate, artemisinin derivatives, or albendazole alone or in combination versus placebo or different doses of same drug; or other relevant antischistosomal drugs.

 

Types of outcome measures

 

Primary

Parasitological failure, defined as treated individuals who remained positive for eggs in the urine at follow up (distinguishing between one to three and three to 12 months post-treatment). Egg reduction rate (one to three or three to 12 months post-treatment).

 

Secondary

 
Laboratory indices

  • Reduction in the percentage of people with a heavy infection (currently defined as ≥ 50 eggs/10 mL urine (WHO 2002).
  • Clearance of haematuria.
  • Measures of anaemia (mean haemoglobin; proportion of participants anaemic).

 
Functional indices (measured by standardized replicable techniques)

Resolution of bladder or urinary tract pathology, as measured by ultrasound, by standard international classification (CWG 1992; Richter 1996), or other standardized methods. Physical growth, including weight-for-age, height-for-age, weight-for-height, upper mid-arm circumference, and triceps skinfold thickness. Physical fitness. Cognitive function and educational achievement.

 

Adverse events

  • Serious (fatal, life-threatening, requiring hospitalization, or discontinuation of treatment).
  • Other.

 

Search methods for identification of studies

We attempted to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and ongoing).

 

Databases

We searched the following databases using the search terms and strategy described in  Table 1: Cochrane Infectious Diseases Group Specialized Register (August 2007); Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (2007, Issue 3); MEDLINE (1966 to August 2007); EMBASE (1974 to August 2007); and LILACS (1982 to August 2007). We also searched the metaRegister of Controlled Trials (mRCT) using 'Schistosoma haematobium' as the search term (August 2007).

 

Researchers and organizations

We contacted individual researchers working in the field and experts from the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) for unpublished data and information on ongoing trials.

 

Reference lists

We checked the reference lists of all studies identified by the above methods.

 

Data collection and analysis

 

Selection of studies

Anthony Danso-Appiah (ADA), with assistance from Vittoria Lutje, the Cochrane Infectious Diseases Group (CIDG) Information Retrieval Specialist, searched the literature and retrieved studies. ADA screened the results to identify potentially relevant trials and assessed the eligibility of trials for inclusion in the review using an eligibility form based on the inclusion criteria; Paul Garner (PG) verified these procedures. ADA scrutinized each trial to ensure it has been included only once. If different parts of the same data were reported in different publications, ADA identified them and linked the data to the parent study. ADA attempted to contact the authors of potentially relevant trials for clarification if eligibility was unclear and listed all potential studies excluded along with the reason for exclusion in the Characteristics of excluded studies.

 

Data extraction and management

ADA extracted data of trial characteristics such as methods, participants, interventions, and outcomes. ADA recorded the data on standard forms, which PG cross-checked. ADA and PG resolved discrepancies through discussion and contacted Jianping Liu (JPL), Piero Olliaro (PO), and Jürg Utzinger (JU) on technical issues. Data were double-entered and cross-checked to make sure there were no errors. ADA scrutinized each trial to identify multiple publications from a single data set and attempted to contact trial authors for clarification, or insufficient or missing data. ADA extracted the number of participants randomized and number analysed in each treatment group, which allowed us assess the most appropriate type of analysis to carry out and to calculate the percentage loss to follow up. For dichotomous outcomes, ADA recorded the number of participants experiencing the event in each group of the trial. For continuous outcomes summarized using geometric mean, ADA extracted means and their standard deviations on the log scale when provided. If the data were provided as arithmetic mean, ADA extracted the means for each group and their standard deviations (SD), standard error (SE), or confidence interval (CI), where possible.

Stratified data were extracted according to the stratifications and follow-up times. Most included trials defined intensity of infection by egg count as light, moderate, and heavy (instead of according to WHO 2002), and we based the treatment failure rate on these categories. We extracted information such as brand of drug used, dose, participant age, diagnostic criteria, endemicity, whether the trial was hospital- or community-based, and whether there had been simultaneous application of other control measures during the trial (eg health education or use of molluscides). To allow assessment of the interdependence between observations in a trial, we extracted data on repeated follow ups and number of communities involved in each trial. Data on haematuria from King 2002 were extracted from graphs.

 

Assessment of risk of bias in included studies

ADA examined design issues relating to internal validity, and PG checked the assessment. Generation of allocation sequence was described as adequate if the method used indicated that the resulting sequences were unpredictable, unclear if trial was randomized but method not described, inadequate if sequences could be predicted, or not described (Jüni 2001). Allocation concealment was described as adequate if methods used prevented prior knowledge of investigators enrolling participants and participants of treatment assignment, inadequate if participants and investigators enrolling participants could foresee upcoming assignment, or not described (Jüni 2001). ADA noted who was blinded to the interventions, such as the participants, care providers, or outcome assessors. The inclusion of all randomized participants in the main analysis was assessed as adequate if more than 90% were included in the analysis, inadequate if 90% or less, or unclear. Given that these cut-offs are arbitrary and subject to sample size for a given study, ADA also reported actual percentages. ADA reported the overall number randomized and the number included in the review for trials not using all the trial arms in the analysis.

 

Data synthesis

Review Manager 4.2 was used for the statistical analyses and dichotomous outcomes (failure rates) were presented as risk ratios (RR) with 95% confidence intervals (CI). To minimize selection bias and the effect of participant attrition, we calculated the proportion of parasitological failure from the total number of participants at follow up and conducted per protocol analysis. We considered RR to be more appropriate because event rates were high. We intended to analyse by intention-to-treat, but this was not possible due to the lack of information in some trial reports. Continuous data were presented as weighted mean differences (WMD) with their standard deviation (SD) or standard error (SE). Egg counts were reported mostly as percentage reduction in geometric mean with rates of reduction over 90% across trials irrespective of background drug or dose. Because treatment effects were obvious in terms of egg excretion, we decided to report them in a table instead of combining in a meta-analysis.

The effects were obvious in comparisons against placebo; therefore we restricted the analysis to the two primary outcomes, three secondary outcomes, and adverse events. We expressed them by number-needed-to-treat (NNT), where possible, and related this to background endemicity.

The impact of follow-up time on cure rate has been elucidated and interpreted from the analysis of available research data; short follow-up times give better treatment effect in terms of parasitological cure than long follow-up times of same background drug and endemicity (Danso-Appiah 2002). To account for this, we analysed treatment failure based on two follow-up categories as short (one to three months) and long (three to 12 months), and also according to dose.

Where data were sufficient we conducted sensitivity analyses to assess the robustness of the results to the quality components. We tested for heterogeneity using the chi-squared and I2 tests, and overall effect with Z score at 95% CI. We attempted to explore potential publication bias using funnel plots, but this was not possible because of the limited number of trials in comparisons.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Twenty-four trials (6315 participants), reported in 35 published articles, met the inclusion criteria (see Characteristics of included studies); none were cluster-randomized. Four articles were published from the same trial data (King 1988), and another three from the same study (Stephenson 1989). Wilkins 1987a reported two trials, but we included one (Nyamari trial named Wilkins 1987a) and excluded the other (Simote trial named Wilkins 1987b) because the latter did not randomize the participants. Nineteen trials were excluded from the review (see Characteristics of excluded studies).

Of the 24 trials included in the analysis, 20 evaluated praziquantel (eight specified Biltricide (Bayer)). Nine trials assessed metrifonate (three specified Bilarcil (Bayer)). Three trials assessed the combination of praziquantel with albendazole, and one trial assessed praziquantel plus artesunate. For the two primary outcomes, 21 trials reported cure rate or failure rate, and 20 reported egg reduction rate. Nine trials reported adverse events. There was lack of uniformity in diagnostic criteria ( Table 2) and classification of intensity of infection across trials ( Table 3). The WHO classifies the intensity of infection as light (1 to 49 eggs/10 mL urine) or heavy (≥ 50 eggs/10 mL urine) (WHO 2002). However, the trials used different classifications for light infection (eg 1 to 5, 1 to 29, 60 to 249, and 250 to 500 eggs/10 mL urine). Moderate and heavy infections were classified the same way with often considerable overlaps between intensity categories.

 

Trial setting and participants

The trials were conducted in Africa: nine in East Africa (six in Kenya and three in Tanzania); five in Southern Africa; four in the Horn of Africa (three in Sudan and one in Somalia); four in West Africa; and two in Central Africa. Nineteen trials were conducted in the 1980s, shortly after praziquantel was introduced in the market, one in the early 1990s, and three in the new millennium. Twenty-two trials involved children aged up to 15 years; the other two trials recruited only boys (Doehring 1985; Befidi-Mengue 1992). Four trials recruited children with mixed infection of S. haematobium and S. mansoni (Jewsbury 1977; Doehring 1985; Kardaman 1985; Taylor 1988). Participants were identified in community surveys in all except two trials that recruited patients attending hospital (Davis 1981) or a combination of patients attending hospital and participants detected during a field survey (Omer 1981).

 

Risk of bias in included studies

See the Characteristics of included studies and summary of the risk of bias ( Table 4).

The methods used to generate the allocation sequence were adequate in the 11 trials that used computer-generated numbers, random-number tables, randomized cards, permutation table, or randomized block design. One trial used sequential allocation (inadequate; Pugh 1983), and the methods used to generate the allocation sequence were unclear in 12 trials. Only three trials used adequate methods to conceal allocation (Aden Abdi 1989; Olds 1999; Borrmann 2001); the methods were unclear in the remaining 21 trials. Eight trials employed blinding and described who was blinded (six were double-blind and two single-blind); the remaining were unclear. For follow up at one to three months, 17 trials included 90% or more participants in the analysis (adequate), and two trials were unclear. For follow up at three to 12 months, 12 trials included 90% or more participants in the analysis (adequate) and five trials were unclear.

 

Effects of interventions

 

1. Metrifonate versus placebo

Four trials made this comparison (Jewsbury 1977; Doehring 1985; Stephenson 1985; Stephenson 1989).

 

Parasitological failure

Jewsbury 1977 measured parasitological failure at one to three months and showed a marked effect in favour of metrifonate (RR 0.42, 95% CI 0.27 to 0.64; 64 participants,  Analysis 1.1), but loss to follow up was high (44%). The effect also favoured metrifonate when failure was measured at three to 12 months in Jewsbury 1977, Stephenson 1985, and Stephenson 1989 (RR 0.53, 95% CI 0.29 to 0.95; 680 participants,  Analysis 1.1), although there was significant heterogeneity.

Loss to follow up was still high in Jewsbury 1977, but less marked in the other two trials (Stephenson 1985; Stephenson 1989). In terms of differences in failure rates, there seemed to be an association with the level of endemicity: Jewsbury 1977 and Stephenson 1989 (high endemicity) led to higher rates of failure at three to 12 months than Stephenson 1985 (low endemicity), but the lower dose used in Stephenson 1989 may confound the observed higher failure rate. There was no obvious association of failure with age (all trials included children of up to 15 years) or follow up (all three trials measured failure at eight months).

 

Egg reduction rate

All four trials measured this at three to 12 months and demonstrated that metrifonate reduced egg excretion by over 90%. The placebo groups ranged from a 5.5% decrease to a 66.2% increase ( Table 5).

 

Mean haemoglobin

Two trials, Stephenson 1985 and Stephenson 1989, showed that participants in the metrifonate group had higher levels of mean haemoglobin than those in the placebo group (RR 0.30, 95% CI 0.28 to 0.32; 607 participants,  Analysis 1.2).

 

Adverse events

Jewsbury 1977 assessed adverse events and recorded none.

 

2. Praziquantel versus placebo

Eight trials made this comparison (McMahon 1979; Oyediran 1981; Doehring 1985; Taylor 1988; Stephenson 1989; Befidi-Mengue 1992; Olds 1999; Borrmann 2001).

 

Parasitological failure

Praziquantel (40 mg/kg x 1 oral) was superior to placebo at one to three months' follow up (RR 0.39, 95% CI 0.27 to 0.55; 534 participants, 4 trials,  Analysis 2.1) and at three to 12 months (RR 0.23, 95% CI 0.14 to 0.39; 433 participants, 3 trials,  Analysis 2.1). There was significant heterogeneity in the meta-analysis, possibly due to loss to follow up, which was high in McMahon 1979 (31.6% and 36.9% for short and long follow-up times, respectively), less than 10% for Stephenson 1989, Olds 1999, and Borrmann 2001, and unreported in Taylor 1988.

 

Egg reduction rate

Praziquantel had egg reduction rates of over 98% (geometric mean) in four trials and a 95% rate in Befidi-Mengue 1992, and these were greater than those achieved with the placebo (5.3% to 64%). Doehring 1985 reported a median reduction rate of 98.7% in the praziquantel group and 48.6% in the placebo group. The trials used different dosing schedules, but there was no clear relationship between the egg reduction rates and dosing schedules ( Table 5).

 

Mean haemoglobin

Stephenson 1989 reported a significant increase in mean haemoglobin with praziquantel (WMD 0.11, 95% CI 0.09 to 0.13; 209 participants,  Analysis 2.2).

 

Adverse events

Olds 1999 recorded 15% excess of mild to moderate adverse events with praziquantel compared with placebo, and Borrmann 2001 reported combined events across comparison groups (127 mild and 6 moderate events); see  Table 6. Neither trial recorded serious adverse events.

 

3. Artesunate versus placebo

One trial, Borrmann 2001, which had two months' follow up, made this comparison.

 

Parasitological failure

There was no obvious benefit with artesunate (118 participants,  Analysis 3.1).

 

Egg reduction rate

There was no significant difference in the egg reduction rate at two months' follow up (ERRlog 0.7 versus 0.4).

 

Haematuria

There was no clear difference between artesunate and placebo at two months (65% versus 53%).

 

Adverse events

Adverse events were reported as combined events (127 mild and six moderate events,  Table 6) and not by comparison group. No serious adverse events were reported.

 

4. Praziquantel plus artesunate versus placebo

One trial with two months' follow up made this comparison (Borrmann 2001).

 

Parasitological failure

There was a clear difference between the combination and placebo for failure rates at two months (RR 0.24, 95% CI 0.15 to 0.38; 118 participants,  Analysis 4.1).

 

Egg reduction rate

The egg reduction rate was high for the combination compared with placebo (ERRlog 1.9 versus 0.4).

 

Haematuria

The urine erythrocyte counts were similar for the combination and placebo (65% versus 53%).

 

Adverse events

There were 127 mild and six moderate adverse events reported, but they were not separated by intervention group ( Table 6).

 

5. Praziquantel plus albendazole versus placebo

Three trials made this comparison (Beasley 1999; Olds 1999; Jinabhai 2001).

 

Parasitological failure

Praziquantel plus albendazole significantly reduced parasitological failures compared to placebo (RR 0.45, 95% CI 0.35 to 0.59; 471 participants, 3 trials,  Analysis 5.1). Jinabhai 2001, which was conducted in a low-endemic area, showed a better effect compared with Beasley 1999 (moderate and high endemicities) or Olds 1999 (very high endemicity).

 

Egg reduction rate

Beasley 1999 reported a geometric mean reduction rate of over 99% with the combination compared to a 12% increase with the placebo ( Table 5).

 

Mean haemoglobin

Beasley 1999 showed marked improvement in mean haemoglobin with the combination (WMD 0.24, 95% CI 0.22 to 0.26; 250 participants,  Analysis 5.2).

 

6. Metrifonate versus praziquantel

Five trials made this comparison (McMahon 1983; Pugh 1983; Wilkins 1987a; King 1988; Stephenson 1989).

 

Parasitological failure

Some early studies investigated a single dose of 10 mg/kg metrifonate (the standard dose is 7.5 to 10 mg/kg three times at 14-day intervals) with the standard single dose of 40 mg/kg praziquantel. Although the single metrifonate dose was inferior in three trials measuring failure at one to 12 months, the 95% CI were too wide for statistical significance (RR 2.31, 95% CI 0.91 to 5.82; 462 participants, Figure 1), due to significant heterogeneity between the trials (I2 93.9%). A possible association with follow-up time was found: Pugh 1983 (RR 1.26 at one month), Wilkins 1987a (RR 2.23 at three months), and Stephenson 1989 (RR 4.62 at eight months).

 FigureFigure 1. Metrifonate (different regimens) vs praziquantel (30 mg/kg or 40 mg/kg, single dose): Parasitological failure.

There was no significant difference in failure when metrifonate (10 mg/kg three times at 14-day intervals) was compared with praziquantel (30 mg/kg) in a small trial involving 54 participants (McMahon 1983,  Analysis 6.1). The metrifonate regimen was then changed to three doses of 10 mg/kg every four months for one year), and this resulted in effects similar to the standard 40 mg/kg of praziquantel (Figure 1).

 
Effect on light and heavy infections

One trial reported a subgroup analysis that showed that there was no significant difference between metrifonate (10 mg/kg every four months for one year) and praziquantel (40 mg/kg) curing light infections (626 participants, 1 trial,  Analysis 7.1), but that this metrifonate dose was better at controlling heavy infections (615 participants,  Analysis 7.2). Given that the subgroup was stratified after randomization, care should be taken in interpreting these results.

 

Egg reduction rate

Both metrifonate (two and three doses of 10 mg/kg) and praziquantel (single dose 40 mg/kg) led to reductions in egg excretion of over 98% in two trials (McMahon 1983; Doehring 1985), while in three trials a single dose of metrifonate (10 mg/kg) also resulted in an egg reduction of over 90% (Pugh 1983; Wilkins 1987a; Stephenson 1989) ( Table 5).

 

Mean haemoglobin

Stephenson 1989 showed that participants in the metrifonate group had greater mean haemoglobin levels than those in the praziquantel group (RR 0.19, 95% CI 0.17 to 0.21; 208 participants,  Analysis 6.2).

 

Adverse events

McMahon 1983 (54 participants) reported similar minor adverse events between metrifonate (10 mg/kg) and praziquantel (30 mg/kg), except for abdominal pain and vomiting, which occurred more frequently in the metrifonate group than the praziquantel group (40% versus 13% and 8% versus 0%). No serious adverse events were reported. Wilkins 1987a (184 participants) compared metrifonate (10 mg/kg x 1) versus praziquantel (40 mg/kg x 1) and reported no serious adverse event. Commonly reported adverse events for the combination treatment included headache, weakness, dizziness, nausea/vomiting, diarrhoea, abdominal pain, general malaise, and fever. Among these events, abdominal pain, general malaise, and fever were reported more frequently in those treated with praziquantel than metrifonate.

 

7. Metrifonate regimens: 5 mg/kg x 3, given in one day versus 7.5 mg/kg x 3, given fortnightly

One trial with 201 participants made this comparison (Aden Abdi 1989).

 

Parasitological failure

There was no significant difference in parasitological failure (201 participants,  Analysis 8.1).

 

Egg reduction rate

Egg reduction rate (geometric mean) was 96% for the one-day regimen versus 97% for the fortnightly regimen ( Table 5).

 

Adverse events

There was little difference in the percentage of mild adverse events reported for the fortnightly regimen (7%) versus the one-day regimen (9%) ( Table 6).

 

8. Metrifonate (10 mg/kg x 1) plus praziquantel (10 mg/kg) versus praziquantel (40 mg/kg)

Wilkins 1987a showed that the combination was inferior to praziquantel at reducing parasitological failure (72 participants,  Analysis 9.1). The same trial reported an egg reduction rate of over 90% for the combination therapy ( Table 5).

 

9. Metrifonate (10 mg/kg x 1) versus metrifonate (10 mg/kg x 1) plus praziquantel (10 mg/kg)

Wilkins 1987a showed no significant difference in parasitological failures with the two interventions (78 participants,  Analysis 10.1).

 

10. Artesunate plus praziquantel versus praziquantel alone

Borrmann 2001 showed no statistically significant difference between the combination and single treatment for parasitological failure (177 participants,  Analysis 11.1). There was no obvious difference in egg reduction rates (ERRlog 1.9 versus 1.2). The trial reported 127 mild and six moderate adverse events, but they were not reported by intervention group ( Table 6).

 

11. Different metrifonate doses

Rey 1984 compared three doses with one and two doses of 10 mg/kg metrifonate. There was no significant difference in the number of parasitological failure between two and three doses at one month and four months ( Analysis 12.1). There were fewer parasitological failures with the three-dose regimen over the one-dose regimen at one month's follow up (RR 2.75, 95% CI 1.29 to 5.85; 93 participants) and four months' follow up (RR 1.52, 95% CI 1.03 to 2.25; 111 participants, Figure 2).

 FigureFigure 2. Metrifonate (10 mg/kg x 1) vs metrifonate (10 mg/kg x 3): Parasitological failure.

 

12. Different praziquantel doses versus standard dose (40 mg/kg x 1 oral)

Ten trials compared the standard dose with various other doses (McMahon 1979; Davis 1981; Oyediran 1981; Omer 1981; Rey 1983; Kardaman 1985; Wilkins 1987a; Taylor 1988; King 1989; King 2002).

 

Parasitological failure

There was no significant difference between the standard dose and 20 mg/kg x 2 (4 trials, Figure 3), 30 mg/kg (6 trials, Figure 4), and 20 mg/kg dose (2 trials, Figure 5); these results were similar for follow up at one, three, and six months.

 FigureFigure 3. Praziquantel (2 x 20 mg/kg) vs praziquantel (standard 40 mg/kg): Parasitological failure.
 FigureFigure 4. Praziquantel (30 mg/kg) vs praziquantel (standard 40 mg/kg): Parasitological failure.
 FigureFigure 5. Praziquantel (20 mg/kg) vs praziquantel (standard 40 mg/kg): Parasitological failure.

Losses to follow up were generally high in some trials, but these did not differ across treatment and control groups within a single trial. There was no significant heterogeneity between the trials, and background endemicities did not seem to play a role; all trial sites had high endemicities except the trial by Davis 1981 (not specified). Examining for a differential effect between heavy and moderate or light infections with 30 mg/kg versus 40 mg/kg, a subgroup analysis of one small trial did not demonstrate a difference (116 participants, King 1989,  Analysis 13.5). Here caution should be exercised in the interpretation of the data since the subgroup was selected after randomization.

 

Egg reduction rate

Five trials all showed no apparent differences in egg reduction rate (geometric mean); all had greater than 95% reduction in both arms, except for Oyediran 1981 in which the 30 mg/kg dose gave an 85.7% reduction compared with 97.7% for the standard dose ( Table 5).

 

Haematuria

Two trials measured haematuria (King 1989; King 2002). King 1989 (117 participants) showed no difference in the rate of clearance between 30 mg/kg x 1 and the standard 40 mg/kg x 1 dose at three months (100% versus 99%). However, King 2002 (200 participants) showed a clear difference at six weeks' follow up between 20 mg/kg x 1 and the standard 40 mg/kg x 1 (40% versus 63%).

 

Adverse events

Davis 1981 recorded similar numbers of mild adverse events for each dose: 19%, 29%, and 17% for 30, 40, and 20 mg/kg x 2, respectively. Kardaman 1985 reported slightly higher rates with 20 mg/kg x 2 than the single dose of 40 mg/kg, but no numbers were reported. Neither trial reported serious adverse events ( Table 6). Oyediran 1981 reported combined adverse events across 40, 30, and 20 mg/kg and recorded only two moderately severe events (umbilical pain). No serious adverse events were recorded.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Most of the 24 included trials were conducted many years ago, mostly in the 1970s and 1980s, and thus the standards of methodological quality did not reach the high standards that we would expect from trials carried out today; for example, only four out of the 24 trials used adequate methods to conceal allocation. However, effect sizes are so marked that it is unlikely that methodological quality will have caused such substantive biases to interfere with the marked effects and differences reported.

Both metrifonate and praziquantel showed good effects, but no trial compared the standard dose of each drug in a head-to-head comparison; instead trials compared different doses of each. Given that no trial compared the standard dose of metrifonate (7.5 to 10 mg/kg 3 times at 14-day intervals) with that of praziquantel (40 mg/kg) in a head-to-head assessment, discussion of adherence to treatment from currently available data is limited. However, the failure rate with the recommended standard dose of metrifonate (7.5 to 10 mg/kg 3 times at 14-day intervals) is 19% to 48%, while that of praziquantel (single 40 mg/kg oral dose) is 0% to 37% at one to three months' follow up. A dose of 7.5 mg/kg metrifonate produced more failures than 10 mg/kg, both doses administered three times at 14-day intervals. There appears to be no difference in effects of metrifonate 10 mg/kg given every four months for one year and the standard dose of praziquantel (40 mg/kg), but this may not be conclusive as the evidence came from only one trial (King 1988). Metrifonate (10 mg/kg 3 times at 14-day intervals) showed a similar effect to praziquantel (30 mg/kg). Public health programmes often recommend multiple-dose regimens, such as for metrifonate (3 doses of 7.5 to 10 mg/kg administered once every 14 days or every 4 months), but these are difficult to implement and might compromise overall compliance.

Both metrifonate and praziquantel showed high degrees of uncertainty around their effect estimates as shown by the wide confidence intervals. The small numbers in some of the trials may explain the levels of uncertainty. In this review we have analysed data mainly around infectivity and assumed statistical significance to be equal to clinical significance because it is not likely that small differences in effect of drugs being evaluated can mean large risks or clinical effects.

A single dose of 20 or 30 mg/kg of praziquantel was similarly efficacious compared to the standard dose of 40 mg/kg in terms of all outcomes measured in this review. Given current emphasis on controlling morbidity in high burden areas and morbidity, especially in children, is associated with the number of eggs in an individual (WHO 2002), this finding suggests lower doses of praziquantel may be effective in morbidity control. However, these results should be considered with caution. While it is true that parasite load (expressed by egg counts) is an important factor in both morbidity for the individual patient and environmental contamination (WHO 2002), a sub-curative dose may unduly put the drug under selective pressure and favour parasite resistance (Doenhoff 1998). Pharmacokinetic data of different doses of praziquantel are few and old, and have been obtained in healthy volunteers rather than in patients with schistosomiasis (Leopold 1978). An exponential increase was found in the area under the curve (AUC) with the praziquantel dose in the range of 5 to 50 mg/kg, with a six-fold increase from 20 to 50 mg/kg (Leopold 1978). However, these data do not come from infected patients, and hence cannot be extrapolated so easily. The artemisinins, best known for their use as antimalarial drugs, have been found to be effective against immature schistosomes in laboratory studies (Utzinger 2001a; Utzinger 2001c; Utzinger 2002). However, results from one low-quality trial show that artesunate is not effective when used alone or when combined with praziquantel. This may, to some extent, be explained by the fact that mature worms are less sensitive to the artemisinins (Utzinger 2007).

It has been suggested that there is a significant infection-associated loss of performance in a person with schistosomiasis that can be improved through antischistosomal treatment (Bergquist 2005; King 2005). This would necessitate any comprehensive assessment of antischistosomal drugs to include outcomes of subtle disease such as resolution of bladder or urinary tract pathology, growth, physical fitness, cognitive function, and educational achievement. Most trials did not investigate these outcome measures because the focus tended to be on measures of infectivity. However, we may include functional outcome measures in future updates if trials provide comprehensive data.

 

Adverse events

The rationale behind the widely spaced dosing interval of metrifonate treatment derives from its long-lasting effect on red blood cells and plasma cholinesterases (Plestina 1972). However, the clinical significance of this effect and why adverse events disappear during the first 12 to 24 hours but the recovery of the enzymes takes more than four to six weeks is not known (Plestina 1972). Safety studies have shown no serious adverse events in patients treated with 5 to 10 mg/kg metrifonate daily for six to 12 days (Snellen 1981), and various reviews of metrifonate's toxicology and pharmacology during its extensive use for urinary schistosomiasis in the 1970s concluded that it had very few adverse events (Holmstedt 1978). Also, metrifonate is currently used in Alzheimer's disease, which requires a high dose and extended regimen, and a systematic review has concluded an overall good tolerability with only mild to moderate adverse events (López-Arrieta 2006). In the current review, although adverse events were generally poorly assessed in the few trials measuring this, no trial recorded a serious adverse event, and no significant differences in the number and type of adverse events between metrifonate and praziquantel were recorded, except for abdominal pain where greater numbers of participants in the metrifonate group were reported with this adverse event.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

 

Implications for practice

Both praziquantel and metrifonate are efficacious (with few adverse events) for treating urinary schistosomiasis, but metrifonate requires multiple administrations and hence is operationally less convenient and more costly in community-based control programmes. However, leaving praziquantel as the only antischistosomal drug raises considerable concern in case resistance develops against this drug. We suggest metrifonate be reconsidered for the WHO Model List of Essential Medicines.

 
Implications for research

Well-designed trials are required to investigate the following areas.

  • Different doses and regimens of metrifonate to identify appropriate doses for treatment and to facilitate adherence.

  • Evaluation of the artemisinins (results are only available for artesunate and these are inconclusive).

  • Combination therapy, ideally with drugs with unrelated mechanisms of action and targeting the different developmental stages of the schistosomes in the human host should be pursued; for example, praziquantel plus metrifonate, and praziquantel plus an artemisinin derivative.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

We would like to express our sincere gratitude to Prof Paul Garner; without his support and guidance this review would not have been possible. We also thank Prof Rashida Barakat, Dr Lester Chitsulo, and Prof Donato Cioli for critically reading this review and for providing useful comments and suggestions, Sarah Donegan for statistical advice, and Gill Gyte for drafting the plain language summary.

This document is funded by the UK Department for International Development (DFID) for the benefit of developing countries. The views expressed are not necessarily those of DFID. J Utzinger acknowledges financial support from the Swiss National Science Foundation (project no. PPOOB-102883 and PPOOB-119-129). P Olliaro is a staff member of the WHO; the authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy, or views of the WHO.

N Squires prepared the original version of this review (Squires 1997) with support from the North West Regional Health Authority, UK, and the European Commission (Directorate General XII), Belgium.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
Download statistical data

 
Comparison 1. Metrifonate vs placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Parasitological failure3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 1 to 3 months
164Risk Ratio (M-H, Random, 95% CI)0.42 [0.27, 0.64]

    1.2 > 3 to 12 months
3680Risk Ratio (M-H, Random, 95% CI)0.53 [0.29, 0.95]

 2 Change in mean haemoglobin (g/dL)2607Mean Difference (IV, Fixed, 95% CI)0.30 [0.28, 0.32]

 
Comparison 2. Praziquantel vs placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Parasitological failure5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 1 to 3 months
4534Risk Ratio (M-H, Random, 95% CI)0.39 [0.27, 0.55]

    1.2 > 3 to 12 months
3433Risk Ratio (M-H, Random, 95% CI)0.23 [0.14, 0.39]

 2 Change in mean haemoglobin (g/dL)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 
Comparison 3. Artesunate vs placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Parasitological failure at 2 months1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 4. Praziquantel plus artesunate vs placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Parasitological failure at 2 months1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 5. Praziquantel plus albendazole vs placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Parasitological failure at 1 to 4 months3471Risk Ratio (M-H, Random, 95% CI)0.45 [0.35, 0.59]

 2 Change in mean haemoglobin (g/dL)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 
Comparison 6. Metrifonate (different regimens) vs praziquantel (30 mg/kg or 40 mg/kg, single dose)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Parasitological failure5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Metrifonate (10 mg/kg, 1 dose) vs praziquantel (40 mg/kg, single dose) at 1 to 8 months
3462Risk Ratio (M-H, Random, 95% CI)2.31 [0.91, 5.82]

    1.2 Metrifonate (10 mg/kg x 3 given fortnightly) vs praziquantel (30 mg/kg, single dose) at 2 months
154Risk Ratio (M-H, Random, 95% CI)1.88 [0.60, 5.90]

    1.3 Metrifonate (10 mg/kg every 4 months for 1 year) vs praziquantel (40 mg/kg, single dose) at 12 months
11241Risk Ratio (M-H, Random, 95% CI)1.19 [0.94, 1.51]

 2 Mean haemoglobin (g/dL)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    2.1 Metrifonate (10 mg/kg x 1) vs praziquantel (40 mg/kg, single dose)
1Mean Difference (IV, Fixed, 95% CI)Not estimable

 
Comparison 7. Metrifonate (10 mg/kg every 4 months for 1 year) vs standard praziquantel dose: effect on infection level

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Parasitological failure at 12 months: light infection1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 2 Parasitological failure at 12 months: heavy infection1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 8. Metrifonate (5 mg/kg x 3, given 1 day) vs metrifonate (7.5 mg/kg x 3, fortnightly)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Parasitological failure at 1 month1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 9. Metrifonate (10 mg/kg x 1) plus praziquantel (10 mg/kg) vs praziquantel (40 mg/kg)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Parasitological failure at 3 months1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 10. Metrifonate (10 mg/kg x 1) vs metrifonate (10 mg/kg x 1) plus praziquantel (10 mg/kg x 1)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Parasitological failure at 3 months1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 11. Artesunate plus praziquantel vs praziqunatel alone

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Parasitological failure at 2 months1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 12. Metrifonate: different doses

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 10 mg/kg x 2 vs 10 mg/kg x 31Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 Parasitological failure rate at 1 month
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    1.2 Parasitological failure rate at 4 months
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 2 10 mg/kg x 1 vs 10 mg/kg x 31Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    2.1 Parasitological failure rate at 1 month
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    2.2 Parasitological failure rate at 4 months
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 
Comparison 13. Praziquantel: different doses vs standard 40 mg/kg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Parasitological failure: 2 x 20 mg/kg4Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 1 month
3374Risk Ratio (M-H, Random, 95% CI)0.98 [0.51, 1.88]

    1.2 3 months
3361Risk Ratio (M-H, Random, 95% CI)0.66 [0.30, 1.45]

    1.3 6 months
3234Risk Ratio (M-H, Random, 95% CI)1.08 [0.78, 1.50]

 2 Parasitological failure: 30 mg/kg6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 1 month
4401Risk Ratio (M-H, Fixed, 95% CI)1.31 [1.01, 1.70]

    2.2 3 months
5517Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.80, 1.39]

    2.3 6 months
5439Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.78, 1.37]

 3 Parasitolotical failure: 20 mg/kg4Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 1 month
2338Risk Ratio (M-H, Random, 95% CI)1.34 [0.90, 2.01]

    3.2 3 months
3330Risk Ratio (M-H, Random, 95% CI)1.37 [1.00, 1.87]

    3.3 6 months
1138Risk Ratio (M-H, Random, 95% CI)1.09 [0.65, 1.82]

 4 Proportion cleared of haematuria2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 2 x 20 mg/kg
2308Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.67, 0.95]

    4.2 30 mg/kg
1116Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.78, 1.19]

 5 Parasitiological failure: 30 mg/kg vs 40 mg/kg at 3 months' follow up1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    5.1 Light infection
1Risk Ratio (M-H, Random, 95% CI)Not estimable

    5.2 Moderate infection
1Risk Ratio (M-H, Random, 95% CI)Not estimable

    5.3 Heavy infection
1Risk Ratio (M-H, Random, 95% CI)Not estimable

 
Comparison 14. Praziquantel: different doses vs standard 40 mg/kg

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Parasitological failure rate at 1 to 12 months9Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Failure rate: 2 x 20 mg/kg vs standard 40 mg/kg
4457Risk Ratio (M-H, Random, 95% CI)1.07 [0.77, 1.50]

    1.2 Failure rate: 30 mg/kg vs standard 40 mg/kg
6597Risk Ratio (M-H, Random, 95% CI)1.25 [1.02, 1.53]

    1.3 Failure rate: 20 mg/kg vs standard 40 mg/kg
4530Risk Ratio (M-H, Random, 95% CI)1.44 [1.09, 1.90]

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Last assessed as up-to-date: 15 October 2007.


DateEventDescription

16 October 2007New citation required and conclusions have changed2008, Issue 3: This review update has been prepared by new authors (A Danso-Appiah, J Utzinger, JP Liu, and P Olliaro). Each section of the review has been rewritten and updated, including the results and conclusions.

16 October 2007New search has been performed2008, Issue 3: This review update, which is authored by a new author team (A Danso-Appiah, J Utzinger, JP Liu, and P Olliaro), is based on a new protocol (unpublished) with modified inclusion criteria, updated methods, and a new literature search. The review includes 24 trials and incorporates new comparisons. Each section of the review has been rewritten and updated, including the results and conclusions.



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Protocol first published: Issue 1, 1996
Review first published: Issue 2, 1997


DateEventDescription

1 May 1997New citation required and conclusions have changedReview first published.



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Anthony Danso-Appiah developed the protocol and carried out the systematic review; this included assessing methodological quality, analysing and interpreting the data, and drafting the manuscript. Jürg Utzinger, Jianping Liu, and Piero Olliaro assisted in the interpretation of the results and revising the text. All authors helped with revisions following the referees' comments.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Internal sources

  • Liverpool School of Tropical Medicine, UK.

 

External sources

  • Department for International Development, UK.
  • Swiss National Science Foundation (project no. PPOOB-102883), Switzerland.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract摘要
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
  20. References to other published versions of this review
Aden Abdi 1989 {published data only}
  • Aden Abdi Y, Gustafsson LL. Field trial of the efficacy of a simplified and standard metrifonate treatments of Schistosoma haematobium. European Journal of Clinical Pharmacology 1989;37(4):371-4.
Beasley 1999 {published data only}
Befidi-Mengue 1992 {published data only}
  • Befidi-Mengue RN, Ratard RC, D'Alessandro A, Rice J, Befidi-Mengue R, Kouemeni LE, et al. The impact of Schistosoma haematobium infection and of praziquantel treatment on the growth of primary school children in Bertoua, Cameroon. Journal of Tropical Medicine and Hygiene 1992;95(6):404-9.
Borrmann 2001 {published data only}
  • Borrmann S, Szlezák N, Faucher JF, Matsiegui PB, Neubauer R, Binder RK, et al. Artesunate and praziquantel for the treatment of Schistosoma haematobium infections: a double-blind, randomized, placebo-controlled study. Journal of Infectious Diseases 2001;184(10):1363-6.
Davis 1981 {published data only}
  • Davis A, Biles JE, Ulrich AM. Initial experiences with praziquantel in the treatment of human infections due to Schistosoma haematobium. Bulletin of the World Health Organization 1979;57(5):773-9.
  • Davis A, Biles JE, Ulrich AM, Dixon H. Tolerance and efficacy of praziquantel in phase II A and II B therapeutic trials in Zambian patients. Arzneimittel-Forschung 1981;31(3a):568-74.
Doehring 1985 {published data only}
  • De Jonge N, Schommer G, Feldmeier H, Krijger GW, Dafalla AA, Bienzle U, et al. Mixed Schistosoma haematobium and S. mansoni infection: effect of different treatments on the serum level of circulating anodic antigen (CAA). Acta Tropica 1991;48(1):25-35.
  • Doehring E, Ehrich JH, Vester U, Feldmeier H, Poggensee U, Brodehl J. Proteinuria, hematuria, and leukocyturia in children with mixed urinary and intestinal schistosomiasis. Kidney International 1985;28(3):520-5.
  • Doehring E, Poggensee U, Feldmeier H. The effect of metrifonate in mixed Schistosoma haematobium and Schistosoma mansoni infections in humans. American Journal of Tropical Medicine and Hygiene 1986;35(2):323-39.
Jewsbury 1977 {published data only}
  • Jewsbury JM, Cooke MJ. Prophylaxis of schistosomiasis - field trial of metrifonate for the prevention of human infection. Annals of Tropical Medicine and Parasitology 1976;70(3):361-3.
  • Jewsbury JM, Cooke MJ, Weber MC. Field trial of metrifonate in the treatment and prevention of schistosomiasis infection in man. Annals of Tropical Medicine and Parasitology 1977;71(1):67-83.
Jinabhai 2001 {published data only}
  • Jinabhai CC, Taylor M, Coutsoudis A, Coovadia HM, Tomkins AM, Sullivan KR. Epidemiology of helminth infections: implications for parasite control programmes, a South African perspective. Public Health Nutrition 2001;4(6):1211-9.
Kardaman 1985 {published data only}
  • Kardaman MW, Fenwick A, el Igail AB, el Tayeb M, Daffalla AA, Dixon HG. Treatment with praziquantel of schoolchildren with concurrent Schistosoma mansoni and S. haematobium infections in Gezira, Sudan. Journal of Tropical Medicine and Hygiene 1985;88(2):105-9.
King 1988 {published data only}
  • King CH, Lombardi G, Lombardi C, Greenblatt R, Hodder S, Kinyanjui H, et al. Chemotherapy based control of schistosomiasis haematobia. I. Metrifonate versus praziquantel in control of intensity and prevalence of infection. American Journal of Tropical Medicine and Hygiene 1988;39(3):295-05.
  • King CH, Lombardi G, Lombardi C, Greenblatt R, Hodder S, Kinyanjui H, et al. Chemotherapy-based control of schistosomiasis haematobia. II. Metrifonate vs. praxiquantel in control of infection-associated morbidity. American Journal of Tropical Medicine and Hygiene 1990;42(6):587-95.
  • King CH, Muchiri E, Ouma JH, Koech D. Chemotherapy-based control of schistosomiasis haematobia. IV. Impact of repeated annual chemotherapy on prevalence and intensity of Schistosoma haematobium infection in an endemic area of Kenya. American Journal of Tropical Medicine and Hygiene 1991;45(4):498-508.
  • King CH, Muchiri EM, Ouma JH. Age-targeted chemotherapy for control of urinary schistosomiasis in endemic populations. Memórias do Instituto Oswaldo Cruz 1992;87 Suppl 4:203-10.
King 1989 {published data only}
  • King CH, Wiper DW 3rd, De Stigter KV, Peters PA, Koech D, Ouma JH, et al. Dose-finding study for praziquantel therapy of Schistosoma haematobium in Coast Province, Kenya. American Journal of Tropical Medicine and Hygiene 1989;40(5):507-13.
King 2002 {published data only}
  • King CH, Muchiri EM, Mungai P, Ouma JH, Kadzo H, Magak P, et al. Randomized comparison of low-dose versus standard-dose praziquantel therapy in treatment of urinary tract morbidity due to Schistosoma haematobium infection. American Journal of Tropical Medicine and Hygiene 2002;66(6):725-30.
McMahon 1979 {published data only}
  • McMahon JE, Kolstrup N. Praziquantel: a new schistosomicide against Schistosoma haematobium. British Medical Journal 1979;2(6202):1396-8.
McMahon 1983 {published data only}
  • McMahon JE. A comparative trial of praziquantel, metrifonate and niridazole against Schistosoma haematobium. Annals of Tropical Medicine and Parasitology 1983;77(2):139-42.
Olds 1999 {published data only}
  • Olds GR, King C, Hewlett J, Olveda R, Wu G, Ouma J, et al. Double-blind placebo-controlled study of concurrent administration of albendazole and praziquantel in schoolchildren with schistosomiasis and geohelminths. Journal of Infectious Diseases 1999;179(4):996-1003.
Omer 1981 {published data only}
Oyediran 1981 {published data only}
  • Oyediran AB, Kofie BA, Bammeke AO, Bamgboye EA. Clinical experience with praziquantel in the treatment of Nigerian patients infected with S. haematobium. Arzneimittel-Forschung 1981;31(3a):581-4.
Pugh 1983 {published data only}
  • Pugh RN, Teesdale CH. Long-term efficacy of single-dose oral treatment in schistosomiasis haematobium. Transaction of Royal Society of Tropical Medicine and Hygiene 1984;78(1):55-9.
  • Pugh RN, Teesdale CH. Single dose oral treatment in urinary schistosomiasis: a double blind trial. British Medical Journal 1983;286(6363):429-32.
Rey 1983 {published data only}
  • Rey JL, Sellin B, Gazere O, Ott D, Reges M, Garrouty P. Comparison study of praziquantel efficiency (30 mg/kg and 40 mg/kg) in a single dose and oltipraz (35 mg/kg) in two doses on schistosoma haematobium in Niger [Comparaison au Niger de l'efficacité sur schistosoma haematobium du praziquantel (30 mg/kg et 40 mg/kg) en une prise et de l'oltipraz (35mg/kg) en deux prises]. Médecine et Maladies Infectieuses 1983;13(6):328-31.
Rey 1984b {published data only}
  • Rey JL, Nouhou H, Sellin B. Comparison of 3 metrifonate dosages in mass chemotherapy of Schistosoma haematobium [Comparaison de trois posologies de metrifonate en chimiotherapie de mass contre Schistosoma haematobium]. Médecine Tropicale 1984;44(1):57-60.
Stephenson 1985 {published data only}
  • Stephenson LS, Latham MC, Kinoti SN, Oduori ML. Regression of splenomegaly and hepatomegaly in children treated for Schistosoma haematobium infection. American Journal Tropical Medicine and Hygiene 1985;34(1):119-23.
  • Stephenson LS, Latham MC, Kurz KM, Kinoti SN, Oduori ML, Crompton DW. Relationships of Schistosoma haematobium, hookworm and malarial infections and metrifonate treatment to growth of Kenyan school children. American Journal of Tropical Medicine and Hygiene 1985;34(6):1109-18.
  • Stephenson LS, Latham MC, Kurz KM, Kinoti SN, Oduori ML, Crompton DW. Relationships of Schistosoma hematobium, hookworm and malarial infections and metrifonate treatment to hemoglobin level in Kenyan school children. American Journal of Tropical Medicine and Hygiene 1985;34(3):519-28.
Stephenson 1989 {published data only}
  • Latham MC, Stephenson LS, Kurz KM, Kinoti SN. Metrifonate or praziquantel treatment improves physical fitness and appetite of Kenyan schoolboys with Schistosoma haematobium and hookworm infections. American Journal of Tropical Medicine and Hygiene 1990;43(2):170-9.
  • Stephenson LS, Kinoti SN, Latham MC, Kurz KM, Kyobe J. Single dose metrifonate or praziquantel treatment in Kenyan children. I. Effects on Schistosoma haematobium, hookworm, hemoglobin levels, splenomegaly and hepatomegaly. American Journal of Tropical Medicine and Hygiene 1989;41(4):436-44.
  • Stephenson LS, Latham MC, Kurz KM, Kinoti SN. Single dose metrifonate or praziquantel treatment in Kenyan children. II. Effects on growth in relation to Schistosoma haematobium and hookworm egg counts. American Journal of Tropical Medicine and Hygiene 1989;41(4):445-53.
Taylor 1988 {published data only}
  • Taylor P, Murare HM, Manomano K. Efficacy of low doses of praziquantel for Schistosoma mansoni and S. haematobium. Journal of Tropical Medicine and Hygiene 1988;91(1):13-7.
Wilkins 1987a {published data only}
  • Wilkins HA, Moore PJ. Comparative trials of regimes for the treatment of urinary schistosomiasis in The Gambia. Journal of Tropical Medicine and Hygiene 1987;90(2):83-92.

References to studies excluded from this review

  1. Top of page
  2. Abstract摘要
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
  20. References to other published versions of this review
Aden-Abdi 1987 {published data only}
  • Aden-Abdi Y, Gustafsson LL, Elmi SA. A simplified dosage schedule of metrifonate in the treatment of Schistosoma haematobium infection in Somalia. European Journal of Clinical Pharmacology 1987;32(5):437-41.
Boulanger 2007 {published data only}
  • Boulanger D, Dieng Y, Cisse B, Remoue F, Capuano F, Dieme JL, et al. Antischistosomal efficacy of artesunate combination therapies administered as curative treatments for malaria attacks. Transaction of The Royal Society of Tropical Medicine and Hygiene 2007;101(2):113-6.
De Clercq 2002 {published data only}
  • De Clercq D, Vercruysse J, Kongs A, Verlé P, Dompnier JP, Faye PC. Efficacy of artesunate and praziquantel in Schistosoma haematobium infected schoolchildren. Acta Tropica 2002;82(1):61-6.
Druilhe 1981 {published data only}
  • Druilhe P, Bourdillon F, Froment A, Kyelem JM. Control of urinary schistosomiasis by 3 annual courses of metrifonate [Essai de controle de la bilharoziose urinarire par 3 cures annuelles de metrifonate]. Annales de la Societe Belge de Medecine Tropicale 1981;61(1):99-109.
Inyang-Etoh 2004 {published data only}
  • Inyang-Etoh PC, Ejezie GC, Useh MF, Inyang-Etoh EC. Efficacy of artesunate in the treatment of urinary schistosomiasis, in an endemic community in Nigeria. Annals of Tropical Medicine and Parasitology 2004;98(5):491-9.
Kardaman 1983 {published data only}
  • Kardaman MW, Amin MA, Fenwick A, Cheesmond AK, Dixon HG. A field trial using praziquantel (BiltricideR) to treat Schistosoma mansoni and Schistosoma haematobium infection in Gezira, Sudan. Annals of Tropical Medicine and Parasitology 1983;77(3):297-304.
N'Goran 2003a {published data only}
  • N'Goran EK, Gnaka HN, Tanner M, Utzinger J. Efficacy and side-effects of two praziquantel treatments against Schistosoma haematobium infection, among schoolchildren from Côte d'Ivoire. Annals of Tropical Medicine and Parasitology 2003;97(1):37-51.
N'Goran 2003b {published data only}
  • N'Goran EK, Utzinger J, Gnaka HN, Yapi A, N'Guessan NA, Kigbafori SD, et al. Randomized, double-blind, placebo-controlled trial of oral artemether for the prevention of patent Schistosoma haematobium infections. American Journal of Tropical Medicine and Hygiene 2003;68(1):24-32.
Rey 1984 {published data only}
  • Rey JL, Sellin E, Sellin B, Simonkovich E, Mouchet F. Efficacite comparee de l'oltipraz (1 dose, 30 mg/kg) et de l'association niridazole (25 mg/kg) - metrifonate (10 mg/kg) contre S haematobium [Comparative efficacy of oltipraz (1 dose, 30 mg/kg) and the combination of niridazole (25 mg/kg) and metrifonate (10 mg/kg) against S. haematobium]. Médecine Tropicale 1984;44(2):155-8.
Saif M 1981 {published data only}
  • Saif M, Abdel-Meguid M. Observations on tolerance and efficacy of praziquantel in Egyptian patients infected simultaneously with S. haematobium and S. mansoni. Arzneimittelforschung 1981;31(3a):604.
Schutte 1983 {published data only}
  • Schutte CH, Osman Y, Van Deventer JM, Mosese G. Effectiveness of praziquantel against the South African strains of Schistosoma haematobium and S. mansoni. South African Medical Journal (Suid-Afrikaanse Tydskrif Vir Geneeskunde) 1983; 64(1):7-10 1983;64(1):7-10.
Snyman 1997 {published data only}
  • Snyman JR, de Sommers K, Steinmann MA, Lizamore D. Effects of calcitriol on eosinophil activity and antibody responses in patients with schistosomiasis. European Journal of Clinical Pharmacology 1997;52(4):277-80.
Taylor 2001 {published data only}
  • Taylor M, Jinabhai CC, Couper I, Kleinschmidt I, Jogessar VB. The effect of different anthelmintic treatment regimens combined with iron supplementation on the nutritional status of schoolchildren in KwaZulu-Natal, South Africa: a randomized controlled trial. Transactions of the Royal Society of Tropical Medicine and Hygiene 2001;95(2):211-6.
Tchuem Tchuente 2004 {published data only}
  • Tchuenté LA, Shaw DJ, Polla L, Cioli D, Vercruysse J. Efficacy of praziquantel against Schistosoma haematobium infection in children. American Journal of Tropical Medicine and Hygiene 2004;71(6):778-82.
Utzinger 2001a {published data only}
Utzinger 2003 {published data only}
  • Utzinger J, Keiser J, Shuhua X, Tanner M, Singer BH. Combination chemotherapy of schistosomiasis in laboratory studies and clinical trials. Antimicrobial Agents and Chemotherapy 2003;47(5):1487-95.
Wilkins 1987b {published data only}
  • Wilkins HA, Moore PJ. Comparative trials of regimes for the treatment of urinary schistosomiasis in The Gambia. Journal of Tropical Medicine and Hygiene 1987;90(2):83-92.

Additional references

  1. Top of page
  2. Abstract摘要
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
  20. References to other published versions of this review
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