TREATMENT OF EXPERIMENTAL TOXOCARA CATI INFECTION IN MICE WITH IVERMECTIN AND MOXIDECTIN

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1 Bull Vet Inst Pulawy 51, , 2007 TREATMENT OF EXPERIMENTAL TOXOCARA CATI INFECTION IN MICE WITH IVERMECTIN AND MOXIDECTIN MELTEM ULUTAS ESATGIL Department of Parasitology, Faculty of Veterinary Medicine, Istanbul University, Avcılar, Istanbul, Turkey Received for publication March 12, 2007 Abstract The aim of this study was to investigate the efficacy of two efficient macrocyclic lactone drugs, ivermectin, and moxidectin, on the numbers and distribution of Toxocara cati larvae in experimentally infected mice. Different post-infection periods (48 h and 7 d) and different administration methods (oral and subcutaneous) were compared. Ivermectin and moxidectin were tested (0.2 mg/kg with a single dose) for their larvicidal effects. Each mouse was infected with embryonated eggs of T. cati. On the 10 d of the infection, the mice in each treatment group and the control group were sacrificed and the presence of T. cati larvae in various organs were determined and compared between groups. Statistically, the treatment regimens in all treatment groups were successful as compared with the controls. The worst results were achieved in the group in which ivermectin was given orally 7 d following egg inoculation. According to the decrease in total larvae recovery, oral administration of moxidectin 48 h following egg inoculation displayed the highest efficacy. The effect of ivermectin administered subcutaneously 7 d following infection was more effective than subcutaneous application of moxidectin after both 48 h and 7 d. Key words: mice, Toxocara cati, visceral larvae migrans, macrocyclic lactones. Toxocara and T. cati inhabit the small intestines of cats and dogs. Both Toxocara cati and T. infection presents a potential risk for human population. Although the presence of T. cati larvae in tissues of mice, chickens, and sheep was described for the first time as early as in 1956 by Sprent (14), there is little information about its spread and its consequences for the paratenic host when compared with T. larvae. Visceral larva migrans (VLM) of these parasites, which penetrate into organs and tissues of the host, are a zoonotic condition threatening human health. Direct contact with contaminated soil in yards and sandpits, lack of hygiene, and geophagia in children are considered to be more critical than contact with cats, as the embryonation of excreted Toxocara ova requires a minimum of two weeks (9, 14). Several drugs with high and broad-spectrum potential against adult nematodes are currently available for the treatment of dogs and cats (3, 4, 7, 12). However, at commercially recommended dose levels, none of these have resulted in near total elimination of the tissue larval stages of Toxocara sp., which are the major source of vertical transmission. The treatment of larvae in the paratenic hosts (such as poultry and mammals including man) is also important to break the life cycle of the parasite. Drugs that are effective on the larvae are important for the treatment of VLM in a man. One of the factors that may account for the variation in anti-larval efficacy of anthelmintic compounds is the possibility that the chemosusceptibility of Toxocara larvae may vary during their parasitising in the paratenic hosts. The migratory larvae during the course of 1 or 2 weeks of infection have been proposed to be more susceptible to drug actions than those already established in the muscles and brain (3, 7). Different efficacy degrees have been reported in studies carried out with various drugs (1-3, 5, 6, 9, 13), in order to cut down the larval stages. The studies were conducted on the infections induced in mice with T. larvae. Additionally, one study (8) was about the treatment of experimental T. cati infection in mice with fenbendazole and glucan. Regarding the treatment of T. cati infection in mice, no study on the use of macrocyclic lactones has yet been published. For the reasons above, the relative susceptibility of T. cati larvae to ivermectin and moxidectin at different post-infection periods in mice was investigated in the present study. At the same time, the impacts of some variables such as mode of drug administration, and distribution of larvae on the efficacy of treatments were also studied. The performed studies are shown in Table 1.

2 372 Table 1 Drugs administered for the treatment of VLM in mice Drug Given egg Administered dose Admin. route 6 mg/kg -1 oral (to food) 0.6 mg/kg -1 oral sc 0.2 mg/kg 1 oral sc Drug efficacy 10 d of application- 7.6% 30 d of application- 33.7% 33.5% 10.5% It was found that with the administration of the drug on the 2 and 7 d following infection a considerable decrease in the number of larvae occurred, but the drug administered on the 8 and 13 d was ineffective (because the larvae migrated to the brain and muscles) Ref. posit mg/kg sc Larvicidal effects were found to be similar to each other. A decrease in the number of larvae in the brain and carcasses was demonstrated. 0.2 mg/kg 0.4 mg/kg im Lower doses did not affect the total parasite amount but decreased the parasite burden in the lungs. The effect was better at higher doses but it was found to be statistically insignificant. Fbz T. 20 mg/kg oral Migration of the larvae stopped, larvae in the lungs cati (twice a day, on 3 and 4 and liver died or were about to die. 8 L.gl d post infection) 5 mg/kg (single dose) im sc - subcutaneous, im - intramuscular, Iv - ivermectin, Fbz - fenbendazole, L.gl: liposomed glucan, Ref. posit. reference position Material and Methods Animals. In the present study, 36 male 3- month-old Balb/c mice, weighing 25 g to 30 g at the time of infection, were used. The animals were kept under observation for 1 week prior to experimentation under usual conditions (20±2ºC and 50±5% humidity). They were kept on standard diet (commercial pellets) and drinking water ad libitum. Infection of animals. Sexually mature females of T. cati were isolated from faeces of naturally infected cats. Eggs of T. cati were isolated from the uterus of female worms and incubated in 1% formalin in dechlorinated tap water in dark at 27ºC for 4 weeks in order to obtain infective larvae (6, 7). The concentration of infective eggs and percentage of embryonation were determined by microscopic observation at the end of this period. One thousand of the embryonated eggs (in 0.2 ml of saline solution) were administered to each mouse in the treatment groups and the control group by intragastric intubation. The mice were randomly assigned to one of 9 groups, each including 4 animals, and the following experimental design was performed: Experimental design. Group n drug applied dose administration route administration time M1 4 moxidectin 0.2 mg/kg subcutaneous 48 h following egg inoculation M2 4 moxidectin 0.2 mg/kg oral 48 h following egg inoculation M3 4 moxidectin 0.2 mg/kg subcutaneous 7 d following egg inoculation M4 4 moxidectin 0.2 mg/kg oral 7 d following egg inoculation I1 4 ivermectin 0.2 mg/kg subcutaneous 48 h following egg inoculation I2 4 ivermectin 0.2 mg/kg oral 48 h following egg inoculation I3 4 ivermectin 0.2 mg/kg subcutaneous 7 d following egg inoculation I4 4 ivermectin 0.2 mg/kg oral 7 d following egg inoculation n number of mice, M - moxidectin, I - ivermectin (diluted in propylene glycol)

3 373 Larval recovery technique. On the 10 d after inoculation, each mouse was killed under ether anaesthesia. The larvae in the brain were counted directly after compressing small amounts between glass slides. Not only the number of larvae, but also their motility was recorded. The liver, lungs, spleen, heart, urogenital organs, and the carcass of each mouse were chopped up into a digest solution containing 0.5% pepsin, and 0.7% HCl in normal saline. The amount of fluid used for the digestion was 200 ml for carcass, 100 ml for the liver, 100 ml for the lungs, and 100 ml for other organs. This mixture was incubated under constant stirring at 37ºC. After digestion, the samples were examined for the presence of larvae and then the larvae were counted using a stereoscopic microscope (6, 7). Statistical analysis. The results were assessed via comparing the group mean larval counts of the treatment groups with those of the controls. One-way analysis of variance (ANOVA) was used in the statistical analysis of the groups. GLM (General Linear Model) procedures were followed in the analysis of the effects of factors. SPSS (Statistical Package for Social Sciences) version 10.0 software was used in implementation of the analysis. Results The effects of moxidectin and ivermectin against T. cati larvae, as determined by larva recovery results and their comparisons with the controls are presented in Tables 2, 3, and 4. In Table 2, the effects of drugs, administration time, and administration method on the quantities of larvae recovered in different organs are displayed along with detailed data of the statistical analyses are presented. According to the results displayed in the Table 2, moxidectin was significantly more effective than ivermectin on the number of larvae recovered from the brain and liver. In addition, it was observed that moxidectin was more effective on the total larva recovery, but this was found to be statistically insignificant. It was found that the drug s administration time was a significant factor regarding lung infection, because the treatment on 7 d after inoculation of eggs was the most effective. No effect of the administration route on the efficacy was observed. Most of the larvae were located in the lungs by 2 d and in the carcass by 7 d. The oral administration of drugs caused higher larval retention in the liver than the subcutaneous route (Table 2). Table 2 The effect of the type of drug, and the time and method of administration on the numbers of larvae recovered in different organs (GLM General Linear Model) Drug Application time after infection Application route Moxidectin Ivermectin 48 h 7 d subcutaneous per os Brain 0.69±0.37 b 2.56±0.45 a 1.56± ± ± ±0.37 Lungs 8.63± ± ±1.90 a 2.56±1.55 b 8.69± ±1.55 Liver 0.88± ± ± ± ± ±0.27 Other organs 0.50±0.60 b 3.13±0.73 a 1.88± ± ± ±0.60 Carcass 8.31± ± ± ± ± ±5.46 Total 19.00± ± ± ± ± ±5.42 heart, spleen, and urogenital organs ab - The differences between the means of groups carrying various letters in the same line are significant (P<0.05). Table 3 The efficacy of moxidectin and ivermectin against larva migrans of T. cati with regard to the rates of recovered larvae compared to control groups Group Drug Application route Application time Larva Efficacy (IE) after infection recovery Control 76.25±4.75 M1 (n=4) moxidectin subcutaneous 48 h 27.50± % M2 (n=4) moxidectin oral 48 h 7.00± % M3 (n=4) moxidectin subcutaneous 7 d 30.00± % M4 (n=4) moxidectin oral 7 d 11.50± % I1 (n=4) ivermectin subcutaneous 48 h - - I2 (n=4) ivermectin oral 48 h 20.75± % I3 (n=4) ivermectin subcutaneous 7 d 13.75± % I4 (n=4) ivermectin sral 7 d 48.00± % (IE) % = [(N-n) / N] x 100, N: average number of larvae in control group, n: average number of larvae in treatment groups

4 374 Table 4 Numbers of recovered larvae from different organs with regard to the groups (ANOVA) Group Brain Lungs Liver Other organs Carcass Total ** *** *** *** ** *** Control 3.50±0.29 a 9.75±0.85 b 25.75±4.61 a 21.00±1.29 a 16.25±1.65 b 76.25±4.75 a M1 0.00±0.00 c 19.75±1.80 a 1.25±0.48 b 0.00±0.00 c 6.50±1.32 b 27.50±2.87 bc M2 0.75±0.25 c 1.75±0.85 c 0.00±0.00 b 0.75±0.48 bc 26.75±19.11 ab 30.00±19.05 bc M3 0.75±0.25 c 6.25±1.65 bc 0.00±0.00 b 0.00±0.00 c 0.00±0.00 b 7.00±1.47 c M4 1.25±1.25 bc 6.75±2.87 bc 2.25±0.85 b 1.25±0.95 bc 0.00±0.00 b 11.50±2.60 c I2 3.25±0.48 ab 0.25±0.25 c 0.00±0.00 b 4.25±1.89 b 6.00±4.24 b 13.75±3.54 c I3 3.00±1.23 ab 12.75±5.19 b 1.00±0.41 b 4.00±1.96 b 0.00±0.00 b 20.75±5.36 bc I4 1.50±0.29 abc 1.50±0.87 c 0.00±0.00 b 0.75±0.48 bc 44.25±13.02 a 48.00±13.83 b M1- moxidectin subcutaneously 48 h following infection; M2- moxidectin orally 48 h following infection; M3- moxidectin subcutaneously 7 d following infection; M4- moxidectin orally 7 d following infection; I2- ivermectin orally 48 h following infection; I3- ivermectin subcutaneously 7 d following infection; I4- ivermectin orally 7 d following infection; heart, spleen, and urogenital organs. abc The differences between the groups at the same column marked with different letters are statistically significant; ** P<0.01, *** P<0.001 Table 5 The effects of moxidectin and ivermectin on the larvae in various organs with regard to the method and time of administration The effect on the recovery rates in the organs Apr Apt Dose Brain Lungs Liver Carcass Other organs 1 Mox Iv Mox Iv Mox Iv Mox Iv Mox Iv sc 48h 0.2mg/kg 100% * - * 95.14% * 60% * 100% * po 48h 0.2mg/kg 78.57% 14.28% 35.89% - 100% 96.11% 100% 100% 100% 80.95% sc 7d 0.2mg/kg 78.57% 7.14% 82.05% 97.43% 100% 100% % 96.43% 79.76% po 7d 0.2mg/kg 64.28% 57.14% 30.76% 84.61% 91.26% 100% 100% % 96.43% *: was not included in the evaluation due to the death of all the animals within 6-8 h following administration of the drug. Apr application route; Apt application time after infection; 1 heart, spleen, and urogenital organs; Mox - moxidectin, Iv - ivermectin, sc - subcutaneous, po - per os Table 6 The number and viability of T. cati larvae and reduction rates obtained in mouse brain after treatment Moxidectin Ivermectin sc po sc po 48 h (M1) 7 d (M3) 48 h (M2) 7 d (M4) 48 h (I1) 7 d (I3) 48 h (I2) 7 d (I4) * 3 m 0 2 n n 1 n 0 * 2 m 6 m 2 m n 1 n 5 m * 4 m 3 1 m n 1 n 0 * 4 m 3 1 m GM 0.00± ± ± ± ± ± ±0.29 R C 1 3 m 2 4 m 3 3 m 4 4 m GM 3.50±0.57 *: was not included in the evaluation due to the death of all the animals within 6-8 h following administration of the drug, n - not motile, m - motile larvae, C - control, GM - geometric mean, sc - subcutaneous, po - per os; R - % of reduction : [(GMc- GMt)/GMc]x100 GM: geometric mean.

5 375 In the Table 4, the recovered larva numbers from different organs according to the groups and the detailed data of statistical analyses are presented. A considerable efficacy was achieved in all treatment groups, as compared with the controls (P<0.05). Among the treatment groups, the lowest efficacy was achieved in the group in which ivermectin was given orally after 7 d following egg inoculation and no statistically significant difference was found between the other groups. Regarding the decreased total larva recovery, oral administration of moxidectin 48 h following egg inoculation showed the highest efficacy, but was not found to be significant statistically. All the mice that received ivermectin subcutaneously 48 h following egg inoculation died within 6 h. The subcutaneous administration of ivermectin 7 d following inoculation was more effective than subcutaneous administration of moxidectin after both 48 h and 7 d (Tables 3, 4). Regarding oral administration, moxidectin was found to be more effective in both administration times. Moxidectin was more effective at administrations 48 h following infection; however, the efficacies of moxidectin and ivermectin treatments after 7 d were found to be close to each other. The effects of moxidectin and ivermectin on larvae with regard to the administration method and administration time in treatment groups are summarised in Table 5. Moxidectin showed the highest efficacy in the brain when administered subcutaneously after 48 h, and in the liver and carcass when administrated orally. In the case of administration after 7 d, the highest effect was seen in the liver when administered subcutaneously and the results of oral administration were similar to that of administration on the 48 h. In the case of the administration 7 d after infection, the highest efficacy was seen in the liver, but the efficiency in carcass was low as compared with the administration performed after 48 h. Oral administration of ivermectin 48 h following inoculation was found to be ineffective in lungs, as compared with the same administration route 7 d after inoculation. The distribution of larvae recovered from the brain and the motility of larvae in non-treated control mice and mice effectively treated with anthelmintics are presented in Table 6. In the group treated with moxidectin (sc), dead larvae were observed in the brain tissue on 7 d post-inoculation. In the group treated with ivermectin (sc), larvae found in the brain tissue on 7 d post-inoculation appeared to be alive. Discussion The role of T. cati as a zoonotic parasite is not always clearly recognised, and the vast majority of reports and experimental studies have been associated with T. infection. It is known that most of the efficient drugs against adult Toxocara forms in the small intestines of cats and dogs are not effective to larval stages of the parasites (7). It has been suggested that the speed of gastrointestinal transit of ingesta may affect the activity of some orally administered anthelmintics (7). Experimental studies have indicated that the quality or quantity of diet changes the gastrointestinal transit time of ingesta both in ruminants and dogs (7), and may influence the time available for drug absorption. In the study of Fok and Kassai (7), the results showed a significantly greater level of the reduction in total larval counts in mice given fenbendazole in dry medicated pellets than in groups, which were drenched (80.5 and 53.9% in groups). The authors mentioned above found that fenbendazole applied at the dose of 6 g/kg ¹ orally with feed for d was in 84.2%-99.7% effective. Additionally, a dose of 1.6 g/kg ¹ of albendazole was in 88.8%-100% effective, a dose of 1.6 g/kg ¹ of flubendazole was in 57.8%-88.2% effective, and a dose of 6 g/kg ¹ of oxibendazole was in 32.0%-81.1% effective. They found the highest efficacy of ivermectin by oral and subcutaneous routes to be 33.7%. Abdel- Hameed (1) stated that repeated oral thiabendazole administrations given to mice were not effective for the inhibition of larval migration. It was demonstrated in the study of Fok and Kassai (7) that the efficacy of fenbendazole, oxibendazole, and albendazole against larvae in mice tested with regards to doses and administration routes was 97%-99.7%, 32.0%-81.1%, and 35.7%-100%, respectively. In our study, oral moxidectin (0.2 mg/kg) administration 48 h following egg inoculation was the most effective (90.81%) with regards to the decrease in total larvae recovery. When the treatments were made after 7 d, the efficacy of moxidectin and ivermectin was found to be similar. Among treatment groups, the lowest efficacy (37.05%) was in the group receiving ivermectin orally 7 d following egg inoculation. Oral administration may be a simple way of improving the efficacy of the treatment. The relationship between digesta transit, delivery kinetics, and drug bioavailability seems to be a worthwhile area of the future studies. Abo-Shehada and Herbert (3) tested the antilarval effects of 4 anthelmintics (levamisole, ivermectin, albendazole, and fenbendazole) administered to mice for 5 to 6 d, beginning on the 2 or 8 d of infection. According to these authors, levamisole hydrochloride treatment from days 2 to 7 of infection did not kill the larvae, but inhibited their migration from the liver to the carcass and brain, when examined 1 d after the termination of the treatment. The same authors found out that levamisole, ivermectin, albendazole, and fenbendazole treatment provided a significant decrease in larva number on the 2 and 7 d, and the application on the 8 and 13 d was not effective since the larvae migrated to the brain and muscles. Levamisole hydrochloride and ivermectin were the most effective drugs. By day 35 of infection, they decreased the parasite burden to 30%-40% of the load in the nontreated controls. Hrckova et al. (8), found out that among fenbendazole and glucan administrations against VLM of T. cati, co-administration of fenbendazole and glucan

6 376 provided the best results. Larvae migration was prevented at the end of the treatment, and it was found out that the larvae in the lungs and liver either died or were dying. During the 84 d of the test, very few of T. cati larvae were found in the lungs, liver, brain, and kidneys. The first larva was found in the liver 12 h following infection and it persisted for 5 d. The larvae were found in the lungs from the 2 until the 5 d of infection. In the kidneys, they were observed from the 2 d of infection until the 6 d. In the brain, larvae were found from the 2 d until the 84 d. In our study, the efficacy of ivermectin administered subcutaneously 7 d following the inoculation was higher (81.96%) than that of subcutaneous administration of moxidectin given both 48 h (63.93%) and 7 d (60.65%) after inoculation. Regarding oral administration, moxidectin was more effective in both administration time-points (after 48 h %, after 7 d %). At the administration 48 h following inoculation, moxidectin was more effective (subcutaneously %, orally %), and in the treatment given 7 d after inoculation, the efficacy of moxidectin and ivermectin was found to be similar. The lowest efficacy in the treatment groups (37.05%) was observed in the group in which oral ivermectin was administered 7 d following egg inoculation. Although the characteristics of physiology of hypobiotic or dormant larvae are not well known, it is tempting to speculate that dormancy is associated with reduced metabolic activity, and hypobiotic larvae may be less prone to becoming affected by anthelmintic compounds than migratory larvae, showing unaffected physiology. However, as our results indicate, dormant larvae also remain susceptible to anthelmintics during their period of quiescence, well past 7 d post inoculation. Toxocara larvae during their early and late phases of migration, and hypobiotic larvae of chronic infections, are readily vulnerable to chemotherapeutic agents. With regard to the results obtained in this study, we propose that active larvae feed externally and are more susceptible to drugs. During hypobiosis, they cannot receive external nutrients and this may account for the lower effectivity of the drugs. Because during the first 48 h the larvae are still active, oral administration of moxidectin has been found to be highly effective. The route of migration of Toxocara larvae in the mouse can be divided into an early hepatopulmonary or visceral phase during the first week after infection, and a following myotropic-neurotropic phase (7). Abo-Shehada and Herbert (3) were able to demonstrate the activity of FBZ, ABZ, and ivermectin against larvae of T. in mice solely up to the 7 d of infection, and claimed that the larvae that reached the brain and musculature, and are no longer susceptible to anthelmintic agents. In other studies however, where larvicidal efficacy of anthelmintic treatment was studied in mice during the first few days to 4 weeks of larval infection, the recorded partial efficacy did not seem to be dependent on the age of larvae (5, 6, 13). In the study by Fok and Kassai (7), multidose treatments with FBZ commencing on 2 or 14 d of infection resulted in a similar efficacy. Hrckova and Velebny (9) found that among mebendazole, albendazole, and fenbendazole, the efficacy of fenbendazole was 91.5% in the muscles of VLM infected mice as well as the efficacy of albendazole in the brain was 92.2%. Samanta and Ansari (13) found out that the larvicidal effects of ivermectin, fenbendazole, and albendazole were similar, while thiabendazole ceased larval migration. Delgado et al. (6) stated that the larvae in the brain could be an indicator of the ability of migration through tissues and blood and albendazole decreased the number of larvae that could reach the brain. Carrillo and Barriga (5) found out that ivermectin at a dose of 0.2 mg/kg did not affect the total parasite amount but it decreased the parasite burden in the lungs. The effect was higher at the dose of 0.2 mg/kg but it was not found statistically significant. It was stated that it was considerable effective only in the brain. The results of this study indicated that moxidectin showed the highest efficacy in the brain (100%) at subcutaneous administration, and in the liver (100%) and carcass (100%) at oral administration. At the administration 7 d following the inoculation; the highest efficacy was seen in the liver (100%), while the results of the oral administration were found to be similar to those obtained at the administration at the 48 h. At the administrations 7 d after inoculation, the highest efficacy was observed in the liver (100%), but the efficacy in the carcass (63.07%) was lower than that at the administration 48 h after inoculation (100%). The dosage of ivermectin 48 h after the inoculation was found to be ineffective in the brain and lungs as compared with the administration made 7 d after inoculation in the same way. All the mice receiving ivermectin subcutaneously 48 h following egg inoculation died within 6 h. The actual cause of the death of the mice is unclear. It was not proved, but these deaths may be attributed to a type-1 hypersensitivity reaction. As the T. cati larvae are active in the lungs 48 h following infection, subcutaneously administered ivermectin might have rapidly killed the majority of the larvae. The mice, developing sensitivity after the initial T. cati artificial infection, might have died of the type-1 hypersensitivity reaction due to the antigens sourcing from the larvae that died in a great number. Because the larvae were no longer active 7 d following the infection, lack of the deaths following the subcutaneous administration at that time strongly supports our suggestion. Moxidectin and ivermectin differ in some structural and physicochemical properties, which are reflected in their formulation flexibility, comparative pharmacokinetic behaviour, and persistence of antiparasitic activity. A markedly longer residence time for moxidectin compared with ivermectin was also observed after oral treatment in sheep (10). Moxidectin is much more lipophilic in nature than ivermectin, and its main reservoir in the body is fat. This appears to have a depository effect. Moxidectin is not metabolised in the body to any greater extent, and is primarily excreted as the parent compound. This contrasts with ivomectin,

7 377 which is excreted primarily as a hydroxylated derivative. Consequently, moxidectin even as an oral drench has a persistent activity against the more susceptible species of parasite (11) whereas this benefit was not demonstrated for orally administered ivermectin (11). Abo-Shehada and Herbert (3) reported a 78%- 79% reduction in the T. larval count in mice receiving orally or subcutaneously 0.2 mg/kg -1 of ivermectin daily for 5-6 d commencing on days 2 or 8 of infection. In another study, a 13 d course of intramuscular treatment with 0.2 or 0.4 mg/kg -1 was performed, starting on day 15 post inoculation. Although the higher dose caused a significant decrease in the larval counts in the brain, the reduction of the total parasites number did not reach the level of significance (5). A 7 d course of subcutaneous ivermectin treatment with a daily dose of 0.2 mg/kg -1 from 1 d after infection resulted in moderate efficacy (13). In the present study, according to the decrease in total larva recovery results, the administration of moxidectin by oral route 48 h following egg inoculation showed the highest efficacy and the lowest effect was obtained in the group in which ivermectin was given orally 7 d following egg inoculation. The differences in activities of moxidectin and ivermectin might source from their pharmacological properties described above. It is difficult to compare the results obtained in the present study with reports of other researchers, as a different parasite (T. ) and different methods were used. To date, this is the first experimental study with T. cati in paratenic hosts evaluating the effect of macrocyclic lactones ivermectin and moxidectin on the numbers and distribution of larvae, when administered at different post-infection periods and through different administration routes. Our study demonstrated that a considerable success was obtained statistically in all treatment groups, as compared with the control group, and moxidectin was considerably more effective than ivermectin on the larvae numbers recovered from brain and liver. It was determined that the administration time of the drug was considerably effective for lungs and treatment on the 7 d was more effective. This was also observed at subcutaneous administration and the results of the oral administration were found to be similar to those obtained at administration of the drug at the 48 h. Acknowledgments: The author wishes to thank Professor Dr. Mufit Toparlak (Parasitology Department in the Faculty of Veterinary Medicine, Istanbul University) and Dr. Omur Kocak (Zootechnics Department) for their kind help. References 1. Abdel-Hameed A.A.: Effect of Thiabendazole on the migration of Toxocara larvae in the mouse. J Parasitol 1984, 70, Abdel-Hameed A.A.: Effects of benzimidazole anthelmintics on the survival and migratory behavior of Toxocara larvae in the mouse. Am J Vet Res 1984, 45, Abo Shehada M.N., Herbert I.V.: Anthelmintic effect of levamisole, ivermectin, albendazole and fenbendazole on larval Toxocara infection in mice. Res Vet Sci 1984, 36, Arther R.G., Cox D.D.: Anthelmintic efficacy of febantel combined with praziquantel against Ancylostoma tubaeforme, Toxocara cati, and Taenia taeniaformis in cats. Am J Vet Res 1986, 47, Carrillo M.S., Barriga O.O.: Anthelmintic effect of levamisole hydrochloride or ivermectin on tissue toxocarosis. Am J Vet Res 1987, 48, Delgado O., Botto C., Mattei R.: Effect of albendazole in experimental toxocariasis of mice. Ann Trop Med Parasitol 1989, 83, Fok E., Kassai T.: Toxocara infection in the paratenic host: a study on the chemosusceptibility of the somatic larvae in mice. Vet Parasitol 1998, 74, Hrckova G., Velebny S., Tomasovicova O., Medved'ova M., Pajersky A.: Pathomorphological changes in mice infected with Toxocara cati following administration of fenbendazole and glucan. Acta Parasitol 2001, 46, Hrckova G., Velebny S.: Treatment of Toxocara infections in mice with liposome-incorporated benzimidazole carbamates and immunomodulator glucan. J Heminthol 2001, 75, Lifschitz A., Virkel G., Ballent M., Sallovitz J, Pis A., Lanusse C.: Moxidectin and ivermectin metabolic stability in sheep ruminal and abomasal contents. J Vet Pharmacol Therap 2005, 28, Murphy A.W., McDonald R., Ramsay M.: A comparison of production responses in lambs drenched with moxidectin or ivermectin. New Zealand J Agricult Res 1995, 38, Ridley R.K., Terhune K.S., Granstrom D.E.: The efficacy of pyrantel pamoate against ascarids and hookworms in cats. Vet Res Commun 1991, 15, Samanta S., Ansari M.Z.: Anthelmintic effect of ivermectin, albendazole, fenbendazole and thiabendazole on larval Toxocara infection in mice. Indian J Anim Sci 1990, 60, Soulsby E.J.L.: Helminths, Arthropods and Protozoa of Domesticated Animals, BailliereTindall-London, 1982, pp