Dose related effects of the kappa agonist U-50, 488H on behaviour, nociception and autonomic response in the horse

Current opiate receptor theory suggests that kappa agonists should provide good analgesia without producing marked central nervous system stimulation. U-50,488H is an experimental narcotic analgesic that is a selective kappa agonist. In the present study, U-50,488H produced good analgesia in horses using both the skin twitch and hoof withdrawal reflex assays. Further, the analgesia was relatively long lasting (120 mins) compared to other mu-agonists tested in horses. The locomotor response to U-50,488H was less than observed with ethylketazocine and butorphanol, and has yielded the smallest locomotor response of any of the narcotic analgesics tested to date. Other work showed that the autonomic responses to U-50,488H were less than those of other narcotic analgesics, and that the analgesic response to this drug was blocked by naloxone. Based on its ability to produce analgesia with little other stimulatory action, U-50,488H shows promise of becoming a useful narcotic analgesic in equine medicine.     

Pharmacology of narcotic analgesics in the horse: selective blockade of narcotic-induced locomotor activity

The locomotor responses of horses given morphine and fentanyl were blocked or lessened by administration of naloxone or acepromazine. Naloxone given at the dosage of 0.015 mg/kg completely blocked the locomotor activity induced in horses given fentanyl (0.020 mg/kg of body weight). The locomotor stimulation produced by morphine given at the dosage of 2.4 mg/kg was reduced by 75% of naloxone (0.020 mg/kg). Acepromazine partially blocked the locomotor responses to fentanyl and morphine. This blockade activity reached its peak about 30 minutes after acepromazine was given (IV) and lasted more than 6 hours. Simultaneous administration of acepromazine and morphine was associated with substantial respiratory depression for more than 4 hours after administration of both drugs. In other experiments, fentanyl did not add to the partial locomotor response observed after large doses of pentazocine were given--this being consistent with the concept that pentazocine possesses both antagonist and agonist actions at the narcotic receptor. Furosemide and phenylbutazone, given at usually used clinical doses, had no effect on the locomotor response to fentanyl, indicating that the usual clinical dosages of neither drug exerted stimulant or depressant actions.     

Comparative effects of mu and kappa opiate agonists on the cecocolic motility in the pony.

The electrical and mechanical activity of the large intestine and its response to administration of opiate mu and kappa agonists were assessed from electrodes and inductograph coils chronically implanted on the cecocolic segment in six ponies given a diet of hay and concentrates. Before the drugs were given, migrating complexes propagating from the cecum into the colon occurred at the rate of 1.5 to 16/hour. During this propulsive activity, the cecocolic sphincter opened and closed allowing the outflow of cecal contents and preventing the backflow of colic contents. Each pony was used as its own control and was given fentanyl (0.01 and 0.05 mg/kg of body weight, IV) and U50488H (0.1 and 0.5 mg/kg, IV) at weekly intervals. The mu agonist fentanyl elicited a marked phase of inhibition of the propulsive activity and a closure of the cecocolic sphincter that lasted one to two hours depending on the dose. The kappa agonist U50488H induced an inhibition of the short spiking activity, i.e. of the resting muscle tone. It did not disturb the occurrence of migrating complexes nor that of the openings of the cecocolic sphincter. These kappa compounds may be drugs of choice to alleviate visceral pain in colic stases without inducing delay of transit unlike mu compounds.     

Narcotic analgesics, their detection and pain measurement in the horse: a review

Narcotic analgesics produce pharmacological effects by interacting with specific opiate receptors. At least five major types of opiate receptors have been recognised. These include mu (morphine) and kappa (ethylketazocine) receptor types. Narcotic analgesics which interact with mu receptors produce locomotor and autonomic stimulation at doses that produce little or no analgesia. Therefore, use of these drugs as analgesics in equine medicine has not been very satisfactory. Theoretical considerations suggested that the role of kappa agonists in equine analgesia be investigated. Using a pure kappa agonist, U-50, 488H, good analgesia was produced in the horse with little or no locomotor stimulation or autonomic effects. These data suggest that kappa agonists may be superior analgesics for clinical use in the horse. On the other hand, the locomotor stimulant effects of mu agonist analgesics enable their use as illegal medications. Specifically, these agents produce a good running response, signs of central nervous stimulation and analgesia, all potentially useful effects in a racehorse. Regulatory control of most narcotic analgesics can be obtained by high performance thin layer chromatographic screening. However, effective screening for the fentanyls and small doses of etorphine can only be achieved by use of immunoassay.     

The pharmacokinetics and locomotor activity of alfentanil in the horse

The pharmacokinetics of alfentanil were investigated in the horse. Four doses of alfentanil (4, 10, 20 and 40 micrograms/kg) were given to four horses at different times and their locomotor activity monitored. Doses of 20 and 40 micrograms/kg produced a significant increase in locomotor activity. The plasma concentrations of alfentanil were measured in six standing horses and the pharmacokinetics calculated. It was found that the decay curves were best described by a biexponential equation. The elimination half-life (t1/2 beta) was 21.65 +/- 3.99 min and the clearance (Cl) was 14.1 +/- 0.7 ml/kg/min. The same horses were anaesthetized with xylazine-ketamine and maintained with halothane in oxygen for the first experiment and isoflurane in oxygen for the second experiment. The pharmacokinetics were again calculated from measured plasma alfentanil concentrations. There were significant differences between the kinetics in the conscious and the anaesthetized animals but there were no significant differences in alfentanil kinetics between the two anaesthetic agents. The t1/2 beta for alfentanil under halothane and isoflurane anaesthesia were 55.95 +/- 20.77 and 68.03 +/- 23.22 min, respectively, and the Cl values were 14 +/- 1.7 and 13.6 +/- 1.32 ml/kg/min.     

A comparison of the sedative effects of three α2-adrenoceptor agonists (romifidine, detomidine and xylazine) in the horse

The sedative effects of a new alpha 2-adrenoceptor agonist, romifidine, were compared with those of xylazine and detomidine. Five horses were treated with two doses of romifidine (40 micrograms/kg body weight and 80 micrograms/kg body weight), two doses of detomidine (10 micrograms/kg body weight and 20 micrograms/kg body weight) and one dose of xylazine (1 mg/kg body weight) given by intravenous injection using a Latin-square design. The dose of 80 micrograms/kg romifidine appeared equipotent to 1 mg/kg xylazine and 20 micrograms/kg detomidine, although at these doses both xylazine and detomidine had a shorter action. Detomidine 20 micrograms/kg and xylazine both produced greater lowering of the head and a greater degree of ataxia than romifidine at either dose. Romifidine produced sedation similar to that of the other drug regimes. The effect upon imposed stimuli was similar.     

Pharmacologic effects and detection methods of methylated analogs of fentanyl in horses

Pharmacologic effects of alpha-methylfentanyl and 3-methylfentanyl, analogs of fentanyl, were investigated in mares. The ability of an 125I-labeled fentanyl radioimmunoassay (125I-RIA) to detect these methylated fentanyl analogs in individual and pooled urine samples from horses was evaluated. Also, the ability of 7 fentanyl antibodies to react with fentanyl and fentanyl derivatives (sufentanil, alfentanil, and carfentanil) was investigated. Mares were studied in a locomotor test to determine the amount of stimulation methylated fentanyl analogs might induce. Two mares each were given alpha-methylfentanyl at 1, 2, 4, 8, or 13 micrograms/kg of body weight, IV, or 3-methylfentanyl at 0.4, 0.7, or 1 microgram/kg IV. The cross-reactivity of sufentanil, alfentanil, carfentanil, alpha-methylfentanyl, and 3-methylfentanyl with 7 fentanyl antibodies was studied, using the 125I-RIA. All fentanyl analogs, with the exception of alfentanil, cross-reacted well with a C1 antibody raised to fentanyl. Less satisfactory cross-reactivity was determined with 6 other antibodies raised to fentanyl derivatives. When the C1 antibody was combined with an iodinated analog to fentanyl, good detectability of alpha-methylfentanyl and 3-methylfentanyl, in terms of fentanyl equivalents, was obtained from urine samples of dosed mares. The ability of the 125I-RIA to detect methylated fentanyl analogs in forensic urine samples pooled in groups of up to 20 samples was evaluated. When these methylated analogs were administered to mares in doses that induced measurable locomotor stimulation, the analog's presence was readily detected in individual or pooled samples.     

Cardiovascular effects of romifidine in the standing horse

The cardiovascular effects of romifidine, an alpha-2 adrenoreceptor agonist, were investigated in six horses using two doses (80 and 120 microg kg(-1)) in a cross-over study design. Cardiac index and mixed venous oxygenation were significantly decreased at 15 and 30 minutes after both doses of romifidine. Systemic vascular resistance was significantly increased with romifidine (120 microg kg(-1)). Arterial blood pressure increased initially and then gradually decreased; the doses of decrease was significant at 90 and 120 minutes with romifidine 80 and 120 microg kg(-1). There were minimal differences between the two doses of romifidine, and both should be used with care especially in horses with cardiovascular compromise, or when used in combination with other cardiovascular depressant drugs.     

Development and characterization of an equine behaviour chamber and the effects of amitraz and detomidine on spontaneous locomotor activity

This report describes the development of a behaviour chamber and the validation of the chamber to measure locomotor activity of a horse. Locomotor activity was detected by four Mini-beam sensors and recorded on a data logger every 5 min for 22 h. Horses were more active during daytime than in the evening, which was at least partially related to human activity in their surroundings. To validate the ability of the chambers to detect changes in activity, fentanyl citrate and xylazine HCl, agents well-characterized as a stimulant and a depressant, respectively, were administered to five horses. Fentanyl citrate (0.016 mg/kg) significantly increased locomotor activity which persisted for 30 min. Xylazine HCl (1 mg/kg) significantly reduced locomotor activity for 90 min. Amitraz produced a dose-dependent decrease in locomotor activity, lasting 75 min for the 0.05 mg/kg dose, 120 min for the 0.10 mg/kg dose, and 180 min for the 0.15 mg/kg dose. In a separate experiment, yohimbine administration immediately reversed the sedative effect of amitraz. This suggests there is a similarity in the mode of action of amitraz, xylazine and detomidine, as yohimbine acts primarily by blocking central α 2 -adrenoceptors that are stimulated by agents like xylazine. There was also a significant decrease in locomotor activity following injection of detomidine (0.02, 0.04 and 0.08 mg/kg) for 1.5, 3.5 and 5.0 h, respectively. The locomotor chamber is a useful, sensitive and highly reproducible tool for measuring spontaneous locomotor activity in the horse, which allows investigators to determine an agent's average time of onset, duration and intensity of effect on movement.     

Comparison of the sedative effects of medetomidine and xylazine in horses.

The sedative effects in horses of the new alpha 2 agonist medetomidine were compared with those of xylazine. Four ponies and one horse were treated on separate occasions with two doses of medetomidine (5 micrograms/kg bodyweight and 10 micrograms/kg bodyweight) and with one dose of xylazine (1 mg/kg bodyweight) given by intravenous injection. Medetomidine at 10 micrograms/kg was similar to 1 mg/kg xylazine in its sedative effect but produced more severe and more prolonged ataxia, and one animal fell over during the study. Medetomidine at 5 micrograms/kg produced less sedation but a similar degree of ataxia to 1 mg/kg xylazine.     

Pharmacology, pharmacokinetics, and behavioral effects of caffeine in horses

Caffeine (4 mg/kg) was given by rapid IV injection to 4 horses. Plasma concentrations of the drug peaked at 10 micrograms/ml and decreased rapidly at first, and then more slowly, with an apparent beta-phase half-life of 18.2 hours. Urinary concentrations of caffeine were remarkably consistent at about 3 times plasma values of the drug. Caffeine was detectable in both plasma and urine of the horses for up to 9 days after dosing. After oral administration, caffeine was absorbed poorly with an apparent bioavailability of 39%. Although blood concentrations of caffeine peaked rapidly after oral administration, its apparent plasma half-life by this route was about 42 hours. These observations identify the possible existence of a slowly absorbed pool of caffeine in the gastrointestinal tract after oral administration. When caffeine-treated horses were given fentanyl, the locomotor response to fentanyl was enhanced. This potentiation of the fentanyl response peaked at between 0 and 4 hours after dosing and was gone by 72 hours after caffeine dosing. The data indicate that the probability of behavioral stimulation due to caffeine by 72 hours after dosing may be small.     

Pharmacokinetics of fentanyl following intravenous and transdermal administration in horses

REASONS FOR PERFORMING STUDY: Although fentanyl has been reported to cause CNS excitation in horses, a transdermal therapeutic system (TTS) containing this mu agonist has recently been used empirically in equine medicine to treat moderate to severe pain. A better understanding of the disposition of fentanyl following transdermal administration would facilitate the clinical use of TTS fentanyl to obtain analgesia in horses. OBJECTIVES: To determine the pharmacokinetics of fentanyl following i.v. and TTS patch administration in healthy, mature horses and to evaluate the tolerance of horses to TTS fentanyl administration. METHODS: The pharmacokinetics of fentanyl in serum were assessed following a single i.v. dose, a single TTS dose, and multiple TTS doses in 6 healthy horses. Physical examinations, haematology and serum biochemistry analyses during transdermal fentanyl application were then performed to determine tolerance of continuous fentanyl administration. RESULTS: Fentanyl was very rapidly and completely absorbed following a single TTS dose. Mean serum fentanyl concentrations consistent with analgesia in other species were reached by 1 h and maintained until 32 h after patch application. Similar steady state serum concentrations were obtained when multiple doses of TTS fentanyl were administered every 48 or 72 h over 8 or 9 days, with less fluctuation in serum concentrations during the 48 h dosing interval. Three horses exhibited brief (< 12 h) episodes of increased body temperature; however, transdermal fentanyl administrations were not associated with other significant changes in haematology and biochemistry panels or physical examination findings. CONCLUSIONS AND POTENTIAL RELEVANCE: Although the pharmacodynamics of fentanyl have not been investigated fully in horses, transdermally-administered fentanyl exhibited a favourable pharmacokinetic profile without clinically relevant side effects and may be a useful analgesic in equine patients.     

Verification of ineffectual activity of ivermectin against adult Onchocerca spp in the ligamentum nuchae of horses

Ivermectin paste formulation (200 micrograms/kg) was administered orally to 27 horses (13 Thoroughbreds and 14 of mixed breeding) to evaluate activity against adult Onchocerca spp in the ligamentum nuchae. Ages, known or estimated, of the horses ranged from 1 to 22 years. Single or multiple doses (1 to 5) of the drug were given to each horse. When multiple doses were administered, the intervals between treatments ranged from 7 to 92 days. At 27 to 171 days after initial treatment (single dose or first of multiple doses), the horses were killed. Some of the horses treated more than once were killed as soon as 7 days after the last treatment. At necropsy, Onchocerca spp were found in the ligamentum nuchae of 24 (89%) of the 27 horses. All of the specimens were pieces of worms, apparently adult, which appeared to be alive. The only noninfected horses were 2 to 3 years old. In 18 (75%) of the 24 infected horses, microfilariae, most being obviously viable, were found in the worm specimens or ligamentum nuchae.     

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.     

Influence of general anaesthesia on the pharmacokinetics of intravenous fentanyl and its primary metabolite in horses

REASONS FOR PERFORMING STUDY: In order to evaluate its potential as an adjunct to inhalant anaesthesia in horses, the pharmacokinetics of fentanyl must first be determined. OBJECTIVES: To describe the pharmacokinetics of fentanyl and its metabolite, N-[1-(2-phenethyl-4-piperidinyl)maloanilinic acid (PMA), after i.v. administration of a single dose to horses that were awake in Treatment 1 and anaesthetised with isoflurane in Treatment 2. METHODS: A balanced crossover design was used (n = 4/group). During Treatment 1, horses received a single dose of fentanyl (4 microg/kg bwt, i.v.) and during Treatment 2, they were anaesthetised with isoflurane and maintained at 1.2 x minimum alveolar anaesthetic concentration. After a 30 min equilibration period, a single dose of fentanyl (4 microg/kg bwt, i.v.) was administered to each horse. Plasma fentanyl and PMA concentrations were measured at various time points using liquid chromatography-mass spectrometry. RESULTS: Anaesthesia with isoflurane significantly decreased mean fentanyl clearance (P < 0.05). The fentanyl elimination half-life, in awake and anaesthetised horses, was 1 h and volume of distribution at steady state was 0.37 and 0.26 l/kg bwt, respectively. Anaesthesia with isoflurane also significantly decreased PMA apparent clearance and volume of distribution. The elimination half-life of PMA was 2 and 1.5 h in awake and anaesthetised horses, respectively. CONCLUSIONS AND POTENTIAL RELEVANCE: Pharmacokinetics of fentanyl and PMA in horses were substantially altered in horses anaesthetised with isoflurane. These pharmacokinetic parameters provide information necessary for determination of suitable fentanyl loading and infusion doses in awake and isoflurane-anaesthetised horses.     

Effects of fenoldopam on cecal blood flow and mechanical activity in horses

Lateral cecal arterial blood flow, carotid arterial pressure, heart rate, and mechanical activity in the duodenum, right ventral colon, cecal body, and cecal apex were measured in 6 conscious healthy horses for 60 minutes during and for 120 minutes after IV infusion of 0.9% NaCl solution (control) or fenoldopam. There were no significant changes in these measurements during or after infusion of 0.9% NaCl (saline) solution. Fenoldopam, a selective dopamine-1 receptor agonist, was administered in saline solution at dosages of 0.01, 0.05, and 0.1 micrograms/kg/min. Intravenous infusion of fenoldopam at 0.01 microgram/kg/min significantly increased heart rate, but did not change average carotid arterial pressure or lateral cecal arterial blood flow. Intravenous infusion of fenoldopam at both 0.05 and 0.1 microgram/kg/min significantly increased heart rate, significantly decreased average carotid arterial pressure, and significantly increased lateral cecal arterial blood flow. Intravenous infusion of fenoldopam at 0.01, 0.05, and 0.1 microgram/kg/min did not significantly change the mechanical activity measured by the area under the strain gauge deflection curve for the duodenum, right ventral colon, cecal body, or cecal apex. These results suggest that dopaminergic-1 receptors are present on the colonic vasculature of horses. There was no evidence, however, that dopaminergic-1 receptors exist on the visceral smooth muscle of the duodenum, right ventral colon, cecal body, or cecal apex of horses.     

The Influence of Detomidine and Epinephrine on Heart Rate, Arterial Blood Pressure, and Cardiac Arrhythmia in Horses

Detomidine (10 micrograms/kg and 20 micrograms/kg) was administered to seven horses with and without epinephrine infusion (0.1 microgram/kg/min) from 5 minutes before to 5 minutes after detomidine injection. One or more single supraventricular premature heartbeats were observed in three horses after detomidine administration. Epinephrine infusion did not modify the incidence of cardiac arrhythmias in detomidine-treated horses at the doses tested. Relatively high momentary peak systolic pressures were registered in some horses after detomidine administration during epinephrine infusion. The highest systolic arterial blood pressure was 290 mm Hg, but this value was not higher than that reported in horses during maximum physical exercise. Epinephrine infusion did not alter blood gases, arterial pH, or base excess.     

The prokinetic effect of mosapride citrate on horse gastric emptying rates

The prokinetic effect of the 5-HT4 receptor agonist mosapride was evaluated in seven healthy thoroughbreds. Mosapride was orally administered at doses of 0.5, 1.0 or 1.5 mg/kg. The breath 13CO2/12CO2 rate (Delta13CO2), an indirect indicator for the rate of gastric emptying, was measured at appropriate points for 4 hr after drug administration. There was a significant increase compared with the control value at 15, 20 and 165 min for 0.5 mg/kg, 30 min at 1.0 mg/kg and 165 min for 1.5 mg/kg. The results suggest that mosapride may facilitate the gastric emptying in horses.     

Effects of dopamine antagonists on alfentanil-induced locomotor activity in horses

Objective To determine whether specific dopamine receptor antagonists block alfentanil‐induced locomotor stimulation in horses. Study design Randomized, prospective, crossover experiment. Animals Eight adult horses (462–604 kg). Methods Doses of dopamine‐1 (D1) (NNC 01–0756) and dopamine‐2 (D2) antagonists (eticlopride) were selected in a pilot study prior to a three part, blinded, cross‐over study. In part 1, horses received 7.5 µg kg^?1 eticlopride, 5 µg kg^?1 NNC 01–0756 or an equal volume of saline. In part 2, they received both antagonists and in part 3, acepromazine at 0.05 mg kg^?1. Locomotor activity was assessed by counting the steps taken by a marked forefoot per 2 minutes. The D antagonist was injected IV after a 20‐minute control period. The horses were observed for 10 minutes before alfentanil (20 µg kg^?1) was injected IV. Locomotor activity was then monitored for 60 minutes. Statistical analysis was performed on step counts following alfentanil normalised by subtracting the mean control step count from each value recorded after alfentanil. Data were analysed using Friedman tests and Tukey‐Kramer comparisons. Results Alfentanil increased locomotor activity for 10 minutes. NNC 01–0756 tended to reduce locomotor activity between 0 and 10 minutes (p = 0.261), but neither D antagonist suppressed it significantly. The combination of D antagonists induced more step counts than saline or acepromazine (p = 0.0265) in the 20–40‐minute period and more than saline, acepromazine or eticlopride between 40 and 60 minutes (p = 0.0003). Conclusions Neither D1 nor D2 antagonists inhibited alfentanil‐induced locomotor activity. Both drugs appeared to cause locomotor stimulation of their own. Clinical relevance D1 and D2 antagonism did not reduce opioid‐induced excitement in horses and is not suitable for reducing the incidence of this unwanted side‐effect of opioids.     

Effects of epidural opioid analgesics on heart rate, arterial blood pressure, respiratory rate, body temperature, and behavior in horses

Heart rate, arterial blood pressures, respiratory rate, body temperature, and central nervous system excitement were compared before and after epidural administration of morphine (0.1 mg/kg), butorphanol (0.08 mg/kg), alfentanil (0.02 mg/kg), tramadol (1.0 mg/kg), the k-opioid agonist U50488H (0.08 mg/kg), or sterile water using an incomplete Latin square crossover design in five conscious adult horses. Treatments were administered into the first intercoccygeal epidural space. Significant (P <.05) reductions in respiratory rate were detected after epidural administration of morphine, alfentanil, U50488H, and sterile water. Additionally, significant (P <.05) head ptosis was observed within the first hour after administration of morphine, U50488H, and tramadol, but neither of these changes appeared to be of clinical significance. No treatment-related changes in motor activity or behavior were observed.