莫西菌素在畜牧业中的应用研究进展

莫西菌素（moxidectin,MOX）是由链霉菌发酵产生的奈马菌素经衍生化得到,具有良好的驱虫活性且对哺乳动物安全,主要应用于畜牧业。莫西菌素相较于其他阿维菌素类药物具有更好的脂溶性和水溶性,在动物体内脂肪组织中分布最高。莫西菌素通过与γ-氨基丁酸（GABA）结合,使Cl^-大量内流造成神经膜电位超极化,导致虫体麻痹死亡。给药途径和动物生理状况的不同会影响其峰血浆浓度和药物半衰期。莫西菌素在牛、羊、犬等动物体内具有很好的驱虫活性,其应用范围从哺乳动物逐渐扩展到鸟类,防治对象从线虫逐渐扩展到螨虫和部分病原菌,研究方向也从驱虫活性延伸至治疗人类疾病。随着莫西菌素应用范围的扩大和时间的延长,耐药性开始出现,可以采用莫西菌素和其他药剂混合等方式降低耐药性的产生速度。探究其更广泛的作用,需要不同研究领域研究人员的共同努力。     

Moxidectin toxicosis in a puppy successfully treated with intravenous lipids

Objective – To describe successful treatment of canine moxidectin toxicosis with the novel therapy of IV lipid administration.
Case Summary – A 16-week-old female Jack Russell Terrier was presented with acute onset of seizures followed by paralysis and coma shortly following suspected exposure to an equine formulation of moxidectin. Moxidectin toxicity was later confirmed. Initial therapy consisted of diazepam, glycopyrrolate, and IV fluids. Mechanical ventilation and supportive nursing care were provided as needed. An emulsion of 20% soybean oil in water, commonly used as the fat component of parenteral nutrition, was administered intravenously as a bolus of 2 mL/kg followed by 4 mL/kg/h for 4 hours beginning 10 hours after exposure and was administered again at a rate of 0.5 mL/kg/min for 30 minutes beginning 25.5 hours post-exposure. Mild improvement was seen after the first dose, and dramatic improvement was noted within 30 minutes of the second dose. The puppy's neurologic status returned to normal within 6 hours of the second administration, with no relapses.
Unique Information Provided – IV lipid therapy is a novel treatment approach for moxidectin toxicity. Its use is supported by recent research and case studies involving IV lipid administration for bupivacaine and other fat-soluble toxins. Lipid administration appeared to reverse the signs of toxicity and may prove to be a highly effective therapy for moxidectin and other fat-soluble toxins.     

Estimation of absolute oral bioavailability of moxidectin in dogs using a semi-simultaneous method: influence of lipid co-administration

Moxidectin is a long-acting anthelmintic drug for which little is known about its kinetic behaviour in dogs and its oral absolute bioavailability has never been reported. We studied the pharmacokinetics of moxidectin in dogs, with a special emphasis on oral bioavailability and the influence of lipid co-administration, by using a semi-simultaneous method of administration. Ten Beagle dogs were dosed orally and then intravenously (i.v.) with 0.2 mg/kg moxidectin. The oral application was conducted with or without corn oil co-administration. Moxidectin concentration-time profiles in plasma were analysed using a compartmental modelling approach, designed to fit the oral and i.v. kinetic disposition curves simultaneously. In contrast to what happens in other species, our study indicates that the bioavailability of orally given moxidectin in dogs is nearly total (90.2 +/- 7.4%), and is not enhanced by lipid co-administration. The clearance, the volume of distribution, the mean residence time and the terminal half-life were similar to what was already described for other species. Finally our trial suggests that the body condition (degree of obesity) is likely to be a major determinant of moxidectin kinetics in dogs because of its modulation of the volume of distribution that indirectly controls the terminal half-life of the drug.     

A review of the use of moxidectin in horses

Moxidectin has broad‐spectrum anti‐nematodal and anti‐arthropodal activities in the horse but is not effective against tapeworms or flukes. Moxidectin and ivermectin have the same efficacy against internal, adult parasites of horses. Moxidectin, however, is highly effective in eliminating encysted and hypobiotic larval stages of cyathostomins, whereas ivermectin is not. Treatment of horses with moxidectin results in an egg‐reappearance period (ERP) of 15–24 weeks. Because of its long ERP, moxidectin is labelled to be used at 12 week intervals. Moxidectin may provide protection against infection by ingested cyathostomin larvae for 2–3 weeks after it is administered. The larvicidal activity of moxidectin has often been compared to that of fenbendazole administered at either 7.5 or 10 mg/kg bwt for 5 consecutive days. The efficacy of fenbendazole, when administered daily for 5 consecutive days at 7.5 or 10 mg/kg bwt, against all stages of cyathostomins is often less than that of moxidectin because resistance of cyathostomins to benzimidazoles is prevalent worldwide, and the 5 day course of fenbendazole does not overcome this resistance. There are now reports of resistance of ascarids to moxidectin. Overt resistance of cyathostomins and a shortened egg re‐emergence period after treatment with moxidectin have been reported. Rapid removal of manure by natural fauna can significantly reduce larval nematode concentrations and thereby reduce intervals of anthelmintic treatment. Of the macrocyclic lactones, moxidectin has the least deleterious effect on faecal fauna.     

Oral administration of moxidectin for treatment of murine acariosis due to Radfordia affinis

A field trial was conducted to assess the safety and efficacy of oral administration of moxidectin in mice naturally infected with the fur mites Radfordia affinis. The natural infection was diagnosed in two colonies within a large academic institution by direct hair examination. Animals received moxidectin (1% Cydectin, FortDodge) at an oral dosage of approximately 2 mg/kg body weight by micropipette; administration was repeated after 15 days. Forty mice served as an untreated control group. Moxidectin treatment resulted in clinical improvement within a few days after initial treatment, and mites were eradicated from all infested animals at day 30. No side effects or signs of ill health were observed in any of the treated animals. To our knowledge, this is the first report of oral moxidectin for treatment of murine acariosis.     

Coma and respiratory failure due to moxidectin intoxication in a dog

Objective: To describe the clinical consequences following ingestion by a dog of a moxidectin‐containing equine deworming product. Few reports exist concerning the treatment and outcome of severe moxidectin toxicity. Treatment, known factors influencing intoxication, and prognosis are reviewed. Case summary: A 10‐month‐old female Border Collie ingested an unknown quantity of a moxidectin‐containing equine deworming product several hours before presentation. Severe neurological signs subsequently developed and included: ataxia, seizures, coma, and respiratory failure. The dog was treated with supportive care including intravenous fluids, activated charcoal, and positive pressure ventilation. Normal spontaneous respiration returned in 34 hours and the patient was discharged 58 hours after ingestion. Full recovery occurred within 1 week of intoxication. New information provided: This report describes moxidectin intoxication and associated respiratory failure in a dog that required mechanical ventilation. The dog's recovery was rapid. Despite severity of signs, the prognosis for patients with moxidectin intoxication is good with appropriate supportive care.     

Field evaluation of moxidectin/praziquantel oral gel in horses

The safety and efficacy of 2% moxidectin/12.5% praziquantel oral gel administered at a rate of 0.4 mg moxidectin and 2.5 mg praziquantel/kg was studied in client-owned horses under field use conditions. Four hundred horses (300 treated with moxidectin/praziquantel oral gel and 100 treated with vehicle) were enrolled, feces were collected, and eggs were counted. Investigators as well as horse owners were masked to treatment assignment. No adverse reactions to treatment were observed in any horses. Moxidectin/praziquantel gel reduced Anoplocephala spp by more than 99% and provided a significant (P <.05) reduction (> 98%) in the strongyle egg count of treated horses.     

Reduced efficacy of ivermectin, abamectin and moxidectin against field isolates of Haemonchus contortus

OBJECTIVES: To investigate the reduced efficacy of ivermectin, abamectin and moxidectin against two field isolates of Haemonchus contortus. These isolates were identified on separate properties in the New England region of New South Wales. PROCEDURE: Reduced efficacy of macrocyclic lactone anthelmintics against two field isolates of H contortus was suspected. These isolates were obtained from sheep on separate farms and pen trials were performed to investigate the efficacy of macrocyclic lactones. The percentage efficacy was calculated for moxidectin, ivermectin and closantel against the isolate from one farm (VHR23) and for moxidectin, ivermectin and abamectin against the isolate from the second (VHR29). The persistent activity of moxidectin against both isolates was investigated. RESULTS: Ivermectin and closantel were found to have efficacies below 80% against established populations of VHR23. Moxidectin was effective against an established population of VHR23 but the persistent activity was reduced to 7 days. Moxidectin was also found to be effective against established populations of VHR29, however, ivermectin and abamectin were found to have efficacies below 80%. There was no evidence of persistent activity of moxidectin against VHR29. CONCLUSION: A reduction in efficacy of abamectin and/or ivermectin against field isolates of H. contortus was identified from two farms in the New England region of New South Wales. The persistent effect of moxidectin was reduced against both isolates.     

Respiratory failure attributable to moxidectin intoxication in a dog

A 5-month-old 22-kg (48.4-lb) sexually intact male Collie was examined after ingesting a moxidectin-containing deworming medication. The dog was comatose and had respiratory arrest after progressively worsening lethargy, ataxia, and seizures. Exposure was confirmed by isolation of moxidectin from a biopsy specimen of adipose tissue, using liquid chromatography-mass spectroscopy methods. Treatment included use of intermittent positive-pressure ventilation, activated charcoal and cathartic administered enterally, nutrients administered via nasogastric tube, and intensive supportive care. The dog was weaned from a ventilator on day 6 after ingestion and was discharged on day 10. The dog was considered clinically normal during examination 24 days after ingestion. On the basis of the dog reported here and toxicologic data provided by the manufacturer of the deworming product, some Collies may have increased susceptibility to products containing high doses of moxidectin.     

Moxidectin against ivermectin-resistant nematodes—a global view

SUMMARY Macrocyclic lactone endectocides include two chemically distinct compounds moxidectin, a milbemycin, and ivermectin, an avermectin. The significance of the chemical differences between these compounds in relation to nematode resistance remains to be established. Reported studies indicate that moxidectin at the recommended dose rate of 0.2 mg/kg controls identified strains of nematodes, isolated from sheep and goats, with demonstrated resistance to ivermectin. This reflects the significantly greater potency of moxidectin against the 3 genera of nematodes most commonly involved in anthelmintic resistance, Haemonchus, Ostertagia and Trichostrongylus. Moxidectin, in recommended strategic treatment programmes, should reduce the risk of further development of resistance to the macrocylic lactone endectocides.     

Persistent activity of moxidectin pour-on and injectable against sucking and biting louse infestations of cattle

To evaluate the persistent activity of pour-on and injectable moxidectin against natural challenge by sucking (predominantly Linognathus vituli) and chewing (Bovicola bovis) cattle lice, 96 mixed-breed calves that had been treated to remove all lice were blocked by body weight and randomly allocated to three treatments: untreated control, moxidectin at 500 microg/kg by topical application and moxidectin at 200 microg/kg by subcutaneous injection. Twelve pens were blocked into groups of four and randomly allocated to four challenge times: 14, 21, 28 and 35 days post-treatment. Treatment groups were assigned to challenge pens randomly. Two donor calves, with demonstrated infestations of both sucking and chewing lice, were introduced into each pen containing eight principal calves at the start of each challenge time. Donors remained in the challenge pen for 7 days. Principal calves were examined for lice, 7, 14, 21 and 28 days after donor removal using a standardized hair-parting technique. Moxidectin injectable prevented re-infestation with L. vituli for up to 42 days, but did not provide persistent activity against B. bovis longer than 35 days post-treatment. Moxidectin pour-on demonstrated persistent activity against both B. bovis and L. vituli for 42 days.     

Field efficacy of moxidectin in dogs and rabbits naturally infested with Sarcoptes spp., Demodex spp. and Psoroptes spp. mites

The efficacy of moxidectin 1% injectable for cattle was evaluated in dogs and rabbits with naturally acquired sarcoptic, demodectic or psoroptic mites. Twenty-two dogs with generalised demodicosis were orally treated with 0.4mg/kg moxidectin daily. Forty-one dogs suffering from sarcoptic mange were treated with 0.2-0.25mg/kg moxidectin either orally or subcutaneously every week for three to six times. Seven rabbits were treated orally with 0.2mg/kg moxidectin twice 10 days apart. Of the 22 dogs with demodicosis, 14% were stopped treatment because of side effects, 14% were lost and of the remaining 72% all were cured (mean therapy duration 2.4 months). Thirty-seven of the sarcoptic mange-infected dogs finished treatment and were cured. In 17% of dogs, side effects were noted. All seven rabbits treated for psoroptic mange were cured and did not show any side effect. Our results indicate that moxidectin is effective and a good alternative for the treatment of demodicosis and scabies in dogs and psoroptic mange in rabbits. Side effects seem to occur more frequently if applied subcutaneously, therefore the oral route should be preferred.     

Efficacy and safety of imidacloprid/moxidectin spot-on solution and fenbendazole in the treatment of dogs naturally infected with Angiostrongylus vasorum (Baillet, 1866)

A randomized, blinded, controlled multicentre field trial study was conducted to evaluate the efficacy and safety of imidacloprid 10%/moxidectin 2.5% spot-on solution and fenbendazole in treating dogs naturally infected with Angiostrongylus vasorum. Dogs were randomly treated either with a single dose of 0.1 ml/kg bodyweight of imidacloprid 10%/moxidectin 2.5% spot-on solution or with 25 mg/kg bodyweight fenbendazole per os for 20 days. The study period was 42 days with dogs being examined on days 0, 7 and 42. The primary efficacy parameter was the presence of L1 larvae in faecal samples evaluated by a Baermann test from three consecutive days. Thoracic radiographs performed on each visit were being taken as a paraclinical parameter to support the results of the Baermann test. Twenty-seven dogs in the imidacloprid/moxidectin group and 23 dogs in the fenbendazole group completed the study according to protocol. The efficacies of the two treatment protocols were 85.2% (imidacloprid/moxidectin) and 91.3% (fenbendazole) with no significant difference between treatment groups. On radiographic evaluation pulmonary parenchyma showed similar improvement in each group. No serious adverse effects to treatment were recorded: most of the minor adverse effects were gastrointestinal such as diarrhea (nine dogs), vomitus (eight dogs) and salivation (three dogs). In general, these adverse effects were of short duration (1-2 days) within the first few days after treatment start and required little or no treatment. This prospective study demonstrates that both treatment protocols used are efficacious under field conditions, that treatment of mildly to moderately infected dogs with either of these protocols is safe and yields an excellent prognosis for recovering from the infection.     

Milk kinetics of moxidectin and doramectin in goats

The milk kinetics of doramectin after a single subcutaneous administration and moxidectin following a single subcutaneous or oral drench were studied in goats (n = 15) at a dosage of 0.2 mg kg(-1). Doramectin could be detected in the milk for 21.0+/-2.9 days after subcutaneous treatment, and the total fraction of the dose recovered from the milk was estimated to be 2.9+/-0.88 per cent. Moxidectin, after either oral or subcutaneous administration, could be detected in the milk up to day 40 and the total fractions of the dose recovered from the milk were estimated to be 5.7+/-1.04 per cent and 22.53+/-1.09 per cent, respectively. The mean residence time after subcutaneous administration indicated that moxidectin delivered by the milk persists three times longer than doramectin; furthermore, the total fraction of the dose of moxidectin recovered from the milk was 7.7 times higher than that of doramectin.     

Effect of prolonged status epilepticus as a result of intoxication on epileptogenesis in a UK canine population

The aim of the present study was to investigate if prolonged status epilepticus (SE), secondary to a chemoconvulsant, can induce spontaneous recurrent seizures in dogs. Clinical records at two UK referral hospitals were searched for dogs that presented in SE secondary to intoxication. Dogs were only included in the study if there was clear historical evidence of intoxication and a prolonged SE. Clinical and follow-up information was retrieved and verified by using a combination of clinical records from the two hospitals and the referring veterinarian and by contacting the owners using a telephone questionnaire. Twenty dogs met the inclusion criteria: 17 presented for metaldehyde toxicity, one for moxidectin toxicity, one for theobromine toxicity and one for mycotoxin toxicity. Of these 20 dogs, three dogs had an SE duration between 0.5 and one hour, four dogs between one and 12 hours, 10 dogs between 12 and 24 hours and three dogs greater then 24 hours. Median follow-up time for the 20 dogs was 757 days (range 66 to 1663 days). No dog had any further seizures after its SE. The present study supports the view that dogs with a prolonged SE following intoxication with the aforementioned toxins might not need long-term treatment with antiepileptic drugs after the SE has been controlled.     

Dermal safety study with imidacloprid/moxidectin topical solution in the ivermectin-sensitive collie

A study was conducted to determine the safety of the dermal application of 10% imidacloprid/2.5% moxidectin topical solution in ivermectin-sensitive collies. Each milliliter of this solution contains 100mg of imidacloprid and 25mg of moxidectin. A total of 21 collies were prescreened for ivermectin-sensitivity and heartworm negative status prior to selection for the study. Animals were assigned based on the maximum ivermectin-sensitivity score demonstrated during the prestudy screening. Treatment groups included a 3x and 5x test article group, and a 3x and 5x mineral oil control group. The 3x and 5x doses were administered at three and five times, respectively, the 1x dose based on the animal's body weight. On day 0, 3 of the 21 dogs were treated with dermal applications of a preliminary dose of 3x test article to screen for unexpected signs of toxicity with the remaining 18 dogs being treated with 3x mineral oil to blind for the volume of liquid applied. After no signs of toxicity were observed, these same three dogs were treated with 3x of test article and 2x mineral oil on days 28 and 56. The remaining 18 animals were equally allocated to either a 5x test article group or a 5x control group and were each treated on days 28, 56, and 84. Personnel performing observations were blinded to treatment. Observations were made for clinical signs of ivermectin sensitivity twice daily during non-dosing days. On treatment days, dogs were observed hourly for the first 4h post-treatment and at 6, 8, 12, 18 and 24h. Signs of toxicosis were not observed in any of the dogs throughout the observation period. This study demonstrated the safety of imidacloprid/moxidectin, when administered to collies testing positive for ivermectin sensitivity at dosages up to five times the maximum recommended dose.     

Efficacy of moxidectin and other anthelmintics against small strongyles in horses

Objective To compare the efficacy of moxidectin to ivermectin, oxibendazole and morantel against some gastrointestinal nematodes in horses.
Design Faecal egg count reduction after treatment.
Procedure A farm was selected where the population of small strongyles in horses was known to be resistant to oxibendazole. Horses were allocated to treatment groups based on faecal egg counts. After treatment, faecal samples were taken up to 109 days after treatment and faecal egg counts estimated. Faecal cultures were used to estimate the contribution of small and large strongyles to the faecal egg counts at each sampling.
Results Moxidectin (0.4 mg/kg) suppressed faecal egg counts for 109 days after treatment in most horses compared to 40 days with ivermectin (0.2 mg/kg), 13 days with morantel (9.4 mg/kg) and less than 13 days with oxibendazole (10 mg/kg). Most of the faecal egg count was attributable to small strongyles based on faecal culture, although Strongylus vulgaris was present in some samples in low numbers. Oxibendazole resistance in small strongyles was confirmed and a less than expected efficacy of morantel was also seen.
Conclusion Moxidectin was highly effective in reducing faecal egg counts after treatment for at least 12 weeks and up to 16 weeks in most horses. These horses were infected with a population of small strongyles known to be resistant to oxibendazole and possibly morantel. The duration of the reduction in faecal egg counts after treatment with moxidectin (0.4 mg/kg) was at least twice that of ivermectin (0.2 mg/kg) and greater than four times that for morantel and oxibendazole.     

New approaches to the treatment of canine demodicosis.

Topical amitraz is the only approved treatment for CGD; however, it is not always effective or well tolerated. Extra-label use of amitraz, milbemycin oxime, ivermectin, and moxidectin may be effective therapeutical alternatives for dogs with resistant CGD or dogs that have an intolerance to the licensed amitraz protocol. It appears that oral administration of milbemycin oxime (1-2 mg/kg), ivermectin (400-600 micrograms/kg), and moxidectin (400 micrograms/kg) daily is a practical therapeutical alternative and would provide similar cure rates. Nevertheless, milbemycin oxime is expensive, ivermectin is potentially more toxic, and only limited information is available on moxidectin. The average treatment duration with these new regimens is 4 months, with an expected range of 3 to 10 months. Treatment should be administered daily for a minimum of 3 months and for at least 1 month after a series of negative skin scrapings. For chronic cases or cases that take a relatively long time to respond to therapy, 2 to 3 months of treatment beyond negative scrapings may be more appropriate. Dogs with CGD always approach clinical normalcy weeks to months before negative skin scrapings are obtained. All dogs respond at their own rate; as long as the skin scrapings at each visit show fewer mites, the current therapy should be continued for an additional month. If the mite count starts to increase, this may suggest that the treatment protocol is not being followed or it may be that the therapy chosen was suboptimally effective. Although CGD is still a disease that is not easily treated, the prognosis for dogs with this disorder has dramatically improved in the past few years. It must be remembered, however, that the treatment alternatives for CGD described above are not approved and should not be used unless the approved therapeutical regimen has failed.     

Safety evaluation of moxidectin sustained-release injectable in 10-week-old puppies

A study was conducted to evaluate the safety of a commercial formulation of moxidectin sustained-release injectable for dogs (ProHeart 6, Fort Dodge Animal Health) administered as a single subcutaneous dose to 10-week-old puppies. Twelve male and 12 female purpose-bred beagles 10 weeks of age were blocked by weight within gender and randomly allocated to three treatment groups. Puppies in two groups were treated with moxidectin sustained-release injectable for dogs at three or five times the labeled dose rate of 0.17 mg moxidectin/kg. The third group was treated with saline solution as controls. Physical and neurologic status, hematologic parameters, clinical chemistries, urine samples, body weight, and food consumption were evaluated before and up to 12 weeks after treatment. When compared to controls, mild depression of erythropoiesis, characterized by reduced hemoglobin, reticulocytes, erythrocytes, and hematocrit, was noted in puppies treated with five times the label dose of moxidectin sustained-release injectable. Values for these parameters remained within normal ranges and increased during the study, but at a reduced rate relative to saline-treated controls. Other parameters evaluated remained within normal limits for all treatment groups. Based on results of this study, the no observed adverse effect level for moxidectin sustained-release injectable (ProHeart 6) treatment in 10-week-old puppies was determined to be three times the recommended rate.     

Efficacy of ivermectin and moxidectin against Otostrongylus circumlitus and Parafilaroides gymnurus in harbour seals (Phoca vitulina)

Verminous bronchopneumonia caused by infection with Otostrongylus circumlitus and Parafilaroides gymnurus is an important cause of death during the rehabilitation of harbour seals (Phoca vitulina). During the winter of 2000/01, 35 juvenile harbour seals with severe clinical signs of verminous bronchopneumonia were treated with either 0.2 mg/kg ivermectin orally or 0.2 mg/kg moxidectin subcutaneously, and monitored for 30 days. The efficacy of the anthelmintics was determined by the pattern of larval excretion (Baermannisation) and the progress of the clinical signs. Both anthelmintics had reduced larval excretion by at least 99 per cent after 10 days, but the seals' rapid breathing rate and and dyspnoea returned to normal more quickly in the animals treated with moxidectin. The pharmacokinetics of the anthelmintics were determined by solid-phase extraction, and high-performance liquid chromatography with fluorescence detection. Moxidectin had a mean (sd) residence time of 9.04 (2.12) days compared with 4.83 (1.14) days for ivermectin.