Drugs for the Treatment of Helminth Infections: Anthelmintics 13 Tad B
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Drugs for the Treatment of Helminth Infections: Anthelmintics 13 Tad B. Coles and Randy C. Lynn Chapter Outline ANTHELMINTICS BROAD-SPECTRUM COMBINATIONS Macrolides Emodepside Plus Praziquantel Benzimidazoles Pyrantel Plus Praziquantel Tetrahydropyrimidines Pyrantel Plus Praziquantel Plus Febantel Cyclic Depsipeptides Ivermectin Plus Pyrantel Piperazines Ivermectin Plus Pyrantel Plus Praziquantel Isoquinolones Milbemycin Oxime Plus Lufenuron Arsenicals Imidacloprid Plus Moxidectin Miscellaneous Practicing veterinarians commonly use drugs to treat and KEY POINT 13-1 Helminth infections are common in pets. prevent helminth infections in small animals. Th e life cycle and biology of the most important parasites are well under- stood by graduate veterinarians and are not discussed here; KEY POINT 13-2 Testing, treatment, and prevention of however, current textbooks of parasitology may be consulted helminth infections in pets have profound zoonotic for review. 1-4 Gastrointestinal parasites are among the most implications. common infectious agents that veterinarians in small animal practice face. A landmark parasite prevalence study evalu- Although these parasites are important to the health of ated more than 6000 canine fecal specimens from all 50 states dogs, several are also important zoonotic pathogens. Asca- and the District of Columbia.5 Th e results indicate that para- rid larvae migrate through human tissues, causing a variety sites are common in American dogs. Nationwide, 36% of the of signs correlated to the location of the migration. Th ese are samples tested were positive for roundworm (Toxocara canis) , primarily Toxocara species ascarids, but the raccoon ascarid, hookworm (Ancylostoma caninum) , or whipworm (Trichuris Baylisascaris procyonis, is being increasingly implicated as a vulpis) . Even more surprising, 52% of the samples from the cause of human disease in the United States.10 Th e Centers for southeastern United States were positive for at least one nema- Disease Control and Prevention (CDC) have published Guide- tode. In a recent study of the results of heartworm and fecal lines for Veterinarians: Prevention of Zoonotic Transmission of testing in the western United States, the importance of annual Ascarids and Hookworms of Dogs and Cats, which is an excel- testing and routine use of preventives was highlighted. 6 Clin- lent resource and is available online as a PDF download. 11 ics in 11 states were surveyed, and local dogs with no history of travel were diagnosed with heartworms in every state but KEY POINT 13-3 The raccoon ascarid is an emerging Idaho and Wyoming. Th e prevalence of intestinal parasites zoonotic threat. in companion animals in Ontario and Quebec, Canada, dur- ing the winter was recently evaluated.7 Th e fact that 30% of feline and 39% of canine fecal samples were positive for gas- Worldwide, helminth infections are a major animal and trointestinal parasites prompted the authors to recommend human health concern, 12 with hookworms infecting large that all veterinarians follow the Companion Animal Parasite numbers of people worldwide, especially those of low eco- Council (CAPC) guidelines8 regarding use of year-round nomic status. 13 More than 30% of the human population, in broad-spectrum deworming protocols. Another reason for vast areas of South America and Asia, is infected with hook- following CAPC guidelines, in this instance regarding routine worms. More than half of the population is infected with heartworm testing and prophylaxis, is concern about animals hookworms in many southern areas of the African continent. moving from heartworm-endemic areas to those with limited Experts estimate that a billion people, more than a fi ft h of the heartworm exposure. Th ese concerns were realized when Hur- planet’s human inhabitants, harbor hookworms. 14 One study ricane Katrina resulted in thousands of dogs and cats being showed that nearly all dogs in a remote community of north- shipped from Louisiana, where heartworm prevalence is quite eastern India were infested with one or more zoonotic gas- high, to shelters across the United States.9 trointestinal parasites.15 Th is study demonstrated that dogs 451 452 Drugs Targeting Infections or Infestations SECTION 2 played a major zoonotic role both in transmitting parasites that use dogs as their defi nitive and paratenic host and in Macrolides mechanically transmitting and spreading the dissemination Macrolides, which include both avermectins and milbemycins, range of an array of human-specifi c parasites. A recent feline have revolutionized the control of parasites in both humans study in metropolitan Rio de Janeiro revealed an 89.6% preva- and animals. Ivermectin is the best known agent in this class. lence of overall gastrointestinal helminth parasites in cats. 16 Th e dual activity of some macrolides, such as ivermectin and selamectin, against endoparasites, such as helminths, and ecto- KEY POINT 13-4 The practicing veterinarian who judiciously parasites, such as fl eas, gave rise to the term endectocide . Th ese uses anthelmintics is in a unique position to have a products are similar in that they are large complex macrocyclic dramatic impact on the health of pets and people. structures produced by soil microorganisms in the Streptomy- ces genus. Th ey are generally regarded as the most eff ective and least toxic parasiticides yet developed. Commercially, they Th rough the prudent use of anthelmintics in companion ani- have crushed the competition. Many conventional drugs that mals, the practicing veterinarian is in a unique position to posi- were direct competitors of this class were retired from com- tively aff ect not only the patient’s health but also public health. mon use and eventually discontinued by the manufacturer. ANTHELMINTICS KEY POINT 13-5 Macrolides are large complex macrocyclic products of soil microorganisms. This class includes the In this chapter anthelmintics that are approved by the U.S. most effective, least toxic parasiticides. Food and Drug Administration (FDA) and commercially available in the United States are grouped together by class according to their generic names. Th e literature on antipara- Macrolides are excreted in the feces as active drug. Drugs in sitic drugs is enormous. In the interest of both economy and this class, especially the avermectins, are toxic to dung-feeding readability, only a few references are listed for each drug. Th ese insects, but not birds, plants, and earthworms. Elimination of will guide the veterinarian who needs more specifi c informa- coprophagous insects appears to delay processing of nutrients, tion about the subject. Table 13-1 provides a general overview but the overall environmental impact of this fi nding is unclear.23 of anthelmintic drug spectrum against the common canine Although originally believed to act by disturbing gamma- and feline helminths. aminobutyric acid (GABA) – mediated neurotransmission, it Since the last edition of this text was published, there have now appears that they act with high affi nity to a nematode- been considerable changes, most notably the more widespread specifi c glutamate-gated chloride channel. 24,25 Macrolides use of ivermectin and the emergence of other macrocyclic trigger chloride ion infl ux, which hyperpolarizes the para- lactones. New information on avermectin toxicity is covered site neuron and prevents initiation or propagation of normal in the ivermectin section. Drug manufacturers have discon- action potentials. Th e selectivity of macrolides is due to diff er- tinued production of many tried-and-true anthelmintics such ent glutamate function in invertebrates compared with that of as dichlorvos (Task Capsules) and diethylcarbamazine citrate vertebrates. Glutamate acts as an inhibitory neurotransmitter (Filaribits). In addition, some drugs, such as N-butyl chloride, in invertebrates and an excitatory neurotransmitter in mam- have simply been superseded. For simplicity’s sake, discon- mals. 2 Th e net eff ect is paralysis and death of the target parasite. tinued products and drugs that are not widely available do Despite their benefi cial activities, macrocyclic lactones not appear in the current edition; however, an earlier edition have several fl aws. Th ey are ineff ective against cestodes and of this text can certainly be consulted for information about trematodes, and they are sometimes expensive. Th at said, the them. Th e latest information about diethylcarbamazine citrate U.S. patent on ivermectin has now expired, allowing generic can be obtained from the American Heartworm Society 2005 competitors to enter the market and reduce the cost of iver- guidelines for the diagnosis, prevention, and management of mectin treatment, but to date the cost savings have not been heartworm infection in dogs.17 Th is organization produced realized on products for dogs and cats to the same degree as similar guidelines for cats in 2007 18 and updated the guide- those for horses and food animals. Although macrolides are lines for dogs in 2010.18a generally regarded as the most eff ective and least toxic para- New anthelmintic products are continuously researched and siticides yet developed, toxicity may occur with overdosage, frequently launched. Th e Compendium of Veterinary Prod- especially in Collies, many of which are unusually sensitive to ucts provides a comprehensive list of commercially available macrolide endectocides. An excellent summarized overview products approved by the FDA. 19 An exhaustive review of the of the pharmacology,