54 Anthelminthic drugs
Overview
Among the most widespread of all chronic infections are those caused by various species of parasitic helminths (worms). It is estimated that over half the world’s population is infected with gastrointestinal helminths. Inhabitants of tropical or subtropical low-income countries are most at risk; children often become infected with one or more species at birth and may remain so throughout their lives. In some cases (e.g. threadworms), these infections result mainly in discomfort and do not cause substantial ill health, but others, such as schistosomiasis (bilharzia) and hookworm disease, are associated with serious morbidity. Because of its prevalence, the treatment of helminthiasis is therefore of great practical therapeutic importance. Worm infections are also a major cause for concern in veterinary medicine, affecting both domestic pets and farm animals. In some parts of the world, fascioliasis is associated with significant loss of livestock.
Helminth Infections
The helminths comprise two major groups: the nemathelminths (nematodes, roundworms) and the platyhelminths (flatworms). The latter group is subdivided into the trematodes (flukes) and the cestodes (tapeworms). Almost 350 species of helminths have been found in humans, and most colonise the gastrointestinal tract.
Helminths have a complex life cycle, often involving several host species. Infection by helminths may occur in many ways, with poor hygiene a major contributory factor. Many enter by the mouth in unpurified drinking water or in undercooked flesh from infected animals or fish. However, other types can enter through the skin following a cut, an insect bite or even after swimming or walking on infected soil. Humans are generally the primary (or definitive) host for helminth infections, in the sense that they harbour the sexually mature form that reproduces. Eggs or larvae then pass out of the body and infect the secondary (intermediate) host. In some cases, the eggs or larvae may persist in the human host and become encysted, covered with granulation tissue, giving rise to cysticercosis. Encysted larvae may lodge in the muscles and viscera or, more seriously, in the eye or the brain. Approximately 20 helminth species are considered to be clinically significant, and these fall into two main categories—those in which the worm lives in the host’s alimentary canal, and those in which the worm lives in other tissues of the host’s body.
The main examples of intestinal worms are:
The main examples of worms that live elsewhere in host tissues are:
Some nematodes that usually live in the gastrointestinal tract of animals may infect humans and penetrate tissues. A skin infestation, termed creeping eruption or cutaneous larva migrans, is caused by the larvae of dog and cat hookworms often entering through the foot. Toxocariasis or visceral larva migrans is caused by larvae of cat and dog roundworms of the Toxocara genus.
Anthelminthic Drugs
Mankind has attempted to treat helminth infections since antiquity. Extracts of herbs or plants such as male fern formed the basis of many early ‘cures’, but the 20th century saw the advent of a new group of drugs based on toxic metals such as arsenic (atoxyl) or antimony (tartar emetic), which were effective in trypanosome and schistosome infestations.
Current anthelminthic drugs act either by paralysing the parasite (e.g. by preventing muscular contraction), or by damaging the worm such that the immune system can eliminate it, or by altering its metabolism (e.g. by affecting microtubule function). Because the metabolic requirements of these parasites vary greatly from one species to another, drugs that are highly effective against one type of worm may be ineffective against others. To be effective, a drug must be able to penetrate the tough exterior cuticle of the worm or gain access to its alimentary tract. This may present difficulties, because some worms are exclusively haemophagous (blood eating), while others are best described as ‘tissue grazers’. A further complication is that many helminths possess active drug efflux pumps that reduce the concentration of the drug in the parasite. The route of administration and dose of anthelminthic drugs are therefore important.
Some individual anthelminthic drugs are described briefly below, and indications for their use are given in Table 54.1. Several of these drugs (i.e. albendazole, ivermectin, levamisole, niclosamide, praziquantel and tiabendazole) are available in the UK only on a ‘named patient’ basis.1 For a more comprehensive coverage of antiparasitic drugs and their use in humans and animals, you are directed to the literature cited in the bibliography.
Table 54.1 Principal drugs used in helminth infections
| Helminth(s) | Drug(s) used |
|---|---|
| Threadworm (pinworm) | |
| Enterobius vermicularis Strongyloides stercoralis (threadworm in the USA) |
Mebendazole, albendazole, piperazine Albendazole, ivermectin |
| Common roundworm | |
| Ascaris lumbricoides | Levamisole, mebendazole, piperazine |
| Other roundworm (filariae) | |
| Wuchereria bancrofti, Loa loa Onchocerca volvulus Guinea worm (Dracunculus medinensis) Trichiniasis (Trichinella spiralis) Cysticercosis (infection with larval Taenia solium) Tapeworm (Taenia saginata, Taenia solium) Hydatid disease (Echinococcus granulosus) Hookworm (Ankylostoma duodenale, Necator americanus) Whipworm (Trichuris trichiura) |
Diethylcarbamazine, ivermectin Ivermectin Praziquantel, mebendazole Tiabendazole, mebendazole Praziquantel, albendazole Praziquantel, niclosamide Albendazole Mebendazole, albendazole Mebendazole, albendazole, diethylcarbamazine |
| Blood flukes (Schistosoma spp.) | |
| S. haematobium S. mansoni S. japonicum |
Praziquantel Praziquantel Praziquantel |
| Cutaneous larva migrans | |
| Ankylostoma caninum | Albendazole, ivermectin, tiabendazole |
| Visceral larva migrans | |
| Toxocara canis | Albendazole, tiabendazole, diethylcarbamazine |
(Sourced mainly from the British National Formulary 2008.)
Benzimidazoles
One of the principal groups of anthelminthics used clinically are the substituted benzimidazoles. This group of broad-spectrum agents includes mebendazole, tiabendazole and albendazole. They are thought to act by inhibiting the polymerisation of helminth β-tubulin, thus interfering with microtubule-dependent functions such as glucose uptake. They have a selective inhibitory action, being 250–400 times more effective in producing this effect in helminth than in mammalian tissue. However, the effect takes time to develop and the worms may not be expelled for several days. Cure rates are generally between 60% and 100% with most parasites.
Only 10% of mebendazole is absorbed after oral administration, but a fatty meal increases absorption. It is rapidly metabolised, the products being excreted in the urine and the bile within 24–48 h. It is generally given as a single dose for threadworm, and twice daily for 3 days for hookworm and roundworm infestations. Tiabendazole is rapidly absorbed from the gastrointestinal tract, very rapidly metabolised and excreted in the urine in conjugated form. It is given twice daily for 3 days for guinea worm and Strongyloides infestations, and for up to 5 days for hookworm and roundworm infestations. Albendazole is also poorly absorbed but, like mebendazole, this may be increased by food, especially fats. It is metabolised extensively by first-pass metabolism to the sulfoxide and sulfone metabolites. The former is likely to be the pharmacologically active species.
Unwanted effects are few with albendazole or mebendazole, although gastrointestinal disturbances can occasionally occur. Unwanted effects with tiabendazole are more frequent but usually transient, the commonest being gastrointestinal disturbances, although headache, dizziness and drowsiness have been reported and allergic reactions (fever, rashes) may also occur. Mebendazole is unsuitable for pregnant women or children less than 2 years old.
Praziquantel
Praziquantel is a highly effective broad-spectrum anthelminthic drug that was introduced over 20 years ago. It is the drug of choice for all forms of schistosomiasis and is the agent generally used in large-scale schistosome eradication programmes. It is also effective in cysticercosis. The drug affects not only the adult schistosomes but also the immature forms and the cercariae—the form of the parasite that infects humans by penetrating the skin.
The drug apparently disrupts Ca2+ homeostasis in the parasite by binding to consensus protein kinase C-binding sites in a β subunit of schistosome voltage-gated calcium channels (Greenberg, 2005). This induces an influx of the ion, a rapid and prolonged contraction of the musculature, and eventual paralysis and death of the worm. Praziquantel also disrupts the tegument of the parasite, unmasking novel antigens, and as a result it may become more susceptible to the host’s normal immune responses.
Given orally, praziquantel is well absorbed; much of the drug is rapidly metabolised to inactive metabolites on first passage through the liver, and the metabolites are excreted in the urine. The plasma half-life of the parent compound is 60–90 min.
Praziquantel is considered to be a very safe drug with minimal side effects in therapeutic dosage. Such unwanted effects as do occur are usually transitory and rarely of clinical importance. Effects may be more marked in patients with a heavy worm load because of products released from the dead worms. Praziquantel is considered safe for pregnant and lactating women, an important property for a drug that is commonly used in national disease control programmes. Some resistance has developed to the drug (see below).
Piperazine
Piperazine can be used to treat infections with the common roundworm (A. lumbricoides) and the threadworm (E. vermicularis). It reversibly inhibits neuromuscular transmission in the worm, probably by mimicking GABA (Ch. 37), at GABA-gated chloride channels in nematode muscle. The paralysed worms are expelled alive by normal intestinal peristaltic movements. It is administered with a stimulant laxative such as senna (Ch. 29) to facilitate expulsion of the worms.
Piperazine is given orally and some, but not all, is absorbed. It is partly metabolised, and the remainder is eliminated, unchanged, via the kidney. The drug has little pharmacological action in the host. When used to treat roundworm, piperazine is effective in a single dose. For threadworm, a longer course (7 days) at lower dosage is necessary.
Unwanted effects may include gastrointestinal disturbances, urticaria and bronchospasm. Some patients experience dizziness, paraesthesias, vertigo and incoordination. The drug should not be given to pregnant patients or to those with compromised renal or hepatic function.
Niclosamide
Niclosamide is widely used for the treatment of tapeworm infections together with praziquantel. The scolex (the head of the worm that attaches to the host intestine) and a proximal segment are irreversibly damaged by the drug, such that the worm separates from the intestinal wall and is expelled. For T. solium, the drug is given in a single dose after a light meal, usually followed by a purgative 2 h later in case the damaged tapeworm segments release ova, which are not affected by the drug. For other tapeworm infections, this precaution is not necessary. There is negligible absorption of the drug from the gastrointestinal tract.
Unwanted effects: nausea, vomiting, pruritus and lightheadeness may occur but generally such effects are few, infrequent and transient.
Diethylcarbamazine
Diethylcarbamazine is a piperazine derivative that is active in filarial infections caused by B. malayi, W. bancrofti and L. loa. Diethylcarbamazine rapidly removes the microfilariae from the blood circulation and has a limited effect on the adult worms in the lymphatics, but it has little action on microfilariae in vitro. It may act by changing the parasite such that it becomes susceptible to the host’s normal immune responses. It may also interfere with helminth arachidonate metabolism.
The drug is absorbed following oral administration and is distributed throughout the cells and tissues of the body, excepting adipose tissue. It is partly metabolised, and both the parent drug and its metabolites are excreted in the urine, being cleared from the body within about 48 h.
Unwanted effects are common but transient, subsiding within a day or so even if the drug is continued. Side effects from the drug itself include gastrointestinal disturbances, arthralgias, headache and a general feeling of weakness. Allergic side effects referable to the products of the dying filariae are common and vary with the species of worm. In general, these start during the first day’s treatment and last 3–7 days; they include skin reactions, enlargement of lymph glands, dizziness, tachycardia, and gastrointestinal and respiratory disturbances. When these symptoms disappear, larger doses of the drug can be given without further problem. The drug is not used in patients with onchocerciasis, in whom it can have serious unwanted effects.
Levamisole
Levamisole is effective in infections with the common roundworm (A. lumbricoides). It has a nicotine-like action (Ch. 13), stimulating and subsequently blocking the neuromuscular junctions. The paralysed worms are then expelled in the faeces. Ova are not killed. The drug is given orally, is rapidly absorbed and is widely distributed. It crosses the blood–brain barrier. It is metabolised in the liver to inactive metabolites, which are excreted via the kidney. Its plasma half-life is 4 h.
When single-dose therapy is used, unwanted effects such as mild gastrointestinal disturbances are generally few and soon subside.
Ivermectin
First introduced in 1981 as a veterinary drug, ivermectin is a safe and highly effective broad-spectrum antiparasitic in humans; it is frequently used in global public health campaigns,2 and is the first choice of drug for the treatment of filarial infections. It has also given good results against W. bancrofti, which causes elephantiasis. A single dose kills the immature microfilariae of O. volvulus but not the adult worms. Ivermectin is the drug of choice for onchocerciasis, which causes river blindness and reduces the incidence of this by up to 80%. It is also active against some roundworms: common roundworms, whipworms, and threadworms of both the UK (E. vermicularis) and the US variety (S. stercoralis), but not hookworms.
Chemically, ivermectin is a semisynthetic agent derived from a group of natural substances, the avermectins, obtained from an actinomycete organism. The drug is given orally and has a half-life of 11 h. It is thought to kill the worm either by opening glutamate-gated chloride channels (found only in invertebrates) and increasing Cl− conductance; by binding to a novel allosteric site on the acetylcholine nicotinic receptor to cause an increase in transmission, leading to motor paralysis; or by binding to GABA receptors.
Unwanted effects include skin rashes and itching but in general the drug is very well tolerated. One interesting exception in veterinary medicine is the CNS toxicity seen in collie dogs (Ch. 8).
Resistance to Anthelminthic Drugs
Resistance to anthelminthic drugs is a widespread and growing problem affecting not only humans but also the animal health market. During the 1990s, helminth infections in sheep (and to a lesser extent cattle) developed varying degrees of resistance to a number of different anthelminthic drugs. Parasites that develop such resistance pass this ability on to their offspring, leading to treatment failure. The widespread use of anthelminthic agents in farming has been blamed for the spread of resistant species.
There are probably several molecular mechanisms that contribute to drug resistance. The presence of the P-glycoprotein transporter (Ch. 8) in some species of nematode has already been mentioned, and agents such as verapamil that block the transporter in trypanosomes can partially reverse resistance to the benzimidazoles. However, some aspects of benzimidazole resistance may be attributed to alterations in their high-affinity binding to parasite β-tubulin. Likewise, resistance to levamisole is associated with changes in the structure of the target acetylcholine nicotinic receptor.
Of great significance is the way in which helminths evade the host’s immune system. Even though they may thrive in immunologically exposed sites such as the lymphatics or the bloodstream, many are long-lived and may co-exist with their hosts for many years without seriously affecting their health, or in some cases without even being noticed. It is striking that the two major families of helminths, while evolving separately, deploy similar strategies to evade destruction by the immune system. Clearly, this must be of major survival value for the species.
In Chapter 6, we discussed the two main types of adaptive immune strategy, termed the Th1 and the Th2 responses, the latter being characterised by the development of an antibody-mediated response rather than the development of a cell-mediated immune response. It appears that many helminths can actually exploit this mechanism by steering the immune system away from a local Th1 response, which would be potentially more damaging to the parasite, and promoting instead a modified systemic Th2 type of response. This is associated with the production of ‘anti-inflammatory’ cytokines such as interleukin-10 favourable to, or at least better tolerated by, the parasites. The immunology underlying this is complex (see Pearce & MacDonald, 2002; Maizels et al., 2004).
Ironically, the ability of helminths to modify the host immune response in this way may confer some survival value on the hosts themselves. For example, in addition to the local anti-inflammatory effect exerted by helminth infections, rapid wound healing is also seen. Clearly, this is of advantage to parasites that must penetrate tissues without killing the host but may also be beneficial to the host as well. It has been proposed that helminth infections may mitigate some forms of malaria and other diseases, possibly conferring survival advantages in populations where these diseases are endemic. Indeed, the deliberate infestation of Crohn’s disease patients with helminths has been evaluated as a strategy to induce remission of the disease (see Hunter & McKay, 2004; Reddy & Fried, 2007). On the negative side, however, they may also undermine the efficacy of tuberculosis vaccination programmes that depend upon a vigorous Th1 response (Elias et al., 2006).
On the basis that Th2 responses reciprocally inhibit the development of Th1 diseases, it has also been hypothesised that the comparative absence of Crohn’s disease, as well as some other autoimmune diseases, in the developing world may be associated with the high incidence of parasite infection, and that the rise of these disorders in the West is associated with superior sanitation and reduced helminth infection! This type of argument is generally known as the ‘hygiene hypothesis’.
Vaccines and Other Novel Approaches
Despite the enormity of the clinical problem, there have been few new anthelminthic drugs recently. On a more positive note, the sequencing of the transcriptomes of several helminths may make it possible to create a transgenic species that expresses mutations found in resistant parasitic worms, thus providing insights into the mechanisms underlying resistance. In addition, such databases may reveal new drug targets, as well as opening the way for other types of anthelmithic agent, such as those based on antisense DNA or small interfering RNA (see Boyle & Yoshino, 2003).
More progress has been made in the field of anthelminthic vaccines through the use of recombinant DNA technology. Protein antigens on the surface of the (highly infectious) larval stage have been cloned and used as immunogens. Considerable success has been achieved in the veterinary field with vaccines to organisms such as T. ovis and E. granulosus (in sheep) as well as T. saginata (in cattle) and T. solium (in pigs), with cure rates of 90–100% often reported (see Dalton & Mulcahy, 2001; Lightowlers et al., 2003). Qualified success has also been obtained with vaccines to other helminth species (see Capron et al., 2005; McManus & Loukas, 2008).
Efficacious helminth vaccines would revolutionise the treatment of these widespread infections, minimise the problem of drug resistance as well as reducing the environmental burden of residual pesticide residues, which sometimes occurs as a consequence of overenthusiastic anthelminth control campaigns. Looking further into the future, it may be possible to develop DNA vaccines against these organisms without having to produce any protein-based immunogen at all.
References and Further Reading
General papers on helminths and their diseases
Drake L.J., Bundy D.A. Multiple helminth infections in children: impact and control. Parasitology. 2001;122(Suppl.):S73-S81. (The title is self-explanantory)
Horton J. Human gastrointestinal helminth infections: are they now neglected diseases? Trends Parasitol.. 2003;19:527-531. (Accessible review on helminth infections and their treatments)
Boyle J.P., Yoshino T.P. Gene manipulation in parasitic helminths. Int. J. Parasitol.. 2003;33:1259-1268. (Deals with approaches such as antisense therapy; for the interested reader only)
Burkhart C.N. Ivermectin: an assessment of its pharmacology, microbiology and safety. Vet. Hum. Toxicol.. 2000;42:30-35. (Useful paper that focuses on ivermectin pharmacology)
Croft S.L. The current status of antiparasite chemotherapy. Parasitology. 1997;114:S3-S15. (Comprehensive coverage of current drugs and outline of approaches to possible future agents)
Dayan A.D. Albendazole, mebendazole and praziquantel. Review of non-clinical toxicity and pharmacokinetics. Acta Trop.. 2003;86:141-159. (Comprehensive review of the pharmacokinetics and toxicity of these important drugs)
Geary T.G., Sangster N.C., Thompson D.P. Frontiers in anthelmintic pharmacology. Vet. Parasitol.. 1999;84:275-295. (Thoughtful account of the difficulties associated with drug treatment)
Greenberg R.M. Are Ca2+ channels targets of praziquantel action? Int. J. Parasitol.. 2005;35:1-9. (Interesting review on praziquantel action for those who wish to go into it in depth)
Liu L.X., Weller P.F. Antiparasitic drugs. N. Engl. J. Med.. 1996;334:1178-1184. (Excellent general coverage of antiparasitic drugs and their clinical use)
Prichard R., Tait A. The role of molecular biology in veterinary parasitology. Vet. Parasitol.. 2001;98:169-194. (Excellent review of the application of molecular biology to understanding the problem of drug resistance and to the development of new anthelminthic agents)
Robertson A.P., Bjorn H.E., Martin R.J. Pyrantel resistance alters nematode nicotinic acetylcholine receptor single channel properties. Eur. J. Pharmacol.. 2000;394:1-8. (A research paper that deals with the interactions of praziquantel and levamisole with the nematode nicotinic receptor and a proposed mechanism of drug resistance. Interesting but maybe a little technical for the general reader)
Capron A., Riveau G., Capron M., Trottein F. Schistosomes: the road from host–parasite interactions to vaccines in clinical trials. Trends Parasitol.. 2005;21:143-149. (Good general review dealing with the immune response to parasite infection and vaccine development)
Dalton J.P., Mulcahy G. Parasite vaccines—a reality? Vet. Parasitol.. 2001;98:149-167. (Interesting discussion of the promise and pitfalls of vaccines)
Dalton J.P., Brindley P.J., Knox D.P., et al. Helminth vaccines: from mining genomic information for vaccine targets to systems used for protein expression. Int. J. Parasitol.. 2003;33:621-640. (Very comprehensive but may be overcomplicated in parts for the non-specialist)
Lightowlers M.W., Colebrook A.L., Gauci C.G., et al. Vaccination against cestode parasites: anti-helminth vaccines that work and why. Vet. Parasitol.. 2003;115:83-123. (Very comprehensive review for the dedicated reader!)
McManus D.P., Loukas A. Current status of vaccines for schistosomiasis. Clin. Microbiol. Rev.. 2008;21:225-242. (Very comprehensive survey of the theory and development of vaccines for schsistosomiasis. Good for the serious enquirer)
Immune evasion by helminths and its potential therapeutic uses
Elias D., Akuffo H., Britton S. Helminthes could influence the outcome of vaccines against TB in the tropics. Parasite Immunol.. 2006;28:507-513. (Easy-to-read introduction to this phenomenon for those who want to follow up this topic)
Hunter M.M., McKay D.M. Review article: helminths as therapeutic agents for inflammatory bowel disease. Aliment. Pharmacol. Ther.. 2004;19:167-177. (Fascinating review on potential therapeutic uses of helminths and why they work)
Maizels R.M., Balic A., Gomez-Escobar N., et al. Helminth parasites—masters of regulation. Immunol. Rev.. 2004;201:89-116. (Excellent and very comprehensive review dealing with mechanisms of immune evasion; complicated in parts for the non-specialist)
Pearce E.J., MacDonald A.S. The immunobiology of schistosomiasis. Nat. Rev. Immunol.. 2002;2:499-512. (Deals mainly with the immunology of schistosome infections in mice)
Reddy A., Fried B. The use of Trichuris suis and other helminth therapies to treat Crohn’s disease. Parasitol. Res.. 2007;100:921-927. (Excellent review of this interesting therapeutic area)
1A relatively rare situation in which the physician seeks approval from a pharmaceutical company to use one of their drugs in a named individual. The drug is either a ‘newcomer’ that has shown particular promise in clinical trials but has not yet been licensed or, as in these instances, an established drug that has not been licensed because the company has not applied for a product licence (possibly for commercial reasons).
2Ivermectin is supplied by the manufacturers free of charge in countries where river blindness is endemic. Because the worms develop slowly, a single annual dose of ivermectin is sufficient to prevent the disease.