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In three separate studies, the efficacy of a single treatment with a 12.5% pyriprole spot-on solution was investigated against induced infestation with Ixodes ricinus, Dermacentor reticulatus and Rhipicephalus sanguineus on dogs (both sexes; Beagles in Studies 1 and 2, mixed-breed in Study 3). For each tick species, one group of 8 dogs left untreated (Studies 1 and 2) or treated with a placebo solution (Study 3) was compared with another group treated once with the spot-on solution at a dose rate of at least 12.5 mg/kg. The dogs were infested with 50 unfed adult ticks of the respective species at various time-points before and after treatment and the surviving attached and unattached ticks were recorded 48 h after re-infestation. For each tick species, efficacy was assessed for each time-point and cumulatively for the whole evaluation period. The dogs were submitted to general health observations and clinical assessments during the study. Efficacy against I. ricinus and R. sanguineus was 100% during the whole evaluation period of 30 days. For D. reticulatus cumulative efficacy for the 30 days after treatment was 98.9%. The product was well tolerated by all the animals.

The efficacy of a single treatment with a 12.5% pyriprole spot-on formulation against induced infestations with R. sanguineus ticks and cat fleas (C. felis) as well as its persistence after repeated washing and shampooing was investigated in four separate studies. In a first study on R. sanguineus involving 32 beagle dogs, the efficacy at various time-points during the 30 days that followed treatment assessed 48 h after re-infestation ranged from 100% to 99.3%. No engorged ticks, alive or dead, were found in the treated animals. Shampooing 2 days after treatment and weekly washings did not affect the efficacy. In a second study on R. sanguineus involving 32 beagle dogs, the efficacy at various time-points during the 30 days that followed treatment assessed 48 h after re-infestation ranged from 100% to 96.8%. Single washing 8 h after treatment and single shampooing 24 h after treatment had no negative impact on the efficacy of the product. In a third study on C. felis involving 28 beagle dogs, the efficacy at various time-points during the 30 days that followed treatment assessed 48 h after re-infestation was always 100% and weekly washings did not diminish the efficacy. In a last study on C. felis involving 24 beagle dogs, the efficacy at various time-points during the 5 weeks that followed treatment assessed 48 h after re-infestation ranged from 100% to 99.8%, and shampooing 24 h after treatment did not reduce the efficacy. The product was well tolerated by the dogs.

The inhibitory activities of fipronil (10% (w/v) solution), (S)-methoprene (9% (w/v) solution), and fipronil/(S)-methoprene (10 and 9% (w/v) solution, respectively) combination against eggs and emerging adult cat fleas (Ctenocephalides felis) and adulticidal activity were tested on experimentally infested dogs. Thirty-two Beagle dogs were selected for this study and eight replicates of four animals were formed based on body weight within sex. One dog in each replicate was randomly allocated to treatment with: (1) untreated control; (2) fipronil 10% (w/v) solution, (3) (S)-methoprene 9% (w/v) solution, and (4) fipronil 10% (w/v) and (S)-methoprene 9% (w/v) combination solution. Treatments were applied once topically on Day 0 at the rate of 0.067 ml/kg. On Days -12, -1, 21, and weekly to Day 84 each dog was infested with approximately 200 fleas and comb counted approximately 24h later, or 2 days (our 48 h) after in the case of Day -1 infestation. On Days -11, 1, 22, and weekly to Day 85 each dog was again infested with approximately 200 fleas. Flea eggs were collected over approximately 24 h beginning 3 days after infestation. Fleas were combed off of the dogs and counted at the end of the egg collection period (approximately 96 h count). One aliquot of up to about 100 eggs, if available, from each animal at each infestation time was incubated for approximately 72 h to determine larval hatch and the other for 35 days to determine the number of adults that developed. The 10% (w/v) fipronil spot-on provided excellent control (>95%) of adult fleas on dogs for 5 weeks. Similarly, the combination spot-on of 10% (w/v) fipronil and 9% (w/v) (S)-methoprene provided excellent control of adult fleas, i.e., >95% for 5 weeks. From week 6 post-treatment onward, the relatively low inhibition of adult flea emergence substantiated the lack of significant ovicidal/larvicidal activity in the fipronil (10%, w/v) treatment group. However, the combination product provided excellent (>90%) ovicidal activity for 8 weeks and high (91.4%) inhibition of adult flea emergence for 12 weeks. In addition, a synergistic effect of the two compounds in combination was demonstrated with fipronil enhancing the ovicidal and inhibition of adult flea emergence activity of (S)-methoprene against cat flea eggs. When all stages of the life cycle of the cat flea are considered, the combination spot-on product provided a high level of total flea control yielding a curative effect against adult fleas and inhibition of flea development stages with little to no potential reinfestation pressure on the animal or in the environment for 12 weeks.

The efficacy of selamectin against adult ascarids was evaluated in eight controlled and masked studies in dogs. Three laboratory studies evaluated selamectin against experimentally induced infections of Toxocara canis ; three laboratory studies evaluated selamectin against naturally acquired infections of T. canis ; one laboratory study evaluated selamectin against naturally acquired infections of both T. canis and Toxascaris leonina ; one field study evaluated selamectin against naturally acquired infections of ascarids ( T. canis and/or T. leonina ) in dogs presented as veterinary patients. Selamectin was administered topically to the skin of dogs in unit doses designed to deliver a minimum of 6 mg kg −1 (range, 6–12 mg kg −1 ). In all studies, dogs were allocated randomly to treatment assignments (selamectin or vehicle control in laboratory studies: selamectin or reference product in the field study) on the basis of pretreatment fecal egg counts. For induced infections, there were significant reductions in geometric mean numbers of adult T. canis after a single application of selamectin (93.9–98.1%, P =0.0001), after two monthly applications (≥88.3%, P ≤0.0001), and after three monthly applications (100%, P ≤0.0002). In the natural infection laboratory studies, when selamectin was administered twice at an interval of 30 days, the percentage reductions in geometric mean numbers of adult T. canis at necropsy were 84.6, 91.3, and 97.9%, and when selamectin was administered on days 0, 14, and 30, the percentage reductions were 91.1 and 97.6%. Geometric mean fecal T. canis egg counts were reduced by ≥92.9% ( P ≤0.0067) at the end of the studies. In the field study, geometric mean fecal ascarid egg counts were reduced by 89.5 and 95.5% ( P =0.0001) for 14 and 30 days, respectively, after a single treatment with selamectin, and by 94.0% ( P =0.0001) 30 days after the second treatment with selamectin. These reductions compared favorably with the egg count reductions from dogs treated with a reference product containing praziquantel, pyrantel embonate, and febantel. There were no adverse drug experiences or treatment-related mortalities during any of the studies. Selamectin, when administered topically in a unit dose providing a minimum dosage of 6 mg kg −1 , was safe and effective against adult T. canis and T. leonina and in reducing the fecal excretion of T. canis eggs in dogs.

Seven controlled studies were conducted to investigate the efficacy of selamectin against weekly infestations of dogs with Rhipicephalus sanguineus and Dermacentor variabilis. Treatments (selamectin or vehicle alone) were applied topically at weekly, 2-week, or monthly intervals or in a "Monthly Plus" regimen (monthly treatment with an additional treatment at 14 days after the first treatment). Selamectin was supplied in unit dose tubes designed to deliver a minimum dosage of 6mgkg(-1). The studies ranged in duration from 37 to 90 days. Fifty adult ticks (+/-2) were applied approximately weekly, and tick counts were performed 3, 4, and 5 days after each infestation. The efficacy of selamectin was expressed as the percentage reduction in geometric mean tick counts on selamectin-treated dogs compared with those for dogs treated with the vehicle alone (negative-control). In one study, the engorgement of Dermacentor variabilis was assessed by weighing ticks after removal on the fifth day after each infestation. Weekly and 2-week interval treatments with selamectin provided efficacies against R. sanguineus of >89% across the entire study periods, with 100% efficacy being achieved from 21 days after the first dose and thereafter (study duration, 37 days for the weekly regimen and 44 days for the 2-week interval regimen). D. variabilis also was well controlled by the 2-week interval treatment regimen, with >96% efficacy being achieved from 21 days after the first treatment and thereafter until the end of the study (study duration: 90 days). In five of six studies incorporating three treatments at monthly intervals, the percentage reduction in R. sanguineus and D. variabilis counts 5 days after infestation ranged from 90 to 100% in the second and third months after treatment began. In the sixth study, reductions of > or =95% in D. variabilis counts 5 days after infestation were achieved for 2 weeks after each treatment in the second and third months. For the Monthly Plus regimen, from the second treatment (day 14) onwards, selamectin achieved 83-100% reductions in R. sanguineus and D. variabilis counts 3 days after infestation, and 94-100% reductions 5 days after infestation in three of the four studies. In the fourth study, selamectin demonstrated good efficacy against D. variabilis for 2 weeks after each treatment. In all seven studies, the counts from the selamectin-treated dogs were significantly (P< or =0.018) lower than those from the vehicle-treated dogs on 77 of the 80 assessments made 5 days after infestation. Selamectin also significantly (P< or =0.0105) reduced engorgement of female D. variabilis. These studies demonstrated that selamectin, administered topically to the skin in a single spot at a minimum dosage of 6mgkg(-1) at monthly intervals, was effective in the control of experimentally induced R. sanguineus and D. variabilis infestations on dogs.

The progressive osteopenic changes in tibial compact bone in adult male monkeys (Macaca nemestrina) were examined histologically during chronic studies of immobilization. The animals were restrained in a semirecumbent position, which reduces normally occurring stresses in the lower extremities and results in bone mass loss. The longest immobilization studies were of 7 months duration. Losses of haversian bone tended to occur predominantly in the proximal tibia and were characterized by increased activation with excessive depth of penetration of osteoclastic activity. There was no apparent regulation of the size and orientation of resorption cavities. Rapid bone loss seen during 10 weeks of immobilization appeared to be due to unrestrained osteoclastic activity without controls and regulation, which are characteristic of adaptive systems. The general pattern of loss persisted throughout 7 months of immobilization. Clear-cut evidence of a formation phase in haversian bone was seen only after 2 months of reambulation. During this period osteoblasts accumulated within resorption cavities, and there was matrix apposition. Within 6 months of recovery there was increased bone turnover, and resorption cavities with diameters of 500-1500 micron were filled partially with new bone; the mean wall thickness of new bone was 2 to 3 times larger than normal. In addition there were numerous remodeling sites that were of normal size and orientation. Trabecular bone was lost during immobilization, and it is probable that losses of large trabecular plates are not replaced, and consequently original bone volume in the cross section is not recovered. In this immobilization model we observed bone resorption occurring for long periods without apparent interruption.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantification of collagen cross-links of monkey bone (tibia), from various time periods of immobilization (up to 7 months) and their subsequent reambulation (up to 40 months) was determined. Results indicated reducible cross-link concentrations markedly increased and peaked at the seven-month period of immobilization and returned to control values after 40 months of recovery. Chromatographic profiles of the major cross-linked peptides indicated that the increased cross-linking after seven months immobilization occurred between residue Hyl ald -16 c as well as Lys ald -16 c of the α1 chains and residue 87 Hyl of α chains of type I collagen. Mature, stable cross-link concentrations as well as their molecular loci remained constant throughout immobilization and reambulation. These results strongly suggest that rapid new bone collagen synthesis occurred during the osteoporotic state due to immobilization. With long-term recovery, the rate of collagen synthesis apparently returned to match the control bone.