Invited Review
Unresolved issues in anthelmintic pharmacology for helminthiases of humans

https://doi.org/10.1016/j.ijpara.2009.11.001Get rights and content

Abstract

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.

Introduction

Helminth parasitism remains an underappreciated scourge of humans in most of the developing world. As many as two billion individuals harbour these parasites, with millions typically simultaneously infected with filariae, hookworms, whipworm, large roundworms and/or schistosomes (Brooker et al., 2006, Hotez et al., 2008), all of which often result in chronic, debilitating morbidity. During the past few years, the renewed acknowledgement of the burden imposed by these infections has led to mass drug administration (MDA) programmes for the control and possible elimination of the major human helminths, which are underway or under consideration in most economically poor regions of the world (Molyneux et al., 2005). The drugs (anthelmintics) involved are in many cases donated by pharmaceutical companies or are available as relatively cheap generic preparations. Billions of doses have been taken by humans, but aside from the longstanding Mectizan Donation Program for onchocerciasis and the Global Program for the Elimination of Lymphatic Filariasis (GPELF), this has rarely been done in a systematic fashion. In general, these drugs are safe and at least moderately effective. However, compared with the knowledge base that supports drugs used in wealthier countries and despite notable efforts in this area (e.g., de Silva et al., 1997, Albonico et al., 1999, Albonico et al., 2004, Horton, 2000, Dayan, 2003, Utzinger and Keiser, 2004, Danso-Appiah et al., 2009), many gaps remain in our understanding of the pharmacology of drugs used or advocated for MDA programmes for helminth parasites. These gaps represent a challenge to the continued successful use of these medicines, as they leave us ill-equipped to understand or monitor the emergence of drug resistance and constrain the search for new treatment options. Furthermore, they present an ethical dilemma: why are we satisfied with a lower volume of research-based knowledge about drugs used for poor people than for those used in richer countries, and apparently content with a very limited number of drugs which do not meet all of our needs in terms of efficacy?

Several factors suggest an urgent need to identify and close these gaps. First, the available pharmacopeia for human helminth infection is exceptionally restricted. For some of the most common infections, only one drug is available for human use and the range for even the best served infections is undeniably sub-optimal; understanding more about how current drugs work may illuminate ways to improve this situation. Second, there is no guarantee that the current state of affairs, especially with regard to the so-far limited development and spread of anthelmintic resistance in humans, will continue. We understand relatively little about the variables that govern how resistance to anthelmintic drugs may be selected and spread in humans. More research in this area may pay dividends as MDA programmes are enlarged. Finally, while there is substantial experience in and understanding of the epidemiology of these infections, best-practices for MDA programmes also need to be based on sound scientific understanding of the basic and clinical pharmacology of the drugs used.

In an attempt to highlight how much and/or how little we know, we here indicate some gaps in knowledge about the pharmacology of anthelmintic drugs commonly used in humans and identify important areas for research to address these issues.

Section snippets

Macrocyclic lactones (MLs)

This class, of which ivermectin is the only example currently approved for use in humans, has revolutionized the treatment of nematode infections in livestock, companion animals and, in humans, filarial infections. Ivermectin is an exceptionally potent and usually very safe drug used for the control of onchocerciasis and lymphatic filariasis in MDA campaigns. It has been donated by Merck & Co. for these indications and has changed the prospects for management of these diseases (Greene et al.,

Optimal dosing regimens for benzimidazoles for treatment of human STH infections

Benzimidazoles such as albendazole and mebendazole are the mainstay of therapy to control human infections with Ascaris lumbricoides, T. trichiura and hookworms. A great deal of clinical experience suggests that a single-dose regimen with either albendazole (400 mg) or mebendazole (500 mg) provides good to excellent efficacy against A. lumbricoides, but single doses are less efficacious against hookworms (although Ancylostoma duodenale appears to be generally more sensitive to benzimidazoles than

Chemotherapy of schistosomiasis

Although ‘anthelmintics’ is a term used to describe drugs that are effective against nematodes, trematodes or cestodes, these organisms are separated by an enormous evolutionary and phylogenetic gulf. Several species of schistosomes, together with other trematode species, continue to present large and serious global health problems; schistosome infections outnumber those from other trematode species by a considerable margin and are the focus of this review. No single drug available today has

Conclusion

Major gaps remain in our understanding of the pharmacology of anthelmintics in humans. While experience gives us some confidence about the safety and efficacy of drugs in current use, this review shows that there are urgent requirements – on ethical and scientific grounds – to develop a fuller understanding of the pharmacology of these drugs if they are to continue to be given to tens of millions of people every year. The current and planned MDA programmes should be supported by a research

Acknowledgements

This paper was produced as a result of a Joint World Bank/World Health Organization Meeting on “Monitoring of Drug Efficacy in Large Scale Treatment Programmes for Human Helminthiases”, held in Washington, DC, USA at the World Bank, 31 October–2 November 2007. This paper reflects the personal views of the authors and should not be interpreted to represent official policies or positions of their respective institutions.

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