Efficacy and safety of praziquantel 40 mg/kg in preschool-aged and school-aged children: a meta-analysis

BACKGROUND: Children carry most of the schistosomiasis burden. While school-aged children are the principal target group of preventive chemotherapy with praziquantel, limited information on efficacy and safety exists for preschool-aged children. METHODS: Here, we conducted a meta-analysis of clinical trials of praziquantel for treating children with any form of schistosomiasis. Efficacy was reported as cure rate (CR) and egg reduction rates (ERR); statistical corrections were applied based on methodological disparities across trials to derive the predicted geometrical mean ERR (pERRgm). Safety was reported as frequencies of adverse events. RESULTS: Forty-seven comparative and non-comparative studies were identified, enrolling 15,549 children of whom 14,340 (92%) were assessed between 3 and 8 weeks post-treatment with praziquantel 40 mg/kg (the WHO-recommended treatment, n = 8,380, 56%) or comparators (n = 5,960, 44%). The median age was 10 years (range 1-19), 11% (n = 1,694) were preschool-aged. The CR and pERRgm with praziquantel 40 mg/kg were respectively: S. haematobium, 73.6% (95% CI: 63.5-81.40, 25 study arms) and 94.7% (95% CI: 92.7-96.4); S. mansoni, 76.4% (95% CI: 71.5-81.0, 34 arms) and 95.3% (95% CI: 94.2-96.2); S. mansoni/S. haematobium, 67.6% (95% CI: 54.1-80.7, 5 arms) and 93.4% (95% CI: 89.9-96.2); S. japonicum, 94.7% (95% CI: 92.2-98.0) and 98.7% (95% CI: 98.3-99.2). Mixed-effect multivariate analysis found no significant difference between preschool- and school-aged children for CR or pERRgm in S. haematobium (P = 0.309 and P = 0.490, respectively) or S. mansoni (P = 0.982 and P = 0.895) after controlling for time of assessment, formulation, intensity of infection and detection method. Praziquantel was reportedly safe at all ages, with only mild reported adverse events which cleared rapidly after treatment. CONCLUSIONS: Praziquantel 40 mg/kg was effective at reducing infection intensity in all Schistosoma species without differences between preschool- and school-aged children. However, conclusions should be tempered because of the limited number of preschool-aged children enrolled, disparities in study procedures and limited information made available in publications, as well as the current imperfect test-of-cure. Also, although reportedly well-tolerated, safety was inconsistently assessed. Studies in target groups, individual-data meta-analysis and standardised methodologies are needed for more robust evidence-base

Managing the risks of making the wrong diagnosis: First, do no harm

The appropriate use of diagnostics is important as misdiagnosis may have serious consequences. Confidence in a diagnostic test result depends on the test's accuracy (sensitivity and specificity) in the context of the use-case (who is tested and why) and the prevalence of the condition investigated. Here, we offer an approach to diagnostics focused on the risks and effects of making the wrong diagnosis. We propose ‘fitness brackets’ for a given test to define the range within which the test is fit-for-purpose, based on the use-case and risk-management principles. We use as exemplars tests for dengue pre-vaccination screening and tests for diagnosing Covid-19 in different settings

Miltefosine in the treatment of leishmaniasis: Clinical evidence for informed clinical risk management

Visceral leishmaniasis (VL) is a life-threatening disease. Traditional treatment with pentavalent antimony injections has become ineffective in the area with the world’s highest prevalence of disease (North Bihar, India) and is becoming less effective elsewhere as well. A replacement is needed, best if it can be given to more patients outside the hospital. Miltefosine is the first oral drug registered for VL. Given daily under medical supervision for 4 weeks, it cures 94% of patients (both children and adults) and is reasonably safe. Miltefosine has great potential for improving access to treatment and overall control of VL and will be critical in the VL elimination campaign in the Indian subcontinent, but must be safeguarded or will be lost if misused. Its main limitations are adherence (and hence potential for selection of drug resistant parasites) and teratogenicity (pregnancy must be avoided during treatment and the following two months). This calls for responsible deployment, setting in place mechanisms to protect female patients in child-bearing age, monitoring effects and optimizing adherence in real-life conditions through directly observed therapy. One option to protect the useful life-span of miltefosine consists in shortening treatment duration by combining it with another drug

Implementation of intermittent preventive treatment in pregnancy with sulphadoxine/pyrimethamine (IPTp-SP) at a district health centre in rural Senegal

<p>Abstract</p> <p>Background</p> <p>Intermittent preventive treatment with <it>s</it>ulphadoxine-pyrimethamine (SP) is recommended for reducing the risk of malaria in pregnancy and its consequences on mothers and babies (IPTp-SP). Indicators of implementation and effects of IPTp-SP were collected in a rural clinic in Southern Senegal.</p> <p>Methods</p> <p>Women seen routinely at the antenatal clinic (ANC) of a rural dispensary during 2000–2007. Deployment of IPTp-SP started in January 2004. Inspection of antenatal and outpatient clinic registries of the corresponding period.</p> <p>Results</p> <p>Between 1^stJanuary 2000 and 30^thApril 2007, 1,781 women of all gravitidities and parities attended the ANC with 965 deliveries (606 and 398 respectively since 1^stJanuary 2004, when IPTp-SP was started.) 69% of women were seen ≥ 3 times; 95% received at least one dose and 70% two doses of SP (from 61% in 2004 to 86% in 2007). The first visit, first and second dose of SP occurred at a median week 20, 22 and 31. The probability of receiving two doses was > 80% with ≥ 3 antenatal visits and a first dose of SP by week 20.</p> <p>The prevalence of maternal malaria was low and similar pre- (0.7%) and during IPTp (0.8%). Effects on of low birth weight (LBW, < 2.5 kg) were non-statistically significant. The prevalence of LBW was 10.8% pre- and 7.7% during IPTp deployment (29% risk reduction, p = 0.12).</p> <p>Unfavourable pregnancy outcomes numbered 72 (7.5% of pregnancies with known outcome), including 30 abortions and 42 later deaths (late foetal deaths, stillbirth, peri-natal) of which 13 with one or more malformations (1.35% of all recorded deliveries).</p> <p>Conclusion</p> <p>The implementation of IPTp-SP was high. Early attendance to ANC favours completion of IPTp-SP. The record keeping system in place is amenable to data extraction and linkage. A model was developed that predicts optimal compliance to two SP doses, and could be tested in other settings. Maternal malaria was infrequent and unaffected by IPTp-SP. The risk of LBW was lower during IPT implementation but the difference was non-significant and could have other explanations.</p

Drugs for neglected diseases: a failure of the market and a public health failure?

Infectious diseases cause the suffering of hundreds of millions of people, especially in tropical and subtropical areas. Effective, affordable and easy-to-use medicines to fight these diseases are nearly absent. Although science and technology are sufficiently advanced to provide the necessary medicines, very few new drugs are being developed. However, drug discovery is not the major bottleneck. Today's R&D-based pharmaceutical industry is reluctant to invest in the development of drugs to treat the major diseases of the poor, because return on investment cannot be guaranteed. With national and international politics supporting a free market-based world order, financial opportunities rather than global health needs guide the direction of new drug development. Can we accept that the dearth of effective drugs for diseases that mainly affect the poor is simply the sad but inevitable consequence of a global market economy? Or is it a massive public health failure, and a failure to direct economic development for the benefit of society? An urgent reorientation of priorities in drug development and health policy is needed. The pharmaceutical industry must contribute to this effort, but national and international policies need to direct the global economy to address the true health needs of society. This requires political will, a strong commitment to prioritize health considerations over economic interests, and the enforcement of regulations and other mechanisms to stimulate essential drug development. New and creative strategies involving both the public and the private sector are needed to ensure that affordable medicines for today's neglected diseases are developed. Priority action areas include advocating an essential medicines R&D agenda, capacity-building in and technology transfer to developing countries, elaborating an adapted legal and regulatory framework, prioritizing funding for essential drug development and securing availability, accessibility, distribution and rational use of these drugs

Total quality management in the supply chain of a petrochemical organisation

Abstract: The objective was to investigate the extent of the use of total quality management (TQM) practices in a supply chain of a petrochemical organisation. TQM is a method by which management and employees can become involved in the continuous improvement of the production of goods and services. It is a combination of quality and management tools aimed at increasing business and reducing losses due to wasteful practices. The study was carried out in the petrochemical industry, which is of economic significance to the country. An existing TQM questionnaire was used and a total of 200 employees were targeted. The questionnaire had a seven-factor structure with acceptable Cronbach Alpha co-efficients. Overall, there was a significant number of employees who agree that total quality management is not practiced within their work areas and leading to a high number of quality related customer complaints. Management and employees are encouraged to be visibly involved in the development of a TQM transformation. TQM requires support from management, long-term strategic decision-making and motivated personnel

The little we know about the pharmacokinetics and pharmacodynamics of praziquantel (racemate and R-enantiomer)

Praziquantel has been the mainstay of schistosomiasis control since 1984 and widely distributed since 2006 through ‘preventive chemotherapy' programmes to school-aged children or at-risk populations. In addition, preschool-aged children are now recognized as a vulnerable population and a group for targeted treatment, but they may be difficult to dose correctly with the available product—a racemate, based on the biologically active enantiomer (R-praziquantel) and the inactive distomer (S-praziquantel), which contributes the bitter taste and doubles the size of the tablets. Hence, a paediatric formulation is required, possibly enantiomerically pure. Developing such a product and extending its use to younger children should be pharmacologically guided, but limited data exist on pharmacokinetics and pharmacokinetic/pharmacodynamic correlations for praziquantel. This article presents available data on the chemistry, pharmacokinetics and pharmacodynamics of praziquantel, as well as R-praziquantel, and points to gaps in our knowledg

Abstracting strings for model checking of C programs

Data type abstraction plays a crucial role in software verification. In this paper, we introduce a domain for abstracting strings in the C programming language, where strings are managed as null-terminated arrays of characters. The new domain M-String is parametrized on an index (bound) domain and a character domain. By means of these different constituent domains, M-Strings captures shape information on the array structure as well as value information on the characters occurring in the string. By tuning these two parameters, M-String can be easily tailored for specific verification tasks, balancing precision against complexity. The concrete and the abstract semantics of basic operations on strings are carefully formalized, and soundness proofs are fully detailed. Moreover, for a selection of functions contained in the standard C library, we provide the semantics for character access and update, enabling an automatic lifting of arbitrary string-manipulating code into our new domain. An implementation of abstract operations is provided within a tool that automatically lifts existing programs into the M-String domain along with an explicit-state model checker. The accuracy of the proposed domain is experimentally evaluated on real-case test programs, showing that M-String can efficiently detect real-world bugs as well as to prove that program does not contain them after they are fixed