Efficacy of Emodepside plus Praziquantel Tablets (Profender ® Tablets for Dogs) against Mature and Immature Infections with Toxocara canis and Toxascaris leonina in Dogs

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Efficacy of Emodepside plus Praziquantel Tablets (Profender ® Tablets for Dogs) against Mature and Immature Infections with Toxocara canis and Toxascaris leonina in Dogs

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   Abstract The efficacy of emodepside plus praziquanteltablets (Profender ® tablets for dogs) against matureadult, immature adult and larval stages of Toxo-cara canis and Toxascaris leonina was evaluated inten randomised, blinded and placebo-controlleddose confirmation studies in naturally or experi-mentally infected dogs. The tablets were used atthe proposed minimum dose of 1 mg emodepsideand 5 mg praziquantel per kg body weight. Effica-cy was calculated based on worm counts afternecropsy. Five studies demonstrated > 99 % effica-cy against mature adult, > 92 % efficacy againstimmature adult, > 98 % efficacy against L4 and > 94 % efficacy against L3 larval stages of T. canis . Another five studies demonstrated > 99 % efficacyagainst mature and immature adult and > 95 % effi-cacy against L4 larval stages of T. leonina . No sideeffects of the treatment were observed. Emodepside plus praziquantel tablets thus providea comprehensive new treatment option for ascaridinfections in the dog.S1 Efficacy of Emodepside plus PraziquantelTablets (Profender  ® Tablets for Dogs)against Mature and Immature Infectionswith Toxocara canis  and Toxascaris leonina in Dogs Parasitol Res (2009) 105:S1–S8 DOI 10.1007/s00436-009-1489-7 ENDOPARASITESGertraut Altreuther  1 (  ), Annette Schimmel 1 , Iris Schroeder  1 , Thomas Bach 1 , Samuel Charles 2 , Dawid J. Kok  3 , Friederike Kraemer  4 , Sonja Wolken 4 , David Young 5 ,Klemens J. Krieger  1 1 Bayer Animal Health GmbH, Leverkusen, Germany 2 Bayer HealthCare LLC, Shawnee Mission, USA  3 ClinVet International (Pty) Ltd., Bloemfontein, Republic of South Africa 4 Institute for Parasitology, University of Veterinary Medicine Hannover, Germany 5  Young Veterinary Research Services, Turlock, USA   E-mail: gertraut.altreuther@bayerhealthcare.com  Introduction Toxocara canis has a complex developmental cyclethat can involve migration of larval stages throughvarious organs including the lungs, liver and kid-neys before either reaching the small intestine,where development to the adult stage is completedor entering a hypobiotic stage, e.g., in muscle tissue.The different pathways and times for developmentdepend on multiple different factors including theroute of infection (oral or prenatal), infection dose,age and immune status of the dog, so that prepaten-cy can be as short as approximately 3 weeks after aprenatal infection and up to approximately 6 weeksafter an oral infection (Parsons 1987). Recent observations confirmed that not only youngdogs are prone to infection with T. canis ,but alsoadult dogs may be repeatedly infected with this par-asite even under regular anthelmintic treatment(Fahrion et al. 2008; Sager et al. 2006). Sager et al.(2006) observed a yearly incidence of 32 % in dogsthat received anthelmintic treatment four times ayear. Patent infections with T. canis are not only of poten-tial concern to the dog’s health, but also lead to con-tamination of the environment with eggs that maysurvive for years and may be a source for humaninfection. Toxocarosis is a severe zoonosis wheremigrating larvae can cause lesions and granulomasin various organs ( larva migrans visceralis ). If theeye is affected, infection can lead to blindness (Par-sons 1987). Much research has been conducted on the occur-rence of infective T. canis eggs in public places, butrecently it was shown that dogs themselves mayrepresent a source of infection by carrying infectiveeggs in their fur (Wolfe and Wright 2003; Roddie etal. 2008). Because of its zoonotic potential the riskposed by dogs infected with T. canis should there-fore not be underestimated. Toxascaris leonina has a more direct developmen-tal cycle than T. canis. It has a lower prevalenceand is not perceived to play a significant role as azoonotic agent. After oral infection with infectiveeggs or a paratenic host, the larvae enter the smallintestine and develop to the mature adult stage inthe mucosa and lumen of the gastrointestinal tractwithin approximately 7 to 10 weeks. However, to asmall extent, a somatic migration can also occurwith this parasite and infection can cause enteritisin the dog (Parsons 1987). Emodepside plus praziquantel tablets (Profender ® tablets for dogs) are indicated for dogs sufferingfrom, or at risk from, mixed parasitic infectionscaused by nematodes and cestodes, i.e., matureand immature T. canis , T. leonina ,  Ancylostomacaninum, Uncinaria stenocephala, Trichurisvulpis, Echinococcus granulosus , Echinococcusmultilocularis and mature  Dipylidium caninum and Taenia spp. This oral product is the secondintroduction of emodepside as a novel nematocidein veterinary medicine and the efficacy has beenconfirmed in a series of laboratory dose confirma-tion studies and a multicentre field study(Altreuther et al. 2009; Schimmel et al. 2009a,b;Schroeder et al. 2009). This paper reports the findings of five studies (no. 1–5) that were conducted to investigate the effi-cacy of emodepside plus praziquantel tabletsagainst mature and immature stages of T. canis and five studies (no. 6–10) that were conducted toinvestigate the efficacy of emodepside plus prazi-quantel tablets against mature and immaturestages of T. leonina in dogs. Materials and methods The investigations were performed as placebo-con-trolled, blinded and randomised dose confirmationstudies, conducted in accordance with VICH guideline 9 “Good Clinical Practice” (July 2000), and followed the recommendations given in the VICH guidelines 7 “Efficacy requirements foranthelmintics: general requirements” (December2000) and 19 “Efficacy of anthelmintics: Specific rec-ommendations for canines” (July 2001) as well asthe WAAVP guideline for evaluating the efficacy of  S2 ENDOPARASITES  anthelmintics for dogs and cats (Jacobs et al. 1994). The study design is summarised in Table 1, 2. Study animals The dogs used in the studies were either purposebred individuals from different suppliers, animalsowned by the CRO or animals obtained from com-mercial kennels according to the respective localregulations. The dogs were identified by subcuta-neously implanted microchip, ear tattoo or num-bered collar tags. They were housed single or ingroups, however, at least on the day of treatmentand the following day the dogs were housed indi-vidually (exception study no. 4, where dogs werehoused in pairs from 4 h post treatment onwards).The dogs were fed with commercial dry dog foodonce or twice per day and water was available adlibitum . All dogs were acclimatised for at least 7days prior to the start of the study. General requirements for study inclusion weregood health and no recent anthelmintic use thatcould interfere with the study. Dogs included instudies that used experimental infections wererequired to be negative for nematodes as exam-ined by faecal egg counts during acclimationexcept for study no. 3, where dogs were requiredto be negative for nematodes expelled in the fae-ces after an anthelmintic treatment with pyran-tel pamoate and febantel before study start. Dogsincluded in studies that investigated efficacyagainst patent infections (no. 1, 2, 6 and 7) wererequired to demonstrate a positive faecal eggcount for T. canis or T. leonina at least once beforetreatment. Clinical observations In all studies, dogs were physically examined atleast once during acclimation and once before treat-ment. Additionally, all dogs were observed for theirgeneral health once daily. Clinical assessmentswith the aim to detect adverse events were conduct-ed once before treatment and approximately 0.5, 1,2, 3, 4 and 8 hours after treatment. Special atten-tion was paid to vomitus or regurgitation of tabletmatter at the assessments conducted post treat-ment. The assessments were continued twice dailyfor two days after treatment. Infection Two studies (no. 1 and 6) were conducted with nat-urally infected dogs from the USA and the Repub-lic of South Africa, respectively. In the otherstudies, dogs were orally infected with approxi-mately 500 embryonated eggs of T. canis or T. leo -nina . The srcin and age of the isolates that wereused are shown in Table 1, 2. Treatment Dogs of both sexes were randomly assigned toeither treatment or control groups. In all studies,the dogs were treated once with emodepside pluspraziquantel tablets or placebo tablets. For thestudies with an experimental infection, the timesof treatment in relation to the infection are shownin Table 1, 2.In all studies, the dosage of emodepside and prazi -quantel was 1 mg emodepside and 5 mg praziquan-tel per kg body weight. The doses were based on thebody weights taken one or two days before treat-ment. For exact dosing, excess tablet substance wasfiled off until the tablet weight corresponded to thetarget weight for the individual dog. The emodepside plus praziquantel or placebotablets were applied orally by forced dosing over theback of the tongue. Care was taken to ensure thatall animals swallowed the full amount of the treat-ment without loss of product. The dogs wereobserved after dosing to determine whether anytablet matter was regurgitated. Faecal examination Faecal egg counts were conducted to monitor pres-ence or absence of helminths using a modifiedMcMaster or a quantitative double centrifugationmethod. As additional information, worms passed aftertreatment until necropsy were collected from thefaeces in some studies (no. 2 for T. canis , no. 6, 7S3 ENDOPARASITES  Table 2 Study design of controlled studies on the efficacy of emodepside (E) plus praziquantel (P) tablets against matureand immature stages of Toxascaris leonina (p.i.: post infection) S4 ENDOPARASITES Table 1 Study design of controlled studies on the efficacy of emodepside (E) plus praziquantel (P) tablets against matureand immature stages of Toxocara canis (p.i.: post infection) a additional information available for some studies, not required by VICH guidelines b study was conducted in replicates due to availability of litters Studyno.BreedsAge ofdogs Bodyweight (1 or 2daysbeforetreatment) No. ofdogs (EPgroup/controlgroupInfectionOrigin ofnatural infection/isolate (ageof isolate)TreatmentdayNecropsydayFaecalwormcountspost treat-ment a 1Beagle, cross-breeds2.5–4months2.6–9.5 kg6/6NaturalOklahoma,USA07–2Beagle12 weeks4.1–7.0 kg7/7Experimental(~ 500 eggs)Bavaria, Germany (1.5 yrs)0(41/47p.i. b )7yes3Cross-breeds7–9 weeks0.9–6.0 kg 710 /20 Experimental(~ 500 eggs)Bavaria, Germany (10mths–2yrs) 21 p.i.5 p.i.28 p.i.–4Beagle10–12weeks4.3–7.4 kg8/8Experimental(~ 500 eggs)Lower Saxony,Germany (7 yrs)21 p.i.26 p.i.–5Beagle11–12weeks2.9–5.1 kg8/8Experimental(~ 500 eggs)Lower Saxony,Germany (7.5 yrs)5 p.i.35 p.i.– Studyno.BreedsAge ofdogsBody weight(1 or 2 daysbefore treatment) No. of dogs (EPgroup/controlgroup) Infection Origin of natural infection/ isolate (age of isolate) TreatmentdayNecropsydayFaecalwormcountsposttreat-ment a 6Cross-breeds4 months–adult6.0–14.4 kg8/8NaturalRepublic ofSouth Africa07yes7Beagle5–6 weeks2.7–5.2 kg9/9Experimental(~ 500 eggs)Spain (1 yr)0 (57 p.i.)7/8yes8Beagle5–6 weeks3.6–5.6 kg7/7Experimental(~ 470 eggs)Spain (2 yrs)57 p.i.64 p.i.yes9Beagle12–13weeks4.4–7.7 kg78 /8Experimental(~ 500 eggs)Spain (3 yrs)51 p.i.35 p.i.56 p.i.–10Beagle11 weeks5.9–9.6 kg8/8Experimental(~ 500 eggs)Spain (4.5 yrs)35 p.i.50 p.i.– a additional information available for some studies, not required by VICH guidelines  S5 ENDOPARASITES and 8 for T. leonina ) using sieving techniques asdescribed below for the necropsy worm counts. Necropsy  Five to 30 days post treatment the dogs wereeuthanised and subsequently necropsied (Table 1, 2).  At necropsy, the digestive tract from stomach to rec-tum was removed. The intestinal content and theresults of several mucosal strippings of the smallintestine were washed over sieves with aperturesof 50 µm to 150 µm (study no. 1: 425 µm). The sameprocedures were applied to the large intestine usingsieves with apertures of 75 µm to 425 µm. In studies no. 3, 4 and 9, the small intestines wereadditionally soaked in 0.9 % saline at 37 °C forapproximately 3 hours to encourage release andsedimentation of adherent larvae. After soaking the saline solution was passed through a 36 µm or38 µm aperture sieve and the small intestines werestripped and washed again using the same sieve.  All samples were analysed for mature and imma-ture worms and the recovered specimens werecounted and differentiated according to species,developmental stage and sex. Efficacy determination and statistical analysis In all studies, adequacy of infection in the controlgroup was assessed according to the methods sug-gested in VICH guidelines 7 and 19. A minimum of 6 control animals with at least five worms each wasrequired. Additionally, the intensity of infectionwas considered adequate when the lower 95 % confidence limit was greater than 10 % of the cen-tral tendency (geometric mean if all worm countsin the control group > 0, or median if one or moreworm counts in the control group = 0).Percent efficacy for each treatment was calculatedaccording to VICH guideline 7 recommendationsand the WAAVP guideline for evaluating the effi-cacy of anthelmintics for dogs and cats (Jacobs et al. 1994) as follows:Geometric means were calculated following trans-formation using a logarithmic method (averagingthe transformed values, and converting the aver-age using antilog to represent a geometric mean).Because neither the actual worm counts nor the log-arithmically transformed counts were distributednormally, the non-parametric Wilcoxon rank sumtest (two-tailed, using α = 0.05) was used to test forboth gender and treatment group (emodepside pluspraziquantel tablet vs. placebo) effects. The analy-ses were performed using SAS software (SAS ® Institute, Cary, NC, USA).Calculations were performed for each parasitestage that occurred in adequate numbers in the con-trol group as described above. In studies wheretreatment and euthanasia of dogs were more than7 days apart, calculations were performed on totalparasite counts as the stage distribution at necrop-sy was not considered to be representative for thedistribution at treatment. In these cases, the cal-culated efficacies were attributed to the specific lar-val stage based on the time of treatment afterinfection according to VICH GL 19 (i.e., 5 days postinfection for migrating L3/early L4 larvae of T. canis , 35 days post infection for L4 larvae of T. leonina ). Results None of the dogs from the ten studies showed signsof adverse reactions after treatment until necropsy. The requirements for the adequacy of infectionwere fulfilled in all studies except for the numbersof mature adult T. leonina in study no. 6, whereonly four of eight control dogs had the required min- % Effectiveness (reduction) =(N1 – N2)N1 x 100 N1: geometric mean nematode count for the control group N2: geometric mean nematode count for the treatment group
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