Drug Discovery for Kinetoplastid Diseases: Future Directions.

Kinetoplastid parasites have caused human disease for millennia. Significant achievements have been made toward developing new treatments for leishmaniasis (particularly on the Indian subcontinent) and for human African trypanosomiasis (HAT). Moreover, the sustained decrease in the incidence of HAT has made the prospect of elimination a tantalizing reality. Despite the gains, no new chemical or biological entities to treat kinetoplastid diseases have been registered in more than three decades, and more work is needed to discover safe and effective therapies for patients with Chagas disease and leishmaniasis. Advances in tools for drug discovery and novel insights into the biology of the host-parasite interaction may provide opportunities for accelerated progress. Here, we summarize the output from a gathering of scientists and physicians who met to discuss the current status and future directions in drug discovery for kinetoplastid diseases.

Female genital schistosomiasis (FGS): from case reports to a call for concerted action against this neglected gynaecological disease.

In recent years, control of neglected tropical diseases has been increasingly gaining momentum and interventions against schistosomiasis are being progressively scaled-up through expansion of donated praziquantel and preventive chemotherapy campaigns. However, the public health importance of female genital schistosomiasis is not fully recognised nor its control is adequately addressed. Taking a clinical and anatomopathological perspective, we evaluated the available literature to highlight the importance of female genital schistosomiasis and its connections with two sexually transmitted infections of global importance, Human Immunodeficiency Virus (HIV) and Human Papilloma Virus. Outside the long list of clinical descriptive reports beginning in 1899, there is presently a shocking gap in epidemiological assessment and a significant underestimation of the burden of FGS remains. The scarcity of integrated approaches to address female genital schistosomiasis calls for more concerted action in its detection, treatment and prevention alongside other concomitant women's health issues, otherwise female genital schistosomiasis will remain a neglected gynaecological disease.

Diagnosis of O. volvulus infection via skin exposure to diethylcarbamazine: clinical evaluation of a transdermal delivery technology-based patch.

BACKGROUND: Elimination of onchocerciasis in Africa is now regarded as an achievable goal in many areas. This makes monitoring changes in infection prevalence a key component of control programmes. Monitoring is currently based on determining the presence of O. volvulus microfilariae in skin snips, an invasive, labour-intensive method. The Onchocerciasis Control Programme (OCP) had established procedures to detect O. volvulus infections via the localized skin reaction induced by killing of microfilariae upon skin exposure to diethylcarbamazine via a patch (OCP-patch). Large scale OCP - patch use is difficult due to labour-intensive patch preparation. At the request of TDR, a manufacturer specialized in transdermal-delivery systems developed a ready-to-use diethylcarbamazine (DEC) containing patch (LTS-2 patch). To qualify this patch for large scale studies of its sensitivity and specificity, this study evaluated its ease of application, ability to detect infection and DEC exposure related adverse reactions compared to the OCP-patch in 30 infected individuals. METHODS: Each participant with 0.2-36.8 O. volvulus microfilariae/mg skin received the OCP-patch and 4 days later the LTS-2 patch at the left and right iliac crest, respectively, for 24 h. Presence and characteristics of local skin reactions were assessed at patch removal and 6 h later. Skin reaction and Mazzotti reaction rates were compared with Fisher's exact and a paired t-test, respectively. RESULTS: The LTS-2 patch could be applied within 10 s. Mild itching occurred at 63.3 % of OCP-patch (duration 8.9 ± 11.8 h) and 26.7 % of LTS-2 patch sites (duration 1.0 ± 2.5 h) and was the most frequent Mazzotti reaction. At patch removal after 24 h, a diagnostic local skin reaction was present under 90 % of OCP-patches and 83 % of LTS-2 patches; 6 h later, it was present at 93 % of OCP-patch and 100 % of LTS-2 patch sites. CONCLUSIONS: The data suggest that safety, tolerability and ability to detect infections of the LTS-2 patch are comparable to those of the OCP-patch. They qualify the LTS-2 patch for field studies to determine LTS-2 patch sensitivity, specificity and utility during large scale use and thus to inform use of the LTS-2 patch by onchocerciasis control programmes to determine prevalence of infection. TRIAL REGISTRATION: Current controlled Trials ISRCTN76875372 .

Unresolved issues in anthelmintic pharmacology for helminthiases of humans.

Helminth infections are an important constraint on the health and development of poor children and adults. Anthelmintic treatment programmes provide a safe and effective response, and increasing numbers of people are benefitting from these public health initiatives. Despite decades of clinical experience with anthelmintics for the treatment of human infections, relatively little is known about their clinical pharmacology. All of the drugs were developed initially in response to the considerable market for veterinary anthelmintics in high- and middle-income countries. In contrast, the greatest burden caused by these infections in humans is in resource-poor settings and as a result there has been insufficient commercial incentive to support studies on how these drugs work in humans, and how they should best be used in control programmes. The advent of mass drug administration programmes for the control of schistosomiasis, lymphatic filariasis, onchocerciasis and soil-transmitted helminthiases in humans increases the urgency to better understand and better monitor drug resistance, and to broaden the currently very narrow range of available anthelmintics. This provides fresh impetus for developing a comprehensive research platform designed to improve our understanding of these important drugs, in order to bring the scientific knowledge base supporting their use to a standard equivalent to that of drugs commonly used in developed countries. Furthermore, a better understanding of their clinical pharmacology will enable improved therapy and could contribute to the discovery of new products.