Cyclosporin immunosuppression of sheep: pharmacokinetics and allograft survival.

A chronically immunosuppressed sheep model was established using a regimen of cyclosporin A (CsA; 2-3mg/kg twice daily) and ketoconazole (10mg/kg twice daily). Blood CsA concentrations reached a steady-state after 17 days of treatment. The clearance of CsA decreased from a mean (95% CI) of 9.47 (6.2-12.7)ml/min/kg after a single (first) dose (3mg/kg i.v.) to 1.62 (1.38-1.86)ml/min/kg after 18 days of CsA (3mg/kg i.v. twice daily) co-administration with ketoconazole. These data indicated that the combination of CsA and ketoconazole could be used to give stable high concentrations of CsA in the sheep. Using this regimen in the sheep, the long-term survival of skin allografts was monitored as an indicator of effective immunosuppression. CsA in blood was measured daily and CsA dose adjusted to various target concentration ranges. Provided that the trough concentration of blood CsA was maintained between 1500-2500 mg/l, long-term healthy skin allografts were maintained on the sheep without significant adverse effects on haematological or biochemical parameters.

Assessment of the respiratory actions of intramuscular morphine in conscious dogs.

The actions on the respiratory system of 0.25, 0.5 and 1.0 mg kg(-1) morphine given intramuscularly were studied in conscious dogs. Dogs breathed oxygen with 0, 2 and 4 per cent CO(2), in that order, through a mask attached to a flow sensor and connected to a respiratory mechanics monitor. When a steady state period of respiration was reached breathing pure oxygen, respiratory rate, tidal volume, respiratory minute volume, peak expiratory flow rate and end tidal CO(2)(PetCO(2)) were measured. The respiratory minute volume and PetCO(2) were measured when the dogs breathed 2 and 4 per cent CO(2) in oxygen, the points plotted onto a graph and the gradient of the line, describing the PCO(2)/ventilation response, plus the intercept with the y-axis were determined. Measurements for each morphine dose were taken before injection and at 30 minutes, 1, 2, 3, 4, 6 and 8 hours post injection. The incidence of panting after morphine was dose related and it occurred in all dogs given the high dose. Morphine reduced the gradients of the PCO(2)/ventilation response lines and raised the intercept. Other changes were increased respiratory minute volume and peak expiratory flow and decreased PetCO(2) and tidal volume.

Effects of tiletamine/zolazepam premedication on propofol anaesthesia in dogs.

The cardiovascular and pulmonary effects of tiletamine/zolazepam, propofol and tiletamine/zolazepam plus propofol were studied in five mongrel dogs. A cannula inserted into a raised carotid artery was used to measure mean arterial pressure (MAP) and heart rate continuously and to collect arterial blood for the determination of pH, PO2, PCO2, bicarbonate and base balance. Respiratory frequency and rectal temperature were also recorded. In the two propofol groups premedication had no significant effect on the time to rejection of an endotracheal tube and the return to sternal recumbency. The MAP and heart rate increased after tiletamine/zolazepam alone and after tiletamine/zolazepam plus propofol, although propofol alone reduced MAP and transiently increased heart rate. Respiratory frequency decreased transiently in both propofol groups in association with a significant increase in PaCO2 and decrease in PaO2. The most notable change was the hypoxaemia in the tiletamine/zolazepam plus propofol group in which the PaO2 was reduced. In all the dogs given tiletamine/zolazepam alone undesirable side effects were observed, effects which also occurred during the recovery of the dogs given tiletamine/zolazepam plus propofol.

Medetomidine sedation in dogs and cats: a review of its pharmacology, antagonism and dose.

Medetomidine is a relatively new sedative analgesic in dogs and cats but some precautions are required when using it. It is a potent alpha 2-adrenoceptor agonist and stimulates receptors centrally to produce dose-dependent sedation and analgesia and receptors centrally and peripherally to cause marked bradycardia and decrease the cardiac output. While hypotension occurs frequently, higher doses of the sedative can raise the blood pressure due to an affect on peripheral receptors. Slowing of the respiratory rate is a frequent effect of medetomidine with some dogs showing signs of cyanosis. Other actions that follow medetomidine use are slowing of gastrointestinal motility, hypothermia, changes to endocrine function and, occasionally, vomiting and muscle twitching. The clinical use of medetomidine in dogs and cats is discussed. Recommended dose rates are presented along with precautions that should be taken when it is used alone for sedation, as an anaesthetic premedicant or in combination with ketamine, propofol or opioids. Hypoxaemia occurs frequently in dogs given medetomidine and propofol. The actions of medetomidine can be rapidly reversed with the specific alpha 2-adrenoceptor antagonist, atipamezole, which is an advantage because undesirable and sedative actions of medetomidine can be terminated.

Amitraz depresses cardiovascular responses to bilateral carotid occlusion.

The ectoparasiticide amitraz stimulates alpha 2-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 micrograms/kg and above significantly depressed pressor responses to carotid occlusion. By comparison, 2 micrograms/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 micrograms/kg) prevented the depressant effects of amitraz on the reflex, but prazosin (20 micrograms/kg), in separate experiments, had no effect.

Biochemical and haematological changes following prolonged halothane anaesthesia in horses.

Six healthy horses were anaesthetised with halothane (1.2 times the horse minimal alveolar concentration) in oxygen for more than 12 hours. Serum bilirubin, aspartate aminotransferase, alkaline phosphatase and L-iditol dehydrogenase values were significantly (P < 0.05) increased for up to nine days after anaesthesia. These changes suggest an anaesthesia related liver dysfunction. Creatine kinase increased to an average of more than 1400 IU litre-1 24 hours after anaesthesia and this change is indicative of muscle cell disruption. Renal-associated biochemical results, (that is serum creatinine and inorganic phosphate concentrations) were significantly increased transiently and are indicative of reduced renal function during and immediately after anaesthesia. Plasma concentrations of eicosanoids (6-keto-PGF1a, PGF2a, PGE and thromboxane) following anaesthesia were not different from preanaesthetic values. The magnitude of liver and muscle cell related increases in serum enzyme activities resulting from prolonged halothane anaesthesia was in excess of that previously reported for anaesthesia of shorter duration.

Circulatory and respiratory responses of spontaneously breathing, laterally recumbent horses to 12 hours of halothane anesthesia.

Cardiovascular and respiratory changes that accompany markedly long periods (12 hours) of halothane anesthesia were characterized. Eight spontaneously breathing horses were studied while they were positioned in left lateral recumbency and anesthetized only with halothane in oxygen maintained at a constant end-tidal concentration of 1.06% (equivalent to 1.2 times the minimal alveolar concentration for horses). Results of circulatory and respiratory measurements during the first 5 hours of constant conditions were similar to those previously reported from this laboratory (ie, a time-related significant increase in systemic arterial blood pressure, cardiac output, stroke volume, left ventricular work, PCV, plasma total solids concentration, and little change in respiratory system function). Beyond 5 hours of anesthesia, arterial blood pressure did not further increase, but remained above baseline. Cardiac output continued to increase, because heart rate significantly (P < 0.05) increased. Peak inspiratory gas flow increased significantly (P < 0.05) in later stages of anesthesia. There was a significant decrease in inspiratory time beginning at 4 hours. Although PaO2 and PaCO2 did not significantly change during the 12 hours of study, PVO2 increased significantly (P < 0.05) and progressively with time, beginning 6 hours after the beginning of constant conditions. Metabolic acidosis increased with time (significantly [P < 0.05] starting at 9 hours), despite supplemental IV administered NaHCO3. Plasma concentrations of eicosanoids: 6-keto-prostaglandin F1 alpha (PGF1 alpha, a stable metabolite of PGI2), PGF2 alpha, PGE, and thromboxane (TxB2, a stable metabolite of TxA2) were measured in 5 of the 8 horses before and during anesthesia. Significant changes from preanesthetic values were not detected. Dynamic thoracic wall and lung compliances decreased with time.

Xylazine or medetomidine premedication before propofol anaesthesia.

The duration of action and cardiopulmonary effects of propofol (6.55 mg/kg intravenously), xylazine (0.8 mg/kg intramuscularly), medetomidine (30 micrograms/kg intramuscularly), xylazine plus propofol (3 mg/kg intravenously) and medetomidine plus propofol (3 mg/kg intravenously) were compared in dogs. A cannula inserted into a raised carotid artery before the drugs were given allowed the continuous recording of blood pressure and heart rate and the measurement of arterial pH, PCO2, PO2, bicarbonate and base balance. Xylazine and medetomidine premedication prolonged propofol anaesthesia in dogs. Propofol alone reduced blood pressure and transiently raised heart rate. The apnoea and hypoxaemia induced by propofol alone also occurred in the premedicated groups with hypoxaemia being most evident in the medetomidine/propofol group. Bradycardia was a common feature in all the dogs given xylazine or medetomidine, but hypertension was consistently recorded in all the dogs given medetomidine.

Effects of general anesthesia on myoelectric activity of the intestine in horses.

Myoelectric activity was monitored from the terminal ileum, cecum, and colonic pelvic flexure by use of AgpAgCl bipolar electrodes in 4 adult horses before, during, and after general anesthesia. Horses were anesthetized by way of 3 commonly used regimens, including xylazine (1.1 mg/kg of body weight) and ketamine hydrochloride (2.2 mg/kg); thiopental sodium (7.7 mg/kg), followed by halothane vaporized in oxygen; and thiopental sodium (2.5 g) in guaifenesin (100 mg/ml) solution given to effect, followed by halothane in oxygen. All 3 anesthetic regimens decreased intestinal spike-burst activity in the areas monitored. The slowest return to preanesthetic myoelectric activity was observed after xylazine and ketamine administration. After both of the barbiturate/halothane anesthetic regimens, there was a rebound increase in spike-burst frequency, without alteration in the proportion of propagative myoelectric events. All 3 anesthetic regimens appeared to reset the timing of the small and large intestinal migrating myoelectric complexes. By 9 hours after recovery from anesthesia, the effects of anesthesia, irrespective of regimen, had disappeared. Although anesthesia significantly (P less than 0.05) altered intestinal myoelectric activity, no particular anesthetic regimen had a prolonged effect. Results of our study indicate that the particular chosen regimen of general anesthesia is unimportant in development of motility disturbances in horses after anesthesia.

Efficiency of trained cyclists using circular and noncircular chainrings.

The purpose of this study was to determine oxygen consumption (VO2), heart rate (HR) response, and rating of perceived exertion (RPE) of trained cyclists using noncircular and circular chainrings over a range of gears and pedal cadences. The subjects included 7 male cyclists (6 USCF licensed riders, 1 national qualifying triathlete). Each subject rode his own bicycle mounted on a wind-trainer at gears of 5.92 and 7.33 meters with noncircular and circular chainrings at pedal cadences of 50, 70, and 90 rpm. VO2, HR, RPE, and respiratory exchange ratio (RER) measurements were made during each of the 12 rides. Mean percent VO2max for each condition ranged from 28.7 +/- 2.1% with the 5.92 meter gear at 50 rpm to 83.4 +/- 4.3% using the 7.33 meter gear at 90 rpm. The results indicate no significant difference in any of the parameters measured between the two chainrings for any of the experimental conditions. The data indicate that the noncircular chainrings used in this study were not more efficient than the standard circular chainring for trained cyclists.

Central and peripheral alpha-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.

Effects of amitraz on nerve conduction and neuromuscular transmission in anaesthetised dogs.

Ataxia is an occasional side effect of amitraz when used as a wash to treat dogs with demodectic mange. In the present study, successive doses of 0.5, 2, 5 and 10 mg kg-1 amitraz were given intravenously at intervals of nine minutes to thiopentone/methoxyflurane/oxygen anaesthetised dogs. The amplitude of the evoked muscle action potential to electrical stimulation of the right ulnar nerve and the muscle refractory period were unchanged by increasing doses of amitraz but there was a progressive and significant decrease in nerve conduction velocity. The minimum recorded nerve conduction velocity (50.7 +/- 1.5 m s-1) was still within an adequate range. From these results it appears that the ataxia following amitraz is unlikely to be attributable to peripheral mechanisms. The concurrent amitraz-induced rise in mean arterial pressure and bradycardia was consistent with previous findings in which alpha 2-adrenoceptors were shown to be the major mediators.

Effect of high PaCO2 and time on cerebrospinal fluid and intraocular pressure in halothane-anesthetized horses.

The effects of different arterial carbon dioxide tensions (PaCO2) on cerebrospinal fluid pressure (CSFP) and intraocular pressure (IOP) were studied in 6 male halothane-anesthetized horses positioned in left lateral recumbency. Steady-state anesthetic conditions (1.06% end-tidal halothane concentration) commenced 60 minutes following anesthetic induction with only halothane in oxygen. During atracurium neuromuscular blockade, horses were ventilated, and respiratory rate and peak inspiratory airway pressure were maintained within narrow limits. The CSFP and IOP were measured at 3 different levels of PaCO2 (approx 40, 60, and 80 mm of Hg). The PaCO2 sequence in each horse was determined from a type of switchback design with the initial PaCO2 (period 1), established 30 minutes after the commencement of steady-state anesthesia, being repeated in the middle (period 3) and again at the end (period 5) of the experiment. Measurements taken from the middle 3 periods (2, 3, and 4) would form a Latin square design replicated twice. The interval between each period was approximately 45 minutes. Data from periods 2, 3, and 4 indicated that CSFP (P less than 0.05) and mean systemic arterial pressure increased significantly (P less than 0.05) with high PaCO2. Mean central venous pressure, heart rate, and IOP did not change significantly during these same conditions. Measurements taken during periods 1, 3, and 5 were compared to assess the time-related responses to anesthesia and showed a significant increase in CSFP, a significant decrease in mean central venous pressure, and a small (but not statistically significant) increase in mean systemic arterial pressure.

Cardiovascular responses to amitraz in the presence of autonomic antagonists and agonists.

Blood pressure and heart rate were recorded continuously in methoxyflurane anaesthetized dogs. Amitraz (i.v.) caused a dose-dependent rise in blood pressure with a fall in heart rate at lower doses. Pressor responses to amitraz were reduced by phentolamine and slightly enhanced by atropine and hexamethonium, while bradycardia was reduced by phentolamine, atropine and hexamethonium. Amitraz reduced the responses to acetylcholine and enhanced pressor responses to tyramine, while reducing bradycardia. Pressor responses to DMPP were reduced, but there was little effect on responses to noradrenaline, isoprenaline or histamine. It is possible that amitraz exerts its cardiovascular effects by stimulation of alpha 2-adrenoceptors and has some similarities to clonidine and xylazine in action.

Anaesthesia in two species of large Australian skink.

The use of ketamine hydrochloride and sodium pentobarbitone in the anaesthesia of two species of Australian skink was examined. The effects of ketamine at ambient temperatures of 15 degrees C and 30 degrees C were studied. Ketamine produced consistent responses up to and including anaesthesia at dose rates of 170 to 230 mg/kg at 30 degrees C. The effect of temperature on the anaesthetic dose, respiratory and cardiac rates, muscle relaxation, analgesia and the onset and duration of anaesthesia was examined. Respiration in both species was depressed but heart rate was increased in Bobtail skinks (Tiliqua rugosa) and depressed in King's skinks (Egernia kingii). Muscle relaxation was good when anaesthetic doses were given. Generally, the onset and duration of anaesthesia were extended at 15 degrees C while the dose rates required for this effect were reduced. Although there was individual variation in the response to ketamine, it was found to be a useful and practical agent for the anaesthesia of large skinks. Pentobarbitone was found to be unsuitable as an anaesthetic agent because it produced inconsistent results and several fatalities.

Venoconstriction causes different effects in the hindquarters venous compartment of cats and dogs.

1. A study was made of venoconstrictor mechanisms in the hindquarters region of cats and dogs by the use of autoperfused hindquarter preparations, together with the measurement of vena cava blood flow (VCBF). 2. Noradrenaline, adrenaline and angiotensin II (AII) were all administered intraarterially and their ability to alter perfusion pressure and VCBF was examined. 3. All three drugs increased perfusion pressure in both cats and dogs as a result of increases in arterial resistance. At the same time, noradrenaline and adrenaline increased VCBF in cats, while AII had a variable effect. In contrast, all three drugs decreased VCBF in dogs. 4. These differences in the venoconstrictor responses obtained in cats and dogs may be explained by an action of the drugs at different loci within the venous compartment of the two species.

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.