首页 | 本学科首页   官方微博 | 高级检索  
相似文献
 共查询到20条相似文献，搜索用时 31 毫秒
1.
The antiparasitic drug emodepside (EMO) is a substrate of the P‐glycoprotein multidrug efflux carrier (P‐gp; syn. MDR1, ABCB1), which has an important function in protecting the brain from potentially toxic compounds by functional drug efflux at the blood–brain barrier (BBB). Many dogs of the Collie breed and even dogs of many other breeds have a loss‐of‐function 4‐bp deletion mutation in the MDR1 gene. In these dogs, brain penetration of many P‐gp‐transported drugs is increased and so their therapeutic usage is restricted. To elucidate the role of P‐gp at the BBB for the brain penetration of EMO, we applied EMO at 1 mg/kg to mdr1‐deficient (PGPmut) and mdr1‐intact (PGPWT) CF1 mice. Whereas in the brain of the PGPWT mice, EMO was below the detection level of 10 ng/g, its concentration was at 43.7 ng/g in the PGPmut mice. Furthermore, appearance of neurological toxicity was analyzed in these mice after application of 1 mg/kg EMO using a rotarod setup. In all PGPmut mice, but not in the PGPWT mice, the walking performance on the rotarod was impaired by EMO with clear differences in the degree and duration of neurological toxicity. Some of the mice were completely unable to walk on the rotarod already at 2 h after drug application and showed long‐lasting ataxia over >24 h. Others even showed significantly reduced walking performance, but completely recovered within 1 day. In conclusion, P‐gp restricts brain penetration of EMO and prevents neurological toxicity of this drug in mice.  相似文献   

2.
Malreddy, P. R., Coetzee, J. F., KuKanich, B., Gehring, R. Pharmacokinetics and milk secretion of gabapentin and meloxicam co‐administered orally in Holstein‐Friesian cows. J. vet. Pharmacol. Therap.  36 , 14–20. Management of neuropathic pain in dairy cattle could be achieved by combination therapy of gabapentin, a GABA analog and meloxicam, an nonsteroidal anti‐inflammatory drug. This study was designed to determine specifically the depletion of these drugs into milk. Six animals received meloxicam at 1 mg/kg and gabapentin at 10 mg/kg, while another group (n = 6) received meloxicam at 1 mg/kg and gabapentin at 20 mg/kg. Plasma and milk drug concentrations were determined over 7 days postadministration by HPLC/MS followed by noncompartmental pharmacokinetic analyses. The mean (±SD) plasma Cmax and Tmax for meloxicam (2.89 ± 0.48 μg/mL and 11.33 ± 4.12 h) were not much different from gabapentin at 10 mg/kg (2.87 ± 0.2 μg/mL and 8 ± 0 h). The mean (±SD) milk Cmax for meloxicam (0.41 ± 80.16 μg/mL) was comparable to gabapentin at 10 mg/kg (0.63 ± 0.13 μg/mL and 12 ± 6.69 h). The mean plasma and milk Cmax for gabapentin at 20 mg/kg P.O. were almost double the values at 10 mg/kg. The mean (±SD) milk to plasma ratio for meloxicam (0.14 ± 0.04) was lower than for gabapentin (0.23 ± 0.06). The results of this study suggest that milk from treated cows will have low drug residue concentration soon after plasma drug concentrations have fallen below effective levels.  相似文献   

3.
The effect of sesame oil (SSO) and sunflower oil (SFO) (the excipients) on the plasma disposition of ivermectin (IVM) following intravenous (i.v.) and subcutaneous (s.c.) administration at a dosage of 200 μg/kg was investigated in goats. Ten clinically healthy crossbred goats were used in the study. The animals were allocated by weight and sex into two groups of five animals each. Group 1 (n = 5) received the drug and excipient by the i.v. route only and group 2 received drug and excipient by the s.c. route only. The study was designed according to a two‐phase crossover design protocol. In the first phase three animals in group 1 were i.v. administered IVM (0.2 mg/kg) + SSO (1 mL) and the other two animals received IVM (0.2 mg/kg) + SFO (1 mL). In the second phase animals were crossed over and received the alternate excipient with IVM at the same dosages. In group 2 during the first phase, three animals were s.c. administered IVM (0.2 mg/kg) + SSO (1 mL) and the other two animals were received IVM (0.2 mg/kg) + SFO (1 mL). In the second phase animals were crossed over and received the alternate excipient with IVM at the same dosages. A 4‐week washout period was allowed between the two phases. In group 2 significantly increased dermal thickness was observed at the s.c. injection site of the all animals which received IVM during phase I regardless of the excipient. There was almost no change observed at the injection site of any animal during the second phase of the study following s.c. administration. In group 2 the plasma concentrations of IVM in the second phase for both excipient combinations were much higher than the plasma concentrations following first administration and appeared to be related with the dermal changes. The mean plasma disposition of IVM in combination with SSO or SFO was similar following i.v. administration. Longer terminal elimination half‐lives and resultant longer mean resident time were observed after s.c. administration of the both combinations compared with i.v. administration.  相似文献   

4.
P‐glycoprotein (P‐gp), encoded by the ABCB1 (MDR1) gene, dramatically impacts drug disposition. P‐gp is expressed in the intestines, biliary canaliculi, renal tubules, and brain capillaries where it functions to efflux substrate drugs. In this capacity, P‐gp restricts oral absorption, enhances biliary and renal excretion, and inhibits central nervous system entry of substrate drugs. Many drugs commonly used in veterinary medicine are known substrates for canine P‐gp (vincristine, loperamide, ivermectin, others). Because these drugs have a narrow therapeutic index, defective P‐gp function can cause serious adverse drug reactions due to enhanced brain penetration and/or decreased clearance. P‐gp dysfunction in dogs can be intrinsic (dogs harboring ABCB1‐1Δ) or acquired (drug interactions between a P‐gp inhibitor and P‐gp substrate). New human drug candidates are required to undergo assessment for P‐gp interactions according to FDA and EMA regulations to avoid adverse drug reactions and drug–drug interactions. Similar information regarding canine P‐gp could prevent adverse drug reactions in dogs. Because differences in P‐gp substrates have been documented between species, one should not presume that human or murine P‐gp substrates are necessarily canine P‐gp substrates. Thus, our goal was to develop a cell line for assessing drugs as canine P‐gp substrates.  相似文献   

5.
The horse milk gains increasing interest as a food product for sensitive consumers, such as children with food allergies or elderly people. We investigated the plasma and milk disposition, faecal excretion and efficacy of per os ivermectin (IVM) and pour‐on eprinomectin (EPM) in horses. Ten mares were divided into two groups. The equine paste formulation of IVM and bovine pour‐on formulation of EPM were administered orally and topically at dosage of 0.2 and 0.5 mg/kg bodyweight. Blood, milk and faecal samples were analysed using high‐performance liquid chromatography. The plasma concentration and persistence of IVM were significantly greater and longer compared with those of EPM. Surprisingly, EPM displayed a much higher disposition rate into milk (AUCmilk/plasma: 0.48) than IVM (AUCmilk/plasma: 0.19). IVM exhibited significantly higher faecal excretion (AUCfaeces: 7148.54 ng·d/g) but shorter faecal persistence (MRTfaeces: 1.17 days) compared with EPM (AUCfaeces: 42.43 ng·d/g and MRTfaeces: 3.29 days). Faecal strongyle egg counts (EPG) were performed before and at weekly intervals after treatment. IVM reduced the EPG by 96–100% for up to 8 weeks, whereas the reduction in the EPM group varied from 78 to 99%. In conclusion, due to the relatively low excretion in milk, EPM and IVM may be used safely in lactating mares if their milk is used for human consumption. Nevertheless, much lower plasma and faecal availabilities of EPM could result in subtherapeutic concentrations, which may increase the risk of drug resistance in nematodes after pour‐on EPM administration compared with per os IVM.  相似文献   

6.
The family of ATP‐binding cassette (ABC) transporters is composed of several transmembrane proteins that are involved in the efflux of a large number of drugs including ivermectin, a macrocyclic lactone (ML) endectocide, widely used in human and livestock antiparasitic therapy. The aim of the work reported here was to assess the interaction between three different anthelmintic drugs with substrates of the P‐glycoprotein (P‐gp) and the breast cancer resistance protein (BCRP). The ability of ivermectin (IVM), moxidectin (MOX) and closantel (CST) to modulate the intestinal transport of both rhodamine 123 (Rho 123), a P‐gp substrate, and danofloxacin (DFX), a BCRP substrate, across rat ileum was studied by performing the Ussing chamber technique. Compared to the controls, Rho 123 efflux was significantly reduced by IVM (69%), CST (51%) and the positive control PSC833 (65%), whereas no significant differences were observed in the presence of MOX (30%). In addition, DFX efflux was reduced between 59% and 72% by all the assayed drug molecules, showing a higher potency than that observed in the presence of the specific BCRP inhibitor pantoprazole (PTZ) (52%). An ex vivo intestinal transport approach based on the diffusion chambers technique may offer a complementary tool to study potential drug interactions with efflux transporters such as P‐gp and BCRP.  相似文献   

7.
Gastrointestinal nematode (GIN) parasitism is a major constraint to production of goats in the southeastern United States. The conventional method of control used by producers in this region is frequent use of anthelmintics during the warm season. Overuse of anthelmintics has led to an increase in the incidence of anthelmintic resistance in many parts of the world, but data on prevalence of anthelmintic resistance in GIN of goats in the southeastern United States are very limited. To address this issue, anthelmintic efficacy was determined in goat herds at the Fort Valley State University, Agricultural Research Station (FVSU-ARS) and the University of Georgia, College of Veterinary Medicine (UGA-CVM) using fecal egg count reduction (FECR) tests and DrenchRite((R)) larval development assays (LDA). At FVSU-ARS, 2-year-old Spanish goat does were randomly allocated to one of nine different treatment groups (n = 10): albendazole (ABZ; 20mg/kg body weight (BW)), fenbendazole (FBZ; 20mg/kg BW), ivermectin (IVM; 0.4 mg/kg BW), doramectin (DRM; 0.4 mg/kg BW), moxidectin (MOX; 0.4 mg/kg BW), levamisole (LEV; 12 mg/kg BW), morantel tartrate (MOR; 10mg/kg BW), a combination of IVM (0.4 mg/kg BW) and ABZ (20 mg/kg BW), and untreated controls. At UGA-CVM, goats were randomly allocated to one of five different treatment groups (n = 8): ABZ (20 mg/kg BW), IVM (0.4 mg/kg BW), MOX (0.4 mg/kg BW), LEV (12 mg/kg BW), and untreated controls. All drugs in both experiments were administered orally. Anthelmintic efficacy was calculated by comparing 14-day post-treatment FEC of treated and control animals, and percent reductions were interpreted using the World Association for the Advancement of Veterinary Parasitology guidelines for resistance. For the LDA, nematode eggs were isolated from pooled fecal samples of untreated control goats in each herd and used to perform DrenchRite((R)) assays. In the FVSU-ARS herd, MOX, LEV, the combination of IVM and ABZ, IVM, DRM, ABZ, MOR, and FBZ reduced FEC by 100, 91, 88, 78, 76, 62, 48, and 10%, respectively. In the UGA-CVM herd, MOX, LEV, ABZ and IVM, reduced FEC by 100, 94, 87, and 0%, respectively. In both herds moxidectin was the only drug tested that was fully effective. Results of the LDA were in agreement with results of the FECR tests for both herds. These data demonstrate the presence of GINs resistant to all three major anthelmintic classes in both goat herds.  相似文献   

8.
Anthelmintic efficacies against juvenile developing populations of Teladorsagia species that were known to be resistant to anthelmintics from all three broad spectrum families were examined using a controlled efficacy test. Fenbendazole (FBZ), levamisole (LEV), ivermectin (IVM), combinations of these anthelmintics and moxidectin (MOX) were assessed in parasite na?ve lambs artificially infected with 8,000 third stage larvae (Tci5) and treated orally 8-day post-infection with the compounds at the manufacturers recommended dose rates, FBZ, 5 mg/kg body weight (BW); LEV, 7.5 mg/kg BW; IVM, 0.2 mg/kg BW; MOX (0.2 mg/kg BW). The lambs were slaughtered 14-day post-treatment. The arithmetic mean worm burden reductions resulting from oral treatments with FBZ; IVM; LEV; FBZ+IVM; FBZ+LEV; FBZ, LEV+IVM or MOX were 36%, 82%, 38%, 86%, 60%, 88% and 97%, respectively. The results illustrate that combination treatments showed improved efficacies against the juvenile population compared to individually administered treatments but that these improvements were not wholly effective. Moxidectin was the only treatment that was over 95% effective, though caution should be noted when advising the use of MOX prophylactically since 3% of the infection still survived this treatment. Treatments directed at juvenile stages of Tci5 were less effective, with the exception of IVM, compared to a similar trial using Tci5 where the same treatments were directed against a predominantly adult population. No interaction was detected comparing the timings of treatments and its effectiveness with the exception of IVM (two-way ANOVA, p < 0.05). These findings suggest that, on the whole, the selection processes for anthelmintic resistance (AR) may occur at an early stage of development within the parasites, having severe implications for the early detection of AR.  相似文献   

9.
Persistent anthelmintic efficacy of topical formulations (all at a dosage of 500 microg/kg) of doramectin (DOR), ivermectin (IVM), eprinomectin (EPR) and moxidectin (MOX), in comparison with untreated control cattle (CONT), was observed in stocker beef calves during a 112-day winter-spring grazing trial. Five groups of 15 calves per group were grazed on 15 separate 2 ha pastures following random assignment of animals to specific pastures and then to treatment groups. All of the 5 treatments were represented in each of the 15 pastures. All cattle were weighed on study Days 1, 0, 28, 56, 84, 111 and 112. Fecal samples for nematode egg counts were collected on Days 7, 0, at 7 day intervals through Day 56 and at 14 day intervals to Day 1 12. Pooled group fecal cultures for determining generic composition of nematode infections were prepared at 14 day intervals throughout the study. As based on fecal egg counts, anthelmintic activity of EPR and MOX was greater (p < 0.05) than values for IVM or CONT through Day 28. Activity of DOR was greater (p < 0.05) than that of IVM on Days 7 and 14 only. Although significance levels varied little among treated groups from Day 42 to the end of the study, egg counts and percent reduction values of EPR and MOX remained consistently lower numerically than egg counts and higher than reduction values respectively, of DOR and IVM through Day 70. From Day 70 on, IVM counts were numerically, but not significantly higher than values of CONT. Based on larval culture, Cooperia predominated from Day 0 through 28 and again from Days 70 to 98; Ostertagia was second in prevalence with highest percentages, which exceeded those of Cooperia, between Days 42 and 70. Bodyweights of all treated groups, with exception of IVM, were always significantly greater (p < 0.05) than weights of CONT. Weights of IVM were numerically greater, but not significantly greater than CONT only on Days 84 and 112. From Day 56 on, there were no significant differences between weights of DOR, EPR and MOX, however, numerical values for MOX were consistently higher than values for the other two. Final average total bodyweight gains were: 153.7 kg for MOX, 148.5 kg for EPR, 146.9 kg for DOR, 139.7 kg for IVM and 127.7 kg for CONT.  相似文献   

10.
Ballent, M., Lifschitz, A., Virkel, G., Mate, L., & Lanusse, C. Pretreatment with the inducers rifampicin and phenobarbital alters ivermectin gastrointestinal disposition. J. vet. Pharmacol. Therap. 33 , 252–259. The goal of the study was to evaluate the effects of rifampicin (RFP) and phenobarbital (PBT) on the plasma and gastrointestinal disposition kinetics of ivermectin (IVM) subcutaneously administered to Wistar rats. Fifty seven rats were used. Animals in Group I were the noninduced (control) group. Those in Groups II and III received a treatment with RFP (160 mg/day) and PBT (35 mg/day), respectively, both given orally during eight consecutive days as induction regimen. The IVM pharmacokinetic study was started 24 h after the RFP and PBT last administration. Animals received IVM (200 μg/kg) by subcutaneous injection. Rats were sacrificed between 6 h and 3 days after IVM administration. Blood and samples of liver tissue, intestinal wall and luminal content of jejunum were collected from each animal. IVM concentrations were measured by high performance liquid chromatography. IVM disposition kinetics in plasma and tissues was significantly modified by the PBT treatment, but not by RFP. Despite the enhanced CYP3A activity observed after the pretreatment with RPF and PBT, there were no marked changes on the percentages of IVM metabolites recovered from the bloodstream in induced and noninduced animals. An enhanced P‐glycoprotein‐mediated intestinal transport activity in pretreated animals (particularly in PBT pretreated rats) may explain the drastic changes observed on IVM disposition.  相似文献   

11.
High‐density lipoprotein (HDL) is the main lipoprotein in the follicular fluid, and it has anti‐inflammatory, antioxidant and cryoprotectant properties. The anti‐inflammatory potential and antioxidant potential are derived from its lipid composition, especially the apolipoprotein AI (ApoAI) and paraoxonase 1 (PON1). The aim of this study was to evaluate the effect of HDL during in vitro maturation (IVM) on oocyte maturation and early bovine embryo development. For this, cumulus–oocyte complexes (COCs) were obtained from bovine ovaries collected at a local slaughterhouse. COCs (n = 2,250) were allocated into three groups (n = 50 COCs/group) according to the addition of HDL protein (HDL‐P) during IVM for 22 hr: 0 (control), 50 and 150 mg/dl. After IVM, COCs were inseminated (in vitro fertilization) and cultivated for 7 days. Total cholesterol concentration, total protein, triglycerides and ApoAI concentrations on IVM medium increased proportionally to HDL‐P addition. However, PON1 activity was not detected in any treatment. The addition of HDL‐P did not affect nuclear maturation rate, endogenous reactive oxygen species and glutathione levels in COCs (p > 0.05). The highest HDL‐P concentration (150 mg/dl) decreased cleavage and blastocyst rate (p < 0.05). Moreover, the HDL‐P 150 mg/dl group had lower cellular count/blastocyst than the 50 mg/dl group (p < 0.05). However, the addition of HDL‐P did not affect relative gene expression of evaluated genes. In conclusion, the complex HDL/ApoAI obtained from human plasma, in the absence of PON1 activity during in vitro oocyte maturation, decreased initial embryo development.  相似文献   

12.
Permeability glycoprotein (P‐gp) is a membrane‐bound efflux pump that exports various substances out of the cell. Variations in P‐gp expression play an important role in susceptibility to toxic substances, drug efficacy and disease risk. In the present study, the distribution of the MDR1‐gene product P‐gp was determined in normal tissues of domestic shorthair cats using immunohistochemistry. Two monoclonal antibodies C494 and C219 were used, recognizing a different epitope on the human P‐gp molecule. A consistent positive immunolabelling was obtained. The tissue distribution and cellular locations with antibody C494 were similar to those in man and dogs; with liver, colon, adrenal cortex and brain capillaries being consistently and intensely labelled. However, the immunolabelling in the kidney was in contradiction to man and dogs. The C219 antibody seems to react with a specific form of P‐gp, only expressed in feline tissues with a barrier function, i.e. endothelia of the brain, testes and ovaries, and intestinal epithelial cells in contact with the lumen.  相似文献   

13.
The anthelmintic resistance status of two field isolates derived from farms (farm A and B) located near Edinburgh were examined using both controlled efficacy tests (CET) and faecal egg count reduction tests (FECRT). Efficacies against fenbendazole (FBZ), levamisole (LEV) and ivermectin (IVM) and, for one isolate, against combinations of these anthelmintics and moxidectin were determined in na?ve lambs, artificially infected with the isolates and treated with the compounds at the manufacturers recommended dose rates. (FBZ, 5mg/kg bodyweight (BW); LEV, 7.5mg/kg BW; IVM, 0.2mg/kg BW; Moxidectin (MOX) 0.2mg/kg BW). In both field isolates, the predominant species found pre-treatment and the only species found post-treatment was Teladorsagia circumcincta. Resistance to FBZ, LEV and IVM was confirmed in CET and FECRT on farm A and to the latter two compounds on farm B, which had a history of benzimidazole resistance and where TBZ resistance was also demonstrated using an egg hatch assay (EHA). For the farm A isolate CET efficacies against FBZ; IVM; LEV; FBZ + IVM; FBZ + LEV; FBZ, LEV + IVM and MOX were 59, 60, 88, 94,93, 92 and 98%, respectively. The CET efficacies for the farm B isolate were 51% and 72% for LEV and IVM, respectively.  相似文献   

14.
The aim of the current study was to evaluate the in vivo pharmacokinetic of ivermectin (IVM) after the administration of a long‐acting (LA) formulation to sheep and its impact on potential drug‐drug interactions. The work included the evaluation of the comparative plasma profiles of IVM administered at a single therapeutic dose (200 μg/kg) and as LA formulation at 630 μg/kg. Additionally, IVM was measured in different gastrointestinal tissues at 15 days posttreatment with both IVM formulations. The impact of the long‐lasting and enhanced IVM exposure on the disposition kinetics of abamectin (ABM) was also assessed. Plasma (IVM and ABM) and gastrointestinal (IVM) concentrations were analyzed by HPLC with fluorescent detection. In plasma, the calculated Cmax and AUC0‐t values of the IVM‐LA formulation were 1.47‐ and 3.35‐fold higher compared with IVM 1% formulation, respectively. The T1/2ab and Tmax collected after administration of the LA formulation were 2‐ and 3.5‐fold longer than those observed after administration of IVM 1% formulation, respectively. Significantly higher IVM concentrations were measured in the intestine mucosal tissues and luminal contents with the LA formulation, and in the liver, the increase was 7‐fold higher than conventional formulation. There was no drug interaction between IVM and ABM after the single administration of ABM at 15 days post‐administration of the IVM LA formulation. The characterization of the kinetic behavior of the LA formulation to sheep and its potential influence on drug‐drug interactions is a further contribution to the field.  相似文献   

15.
Gokbulut, C., Cirak, V.Y., Senlik, B., Aksit, D., McKellar, Q.A. The effects of different ages and dosages on the plasma disposition and hair concentration profile of ivermectin following pour‐on administration in goats. J. vet. Pharmacol. Therap. 34 , 70–75. The effects of different ages and dosages on the plasma disposition and hair degradation of ivermectin (IVM) were investigated following pour‐on administration in goats. Twenty‐eight female Saanen goats allocated into two groups of 14 animals according to their ages as young (5–6 months old) and old (12–24 months old) groups. Each age group was divided into two further of seven goats and administered pour‐on formulation of IVM topically at the in recommended dosage rate of 0.5 mg/kg bodyweight The recommended cattle dosages rate of 0.5 mg/kg or at the higher dosage of 1.0 mg/kg. Blood samples were collected at various times between 1 h and 40 days. In addition, hair samples (>0.01 g) were collected using tweezers from the application sites and far from application sites of the all animals throughout the blood sampling period. The plasma and hair samples were analyzed by high performance liquid chromatography (HPLC) using fluorescence detection following solid and liquid phase extractions, respectively. Dose‐ and age‐dependent plasma disposition of IVM were observed in goats after pour‐on administration. In addition, relatively high concentration and slow degradation of IVM in hair samples collected from the application site and far from the application site were observed in the present study. The differences between young and old goats are probably related to differences in body condition and/or lengths of haircoat. The systemic availability of IVM following pour‐on administration is relatively much lower than after oral and subcutaneous administrations but the plasma persistence was prolonged. Although, the longer persistence of IVM on hairs on the application site may prolong of efficacy against ectoparasites, the poor plasma availability could result in subtherapeutic plasma concentrations, which may confer the risk of resistance development in for internal parasites after pour‐on administration in goats.  相似文献   

16.
The objective of this study was to evaluate the efficacy of a pour-on solution containing moxidectin plus triclabendazole (MOX plus TCBZ) against immature and adult stages of the liver fluke in cattle and compare the efficacy with other commercially available preparations. To this end, 104 male Holstein-Friesian calves aged between 3 and 4 months, were randomly allocated to 13 groups of eight animals each, and infected with approximately 500 Fasciola hepatica metacercariae. One group remained untreated, four groups were treated with MOX plus TCBZ at a dose rate of 0.1mL/kg, four other groups were treated with ivermectin (IVM) plus clorsulon injectable at a dose rate of 0.02mL/kg, and the remaining four groups were treated with IVM plus closantel pour-on at a dose rate of 0.1mL/kg. Each treatment was applied to one of the groups at 4 weeks, 6 weeks, 8 weeks and 12 weeks after the experimental infection. At necropsy (99-102 days after infection), all untreated animals were infected with a minimum of 30 flukes. The MOX plus TCBZ treated animals had significantly (P<0.0001) lower fluke counts compared to the untreated control animals at all time points after treatment. Efficacy against 8-week old and adult flukes was >99.5%. For 6-week old immature fluke, the efficacy was 98.0% and for 4-week old immature fluke the efficacy was 90.9%. The IVM plus closantel pour-on treated animals had significantly lower fluke counts compared to the untreated control animals for adult and 8-week old flukes (P<0.0001), and for 6-week old flukes (P=0.002). The efficacy was 26.8%, 68.2%, 90.6% and 99.3% against 4-week, 6-week and 8-week old immature flukes, and adult flukes respectively. The IVM plus clorsulon treated animals had significantly lower fluke counts compared to the untreated control animals for adult (P<0.0001) and 8-week old (P<0.05) flukes. The efficacy was 29.7%, 43.4%, 53.2% and 99.2% against 4-week, 6-week and 8-week old immature flukes, and adult flukes respectively. For treatments at 4, 6 and 8 weeks after infection, the fluke counts were significantly (P<0.0001) lower for the MOX plus TCBZ treatment than for IVM plus closantel or IVM plus clorsulon. The results confirm the high efficacy (>90%) of the MOX plus TCBZ pour-on combination against 4-week old to adult liver fluke in cattle. The IVM plus closantel pour-on combination was effective (>90%) against 8-week old and adult flukes, but had low efficacy against 4- and 6-week old fluke. The IVM plus clorsulon injectable combination was effective (>90%) against adult fluke only.  相似文献   

17.
Mealey, K.L., Waiting, D., Raunig, D.L., Schmidt, K.R., Nelson, F.R. Oral bioavailability of P‐glycoprotein substrate drugs do not differ between ABCB1‐1Δ and ABCB1 wild type dogs. J. vet. Pharmacol. Therap. 33 , 453–460. Previous studies have indicated that intestinal P‐glycoprotein (P‐gp) limits the oral bioavailability of substrate drugs and alters systemic pharmacokinetics. In this study, dogs lacking functional P‐gp were used to determine the contribution of P‐gp to the oral bioavailability and systemic pharmacokinetics of several P‐gp substrate drugs. The P‐gp substrates quinidine, loperamide, nelfinavir, cyclosporin and the control (non P‐gp substrate) drug diazepam were individually administered intravenously and per os to ABCB1‐1Δ dogs, which have a P‐gp null phenotype and ABCB1 wildtype dogs. ABCB1‐1Δ dogs have been shown to have greater brain penetration of P‐gp substrates, but limited information is available regarding oral bioavailability of P‐gp substrate drugs in this animal model. Plasma drug concentration vs. time curves were generated and pharmacokinetic parameters were calculated for each drug. There were no differences in oral bioavailability between ABCB1‐1Δ dogs and ABCB1 wildtype dogs for any of the drugs studied, suggesting that intestinal P‐gp does not significantly affect intestinal absorption of these particular substrate drugs in ABCB1‐1Δ dogs. However, small sample sizes and individual variability in CYP enzyme activity may have affected the power of the study to detect the impact of P‐gp on oral bioavailability.  相似文献   

18.
AIM: To determine associations between resistance of Ostertagia (= Teladorsagia) spp to macrocyclic lactone (ML) anthelmintics and history of use of anthelmintics, by type, on commercial sheep farms in temperate regions of southern South Australia and Victoria, Australia.

METHODS: Faecal egg count reduction tests (FECRTs) were conducted during a 2.5-year period (from August 2001 to January 2004) and records of the type of anthelmintic used in the 5 years preceding the FECRTs were collected from commercial sheep farms (n=103) in southern South Australia and Victoria, and data analysed retrospectively. ML resistance was defined as <95% reduction of Ostertagia spp 10–14 days after treatment with ivermectin (IVM), orally, at half the manufacturer's recommended dose rate. Use of anthelmintics in the preceding 5 and 10 years on each property was classified according to the nett number of years each of the following classes of drug had been used: IVM oral liquid (IVO), IVM controlled-release capsules (CRCs), abamectin (ABA), moxidectin (MOX) or a non-ML an- thelmintic. The prevalence of ML resistance, by property, was analysed for associations with prior use of anthelmintics.

RESULTS: Resistance by Ostertagia spp to ML anthelmintics was evident on 51/103 (49.5%) properties. The prevalence of resistance was lowest (23%) on properties on which MOX had not been used, and was significantly higher (64–77%) on properties on which MOX had been used for ≥2 of the preceding 5 years (p<0.001). In contrast, the prevalence of resistance was highest (70–74%) on the properties on which IVM, or IVM and/ or ABA, had not been used in the previous 5 years (on which the use of MOX was predominant), and was markedly lower (20– 42%) on properties that had used IVM or IVM and/or ABA for at least one of the preceding 5 years. Prevalence of resistance was higher for properties on which the only ML anthelmintic used was MOX (19/29=66%) than for those on which the only ML used was IVO (2/19=11%; p<0.001). Properties on which the only ML used was MOX were 2.72 times more likely to have resistance than properties on which the only ML used was IVO (95% confidence interval (CI) = 1.01–5.08).

CONCLUSION: Use of MOX for ≥2 of the preceding 5 years was associated with a higher prevalence of resistance to ML by Ostertagia spp on sheep farms in south eastern Australia than the use of IVO.  相似文献   

19.
Schmid, V. B., Spreng, D. E., Seewald, W., Jung, M., Lees, P., King, J. N. Analgesic and anti‐inflammatory actions of robenacoxib in acute joint inflammation in dog. J. vet. Pharmacol. Therap. 33 , 118–131. The objectives of this study were to establish dose–response and blood concentration–response relationships for robenacoxib, a novel nonsteroidal anti‐inflammatory drug with selectivity for inhibition of the cyclooxygenase (COX)‐2 isoenzyme, in a canine model of synovitis. Acute synovitis of the stifle joint was induced by intra‐articular injection of sodium urate crystals. Robenacoxib (0.25, 0.5, 1.0, 2.0 and 4.0 mg/kg), placebo and meloxicam (0.2 mg/kg) were administered subcutaneously (s.c.) 3 h after the urate crystals. Pharmacodynamic endpoints included data from forceplate analyses, clinical orthopaedic examinations and time course of inhibition of COX‐1 and COX‐2 in ex vivo whole blood assays. Blood was collected for pharmacokinetics. Robenacoxib produced dose‐related improvement in weight‐bearing, pain and swelling as assessed objectively by forceplate analysis (estimated ED50 was 1.23 mg/kg for z peak force) and subjectively by clinical orthopaedic assessments. The analgesic and anti‐inflammatory effects of robenacoxib were significantly superior to placebo (0.25–4 mg/kg robenacoxib) and were non‐inferior to meloxicam (0.5–4 mg/kg robenacoxib). All dosages of robenacoxib produced significant dose‐related inhibition of COX‐2 (estimated ED50 was 0.52 mg/kg) but no inhibition of COX‐1. At a dosage of 1–2 mg/kg administered s.c., robenacoxib should be at least as effective as 0.2 mg/kg of meloxicam in suppressing acute joint pain and inflammation in dogs.  相似文献   

20.
Non-specific mechanisms involving ATP-binding cassette drug efflux transporters may play an important role in xenobiotic clearance in ovine gastro-intestinal nematodes. By using transporter inhibitors, the aim of this trial was to assess the possibility of increasing drug bioavailability in the host in an attempt to improve treatment efficacy. Thirty-six lambs were infected with 5000 multiple-drug resistant Haemonchus contortus third stage larvae and separated into six groups (n=6): ivermectin alone (IVM; 0.2 mg/kg body-weight, BW), ketoconazole alone (KET; 10 mg/kg BW), Pluronic 85 alone (P85; 4 mg/kg BW), IVM+KET, IVM+P85 or untreated control. Ivermectin was administered once on day 28 post-infection for all appropriate groups, whereas KET and P85 were administered as five separate doses on day 26-30 post-infection inclusive. The resultant data showed that concomitant administration of KET or P85 with IVM induced increases in plasma and tissue concentrations of IVM in treated animals, resulting in a two-fold increase in the area under the time-concentration curve (p<0.05). Faecal egg counts and worm burdens of the IVM+KET and IVM+P85 groups were lower than in the untreated, KET and P85 alone control animals. Worm burdens were reduced by between 16% and 51% with IVM+KET and IVM+P85 respectively compared to untreated control animals. The co-administration of P85 with IVM increased the efficacy by 34%, compared with IVM alone, in terms of worm count reduction of the multi-resistant isolate of H. contortus.  相似文献   

设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号