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, indications, dosing, precautions, and pharmacology, mechanism of action, pharmacokinetics, and side eff ects of commercially available macrocyclic lactones is effi cacy of anthelmintics is beyond the scope of this chapter. available online as a PDF download from the United States Th ere are excellent texts available for those interested in more Pharmacopeial Convention, Inc. 23 exhaustive information on anthelmintics.20-22 Pharmacologic activity against nonhelminths, such as fl ukes, fl eas, and ticks, by KEY POINT 13-6 Macrolides are ineffective against some anthelmintics and anthelmintic drug combinations may trematodes and cestodes. be mentioned, but such activity is not the focus of this chapter. CHAPTER 13 Drugs for the Treatment of Helminth Infections: Anthelmintics 453

* F *

C

C

HEARTWORM HEARTWORM C C C C CF CF C C CF C C CF C C C C C C F CF CF CF C C F CF CF C CF C C CF ces. ces. Roundworm HookwormCF Whipworm Preventative laricide Microfi Adulticide CF CF CF C C F CF CF CF CF C C CF DRUG ACTIVITY AGAINST COMMON CANINE & FELINE HELMINTHS TAPEWORMS CF C C F CF CF CF CCC Dipylildium Taenia Echinococcus CF CF Anthelmintic Medications Anthelmintic Medications

13-1 13-1 Table Drug Some activities listed are not approved and may require higher than doses. F = Feline. C = Canine, when used in combination with doxycycline - use caution and only special circumstances after consulting referen * Macrolidex Macrolidex Ivermectin(Iver) Milbemycin(Milb) Moxidectin(Mox) Selamectin Benzimidazoles Albendazole Febantel(Feb) Fenbendazole Combinations Combinations Emodepside+Praz F Tetrahydropyrimidines Tetrahydropyrimidines Pyrantel(Pyr) Arsenicals Melarsomine Miscellaneous Dichlorophen CF Pyr+Praz Pyr+Praz+Feb Iver+Pyr Iver+Pyr+Praz C C Piperazines Piperazines Piperazine Isoquinolones Praziquantel(Praz) Epsiprantel CF Milb+Lufenuron Imidicloprid+Mox 454 Drugs Targeting Infections or Infestations SECTION 2

Ivermectin retrospective poison control center study revealed that clinical Ivermectin was the fi rst commercially available macrolide, signs may develop between 0.2 to 2.5 mg/kg. 30a A wide variety released for use in animals in 1981.24 Th e avermectins were of signs were noted, including more severe signs like coma and isolated from the fermentation broth of Streptomyces avermiti- seizure, at doses below 1 mg/kg. In fact, death was noted in lis. Th e discovery of its anthelmintic activity was made aft er dogs that received 1 to 2.5 mg/kg doses of ivermectin. administration of the actinomycetic broth to mice infected A common presenting history is that of a dog that was in with the nematode Nematospiroides dubius. Ivermectin is close proximity to horses during deworming and later started eff ective against many nematodes and arthropods. In particu- showing signs of disease. Dogs that develop clinical signs lar, ivermectin is very eff ective against immature Dirofi laria within 4 to 6 hours of ivermectin ingestion typically develop immitis. severe clinical signs, whereas dogs with signs developing 10 to 12 hours aft er exposure tend to have much milder clinical 29 KEY POINT 13-7 Ivermectin, the fi rst macrolide used signs. It is not uncommon for dogs with ivermectin toxicity commercially, revolutionized the control of parasites in to have seizures. When seizures are severe and uncontrolled humans and other animals. for a considerable period of time, hemolytic anemia and mus- cle damage may occur. Some severe cases present with seizures and miosis, which warrants a poor prognosis. It is possible that Administration of ivermectin to pregnant rats, mice, and severe seizures and miosis on presentation may be associated rabbits produced teratism only at or near doses that were with severe brain damage.31 maternally toxic. Th ere was no teratogenesis in cattle, sheep, Clinical signs of ivermectin toxicity in cats, in order of and dogs when ivermectin was administered to pregnant ani- frequency, are ataxia, mydriasis, tremors, hyperesthesia, and mals at four times the recommended dose. Although toxicity hypothermia. 28 Dogs are about 10 times as likely as cats to for aquatic animals is high, the binding of ivermectin in soil have ivermectin toxicity. 28 reduces its concentration to levels that have minimal eff ect on Some Collies are unusually sensitive to the toxic eff ects of the environment, as previously discussed. Th e acute oral LD50 ivermectin, although it is safe for all breeds at the approved in mice varied from 11.6 to 87.2 mg/kg; and the LD 50 for rats dose of 0.006 mg/kg (6 mcg/kg). Early studies indicated that was 42.8 to 52.8 mg/kg. In a 14-week study with rats, the “no- some genetic lines of Collies developed severe adverse reac- eff ect” level was 0.4 mg/kg. tions when ivermectin was given at a dose of 100 to 200 mcg/ Ivermectin is well absorbed (95%) aft er oral administration kg (16 to 32 times the label dose), producing mydriasis, ataxia, and well distributed to most tissues except the central nervous tremors, drooling, paresis, recumbency, excitability, stupor, system. It is largely eliminated unchanged in the feces and and coma. At that time Australian Shepherds, Border Col- is metabolized to a small degree in the liver by oxidation. In lies, Shetland Sheepdogs, and Old English Sheepdogs were dogs the terminal half-life is approximately 48 hours. No tera- also reported to be sensitive to ivermectin. Th e lethal dose for tism was observed in fetuses when pregnant bitches received some Collies was reported to be 1/200 th that of Beagles.32 repeated oral doses of ivermectin of 0.5 mg/kg. A single oral Aft er Collies were also found to be more sensitive to lop- dose of 2 mg/kg and repeated oral doses of 0.5 mg/kg per day eramide,33 the canine multidrug resistance (MDR1) gene was for 14 weeks were well tolerated by dogs. 26 identifi ed and found to be mutated in ivermectin-sensitive Avermectin Toxicity . It is important not to administer aver- Collies.34 MDR1 codes for a glycoprotein that is an integral mectins concurrently with drugs that could increase avermec- part of the blood– brain barrier. Th ere are many excellent tin blood – brain barrier penetration, such as ketoconazole, sources of information about the MDR1 gene mutation and itraconazole, cyclosporine, and calcium-channel blockers. 27 mechanisms of ivermectin toxicity associated with increased Selamectin toxicity information is addressed in detail later, GABA activity. 29,30,35 Th e mutant MDR1 allele was found in in the selamectin section. According to a popular veterinary 35% of the 40 Collies that were tested in one study, about the pharmaceutical clinical text, signs of ivermectin toxicity in same percentage of Collies that are sensitive to ivermectin. 36 dogs, in order of frequency, are ataxia, blindness, mydria- A survey of DNA from 4000 purebred dogs revealed that the sis, tremors, and vomiting. 28 Other signs include dehydra- MDR1 mutation was present in seven breeds of Collie lineage tion, depression, diarrhea, hyperthermia, bradycardia, sinus and two sighthound breeds, although the mutation was not arrhythmia, coma, seizures, and death.26,29,30 A recent ret- identifi ed in all breeds known to have ivermectin sensitivity. 37 rospective study of ivermectin toxicosis cases evaluated at a It was found that the potential for ivermectin sensitivity poison control center revealed clinical signs in the following could be estimated by genotypic or polymerase chain reaction order of frequency: ataxia, lethargy, tremors, mydriasis, and (PCR) – based testing for the MDR1 mutation. 38 In this study blindness.30a the mutant MDR1 allele was found in Australian Shepherds, 26 Th e apparent LD 50 for Beagles is 80 mg/kg. Th e pri- Miniature Australian Shepherds, English Shepherds, German mary clinicopathologic sign in dogs is decreased serum iron Shepherd Dogs (white), Longhaired Whippets, McNab Shep- values.22 A common reference used by clinical veterinarians herds, Old English Sheepdogs, Shetland Sheepdogs, Silken states that death could occur with doses above 40 mg/kg, Windhounds, and Longhaired Whippet. 23,37 Sensitivity to tremors at 5 mg/kg, and mydriasis at 2.5 mg/kg and that signs ivermectin was also noted in Australian Cattle Dogs, Bearded of toxicity rarely occur at doses below 1 mg/kg. 28 But a recent Collies, and Border Collies, but the mutant MDR1 allele was CHAPTER 13 Drugs for the Treatment of Helminth Infections: Anthelmintics 455 not found in these breeds.37 More recently, the relationship ivermectin-treated horses as toxic waste and dispose of it in a with P-glycoprotein, the product of the ABCB1 (formerly manner that will prevent the dog from eating it. MDR1) gene, was studied in depth by looking for the ABCB1- Regarding treatment of ivermectin toxicity, although there 1 Δ allele in a DNA study of 5368 dogs. 39 Th e ABCB1-1 Δ allele is some evidence that intravenous administration of physostig- was found in Collies, Longhaired Whippets, Standard and mine may be of some benefi t for dogs 42 and neostigmine may Miniature Australian Shepherds, Shetland Sheepdogs, Old help treat cats43 suff ering from severe ivermectin intoxication, English Sheepdogs, Border Collies, Silken Windhounds, and adverse events associated with these treatments typically out- German Shepherd Dogs. weigh benefi t, thus the mainstay of care given by most veterinar- Th e fact is, until a particular dog is tested, its susceptibil- ians is supportive and symptomatic. 26 Inducing emesis, giving ity to ivermectin toxicity is unknown. Washington State Uni- activated charcoal, providing fl uid therapy, supplying parenteral versity, College of Veterinary Medicine, Veterinary Clinical alimentation, and maintaining respiratory support and normal Pharmacology Lab, provides genetic testing to determine the body temperature are essential. Th is supportive care may be presence of the MDR1 mutant gene. Table 13-2 was adapted needed for an extended period of time because the half-life of from information available at the aforementioned institution’s ivermectin is 2 days and the half-life of moxidectin is 19 days. 30 website.40 Th e general practitioner can also use this table when Th ere is no antidote for ivermectin and moxidectin toxic- presented with a dog that has had a known exposure to iver- ity, but veterinarians should consider lipid rescue, a promis- mectin to determine prognosis and the appropriate level of ing therapy adapted from human medicine. Dr. Guy Weinberg treatment. As noted previously, a common fi nding when tak- initially described the use of an intravenous lipid emulsion ing history on ivermectin and moxidectin exposure cases is (Intralipid) to treat local anesthetic toxicity (bupivacaine) in that the dog was present while the owner was deworming a humans. He coined the term “lipid rescue.” One of the studies to horse. It is not unusual for horses to spit out a small amount support human use of lipid rescue was an experiment on dogs of dewormer, which is ingested by the dog. If the amount that were overdosed with bupivacaine and rescued from cer- ingested can be quantifi ed, then this table can help the vet- tain toxicity with intravenous lipid emulsion. 44 Dr. Weinberg erinarian estimate prognosis and determine how aggressive to established a noncommercial website ( www . lipidrescue . com ) get with treatment. Obviously, the risk of a severe toxicity is to disseminate information and foster discussion of cases. much greater with a Collie than with another breed. Since then, lipid rescue has been used to treat nonbupivacaine Another presentation to consider is dogs with the habit toxicities in other species. Although support is certainly anec- of eating horse feces. Dogs that are not ivermectin sensitive dotal, in 2008 a veterinary online contributor to the lipid res- are probably not at risk, but an ivermectin-sensitive dog that cue website described an ivermectin-overdosed dog that had eats the feces of a horse that has been treated with ivermectin clinical signs of toxicity and recovered nicely aft er activated within the last few days may have a severe, even fatal reac- charcoal, supportive care, and an intravenous lipid emulsion tion. Ivermectin reaches maximum fecal concentration 2 to 3 were administered. More recently, a case report of a puppy days aft er the horse is treated.41 By 4 days posttreatment, 90% with moxidectin toxicosis was published describing the use of the drug has been excreted in the feces. Owners of iver- of an intravenous lipid emulsion given as a bolus of 2 mL/kg, mectin-sensitive coprophagic dogs should treat feces from followed by 4 mL/kg/hr for 4 hours beginning 10 hours aft er exposure and repeated at 0.5 mL/kg/min for 30 minutes beginning 25.5 hours aft er exposure. 45 Th e 16-week-old dog Table 13-2 Breeds Affected by MDR-1 presented with acute onset seizures, paralysis, and coma soon Mutation aft er exposure to moxidectin. Diazepam, glycopyrrolate, and Breed Approximate Frequency intravenous fl uids were given along with respiratory ventila- Collie 70% tion and other supportive care. Th e puppy improved dra- Longhaired Whippet 65% matically within 30 minutes of the second dose of Intralipid. Australian Shepherd 50% Although ideal dosages have not been established, the typical recommendation is for bolus administration of 1.5 mL/kg of Australian Shepherd, Mini 50% intravenous lipid emulsion, followed by 0.25 mL/kg/min for Silken Windhound 30% 30 to 60 minutes. 46 Other brands of intravenous lipid emul- McNab Shepherd 30% sion, such as Liposyn, can also be considered. It is best to have Shetland Sheepdog 15% the product available ahead of time rather than try to acquire English Shepherd 15% it in the midst of an emergency. Dr. Weinberg’s lipid rescue German Shepherd Dog 10% website (mentioned previously) describes preparation of a kit Herding Breed Cross 10% to have on hand. Mixed Breed 5% Dogs . Ivermectin (Heartgard) tablets are administered Old English Sheepdog 5% orally at a dose level of 0.006 mg/kg (6 mcg/kg) at monthly Border Collie < 5% intervals to prevent the establishment of the D. immitis. Th e initial dose should be given within 1 month of the fi rst expo- (Data from Washington State University, College of Veterinary Medicine, Veterinary Clinical Pharmacology Lab. (2010). Affected breeds Retrieved Jan 26, 2010, from sure to mosquitoes and throughout the period of the year http: // www . vetmed . wsu . edu / depts - VCPL / breeds . aspx .) when mosquitoes are active. Th e last treatment must be given 456 Drugs Targeting Infections or Infestations SECTION 2 to dogs within 1 month aft er the last exposure to mosquitoes. Ancylostoma braziliense, Uncinaria stenocephala, Strongyloides Ivermectin alone has minimal activity against the adult heart- stercoralis, Capillaria spp., and Filaroides hirthi .53 At that dose worm in the short term. It is active on the third- and fourth- its activity against Toxascaris leonina and T. vulpis is erratic. 23 stage larvae and the circulating microfi lariae. A single oral When treating respiratory nematode parasites a higher dose, dose of ivermectin administered within 2 months of infection 0.4 mg/kg by subcutaneous injection or orally every 2 weeks prevents the establishment of adult worms in the heart. A sin- for 2 to 3 doses has been recommended recently for Oslerus gle oral dose of 0.05 mg/kg is adequate to clear the circulating (Filaroides) osleri, F. hirthi, Aelurostrongylus abstrusus, and microfi lariae when given to dogs 4 weeks aft er the administra- Capillaria aerophila infections. 54 tion of an adulticide, although ivermectin is not approved as a Several combination products containing ivermectin are microfi laricide.47 Review of the original reference is suggested available. A combination product (Heartgard Plus) containing for more complete information. When ivermectin (0.006 mg/ ivermectin and pyrantel pamoate is available. See the discus- kg) is given to heartworm-positive dogs over several months, sion of combination products for more information. the circulating microfi lariae are eliminated, resulting in an Cats . Ivermectin is FDA approved as a monthly heart- occult infection. Th us dogs receiving monthly ivermectin worm preventive in cats (Heartgard Chewable for Cats). Th e should be tested annually with an occult heartworm test. 17,48,49 approved monthly oral dose of 0.024 mg/kg is eff ective in Knight provides an excellent review of heartworm testing preventing the development of D. immitis and hookworms and suggested chemoprophylaxis timing for various regions in (A. braziliense and Ancylostoma tubaeforme ). 55-57 Feline round- the United States.50 Th e American Heartworm Society guide- worm (Toxocara cati) infections have been controlled with 0.2 lines for diagnosis, prevention, and management of heart- to 0.3 mg/kg of ivermectin and lungworm (A. abstrusus) infec- worm infection in dogs should also be consulted.17 Although tions with 0.4 mg/kg of ivermectin. 58-60 Capillaria species are there is no FDA-approved microfi laricide, macrocyclic lac- rarely implicated in feline cystitis, and infestations are thought tones are the safest and most eff ective microfi laricidal drugs to be self-limiting usually, but in one case a single dose of iver- available for use in heartworm-positive dogs. 17 Compared mectin 0.2 mg/kg, administered subcutaneously, was success- with ivermectin, milbemycin is a more potent microfi laricide fully used to treat the condition in a cat.61 and causes quicker clearance of microfi lariae.17 Short-term use of ivermectin alone has minimal eff ect on Milbemycin Oxime adult heartworms, but when given continuously over a pro- Milbemycin oxime was the second macrocyclic lactone longed period, for 1 to 2 years, or when combined with doxy- approved by the FDA. It is a fermentation product of Strep- cycline, it may have some utility for treating dogs with adult tomyces hygroscopicus aureolacrimosis. It has structural simi- heartworm infection. Th e older the adult heartworms are larities to ivermectin and is believed to work by a similar when fi rst exposed to ivermectin, the longer it takes them to mechanism of action and have similar pharmacokinetic prop- die; because they continue to cause damage during this time, erties with regard to absorption, metabolism, and excretion. long-term ivermectin therapy generally is not a substitute Although an LD50 was never determined for dogs, single oral for melarsomine (Immiticide) therapy.17 In addition, a mild doses of 200 mg/kg were tolerated in laboratory Beagles. Collie hypersensitivity reaction has been observed in dogs with cir- dogs tolerated single oral doses of 10 mg/kg without toxicity. culating microfi lariae that are treated with ivermectin. Many products that contain ivermectin have precautions suggesting KEY POINT 13-8 Milbemycin, the second macrolide used removal of adult heartworms and microfi lariae before initiat- commercially, is similar to ivermectin. ing ivermectin heartworm prophylaxis. Regarding the combination of ivermectin and doxycycline as a heartworm adulticide; it has been found that Wolbachia Dogs . Milbemycin oxime tablets (Interceptor) are formu- spp. bacteria are fi larial species endosymbionts—that is, their lated to deliver a minimum dose of 0.5 mg/kg of body weight. presence is necessary for fi lial worm survival—and that elimi- When given every 30 days it is eff ective in preventing heart- nating this bacteria from heartworm-positive dogs and cats worms (D. immitis) . 62-64 It also kills A. caninum, T. canis, and will decrease host antigenic response. 51,52 In fact, one study of T. vulpis . 65-68,23 One study indicates that milbemycin may help heartworm-positive dogs comparing groups that were treated control raccoon roundworm (B. procyonis) infections in dogs with three drugs (i.e., melarsomine, doxycycline, and iver- and thus decrease the zoonotic potential of a parasite that can mectin), two drugs (i.e., doxycycline and ivermectin), doxycy- have devastating eff ects in humans, including death.69 cline alone, ivermectin alone, and melarsomine alone, led the authors to conclude that the combination of doxycycline and KEY POINT 13-9 Milbemycin is safe for nursing and pregnant ivermectin was synergistic and could eliminate adult heart- animals. worms with less potential for severe thromboembolism than melarsomine alone.52 Th is is discussed in greater depth in the melarsomine section. Milbemycin oxime has been extensively tested with regard Ivermectin given as a single subcutaneous injection or to safety. It is nontoxic to Collies at up to 20 times the recom- orally administered at 0.2 mg/kg demonstrated high effi - mended dose and is safe when given to pregnant and nurs- cacy against the immature and adult T. canis, A. caninum, ing animals.70,71 Milbemycin oxime, like ivermectin, is known CHAPTER 13 Drugs for the Treatment of Helminth Infections: Anthelmintics 457 to kill heartworm microfi lariae and inhibit the release of new pet-owner consent form. Th is is the fi rst veterinary drug to be microfi lariae. Th us all dogs receiving routine monthly heart- marketed under RiskMAP, a strengthened risk minimization worm prophylaxis with milbemycin should be tested with and restricted distribution program.78 Th e new label advises adult antigen tests.72-74,49,17 not to administer the drug to sick, debilitated, or underweight dogs or those with a history of weight loss and states that the KEY POINT 13-10 Use of milbemycin may help control the product should be used with caution in dogs with preexisting raccoon roundworm, which has human health implications. allergic disease, including food allergy, atopy, and fl ea allergy dermatitis. Th e label also warns not to administer moxidectin injection within 1 month of vaccinations. 79 Cats . Milbemycin oxime (Interceptor) is approved for use Injectable moxidectin is indicated for use in dogs 6 months in cats. Th e product is eff ective in preventing in heartworm of age and older for the prevention of heartworm disease. (D. immitis) at a monthly dose of 0.5 mg/kg75 and removing It should be given at 0.17 mg/kg by subcutaneous injection roundworms (T. cati) and hookworms (A. tubaeforme) at a within 1 month of the dog’s fi rst exposure to mosquitoes or monthly dose of 1.5 mg/kg. 76,23 within 1 month of the dog’s last dose of monthly heartworm preventive. Th e sustained-release injection provides a 6-month Moxidectin window of protection from heartworms. 79 However, it does Moxidectin was the third macrolide to enter the parasite mar- not clear microfi lariae or remove adult heartworms. 23 A chal- ket. It is a chemically altered product of Streptomyces aureo- lenge study comparing effi cacy and adverse reactions among lacrimosus noncyanogenus and has a similar range of activity four groups of dogs given placebo or moxidectin at 0.06, 0.17, and safety margin as ivermectin and milbemycin oxime. Mox- or 0.5mg/kg and inoculated with 50 D. immitis third-stage idectin is currently approved in the United States for injectable larvae 180 days later revealed 100% effi cacy at the label dose use as a heartworm ( D. immitis) preventive and hookworm ( A. (0.17 mg/kg).80 However, one of eight dogs given the lower caninum and U. stenocephala) treatment in dogs (ProHeart 6) dose (0.06 mg/kg) was infected. Th e authors speculated that and for topical use in combination with imidacloprid to pre- the failure of protection was a result of individual pharmaco- vent heartworms, treat fl eas, and control and treat ear mites kinetic variation because the moxidectin serum concentration and intestinal parasites in dogs and cats (Advantage Multi). in the unprotected dog was at the limit of quantitation (low- Th e combination product is reviewed later in this chapter. Th e est detectable quantity) 8 days aft er treatment and undetect- oral use of moxidectin in dogs is covered in the previous edi- able thereaft er compared with others in that group that had tion of this text. Moxidectin toxicity was discussed previously detectable concentrations until at least day 14 and for as long in the Avermectin Toxicity section. as 55 days for most of the other dogs.80 Both the frequency and size of injection-site granulomas correlated positively with the KEY POINT 13-11 Moxidectin, the third macrolide used com- moxidectin dose. 80 mercially, is also similar to ivermectin and milbemycin. Moxidectin sustained-release injection is also indicated for the treatment of hookworms A. caninum and U. stenocephala ; KEY POINT 13-12 Moxidectin is available as a sustained- although it will eliminate larval and adult stages of those para- release injectable heartworm preventive and hookworm sites, reinfection may occur in less than 6 months, making its treatment. use less than ideal when attempting to control recurrent hook- worm disease.

KEY POINT 13-13 Moxidectin combined with imidacloprid is Selamectin available as a topical heartworm preventive and fl ea treat- Prepared by semisynthetic modifi cation of doramectin,81 sela- ment that controls ear mites and internal parasites. mectin (Revolution) is the latest macrolide to enter the U.S. marketplace. Th is product is unique among other macrolides Dog . Moxidectin injection (ProHeart 6) was launched in used in small animals in that it is formulated for convenient the United States in 2001 with an indication to prevent heart- topical administration. It is simply “spotted” onto the skin of worms and treat hookworms in dogs. Th e label for the sus- the pet. It was the fi rst macrocyclic lactone approved for use tained-release injectable product instructed that it was to be in dogs and cats to provide activity against both internal and given no more oft en than once every 6 months. Th e FDA had external parasites. However, the discussion here focuses on the concerns about safety as a result of adverse event reports that it activity of selamectin against internal parasites. received, and the manufacturer voluntarily recalled the prod- uct from the U.S market in 2004 to address those safety con- KEY POINT 13-14 Selamectin is the latest macrolide to be cerns.77 During that time the product remained on the market used commercially in the United States. in Australia, Japan, and parts of Europe. In 2008 the product was reintroduced to the U.S. market with a new label under a postmarketing surveillance initiative based on human drug KEY POINT 13-15 Selamectin is unique among macrolides in its topical formulation and extreme broad spectrum against programs and known as a Risk Minimization Action Plan internal and external parasites. (RiskMAP), which includes veterinarian training and use of a 458 Drugs Targeting Infections or Infestations SECTION 2

It is produced as a fermentation product of S. avermitilis, which is then chemically modifi ed. 82 Th e pharmacokinetics Benzimidazoles aft er topical administration has been studied extensively. Th e Th e benzimidazoles represent a large family of broad- topical bioavailability varies greatly among species. In dogs the spectrum agents that have been in widespread use for many bioavailability is only 4%, but it is much greater in cats (74%). years in a vast array of animal species. Several excellent review Th e terminal half-life was much longer in both species aft er articles88-90 discuss the history, mode of action, and spectrum topical administration than aft er intravenous administration, of activity of this useful class of anthelmintics. suggesting sustained release from an extravascular depot. Th e Th iabendazole, the fi rst benzimidazole discovered, repre- half-life aft er topical administration was 11 days for dogs and sented a major step forward when it became available in the 8 days for cats.23 Th e product is absorbed in suffi cient quanti- early 1960s. 91 At the time of its introduction, thiabendazole ties and persists for suffi cient time to control the target para- was a true broad-spectrum product that was very safe to the sites. Th e approved topical dose is a minimum of 6 mg/kg for host animal. Since that time, parasite resistance to the benz- dogs and cats. imidazoles has been discovered in several species. Selamectin is approved for the prevention of heartworm (D. immitis) in both dogs and cats when applied topically KEY POINT 13-17 Introduced to the market in the early every month. 8 Extensive studies proved that the drug’s effi cacy 84,85 1960s, thiabendazole was the fi rst benzimidazole against heartworms remained even when bathing followed used commercially and was a major advancement in application. Th e bathing study demonstrated that aft er topi- anthelmintics. It is not commercially available as an cal application effi cacy is not likely to be decreased by inad- anthelmintic for small animals. vertent swimming or exposure to rainstorms. Th e drug is not eff ective in clearing microfi lariae. In cats selamectin is also eff ective in removing hookworm (A. tubaeforme) and round- Considerable eff ort has been devoted to determining benz- worm (T. cati) . Th is eff ect is undoubtedly due to the greater imidazole mechanism of action. Conventional wisdom holds topical bioavailability observed in cats. 82 Selamectin is eff ec- that benzimidazoles bind to tubulin molecules, which inhibit tive against roundworms in dogs23 and lungworms (A. abstru- the formation of microtubules and disrupt cell division. 92,93 sus) in cats,86 but these are not label-approved indications. Th e It has a much higher affi nity for nematode tubulin versus drug has labeled indications in dogs for activity against ear mammalian tubulin, thus providing selective activity against mites, sarcoptic mange mites, and ticks and in cats for activ- parasites. Evidence also indicates that the benzimidazoles can ity against ear mites, but these indications are not the focus of inhibit fumarate reductase, which blocks mitochondrial func- this chapter. tion and kills the parasite by depriving it of energy. Th e benzimidazoles are poorly soluble and thus are gen- KEY POINT 13-16 Selamectin has much greater bioavailability erally given by mouth. Th ey are more eff ective in horses and after topical administration on cats compared with dogs. ruminants because of their slow transit through the cecum and rumen. Proper use in small animals requires that the benzimidazoles be given for a minimum of 3 days in a row. Th e safety of selamectin has been established in both dogs Th e dose is usually more eff ective when divided into two doses and cats and even for use in puppies and kittens over 6 weeks per day, thus prolonging the contact time with the parasite. of age. It is also safe to use in ivermectin-sensitive Collies and in breeding dogs and cats.84 Selamectin did not cause any KEY POINT 13-18 Benzimidazoles are not very soluble. abnormalities when applied topically to ivermectin-sensitive Collies at 40 mg/kg. 22 However, avermectin-sensitive Collies given a topical overdose of 10 times the label dose had hyper- Because both albendazole and oxfendazole were found salivation.28 Clinical signs of dogs reported to the ASPCA to be teratogenic, their use is limited to nonpregnant ani- Animal Poison Control Center are, in order of frequency, mals. For simplicity, febantel, a nonbenzimidazole drug that hypersalivation, agitation, diarrhea, facial edema, and hyper- is metabolized to a benzimidazole, thus sharing effi cacy and activity. 28 In cats the signs in decreasing frequency are vomit- mechanism of action, is included in this section with the other ing, anorexia, hyperesthesia, hyperthermia, and mydriasis.28 benzimidazoles. If cats are exposed orally to selamectin they invariably have hypersalivation and sometimes vomit, but topical overdoses at Albendazole 10 times the label dose in cats did not cause any abnormality.28 Albendazole is the newest benzimidazole. It has potent broad- Although the insert recommends that dogs should be tested spectrum anthelmintic activity, but is not approved for use in for existing heartworm infections before selamectin adminis- dogs and cats. Albendazole has demonstrated a broad spec- tration, it also notes that hypersensitivity reactions were not trum of anthelmintic activity against gastrointestinal nema- observed when heartworm-infected dogs were treated with todes; lung nematodes, including inhibited larval forms; selamectin at 3 times the label dose.87 Clinical studies have cestodes; and lung and liver trematodes in farm animals, com- confi rmed the wide safety margin demonstrated in the labora- panion animals, and humans. Albendazole (Albenza or Zentel) tory studies. is used overseas to treat humans with intestinal helminth CHAPTER 13 Drugs for the Treatment of Helminth Infections: Anthelmintics 459 infections, hydatid disease, or cysticercosis. It is commonly lifetime studies of rats and mice. In a 6-month toxicity study used for treatment of nematode and trematode infections in in dogs, no eff ect was observed at 4 mg/kg or less. large animals (Valbazen). KEY POINT 13-20 Febantel is metabolized to fenbendazole and oxfendazole, which are probably the active molecules. KEY POINT 13-19 Albendazole is the latest benzimidazole to be used commercially, but it is not approved for use in dogs or cats. KEY POINT 13-21 Fenbendazole is used in a wide variety of species, including dogs, cats, livestock, horses, and zoo animals. Albendazole, like other benzimidazoles, is well absorbed (about 50% bioavailable) and converted in the liver to the active metabolites albendazole sulfoxide and albendazole Fenbendazole is a broad-spectrum anthelmintic with activity sulfone. Th ese active metabolites are thought to bind to tubu- against a wide variety of nematodes and cestodes in dogs, cats, lin and inhibit fumarate reductase. Th e parent drug and its cattle, sheep, goats, horses, and many zoo animals. Absorbed metabolites are excreted primarily in the urine. fenbendazole is metabolized to at least two active metabolites, Because albendazole was shown to be teratogenic, its use oxfendazole sulfoxide and oxfendazole sulfone. It undergoes is limited to nonpregnant animals. Dogs treated with 50 mg/ enterohepatic cycling in ruminants, which prolongs eff ective kg twice daily may develop anorexia. Cats may exhibit leth- blood levels. 96 In the United States fenbendazole is approved argy, depression, and anorexia when treated. 28 When cats were for control of helminth parasites of horses, cattle, and dogs. given 100 mg/kg/day for 14 to 21 days, they displayed weight loss, neutropenia, and mental dullness.28 When used clini- KEY POINT 13-22 Fenbendazole has a broad spectrum of cally, albendazole may be associated with signifi cant toxicity, activity against many nematodes and cestodes. including myelosuppression (leukopenia, anemia, and throm- bocytopenia), abortion, teratism, anorexia, depression, ataxia, vomiting, and diarrhea.94,95 Recent evidence suggests that it Dogs . Fenbendazole is approved only for use in dogs 6 weeks may cause aplastic anemia in dogs and cats. 28 Veterinarians of age and older. Fenbendazole granules (Panacur) are mixed in are advised to use due caution with this product. the feed at a dose level of 50 mg/kg and given to dogs for 3 con- Albendazole is available as an oral suspension (Valbazen) secutive days for the removal of T. canis, T. leonina, A. caninum, containing 113.6 mg/mL. Dogs can be treated for lungworms U. stenocephala, T. vulpis, and Taenia pisiformis. 97 It has shown (F. hirthi) at a dose of 25 to 50 mg/kg twice daily for 5 days, excellent activity against Giardia spp. in dogs at the approved with the treatment repeated in 2 to 3 weeks, and for bladder dose. 95,98 At longer-than-approved duration of therapy (i.e., 50 worms (Capillaria plica) at a dose of 50 mg/kg twice daily mg/kg daily for 10 to 14 days), it has been used to treat the lung for 10 to 14 days. 28 Both dogs and cats can be treated for the fl uke, P. kellicotti, in dogs.28 Fenbendazole is relatively safe, and lung fl uke (Paragonimus kellicotti) at a dose of 25 mg/kg twice there are no known contraindications to its use in dogs. daily for 14 days or 50 mg/kg orally once daily for 21 days.28 Cats . Fenbendazole is not currently approved for use in Although albendazole is eff ective against these uncommon cats. When given at a dose of 50 mg/kg for 5 days, it is eff ec- parasites, ivermectin and praziquantel are more convenient tive against ascarids, hookworms, Strongyloides , and Taenia therapies and likely to be just as eff ective. spp. tapeworms. 28 Treatment of A. abstrusus, P. kellicotti, and C. aerophila may require 14 days of therapy. 28 Febantel Febantel is a prodrug that is metabolized to fenbendazole and Tetrahydropyrimidines oxfendazole, which are undoubtedly the active parasiticides. 90 Th e tetrahydropyrimidines include the numerous salts of pyr- Th e oral acute toxic dose in mice, rats, and dogs is more than antel, morantel, and the investigational compound oxantel, 10 g/kg (10,000 mg/kg). At oral doses above 150 mg/kg per which is available outside the United States. Th ey all act as nic- day for 6 days, transient salivation, diarrhea, vomiting, and otinic agonists, which disturb the neuromuscular system, caus- anorexia may be seen in dogs and cats. Febantel is not available ing contraction and subsequent tonic paralysis. 99-102 In vitro in a single-entity formulation but only in combination with experiments indicate that pyrantel is 100 times more powerful praziquantel and pyrantel, which are discussed in the section than acetylcholine. It seems that the nicotinic acetylcholine on combination products. receptors of invertebrate parasites are essential for neurologic function but diff er in physiology and distribution in mam- Fenbendazole mals. 103 In ruminants these products are rapidly metabolized Fenbendazole (Panacur) is a commercially successful benz- to inactive metabolites; therefore higher doses are required to 20 imidazole that is widely used in dogs. Th e oral LD 50 for rats treat ruminants compared with monogastric animals. and mice is more than 10 g/kg (10,000 mg/kg).28 Fenben- dazole does not have embryotoxic or teratogenic eff ects in KEY POINT 13-23 Tetrahydropyrimidines are nicotinic agonists. They cause contraction and subsequent tonic rats, sheep, or cattle. In the rabbit fenbendazole was fetotoxic paralysis of parasites. but not teratogenic, and no carcinogenesis was observed in 460 Drugs Targeting Infections or Infestations SECTION 2

KEY POINT 13-24 Pyrantel is 100 times more powerful than pamoate is labeled for cats as a combination product with pra- acetylcholine. ziquantel (Drontal), which is described later, in the combina- tion product section.

Pyrantel Cyclic Depsipeptides Pyrantel was introduced in the United States as a broad- Th e cyclodepsipeptide PF1022A, isolated from Mycelia ster- spectrum anthelmintic for sheep in 1966 22 and is now avail- ilia, was found to have low toxicity and strong anthelmintic able under a wide variety of trade names in the form of tablet, properties when tested against Ascaridia galli in chickens, paste, oral suspension, and medicated feed. 104 Th e tartrate salt making it one of the most promising deworming prospects to of pyrantel is a white powder, soluble in water, that is used in emerge since the discovery of avermectins and milbemycin. horses and swine. Pyrantel tartrate is well absorbed aft er oral administration in the rat, dog, and pig. Plasma levels peak Emodepside within 3 to 6 hours. 22 Pyrantel tartrate is rapidly metabolized Emodepside is the fi rst cyclic depsipeptide to be approved for and in dogs is primarily eliminated by way of the urinary tract, use against animal parasites in the United States. It is a semi- but pyrantel pamoate is poorly absorbed from the gastrointes- synthetic derivative of PF1022A, mentioned previously. Th e tinal tract and is primarily eliminated through the feces with product binds to a presynaptic latrophilin receptor in parasitic less than 15% excretion through the urinary tract. 104 nematodes, which results in fl accid paralysis and death. 110 It has low to moderate acute toxicity in mammalian species. Th e oral LD in rats is greater than 500 mg/kg and is more than KEY POINT 13-25 Pyrantel pamoate is poorly absorbed, 50 which contributes to its safety in young animals. 2000 mg/kg when applied to the skin. Studies in rats and rab- bits suggest that emodepside may interfere with fetal develop- ment.111 Women who are pregnant or may become pregnant Th e pamoate salt of pyrantel is a yellow powder, insoluble in should avoid direct contact with emodepside and wear dis- water. It is available as a ready-to-use suspension and as tablets posable gloves if product handling is necessary. Emodepside for dogs and horses. Th e fact that pyrantel pamoate is poorly is only available commercially as a combination product, absorbed from the intestine adds to its safety in very young or combined with praziquantel, and as such is discussed in detail weak animals. Pyrantel salts are stable in solid form but pho- later, in the section on broad-spectrum combinations. todegrade when dissolved or suspended in water, resulting in reduction of potency. KEY POINT 13-26 Emodepside is the fi rst cyclic depsipeptide Dogs . Pyrantel pamoate is available as a tablet, chewable approved in the United States. tablet, and palatable suspension (Nemex and many other trade names) and is indicated for the removal of T. canis, T. leonina, KEY POINT 13-27 Pregnant women should use care if they 105-108 A. caninum, and U. stenocephala from dogs and puppies. must handle this drug. Th e drug has also been used to treat Physaloptera stomach worms in dogs, although such use is not approved.104,109 Pyr- antel may have some eff ect on tapeworms as well, but other Piperazines drugs are commonly used to treat tapeworm infections in Piperazine was used to treat human gout in the early 1900s small animals. Th e recommended dose of 5 mg/kg of pyran- because it acts as an excellent uric acid solvent. Its anthelmin- tel pamoate suspension is administered orally or mixed with tic activity was discovered in the 1950s.22 Since then, a wide a small amount of feed.104 For animals weighing 2.25 kg or variety of piperazine salts have been derived. Th e various salts less, the dose is increased to 10 mg/kg. Tablets may be admin- of piperazine (adipate, hydrochloride, sulfate, monohydrate, istered directly or placed in a small portion of food. Pyran- citrate, and dihydrochloride) are used as anthelmintics in tel pamoate is safe for nursing and weanling pups, pregnant swine, poultry, horses, dogs, and cats. Piperazine is quite safe bitches, males used for breeding, and dogs infected with D. to use in these species but has a narrow spectrum of action, 22 93,27 immitis. Th e oral LD 50 is greater than 690 mg/kg in dogs. limited primarily to roundworms. Anthelmintic activity In chronic toxicity studies dogs had no adverse eff ects when depends on the salt freeing its piperazine base in the gastro- given 20 mg/kg daily for 3 months but did have ill eff ects at 50 intestinal tract. Th e amount of piperazine (base) in each salt mg/kg or above daily.22 Pyrantel pamoate is compatible with varies widely. Th e citrate salt contains 35% piperazine; adipate organophosphates and other antiparasitic and antimicrobial salts, 37%; phosphate salts, 42%; and dihydrochloride salts, agents. 50% piperazine base.96 Cats . Pyrantel pamoate products used in dogs are not labeled Piperazine paralyzes worms by blocking the action of ace- for cats but are considered very safe and eff ective against some tylcholine and GABA at the neuromuscular junctions, and the common feline parasites, the ones that are similar to those worms are eliminated by intestinal peristalsis.20,112 It acts by affl icting dogs and are listed as indications on the canine label. hyperpolarizing nerve membranes at the neuromuscular junc- Th e oral dose range of 5 to 20 mg/kg is reportedly effi cacious tion, leading to fl accid paralysis of the parasite.22 Piperazine against ascarids, hookworms, and Physaloptera spp., with the is also one of the active ingredients in a number of combi- dose repeated in 2 to 3 weeks in some cases.22,27,28,104 Pyrantel nation anthelmintic products. Piperazine should not be used CHAPTER 13 Drugs for the Treatment of Helminth Infections: Anthelmintics 461 in combination with pyrantel pamoate because the modes of Th e oral half-life in dogs is reported to be 30 to 90 minutes 22 action are antagonistic. to 3 hours. 28

KEY POINT 13-28 Piperazine paralyzes worms by blocking KEY POINT 13-30 Praziquantel, the fi rst approved cesticidal acetylcholine and GABA, and the worms are eliminated by isoquinolone in the United States, has marked anthelmintic intestinal peristalsis; thus it may not work well in the face of activity against cestodes and trematodes. gastrointestinal hypomotility.

Piperazine is rapidly absorbed from the gastrointestinal Praziquantel is a very safe anthelmintic. Rats tolerated daily tract and rapidly cleared by urinary excretion. Elimination is administration of up to 1000 mg/kg for 4 weeks, and dogs tol- virtually complete within 24 hours.96 It may not be eff ective erated up to 180 mg/kg per day for 13 weeks. Vomiting is typi- in animals with intestinal hypomotility because the paralyzed cally observed at high dosage rates. Injected doses of 200 mg/kg worms may recover from the drug eff ect before they are passed were lethal in cats.28 Praziquantel did not induce embryotox- in the stool. Piperazine should be used with caution in animals icity, teratogenesis, mutagenesis, or carcinogenesis, nor did it with hepatic or renal dysfunction. Occasional adverse reac- aff ect the reproductive performance of test animals. Occasional tions observed in dogs include ataxia, diarrhea, and vomiting. adverse experiences in clinical use include pain on injection, Piperazine is available as tablets, solution, and soluble pow- anorexia, diarrhea, salivation, vomiting, sleepiness, staggering, der under many proprietary names (Pipatabs, Puppy Paste, and weakness. Overdoses have been reported to cause diarrhea, Happy Jack KittyKat Paste, Tasty Paste). It is practically non- depression, incoordination, tremors, salivation, and vomiting. toxic. Th e oral LD 50 for rats is 4.9 g/kg and for mice is 11.4 g/ kg. Treatment for intoxication is symptomatic and supportive. KEY POINT 13-31 Praziquantel has a wide margin of safety. Piperazine can be administered to animals of all ages.

Dogs and Cats Dogs and cats. Praziquantel (AmTech, Droncit) is adminis- Piperazine is usually administered orally at 45 to 65 mg of base tered orally or injected subcutaneously at 2.5 to 7.5 mg/kg for per kilogram, 96 although higher doses (100 to 250 mg/kg) have the removal of Dipylidium caninum, Taenia taeniaeformis, T. pisi- been reported in the literature. 107,113-115 Piperazine is eff ective formis, T. hydatigena, T. ovis, Mesocestoides corti, Echinococcus against adult roundworms T. canis, T. cati, and T. leonina. granulosus, Echinococcus multilocularis, Spirometra spp., Diphyl- lobothrium latum, D. erinacei, and Joyeuxiella pasquali . 118-124,96 Isoquinolones Th e product insert has extensive information about using this Th e cesticidal isoquinolones are represented by two closely drug to help control E. multilocularis, including the life cycle of related drugs: praziquantel and epsiprantel. Th is cesticidal the parasite, diffi culty of diagnosis, and other public health con- class is the safest and most eff ective yet approved in the United siderations. 125 Praziquantel injection is not intended for use in States. Th ey attack the parasite neuromuscular junction and puppies or kittens younger than 4 weeks of age. Several combina- the tegument. Th ese drugs cause increased cell membrane tion products contain praziquantel; see the section on combina- permeability to calcium and resulting loss of intracellular cal- tion products for more information. cium. Th is eff ect produces an instantaneous contraction and paralysis of the parasite.116 Th e second eff ect is a devastating Epsiprantel vacuolization and destruction of the protective tegument.92, 117 Epsiprantel (Cestex) was the second cesticidal isoquinolone Th e combined eff ects of paralysis and tegmental destruction to be approved in the United States. Unlike its cousin praziqu- provide excellent activity against cestodes. antel, epsiprantel is poorly absorbed aft er oral administra- tion. Less than 0.1% is recovered from the urine; there are no KEY POINT 13-29 Isoquinolones are the safest and most known metabolites.28 It is eliminated in the feces unchanged.22 effective cesticidal drugs approved in the United States. Because of the low bioavailability, systemic toxicity and terato- genic eff ects are very unlikely, but the safety of epsiprantel in pregnant dogs and cats has not been proved. In acute toxicity Praziquantel studies in mice and rats, the oral minimum lethal dose of epsip- Praziquantel was the fi rst cesticidal isoquinolone approved in rantel was shown to be more than 5000 mg/kg. Doses as high as the United States. It has marked anthelmintic activity against a 36 times the label dose were well tolerated in dogs and caused wide range of adult and larval cestodes and trematodes of the vomiting in some kittens.28 Cats given the drug at 40 times the genus Schistosoma. Oral administration results in nearly com- label dose for 4 days had minimal signs. Dogs given 90 times plete absorption and rapid distribution throughout the body the label dose for 14 days had no signifi cant adverse events. 126 and across the blood – brain barrier. Although 80% of the drug is eliminated in the urine, the main site of inactivation is the KEY POINT 13-32 Like praziquantel, epsiprantel, the second liver, with only trace amounts of the unchanged drug excreted cesticidal isoquinolone approved in the United States, has a wide margin of safety, but unlike praziquantel, it is poorly primarily in the urine.22,91 Praziquantel has high oral bioavail- absorbed orally. ability, high protein binding, and a marked fi rst-pass eff ect. 462 Drugs Targeting Infections or Infestations SECTION 2

Epsiprantel treatment as an oral fi lm-coated tablet, at 2.75 About one third of dogs treated will have injection site mg/kg for cats or 5.5 mg/kg for dogs, eff ectively removes reactions, most of which resolve within a week, but fi rm nod- D. caninum, T. taeniaeformis, T. pisiformis, and T. hydatigena ules at the injection site can persist indefi nitely. 28 Additional aft er a single dose. 127,128 Evidence suggests that the drug is adverse reactions include elevated hepatic enzymes, cough- eff ective against E. granulosa and E.multilocularis , but the data ing, gagging, depression, lethargy, anorexia, fever, pulmonary are insuffi cient to recommend a dosage that will completely congestion, and vomiting. 27 Th is drug exemplifi es the problem clear the infection from those treated. 129 Epsiprantel was given of parasite removal by poisoning the patient just enough to concurrently with diethylcarbamazine (in dogs), antiinfl am- kill the parasite, hopefully without damaging the patient too matory drugs, insecticides, and nematocides with no incom- much. It has a narrow therapeutic range. Th e toxic dose is only patibilities observed.126 It should not be used in puppies and 2.5 to 3 times the recommended dose and can result in pant- kittens younger than 7 weeks of age. ing, pulmonary infl ammation, salivation, vomiting, edema, and death. Safety has not been determined in breeding, preg- Arsenicals nant, or lactating dogs. Th at said, clinical studies indicate that Heavy metals like arsenic and antimony are well represented the treatment is well tolerated even in dogs that have clinical in the history of anthelmintics. To date, safer and more signs of heartworm disease.135,137,138 eff ective drugs for the most common parasites have largely As previously mentioned in the ivermectin section of replaced arsenicals. Th eir use is now limited to removal of this chapter, the American Heartworm Society guidelines adult D. immitis. Th iacetarsemide (Caparsolate) is no longer for diagnosis, prevention, and management of heartworm available commercially in the United States130 and thus will infection in dogs should be consulted before treating a heart- not be covered in this chapter. Th e therapeutic eff ect of arseni- worm-infected dog with melarsomine.18a Treatment with a cals depends on a reaction between the arsenic salt and sulf- macrocytic lactone before administration of melarsomine hydryl-containing enzymes.131 Inactivation of parasite enzyme should be considered along with other methods to reduce the systems causes death. Because arsenic is widely known as a potential for melarsomine adverse reactions. For example, as toxin in man and animal, caution is required when using these previously mentioned in the ivermectin section, one study products. of heartworm-positive dogs comparing groups that were treated with three drugs (i.e., melarsomine, doxycycline and KEY POINT 13-33 Arsenicals typically have a narrow margin ivermectin), two drugs (i.e., doxycycline and ivermectin), of safety. doxycycline alone, ivermectin alone, or melarsomine alone led the authors to conclude that the combination of doxycy- cline and ivermectin was synergistic.52 All dogs treated with Melarsomine ivermectin plus doxycycline (with or without melarsomine) Although contraindicated in cats, melarsomine dihydrochlo- were free of microfi lariae in 9 weeks. Th is may be related to ride (Immiticide), the only arsenical anthelmintic commer- the elimination of Wolbachia sp. bacteria, which are fi larial cially available in the U.S. veterinary market, has 92% to 98% endosymbionts. Th e authors found that the administration effi cacy against adult D. immitis in dogs.132-136 Th e arsenic of doxycycline plus ivermectin for several months before (or content of the product is less than that of thiacetarsemide, without) melarsomine resulted in elimination of adult heart- making melarsomine less toxic to the patient. Melarsomine is worms with less severe thromboembolism than did treatment labeled to be administered intramuscularly at a dose of 2.5 mg/ with melarsomine alone.52 kg for two injections given 24 hours apart to dogs at low risk 17 of thromboembolic complications. Dogs that have moderate KEY POINT 13-35 The prudent practitioner will consult risk of thromboembolism may be treated with an alternative American Heartworm Society guidelines before using three-injection regimen of a single injection followed by a rest melarsomine. period of 1 to 2 months, aft er which two standard injections are given.17 Th is later three-injection regimen is reportedly less hazardous for the patient and more effi cacious and there- Miscellaneous fore is the preferred regimen recommended by the American Dichlorophen Heartworm Society, regardless of the stage of disease (unless Dichlorophen (Happy Jack Tapeworm Tablets) is a chlo- melarsomine is otherwise contraindicated). 17, 18a Melarsomine rinated analog of diphenylmethane. It has low toxicity for is contraindicated in dogs with severe heartworm disease mammals. Th e oral LD 50 is 2690 mg/kg for rats, and the acute 28 associated with caval syndrome. Injections should only be oral LD 50 in dogs is 1000 mg/kg. Dichlorophen has bacterio- made deep into the lumbar epaxial muscles along L3 to L5. static, fungicidal, and cesticidal properties. It causes electron Peak blood level is achieved in about 11 minutes aft er injec- transport – linked phosphorylation to uncouple in the para- tion, and the half-life is 3 hours. 28 site mitochondria and is relatively safe in the host because of low gastrointestinal absorption. 91 Dichlorophen may be given orally as an “aid in the removal” of D. caninum and KEY POINT 13-34 Melarsomine is the only commercially T. pisiformis tapeworms from dogs. 139 Th e drug may be admin- available arsenical anthelmintic. istered orally in tablet or capsule form at 220 mg/kg aft er an CHAPTER 13 Drugs for the Treatment of Helminth Infections: Anthelmintics 463 overnight fast. Th e tapeworms are killed, digested, and elimi- D. caninum and T. taeniaeformis. 140-142 Th e topical emodepside – nated in an unrecognizable form. Animals occasionally vomit praziquantel product was very eff ective and safe when used in or develop diarrhea aft er treatment with dichlorophen. a large-scale clinical study comparing it with topical selamectin– oral epsiprantel.143 KEY POINT 13-36 Dichlorophen is not absorbed well from the gastrointestinal tract, which improves its safety profi le. Pyrantel Plus Praziquantel Two-way combination products containing pyrantel and pra- KEY POINT 13-37 Dichlorophen aids in the removal of tape- ziquantel are approved for use in the United States in both worms from dogs. dogs (Virbantel) and in cats (Drontal).

Dogs BROAD-SPECTRUM COMBINATIONS Th e canine product is formulated to deliver 5 mg of praziqu- antel and 5 mg of pyrantel pamoate per kilogram. A single Th e veterinary practitioner is always looking for anthelmintic dose is given to dogs to remove tapeworms (D. caninum and products that cover an ever-increasing spectrum of parasites. T. pisiformis), hookworms (A. caninum, A. braziliense, and Broad-spectrum products provide two important advantages. U. stenocephala), and roundworms (T. canis and T. leonina) . First, they obviate dosing with several diff erent products at once when a patient has a mixed parasite infection, making Cats administration easier. Second, they provide peace of mind Th e feline product is formulated to deliver at least 5 mg of that a treated animal will be cleared of possibly undiagnosed praziquantel and 20 mg of pyrantel pamoate per kilogram. A parasites. For instance, a puppy from the animal shelter will single dose is given to cats and kittens to remove tapeworms be better served by use of a product that is eff ective in remov- (D. caninum and T. taeniaeformis), hookworms (A. tubae- ing both roundworms and hookworms than a product that forme), and roundworms (T. cati) . Th e product is 98% eff ec- is eff ective against only roundworms. Th ere are two ways to tive and well tolerated. Cats maintained in conditions of heavy increase the spectrum of anthelmintics: either by tackling the or constant parasite exposure should be reevaluated in 2 to 4 arduous task of discovering a single broad-spectrum chemical weeks. Th is combination product should not be used in kittens or by combining several compatible active ingredients to build weighing less than 1.5 pounds or those younger than 4 weeks the desired spectrum of activity. of age. Pyrantel Plus Praziquantel Plus Febantel KEY POINT 13-38 Broad-spectrum anthelmintic combinations make treating mixed parasitic infections easier and may A three-way combination of pyrantel, praziquantel, and feb- treat common undiagnosed parasites; therefore they are antel (Drontal Plus) is available in the United States and many associated with increased veterinary and owner confi - other parts of the world. Th is product is formulated to deliver dence. at least 25 mg febantel, 5 mg praziquantel, and 5 mg pyran- tel pamoate per kilogram. A single dose is given to dogs to remove tapeworms (D. caninum, T. pisiformis, E. granulosus, Combination anthelmintic products are briefl y reviewed in E. multilocularis), hookworms (A. caninum, U. stenocephala) , this section, but not combinations that are formulated to treat roundworms (T. canis, T. leonina ) , and whipworms (Trichuris or prevent fl eas or other nonhelminth parasites. In many cases vulpis).144,145 It is interesting to note that a single dose of this combination-product formulation and dosing regimens are combination is eff ective against nematodes, especially whip- diff erent from those of the single-entity drug ingredients. Th e worms, but that febantel alone requires three daily doses to toxicity and mechanism of action of the individual ingredients eff ectively remove nematodes. Th is combination of ingredi- are covered earlier in this chapter. ents may be synergistic. Th is product should not be used in pregnant dogs, dogs weighing less than 2 pounds, or puppies Emodepside Plus Praziquantel younger than 3 weeks of age. Th is product is formulated for use in cats (Profender) as a topical spot-on that contains 1.98% emodepside and 7.94% Ivermectin Plus Pyrantel praziquantel. Th e prefi lled applicators deliver a minimum Ivermectin combined with pyrantel pamoate is available in dose of 3 mg/kg emodepside and 12 mg/kg praziquantel when fl avored chunks or tablets (Heartgard-30 Plus, Iverhart Plus, applied to the skin. Th e active ingredients are readily absorbed Tri-Heart Plus) for dogs. Pyrantel pamoate is added to provide through the skin, enter systemic circulation, and act on target action against gastrointestinal parasites because the heart- parasites in the gastrointestinal tract. It is labeled for use in worm-preventive dose of ivermectin, which is safe for Collies, cats and kittens that are at least 8 weeks of age and is con- is not eff ective against these important parasites. Th e prod- sidered safe to use in heartworm-positive cats. 111 Th e product uct is formulated to deliver a target dose of 0.006 mg (6 mcg) is safe and eff ective in removing roundworms, T. cati (adults of ivermectin and 5 mg of pyrantel pamoate per kilogram of and fourth-stage larvae); hookworms, A. tubaeforme (adults, body weight. Given orally to dogs every 30 days, it treats and immature adults, and fourth-stage larvae); and tapeworms, controls roundworms (T. canis, T. leonina) and hookworms 464 Drugs Targeting Infections or Infestations SECTION 2

(A. caninum, A. braziliense, and U. stenocephala) and pre- Dogs vents heartworms (D. immitis) .146 At a minimum, the product Th e canine product is approved for the prevention of heart- should be given at monthly intervals during the heartworm worms (D. immitis), for the treatment and control of adult season. Adult heartworms do not produce detectable levels of and larval hookworms (A. caninum, U. stenocephala), adult microfi lariae when exposed to ivermectin, so an antigen test and larval roundworms (T. canis, T. leonina), and whipworms should be used to reveal the presence of adult heartworms. 17 (T. vulpis) . 148 Th e canine product has not been tested in Safety tests have revealed that the ivermectin– pyrantel com- dogs that weigh less than 1.36 kg (3 lb) or are younger than bination is well tolerated. 147 Th is medication should not be 7 weeks of age. Nor has it been tested in breeding, pregnant, given to dogs younger than 6 weeks of age. (See the ivermectin or lactating dogs. Dogs should be tested for the presence of section of this chapter for a discussion of administration of heartworm before administration. Th e canine product is not ivermectin to dogs harboring adult heartworms, a procedure eff ective against adult heartworm or for clearing microfi lariae. that carries some risk and is not a labeled indication for use.) It was well tolerated at 5 times the label dose. Oral ingestion of the product by dogs may cause serious reactions, including Ivermectin Plus Pyrantel Plus Praziquantel depression, salivation, dilated pupils, incoordination, panting, Ivermectin combined with pyrantel pamoate and praziquantel and generalized tremors. Th us it is important to prevent dogs is available in fl avored tablets (Iverhart Max) for dogs. Adding from licking the product from the application site. praziquantel to the two-way combination product previously mentioned extends the parasite spectrum to include tape- Cats worms. Th is product is formulated to deliver a target dose of Th e feline product is approved for the prevention of heart- 0.006 mg (6 mcg) of ivermectin, 5 mg of pyrantel pamoate, and worm, D. immitis; for the treatment and control of adult and 5 mg of praziquantel per kilogram. Given orally to dogs every larval hookworm, A. tubaeforme; and adult and larval round- 30 days, it treats and controls roundworms (T. canis, T. leonina) , worm, T. cati. It should not be used on cats that weigh less than hookworms (A. caninum, A. braziliense, and U. stenocephala), 0.9 kg (2 lb) or on cats younger than 9 weeks of age. Th is prod- and tapeworms (D. caninum, T. pisiformis) and prevents heart- uct was well tolerated when given at 5 times the label dose in worms (D. immitis). At a minimum, the product should be 9-week-old kittens. Cats dosed with a single dose at 10 times given at monthly intervals during the heartworm season. Adult the label dose exhibited mild transient hypersalivation. Oral heartworms do not produce detectable levels of microfi lariae ingestion of the product may cause hypersalivation, tremors, when exposed to ivermectin, so an antigen test should be used vomiting, and decreased appetite. to reveal the presence of adult heartworms. 17 Th is medication Th is combination is also eff ective in treating fl eas in dogs should not be given to dogs younger than 8 weeks of age or and cats and ear mites in cats. those with existing heartworm infections. (See the ivermectin section of this chapter for a discussion of administration of REFERENCES ivermectin to dogs harboring adult heartworms, a procedure that carries some risk and is not a labeled indication for use.) 1. Foreyt W J : Veterinary parasitology reference manual , ed 5 , Ames, Iowa , 2001 , Blackwell . Milbemycin Oxime Plus Lufenuron 2. Mehlhorn H , editor: Encyclopedic reference of parasitology: dis- eases, treatment, therapy , ed 2 , New York , 2001 , Springer-Verlag . 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