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Concomitant Simultaneous and Consecutive Treatment Of Concomitant Simultaneous and Consecutive Treatment of Imidacloprid/Moxidectin Spot-on with Emodepside/Praziquantel Tablets in Adult Dogs Eva Maria Krüdewagen1 Annette Schimmel1 1Bayer Animal Health GmbH, Kaiser-Wilhelm-Allee 50, 51373 Leverkusen, Germany KEY WORDS: : Safety, concomitant and emodepside. Neither compound-related treatment, moxidectin, emodepside, dogs adverse reactions nor treatment-related ABSTRACT changes in the blood hematology or chemis- try profile were seen. In this study reported Fourteen healthy adult Beagle dogs were here, it was clearly demonstrated that the included in this clinical study. Dogs ran- concomitant treatment of both products ap- domly allocated to two study groups were plied either simultaneously or consecutively treated on day 0 with a spot-on containing did not lead to any clinical nor laboratory imidacloprid/moxidectin at the maximum abnormalities in adult Beagle dogs. approved dosage of 25 mg imidacloprid/kg INTRODUCTION bodyweight (bw) + 6.25 mg moxidectin/kg bw. Group 1 was treated at the same time A wide range of endo- and ectoparasites can orally with tablets containing emodepside/ concomitantly infect the dog. Although there praziquantel at the maximum approved dos- are already several broad spectrum parasiti- age of 1.9 mg emodepside/kg bw + 9.4 mg cides for dogs on the market, none of them praziquantel/kg bw. Group 2 was treated cover the whole endo- and/or ectoparasitic on day 8 with emodepside/praziquantel spectrum. Concomitant treatment with one tablets at the same dosage. These two dif- or more products is therefore a common ferent treatment scenarios were selected to practice. compare a simultaneous treatment with a In the present study, two broad-spectrum consecutive treatment. In the consecutive antiparasitic products, emodepside/prazi- treatment an 8-day interval was chosen to quantel tablets (Profender®) and imidaclo- ensure overlapping peak serum concentra- prid/moxidectin spot-on (Advocate®), were tions of emodepside and moxidectin. Dogs administered to dogs either simultaneously were fed directly after treatment. Profound or consecutively. safety assessments were performed pre- and Profender® tablets for dogs, authorized post-treatment. Blood samples were drawn in 2008 (Bayer Animal Health GmbH, pre- and post-treatment to evaluate the Leverkusen, Germany), are a combination hematology and clinical chemistry profile product containing emodepside and pra- as well as the serum levels of moxidectin ziquantel. Emodepside is a semi-synthetic 290 Vol. 9, No. 3, 2011 • Intern J Appl Res Vet Med. derivate of PF1022A and belongs to the des felis), treatment of ear mite infestation cyclic depsipeptides. Emodepside binds (Otodectes cynotis), prevention of heart- to a presynaptic latrophilin receptor which worm disease (L3 and L4 larvae of Dirofi- belongs to the group of G-protein coupled laria immitis) and Angiostrongylus vasorum, receptors.33,14. In addition, emodepside acts and treatment of sarcoptic mange (Sarcoptes via a second target, a Ca++-activated K+ scabiei var. canis) and demodicosis (Demo- channel. This channel belongs to the large- dex canis).15,6,20,11,19,12 conductance calcium- and voltage-activated Emodepside/praziquantel tablets and im- potassium channels, termed SLO-1, which idacloprid/moxidectin spot-on were selected generally are important regulators of cell to assess the clinical impact of concomitant excitability. The end effect of emodepside use, since both products may be adminis- is flaccid paralysis and death of the nema- tered simultaneously in a clinical setting. 16 tode. Both emodepside and moxidectin are Praziquantel is an acylated pyrazino- known to be substrates for P-glycoprotein isoquinoline derivative and has been used (P-gp), the product of the multidrug re- in veterinary medicine for many years as an sistance gene 1 (mdr1).7,17 P-gp functions effective active against cestodes and trema- as a drug transport pump in various cell todes.31,5 membranes including the blood brain bar- Emodepside/praziquantel tablets are rier, transporting a variety of drugs from indicated for dogs suffering from, or at risk the brain back into the blood.24Although from, mixed parasitic infections caused by moxidectin is described as a weak P-gp roundworms (immature and mature Toxo- substrate, co-administrations with other P-gp cara canis, Toxascaris leonina, Ancylostoma substrates could cause interactions at the caninum, Uncinaria stenocephala, Trichuris level of the transporter. 13,21 vulpis) and tapeworms (Dipylidium cani- Potential clinical consequences of co-ad- num, Taenia spp, mature and immature ministration of emodepside and moxidectin Echinococcus multilocularis, and E. granu- have not previously been investigated. In the losus).3,26 present study the two parasiticides, emodep- Advocate® spot-on for dogs (Bayer Ani- side/praziquantel tablets and imidacloprid/ mal Health GmbH, Leverkusen, Germany) is moxidectin spot-on, were administered a solution for dermal application containing concomitantly to dogs simulating worst case imidacloprid and moxidectin. Moxidectin scenarios: on the one hand, a simultaneous is a macrocyclic lactone structurally within treatment, and on the other a consecutive the milbemycin family and derived from the treatment with overlapping maximum serum actinomycete Streptomyces cyanogriseus concentrations of emodepside and moxidec- spp Noncyanogenus.28 The primary mode tin. In addition, the maximum therapeutic of action results from moxidectin binding dose of both compounds was applied. To to glutamate-gated chloride channels of the test the worst case scenarios even further, parasites, leading to hyperpolarization of the animals in this study were fed immediately neuronal cells that results in paralysis and after treatment, which is in contrast to the death of the parasite.10 Imidacloprid belongs label instructions to administer emodepside/ to the group of neonicotinoide insecticides praziquantel tablets only to fasted dogs and and acts as an agonist at nicotinic acetylcho- not to feed dogs until 4 hours post-treatment. line receptors (nAChRs) and shows selective MATERIALS AND METHODS 22 toxicity for insects over vertebrates. In Animals addition to efficacy against gastrointesti- Fourteen adult Beagle dogs (1.4 – 7.3 nal nematodes, imidacloprid/moxidection years, 3 male, 11 female) weighing between spot-on is efficacious for treatment and 8.4 and 14.7 kg were enrolled. The dogs prevention of flea infestation Ctenocephali( - were part of a regularly maintained re- Intern J Appl Res Vet Med • Vol. 9, No. 3, 2011. 291 Table 1: Clinical observation and blood sampling time points Group 1 Simultaneous treatment Physical examination for study inclusion Day -3 weighing, randomisation Clinical assessment Day 0: pre-tr., hourly 1 to 6 h, 8 h Day 1 (24 h p.tr.) Day 0 pre-tr. Blood chemistry/haematology* Day 1 (24 h p.tr.) Day 2 (48 h p.tr.) Day 3 (72 h p.tr.) Day 0: pre-tr., 1, 3, 5, 8 h Serum concentration* Day 1 (24 h p.tr.) (moxidectin, emodepside, praziquantel) Day 3 (72 h p.tr.) Day 8 Group 2 Consecutive treatment Physical examination for study inclusion Day -3 weighing, randomisation Day 0: pre-tr. Clinical assessment Day 8: pre-tr., hourly 1 to 6 h, 8 h Day 9 (24 h p.tr.) Day 0 pre-tr. Day 8: pre-tr. Blood chemistry/haematology* Day 9 (24 h p.tr.) Day 10 (48 h p.tr.) Day 11 (72 h p.tr.) Day 0: pre-tr. Serum concentration* Day 3 (72 h p.tr.) (moxidectin, emodepside, praziquantel) Day 8 pre-tr., 1, 3, 5, 8 h Day 9 (24 h p.tr.) Day 11 (72 h p.tr.) Pre-tr. = pre-treatment , p.tr. = post-treatment *±12 minutes (mean: 3 minutes/group 1, 4 minutes/group 2) search colony and were returned to the provided ad libitum. All dogs were exposed colony after study completion. All animal to 12 h light and 12 h darkness. Temperature procedures were approved by the respon- range was between 19° and 23°C and rela- sible authorities and the animal welfare tive humidity between 33% and 50%. officer. Husbandry of animals complied with Clinical observations the European Commission guidelines for the On day -3 a physical examination was accommodation of animals used for experi- performed with special emphasis on behav- mental and other scientific purposes (June ioural attitude, nutritional status, respiratory 18, 2007/526/EC). The dogs were identi- system, gastrointestinal system, and car- fied by ear tattoo number and each animal diovascular system. General health obser- was housed in an individual pen during the vations of the dogs were performed daily study. They were fed once daily with a com- during the whole study period at cleaning mercial dry dog food and water supply was and feeding activities. Clinical assessments 292 Vol. 9, No. 3, 2011 • Intern J Appl Res Vet Med. for signs of abnormal behaviour, salivation, peutic dose, ie, the maximum theoretic vomiting, neurological signs, and tremor dose a dog can receive if it is located at the were performed pre- and post-treatment (see lower margin of the body weight range. Table 1). Day -3 body weights were used for both Treatment groups to calculate the dose on day 0, while The dogs were ranked by descending body day 7 body weights were used to calculate weight, placed into blocks, and were al- the dose on day 8 in group 2. Dogs of both located by random number draw within a study groups were treated on day 0 dermally block to two groups of seven dogs each. As with imidacloprid/moxidectin spot-on. The pre-treatment clinical observations and base- dosage applied was 25 mg imidacloprid/kg line blood samples were performed, each bw + 6.25 mg moxidectin/kg bw. This cor- ® dog acted as its own control. Especially for responded to a volume of 0.25 ml Advocate blood parameters with high inter-individual for dogs/kg bw. Treatment was applied in variations, the direct comparison of post- accordance with the label instructions, ie, treatment to pre-treatment parameters was dermally at one spot between the shoulder regarded as an accurate way to reflect the blades.
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