Cardiovascular and respiratory effects of the acaricide amitraz

Amitraz is a formamidine compound used as a topical acaricide mainly in dogs and cattle. In an initial attempt to explain some of its side-effects, the actions of amitraz were studied on the cardiovascular and respiratory systems in thiopentone/methoxyflurane-anaesthetized dogs. In separate experiments, amitraz, at doses of 1, 2 and 5 mg/kg i.v., dissolved in DMSO, increased blood pressure for 1 hour. Heart rate decreased initially then showed a dose-related return towards control values. Tidal volume, respiratory rate and respiratory minute volume all showed initial transient depression. Hyperventilation was a feature after high doses of amitraz. Cumulative doses of amitraz of 0.5, 1, 2, 5 and 10 mg/kg i.v., at intervals of 5 min, increased blood pressure. Heart rate decreased at lower doses but increased slightly after higher doses. Five minutes after injection, cardiac index had returned to control values while total peripheral resistance showed a dose-related increase. The mechanism of action of amitraz in dogs cannot be determined from these results; however, other reports have described an alpha 2-adrenoceptor agonist action of this formamidine compound.     

Inability to experimentally produce a polyneuropathy in dogs given chronic oral low level lead.

Electromyographic examinations were performed at various times over a 40 week period in four mature dogs receiving chronic oral low doses of lead acetate and a control dog receiving sodium acetate. Blood lead levels in the four dogs were elevated (mean values 1.15, 2.18, 1.13 and 1.72 mumol/liter). No clinical signs of lead intoxication were present. Two dogs had evidence of a nonregenerative anemia. Neither needle electromyographic nor nerve conduction velocity studies showed evidence of a polyneuropathy. Teased nerve fiber preparations of proximal and distal segments of the ulnar and tibial nerves and muscle biopsies of distal appendicular muscles were normal in all dogs. Light microscopic examination of the brain, kidneys and liver revealed no abnormalities in the two dogs necropsied. In conclusion, a polyneuropathy was not produced experimentally in dogs ingesting low doses of inorganic lead for up to 40 weeks.     

Central and peripheral α-adrenoceptor actions of amitraz in the dog

The aim of this study was to determine the contribution of alpha 2- and alpha 1-adrenoceptor agonist activity of the formamidine, amitraz, on peripheral circulation in the dog. Intra-arterial injections of amitraz (0.25-5.0 micrograms/kg) produced a dose-dependent increase in perfusion pressure in the autoperfused hind limbs of methoxyflurane-anaesthetized dogs. A constant blood flow to the hind limbs was maintained using a peristaltic pump. Intravenous phentolamine (0.5 mg/kg), prazosin (35 micrograms/kg) and yohimbine (10 micrograms/kg) in separate experiments antagonized the vasoconstrictor actions of amitraz and produced a parallel shift to the right of the amitraz dose-response curve. Cumulative doses of amitraz (0.5-15 micrograms/kg) given by intracisterna magna (i.c.m.) injections reduced mean arterial pressure and heart rate in a dose-dependent manner. Similar responses were produced by intravenous amitraz but at much higher doses. In separate experiments amitraz-induced hypotension (doses up to 25 micrograms/kg i.c.m.) was prevented by pre-treatment with yohimbine (30 micrograms/kg i.c.m.) but not prazosin (20 micrograms/kg i.c.m.). Both antagonists partially inhibited the bradycardia produced by amitraz. It is concluded that amitraz stimulates alpha 1- and alpha 2-adrenoceptors to produce vascular constriction. The central hypotensive action of amitraz appears to be mediated by alpha 2-adrenoceptors; however, both receptor subtypes appear to be stimulated to produce bradycardia.     

Failure of neuromuscular transmission after complete nerve section in the dog.

After the ulnar nerve was surgically transected, nerve conduction velocity in the distal segment and the evoked motor unit potential (EMUP) from the interosseous muscle were recorded until neuromuscular transmission failed. In five of the six dogs in the experiment, functional conduction ceased by 4.8 days, as determined by failure of both proximal and distal stimulation of the distal segment to evoke a muscle response. From the time of section until neuromuscular failure, the nerve conduction velocity remained unchanged. The amplitude of the EMUP from the interosseous muscle, however, decreased markedly during this time. Changes in other features of the EMUP are also presented. Fibrillation (denervation) potentials did not appear until the first day that muscle response could not be detected by stimulating the nerve. These data present a principle which would enable a determination of relative extent and progression of peripheral nerve damage.     

Amitraz depresses cardiovascular responses to bilateral carotid occlusion

The ectoparasiticide amitraz stimulates α₂,-adrenoceptors to produce side-effects such as bradycardia and hypotension. The actions of amitraz on baroreceptor reflex responses were evaluated in mongrel dogs by occlusion of both carotid arteries for 30-s periods. Incremental doses of amitraz given intravenously showed that doses of 60 μg/kg and above significantly depressed pressor responses to carotid occlusion. By comparison, 2 μg/kg amitraz given by intracisterna magna (i.c.m.) injection significantly depressed both blood pressure and heart rate responses. Pretreatment of dogs with i.c.m. yohimbine (30 μg/kg) prevented the depressant effects of amitraz on the reflex, but prazosin (20 μg/kg), in separate experiments, had no effect.     

Motor nerve conduction velocity and latency in the dog

Supramaximal percutaneous nerve stimulation was used in motor nerve conduction velocity studies conducted in ten middle-aged, clinically normal dogs. Dogs were separated into two groups; dogs in one group weighted less than or equal to 7.5 kg and dogs in the other group weighted greater than or equal to 15.9 kg. Mean values and SEM were recorded for radial (72.1 +/- 1.9 m/s), median 65.6 +/- 2.1 m/s), ulnar (58.9 +/- 1.0 m/s), tibial (68.2 +/- 1.4 m/s), and peroneal (79.8 +/- 1.8 m/s) nerves. Values for latency, amplitude, and duration for proximal and distal evoked potentials were recorded. Analysis of mean nerve conduction velocity values for all nerves between the two groups indicated no statistical difference (P greater than 0.05). However, the two groups were statistically different (P less than 0.05) when values for distal latency and measurements of nerve length were compared. These data suggest that if latency is substituted for velocity measurements, various populations of dogs must be considered to clarify interpretation.     

Transcranial magnetic stimulation of the motor cortex and percutaneous magnetic stimulation of the peripheral nervous structures in the dog

The motor cortex was transcranially and peripheral nervous structures (motor roots, plexus, peripheral nerves) were percutaneously stimulated by magnetic pulses in awake dogs and in dogs awaking from general anesthesia. The compound muscle action potentials were recorded by surface or needle electrodes. The central motor conduction time as an information about central motor tracts was obtained by subtracting the peripheral latency from the corticomuscular latency. The peripheral latency was assessed by high voltage electrical and magnetic stimulation of motor roots and by the F-wave technique. The motor conduction velocity of the tibial nerve was measured by percutaneous magnetic and by electrical stimulation and the resulting values were compared.     

Effect of tissue temperature on ulnar nerve conduction velocity in the dog.

The motor conduction velocity of the ulnar nerve of 19 mature dogs anesthetized with pentobarbital was electromyographically determined before and at tissue temperature decrements of 2 degrees (C) during cooling of the forelimb. Precooling (37 C) conduction velocity was 56 +/- 7.6 m/second (mean +/- standard deviation). At a tissue temperature of 20 C, conduction velocity was reduced to 31 +/- 6.3 m/second. Regression analysis indicated that conduction velocity decreased linearly by 1.7 m/second for each degree of decrease in tissue temperature between 37 and 20 C.     

Motor nerve conduction parameters in the cat

The electrophysiological characteristics of motor conduction in normal cats have been determined using an alligator clip as a surface electrode to record the compound muscle action potential (CMAP) following stimulation of the tibial, ulnar and fibular nerves. Data on nerve conduction velocity, residual latency and the amplitude and area of the CMAP have been determined using a computerised electromyography unit. Motor nerve conduction was substantially faster in cats than dogs and the site of stimulation had less effect on the size and area of the CMAP. Although a small decline in the amplitude of successive CMAPs was observed following repetitive stimulation of the tibial and ulnar nerve at 20 Hz, the decrement was less marked than in the dog.     

Electrophysiological evidence of peripheral nerve dysfunction in six dogs with botulism type C

In six dogs with botulism type C electrophysiological examinations showed: fibrillation potentials and prolonged insertional activity; low amplitude of the evoked muscle action potential; decrease in amplitude of the compound muscle action potential with slow repetitive stimulation; slowing of motor and sensory velocities in the peripheral nerve; and restoration of velocity and amplitude corresponding to clinical improvement. These findings indicate peripheral nerve dysfunction which cannot be explained adequately by current knowledge of the action of botulinum toxin on cholinergic nerve endings. It is therefore suggested that botulinum toxin also interferes with peripheral nerve conduction.     

Electrical stimulation of lumbar spinal nerve roots in dogs

The aim of this study was to test the applicability of electrical stimulation of lumbar spinal nerve roots and obtain normative electrical root stimulation (ERS) data for L7 nerve root and sciatic nerve in dogs. For that purpose ERS and sciatic nerve stimulations were performed consecutively, in totally 40 healthy dogs. ERS was applied in the L7/S1 intervertebral space via monopolar needle electrodes. Muscle responses were recorded from the gastrocnemius muscles on the left and right hind limbs. Sciatic nerve stimulation was performed at the greater trochanter level on the left hind limb, with records obtained from the left gastrocnemius muscle. Mean root latencies of the left and right side were 5.22?±?0.49 ms and 5.29?±?0.53 ms, respectively. There was no significant difference in root latency between the right and left sides. The mean terminal latency was 3.82?±?0.46 ms. The proximal motor nerve conduction velocity of the sciatic nerve was 63.15?±?3.43 m/s. The results of this study show that ERS provides objective data about the integrity of lumbar spinal nerve roots by evaluating the entire population of motor fibres and total length of the motor axon in dogs. ERS can be considered a useful diagnostic method for confirmation of diagnoses of lumbosacral diseases.     

The effect of the tarsal joint positions on the tibial nerve motor action potential latency in dog: electrophysiological and anatomical studies

This study has been carried out to determine the effect of neutral position, hyperextension and hyperflexion of the tarsal joint on the tibial nerve, motor action potential latency and tarsal canal compartment pressure in dogs with the aid of electrophysiological and anatomical methods. Totally twenty healthy mongrel dogs were used. Latency of motor nerve action potential (MNAPL) studies of tibial nerve via surface stimulating and needle recording electrodes was performed on right hind limbs of all the dogs. The compartment pressures of the tarsal canal with the pressure transducer were determined from both limbs from ten of the dogs. In one dog, tarsal regions of both left and right limbs were demonstrated using magnetic resonance imaging (MRI). Two dogs were euthanatized and tarsal regions of the dogs were sectioned for correlative anatomy. Nerve conduction studies showed that the MNAP latency of the tibial nerve were 3.55 +/- 0.097 ms, 3.76 +/- 0.087 ms and 3.39 +/- 0.097 ms in neutral, hyperextension and hyperflexion positions, respectively. Hyperflexion of the tarsal joint caused prolongation of the MNAP latency of the tibial nerve with the highest pressure value being determined in tarsal canal. From the anatomical viewpoint, the distance between the flexor hallucis longus muscle and the superficial digital muscle was the shortest during hyperflexion and the plantar branch of saphenous artery, lateral and medial plantar nerves located more laterally in cadaver and MR imaging sections. As a result of this study, it is thought that tarsal region diseases as well as long time splint in the hyperflexion position as applied in the Ehmer sling can affect the compartment pressure and nerve tension because of occupying in the tarsal canal. Raising pressure and nerve stretching in the tarsal canal compartment could cause deficiencies in the conduction velocity of the tibial nerve. This might be a result of tarsal tunnel syndrome in the dog. Clinicians could consider this syndrome in cases of tarsal region diseases as well as application of long time splint in hyperflexion of tarsal joints in dogs.     

Sensory action potentials in the ulnar and radial nerves of dogs: effect of stimulation site and voltage

The influence of stimulation site and voltage on amplitude, wave form, conduction time, and velocity of sensory action potentials in the ulnar and radial nerves was evaluated in 25 healthy dogs. A 5-fold increase in stimulation voltage above threshold caused a 300% increase in the amplitude of evoked sensory nerve potentials. An additional 2-fold increase in stimulation voltage (to 10 times threshold) resulted in an additional 40% increase in amplitude. An absolute saturation voltage was not found. Latency velocity was increased by increasing stimulation voltage, but conduction velocity was not affected. Multicomponent nerve action potentials were frequently found at the proximal recording sites. The number of components was not affected by stimulation voltage. Proximal displacement of the stimulation site resulted in an increase in amplitude of the nerve action potentials, increased latency velocity, and fewer components; conduction velocity was not affected. As a consequence of these findings, preference was given to simultaneous recording at 2 sites along the nerve, stimulation at the more proximal stimulation site distal to the carpus, and stimulation voltages between 5 and 10 times the threshold. The occurrence of multicomponent wave forms, the absence of an absolute saturation voltage, and the lowering of the number of components by proximal displacement of the site of stimulation may all be related to the relatively small number of sensory nerve fibers that can be activated at the stimulation site.     

Characterization of the antinociceptive and sedative effect of amitraz in horses

Amitraz, an acaricide used to control ectoparasites in animals has a complex pharmacological activity, including α₂-adrenergic agonist action. The purpose of this research was to investigate the possible antinociceptive and/or sedative effect of amitraz in horses. The sedative effect of the intravenous (i.v.) injection of dimethylformamide (DMF, 5 mL, control) or amitraz (0.05, 0.10, 0.15 mg/kg), was investigated on the head ptosis test. The participation of α₂-adrenergic receptors in the sedative effect provoked by amitraz was studied by dosing yohimbine (0.12 mg/kg, i.v.). To measure the antinociception, xylazine hydrochloride (1 mg/kg, i.v., positive control) and the same doses of amitraz and DMF were used. A focused radiant light/heat directed onto the fetlock and withers of a horse were used as a noxious stimulus to measure the hoof withdrawal reflex latency (HWRL) and the skin twitch reflex latency (STRL). The three doses of amitraz used (0.05, 0.10 and 0.15 mg/kg) provoked a dose-dependent relaxation of the cervical muscles. The experiments with amitraz and xylazine on the HWRL showed that after i.v. administration of all doses of amitraz there was a significant increase of HWRL up to 150 min after the injections. Additionally, there was a significant difference between control (DMF) and positive control (xylazine) values up to 30 min after drug injection. On the other hand, the experiments on the STRL show that after administration of amitraz at the dose of 0.15 mg/kg, a significant increase in STRL was observed when compared with the control group. This effect lasted up to 120 min after injection. However, no significant antinociceptive effect was observed with the 0.05 and 0.10 mg/kg doses of amitraz or at the 1.0 mg/kg dose of xylazine.     

A new method for recording and analysing evoked motor potentials from dogs

Normal values for motor conduction in the tibial, ulnar and fibular nerves of dogs have been determined using a new method for recording and analysing evoked motor potentials. The use of an alligator clip as a roving surface electrode for recording, and a personal computer to analyse the evoked potentials has facilitated faster and more reproducible motor conduction studies. Compound muscle action potential (CMAP) and motor nerve conduction velocity data are in good agreement with previous studies. Normal values for CMAP area, residual latency and proximal to distal ratios for CMAP area and amplitude are presented for the first time.     

Laryngeal Paralysis-Polyneuropathy Complex in Young Rottweilers

Five Rottweiler puppies from 3 unrelated litters developed inspiratory stridor at 11–13 weeks of age. Physical examination disclosed tetraparesis in all dogs, and bilateral lenticular cataracts in 4 dogs. Laryngeal examination under light anesthesia showed laryngeal paralysis in all dogs. Electrodiagnostic testing revealed denervation potentials in the distal appendicular muscles of 4 dogs tested and in the intrinsic laryngeal muscles of 2 dogs tested. Motor nerve conduction velocity was slightly low in 1 dog. Neurogenic muscular atrophy was found in distal appendicular muscles (n = 3) and intrinsic laryngeal muscles (n = 2), and degenerative changes were found in peripheral nerves (n = 3) and recurrent laryngeal nerves (n = 2). No abnormalities were detected in the spinal cord, spinal nerve roots, or ganglia of 3 dogs autopsied. The clinical, electrophysiologic, and histopathologic findings support a diagnosis of polyneuropathy and resemble the finding reported in young Dalmatians. Young dogs with laryngeal paralysis should be evaluated neurologically to rule out a more generalized polyneuropathy. The condition is suspected to be hereditary in nature and the prognosis is poor.     

Evaluation of the efficacy and safety of a novel formulation of metaflumizone plus amitraz in dogs naturally infested with fleas and ticks in Europe

The efficacy and safety of a novel spot-on formulation of metaflumizone plus amitraz (ProMeris/ProMeris Duo for Dogs, Fort Dodge Animal Health, Overland Park, KS) was assessed in dogs naturally infested with ticks and/or fleas in a multiregional, clinical field study. Nineteen veterinary clinics in Germany and 11 clinics in France enrolled patients to the study. One hundred eighty one dogs with tick infestation and 170 dogs with flea infestation (plus three dogs harboring both ticks and fleas) qualified as primary patients and were randomly allocated to one of two treatments in a ratio of approximately 2:1 for metaflumizone plus amitraz (minimum dosage of 20 plus 20mg/kg) or fipronil (at the recommended label rate). Clinical examinations and baseline parasite counts were performed on Day 0 prior to treatment. Tick and/or flea counts and safety evaluations were repeated at intervals of about 2 weeks for 8 weeks. Both products resulted in consistent reductions in tick numbers (>81%) throughout the study, with metaflumizone plus amitraz giving consistently higher reductions in tick numbers. The efficacy against tick count compared with Day 0 was 97.6%, 93.5%, 89% and 94% at Day 14, 28, 42 and 56, respectively, for metaflumizone plus amitraz. The corresponding efficacies for fipronil were 86.3%, 81.1%, 84.8% and 86.1%. Within groups, the tick reduction was highly significant (P<0.0001) compared to baseline at all observation periods. Both treatments resulted in consistent (>89%) and highly significant (P<0.0001) reductions in flea numbers relative to the baseline counts throughout the study, although fipronil resulted in numerically higher reductions on each count day. The efficacy against fleas compared to baseline was 91.8%, 88.7%, 91.5% and 92.0% at Day 14, 28, 42 and 56, respectively, for metaflumizone plus amitraz. The corresponding efficacies for fipronil were 98.2%, 96.3%, 95.9% and 96.7%. Metaflumizone plus amitraz was highly effective in controlling existing infestations of fleas and ticks on dogs and was effective against reinfestation for at least 56 days. Metaflumizone plus amitraz showed a good tolerance profile in dogs.     

Dose determination of a novel formulation of metaflumizone plus amitraz for control of cat fleas (Ctenocephalides felis felis) and brown dog ticks (Rhipicephalus sanguineus) on dogs

A novel spot-on formulation containing metaflumizone and amitraz (ProMeris/ProMeris Duo for Dogs, Fort Dodge Animal Health, Overland Park, KS) was evaluated in a laboratory study to determine the appropriate dose for efficacy against fleas and ticks on dogs for 1 month. Thirty-six Beagles were randomly allocated to six equal groups and individually housed. One group remained nontreated. Another was treated with a placebo formulation (solvents with no active ingredients). Three groups of dogs were treated topically with the metaflumizone plus amitraz formulation (150mg of each of metaflumizone and amitraz/ml), at volumes providing doses of 10, 20 and 40mgeachactive/kg. The final group was treated with a commercial spot-on providing 6.7mgfipronil/kg. All treatments were applied to the skin at a single spot between the scapulae on Day 0. Dogs were infested with 50 adult brown dog ticks (Rhipicephalus sanguineus) on each of Days -2, 5, 12, 19, 26, 33 and 40, and with 100 cat fleas (Ctenocephalides felis felis) on Days -1, 6, 13, 20, 27, 34 and 41. Dogs were examined and parasites "finger counted" on Day 1 to estimate knock down efficacy, and all animals were comb counted to determine the numbers of viable fleas and ticks on Days 7, 14, 21, 28, 35 and 42. There were no significant differences in parasite counts between the nontreated control and the placebo-treated control groups for either fleas or ticks (P>0.05) except for very slight reductions on Day 7 for fleas and Day 14 for ticks, demonstrating that the formulation excipients had no activity. The qualitative finger counts on Day 1 indicated that all of the insecticidal treatments resulted in a noticeable reduction in flea and tick numbers within 1 day of treatment. All of the metaflumizone and amitraz treatments and fipronil resulted in significantly lower flea and tick numbers relative to nontreated controls on all posttreatment count days (P<0.05). For the metaflumizone plus amitraz treatments, mean flea and tick counts for the 10mg/kg dose were significantly higher than those for the 20mg/kg dose (P<0.05) from Day 21 on. There was no significant advantage provided by the 40mg/kg dose over the 20mg dose throughout the entire study (P>0.05). The two higher metaflumizone plus amitraz doses provided >95% control of fleas and >90% control of ticks for at least 35 days after treatment, and this level of control was similar to that of the commercial fipronil product. The 20mg/kg dose was selected as the minimum commercial dose rate to provide effective flea and tick control for at least 1 month following a single treatment.     

Pharmacokinetics of metaflumizone and amitraz in the plasma and hair of dogs following topical application

Controlled laboratory studies have shown that a metaflumizone plus amitraz combination (ProMeris/ProMeris Duo for Dogs, Fort Dodge Animal Health, Overland Park, KS) applied topically is effective for the treatment and control of fleas and ticks on dogs. Two studies were conducted to determine the distribution of both metaflumizone and amitraz in the plasma and hair of dogs following treatment at the minimum recommended dose of approximately 20mg/kg of each active ingredient. Six purpose-bred, adult Beagle dogs were used in each study. Plasma or hair samples were collected from each dog just prior to dosing and periodically through 56 days after treatment. Samples were analyzed by HPLC methods validated for the simultaneous determination of metaflumizone and amitraz. Amitraz was detectable (>3.2ng/ml) but not quantifiable (<50ng/ml) in only two plasma samples, collected 1 and 2 days post-treatment from different dogs. Metaflumizone concentrations in plasma were generally detectable (>1.0ng/ml) but not quantifiable (<50ng/ml). Measurable levels were found in one dog 7 days post-treatment, increasing to a maximum of four dogs at 42 days after dosing, with a metaflumizone range of 59-138ng/ml. Analysis of hair samples indicated that both metaflumizone and amitraz were widely distributed at basically similar levels in the hair within 1-day after administration, reaching maximum concentrations between 2 and 7 days post-treatment. Low but quantifiable levels of both compounds were still present on hair at the end of the 56-day study. These studies indicate that the ectoparasitic activity is due to exposure of the parasites to metaflumizone and amitraz on the surface of the host (hair and/or skin), not to exposure via the circulatory system of the host.     

药物治疗犬疥螨病比较试验

为了评估对犬疥螨病的治疗效果,将80只确诊为犬疥螨病的病犬随机分为4组,每组20只.第1组用阿维菌素加杀螨灵治疗；第2组用阿维菌素加双甲脒治疗；第3组用伊维菌素加杀螨灵治疗；第4组用伊维菌素加双甲脒治疗.结果表明,第1组治愈率为85％,第2组治愈率为80％,第3组治愈率为90％,第4组治愈率为95％.结果表明第4组的治...