Invited ReviewUnresolved issues in anthelmintic pharmacology for helminthiases of humans
Graphical abstract
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.
References (122)
- et al.
Control strategies for human intestinal nematode infections
Adv. Parasitol.
(1999) - et al.
Monitoring drug efficacy and early detection of drug resistance in human soil-transmitted nematodes: a pressing public health agenda for helminth control
Int. J. Parasitol.
(2004) - et al.
Development of the egg hatch assay for detection of anthelminthic resistance in human hookworms
Int. J. Parasitol.
(2005) - et al.
Immunocompetence may be important in the effectiveness of Mectizan (ivermectin) in the treatment of human onchocerciasis
Acta Trop.
(2002) - et al.
Hookworm infections and faecal egg counts: an analysis of the biological basis of variation
Trans. R. Soc. Trop. Med. Hyg.
(1985) Endoparasite control
Vet. Clin. North Am. Food Anim. Pract.
(2006)- et al.
Sensitivity to ivermectin and pyrantel of Ancylostoma ceylonicum and Necator americanus
Int. J. Parasitol.
(1993) - et al.
Diagnostic dilemmas in helminthology: what tools to use and when?
Trends Parasitol.
(2009) - et al.
Global epidemiology, ecology and control of soil-transmitted helminth infections
Adv. Parasitol.
(2006) Chemotherapy of schistosomiasis: present and future
Curr. Opin. Chem. Biol.
(2007)
Antischistosomal drugs: past, present…and future?
Pharmacol. Ther.
Chemotherapy of nematode infections of veterinary importance, with special reference to drug resistance
Adv. Parasitol.
Praziquantel: the enigmatic anthelmintic
Parasitol. Today
Albendazole, mebendazole and praziquantel. Review of non-clinical toxicity and pharmacokinetics
Acta Trop.
The anthelmintic of flubendazole on Brugia pahangi
Trans. R. Soc. Trop. Med. Hyg.
The immune dependence of chemotherapy
Parasitol. Today
Comparison of flubendazole and diethylcarbamazine in treatment of onchocerciasis
Lancet
Ivermectin selection on β-tubulin: evidence in Onchocerca volvulus and Haemonchus contortus
Mol. Biochem. Parasitol.
Reconsidering the underestimated burden caused by neglected tropical diseases
Trends Parasitol.
Randomised trial of albendazole and pyrantel in symptomless trichuriasis in children
Lancet
Serious reactions after mass treatment of onchocerciasis with ivermectin in an area endemic for Loa loa infection
Lancet
Effects of standard and high doses of ivermectin on adult worms of Onchocerca volvulus: a randomized controlled trial
Lancet
Ivermectin 20 years on: maturation of a wonder drug
Trends Parasitol.
Advances in filarial chemotherapy and screening
Parasitol. Today
The calcium-activated potassium channel, SLO-1, is required for the action of the novel cyclo-octadepsipeptide anthelmintic, emodepside, in Caenorhabditis elegans
Int. J. Parasitol.
Voltage-gated calcium channel subunits from platyhelminths: potential role in praziquantel action
Int. J. Parasitol.
Determination of the effective dose rate for monepantel (AAD 1566) against adult gastro-intestinal nematodes in sheep
Int. J. Parasitol.
Drug resistance in nematodes of veterinary importance: a status report
Trends Parasitol.
Field evaluation of anthelmintic drug sensitivity using in vitro egg hatch and larval motility assays with Necator americanus recovered from human clinical isolates
Int. J. Parasitol.
Safety, tolerability, efficacy and plasma concentrations of diethylcarbamazine and albendazole co-administration in a field study in an area endemic for lymphatic filariasis in India
Trans. R. Soc. Trop. Med. Hyg.
Benzimidazole resistance in Haemonchus contortus is correlated with a conserved mutation at amino acid 200 in b-tubulin isotype 1
Mol. Biochem. Parasitol.
Where next with Loa loa encephalopathy? Data are badly needed
Trends Parasitol.
Pharmacokinetics of praziquantel in healthy volunteers and patients with schistosomiasis
Trans. R. Soc. Trop. Med. Hyg.
The safety-net story about macrocyclic lactone heartworm preventatives: a review, an update and recommendations
Vet. Parasitol.
Assessment of the effect of diethylcarbamazine on adult Wuchereria bancrofti in vivo
Trans. R. Soc. Trop. Med. Hyg.
Efficacy and safety of drug combinations in the treatment of schistosomiasis, soil-transmitted helminthiasis, lymphatic filariasis and onchocerciasis
Trans. R. Soc. Trop. Med. Hyg.
Prevalence and intensity of Onchocerca volvulus infection and efficacy of ivermectin in endemic communities in Ghana: a two-phase epidemiological study
Lancet
Effectiveness of annual ivermectin treatment for Wuchereria bancrofti infection
Parasitol. Today
In vitro studies on the relative sensitivity to ivermectin of Necator americanus and Ancylostoma ceylonicum
Int. J. Parasitol.
Efficacy of mebendazole and levamisole alone or in combination against intestinal nematode infections after repeated targeted mebendazole treatment in Zanzibar
Bull. WHO
The Caenorhabditis elegans avermectin resistance and anesthetic response gene unc-9 encodes a member of a protein family implicated in electrical coupling of excitable cells
J. Neurochem.
A comparison of the efficacy of single doses of albendazole, ivermectin and diethylcarbamazine alone or in combinations against Ascaris and Trichuris spp.
Bull. WHO
Reducing intestinal nematode infection: efficacy of albendazole and mebendazole
Parasitol. Today
Pharmacology of ivermectin
Parasitol. Today
Changes in visual function and in the posterior segment of the eye during the treatment of onchocerciasis with diethylcarbamazine citrate
Br. J. Ophthalmol.
Praziquantel resistance
Curr. Opin. Drug Disc.
The use of macrocyclic lactones to control parasites of humans
Ivermectin: effectiveness in lymphatic filariasis
Parasitology
Bioavailability of praziquantel increases with concomitant administration of food
Antimicrob. Agents Chemother.
The antiparasitic moxidectin: safety, tolerability, and pharmacokinetics in humans
J. Clin. Pharmacol.
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Present address: Novartis Vaccine Academy, Siena, Italy.