Antagonistic effects of atipamezole, yohimbine, and prazosin on xylazine-induced diuresis in clinically normal cats.

This study aimed to investigate and compare the antagonistic effects of atipamezole, yohimbine, and prazosin on xylazine-induced diuresis in clinically normal cats. Five cats were repeatedly used in each of the 9 groups. One group was not medicated. Cats in the other groups received 2 mg/kg BW xylazine intramuscularly, and saline (as the control); 160 µg/kg BW prazosin; or 40, 160, or 480 µg/kg BW atipamezole or yohimbine intravenously 0.5 h later. Urine and blood samples were collected 10 times over 8 h. Urine volume, pH, and specific gravity; plasma arginine vasopressin (AVP) concentration; and creatinine, osmolality, and electrolyte values in both urine and plasma were measured. Both atipamezole and yohimbine antagonized xylazine-induced diuresis, but prazosin did not. The antidiuretic effect of atipamezole was more potent than that of yohimbine but not dose-dependent, in contrast to the effect of yohimbine at the tested doses. Both atipamezole and yohimbine reversed xylazine-induced decreases in both urine specific gravity and osmolality, and the increase in free water clearance. Glomerular filtration rate, osmolar clearance, and plasma electrolyte concentrations were not significantly altered. Antidiuresis of either atipamezole or yohimbine was not related to the area under the curve for AVP concentration, although the highest dose of both atipamezole and yohimbine increased plasma AVP concentration initially and temporarily, suggesting that this may in part influence antidiuretic effects of both agents. The diuretic effect of xylazine in cats may be mediated by α2-adrenoceptors but not α1-adrenoceptors. Atipamezole and yohimbine can be used as antagonistic agents against xylazine-induced diuresis in clinically normal cats.

La présente étude visait à examiner et comparer les effets antagonistes de l'atipamezole, la yohimbine et le prazosin sur la diurèse induite par la xylazine chez des chats cliniquement normaux. Cinq chats furent utilisés de manière répétée dans chacun des neuf groupes. Un groupe n'était pas médicamenté. Les chats dans les autres groupes reçurent de la xylazine par voie intramusculaire à un dosage de 2 mg/kg de poids corporel (PC), et de la saline (comme témoin); 160 µg/kg PC de prazosin; ou 40, 160, ou 480 µg/kg PC d'atipamezole ou de yohimbine par voie intraveineuse 0,5 h plus tard. Des échantillons d'urine et de sang furent prélevés 10 fois sur une période de 8 h. On mesura le volume, le pH, et la gravité spécifique de l'urine; la concentration plasmatique d'arginine vasopressine (AVP); les valeurs de créatinine, d'osmolalité, et d'électrolytes dans l'urine et le plasma ont également été mesurées. Autant l'atipamezole que la yohimbine ont antagonisé la diurèse induite par la xylazine, mais pas le prazosin. L'effet antidiurétique de l'atipamezole était plus puissant que celui de la yohimbine mais n'était pas dose-dépendant, contrairement à l'effet de la yohimbine aux doses testées. Autant l'atipamezole que la yohimbine ont renversé les diminutions induites par la xylazine de la gravité spécifique et l'osmolalité de l'urine, et l'augmentation de la clairance de l'eau libre. Le taux de filtration glomérulaire, la clairance osmolaire, et les concentrations d'électrolytes plasmatiques n'étaient pas affectés de manière significative. L'antidiurèse de l'atipamezole ou la yohimbine n'était pas liée à la surface sous la courbe de la concentration d'AVP, bien que les doses les plus élevées d'atipamezole et de yohimbine augmentèrent initialement et de manière temporaire la concentration d'AVP plasmatique, suggérant ainsi que ceci pourrait influencer partiellement les effets antidiurétiques de ces deux agents. L'effet diurétique de la xylazine chez les chats peut être médié par des adrénorécepteurs-α2 mais pas par des adrénorécepteurs-α1. L'atipamezole et la yohimbine peuvent être utilisés comme agents antagonistes contre la diurèse induite par la xylazine chez des chats cliniquement normaux.(Traduit par Docteur Serge Messier).

Yohimbine antagonises α1A- and α1D-adrenoceptor mediated components in addition to the α2A-adrenoceptor component to pressor responses in the pithed rat.

We have recently shown that responses to pressor nerve stimulation in the pithed rat are mediated by α(1A)- and α(1D)-adrenoceptors, with no evidence for α(2)-adrenoceptor involvement, and that responses previously identified as α(2)-adrenoceptor mediated are actually α(1D)-adrenoceptor mediated. We have now re-examined the subtypes of α-adrenoceptor involved in pressor responses produced by exogenous agonists in the pithed rat preparation to confirm whether α(2)-adrenoceptors are involved in these responses. The α(2)-adrenoceptor and α(1D)-adrenoceptor antagonist yohimbine (1mg/kg) and the α(2A)-adrenoceptor antagonist methoxy-idazoxan (5 mg/kg) significantly shifted, but the α(1D)-adrenoceptor antagonist BMY 7378 (8-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspir o[4.5]decane-7,9-dione dihydrochloride) (1 mg/kg) did not affect, the pressor potency of the α(2)-adrenoceptor agonist xylazine. α(1)-adrenoceptor antagonists showed low potency against pressor responses to xylazine. The pressor potency of the α(1)-adrenoceptor agonist amidephrine was not affected by BMY 3778 (1 mg/kg) but significantly shifted by prazosin (0.01 mg/kg) and by yohimbine (1 mg/kg). In contrast, the pressor potency of phenylephrine was significantly shifted by both yohimbine and BMY 7378 (1 mg/kg), but to a greater extent by the α(1A)-adrenoceptor antagonist RS 100329 (5-Methyl-3-[3-[3-[4-[2-(2,2,2,trifluroethoxy) phenyl]-1-piperazinyl]propyl]-2,4-(1H,3H)-pyrimidinedione] hydrochloride) (0.1 mg/kg). In conclusion, we have identified and separated α(1A)-, α(1D)- and α(2A)-adrenoceptor antagonist actions of yohimbine against pressor responses. Pressor responses to exogenous agonists in the pithed rat involve both α(1A)- and α(1D)-adrenoceptors and in addition, α(2A)-adrenoceptors.

Antagonistic effect of atipamezole, flumazenil and naloxone following anaesthesia with xylazine, tramadol and tiletamine/zolazepam combinations in pigs.

OBJECTIVE: To evaluate the antagonistic effects of atipamezole (ATI), flumazenil (FLU) and naloxone (NAL) alone and in various combinations following administration of tiletamine-zolazepam-xylazine-tramadol. STUDY DESIGN: Prospective, experimental, randomized cross-over study. ANIMALS: Eight Chinese miniature pigs (three females and five males) mean age 8 (range 7-10) months and bodyweight 57.5 (52.4-62.1) kg. METHODS: All animals were anaesthetized with tiletamine/zolazepam (3.0 mg kg(-1)), xylazine (1.2 mg kg(-1)) and tramadol (1.6 mg kg(-1)) given intramuscularly (IM). Thirty minutes later, one of eight treatments was administered IM: saline control, ATI (0.12 mg kg(-1)), FLU (0.1 mg kg(-1)), NAL (0.03 mg kg(-1)), ATI-FLU, FLU-NAL, ATI-NAL or ATI-FLU-NAL. After injection of antagonists the following times were recorded: to recovery of the palpebral, pedal and tail clamp reflexes, to head movement, sternal recumbency, standing and walking. Posture, sedation, analgesia, jaw relaxation and auditory response were scored at set times until 120 minutes after injection of antagonists. Heart rates, respiratory rates and rectal temperature were measured at those times. Data were analyzed by anova for repeated measures, followed by the Tukey's test to compare differences between means, or by Kruskal-Wallis test as appropriate. RESULTS: FLU, NAL alone, or FLU-NAL did not effectively antagonize anaesthesia induced by tiletamine/zolazepam-xylazine-tramadol. ATI, ATI-FLU, ATI-NAL and ATI-FLU-NAL produced an immediate and effective recovery from anaesthesia. The combination of ATI-FLU-NAL was the most effective combination in antagonizing the anaesthetic effect. Adverse effects such as tachycardia, tachypnoea, excitement and muscle tremors were not observed during this study. CONCLUSION AND CLINICAL RELEVANCE: ATI-FLU-NAL is the most effective combination for antagonizing tiletamine/zolazepam-xylazine-tramadol anaesthesia in pigs. However, ATI alone or in various combinations also provides effective antagonism.

Action of a Novel PDE4 inhibitor ZL-n-91 on lipopolysaccharide-induced acute lung injury.

In the present study, we investigated the effect of classic PDE4 inhibitor rolipram and novel PDE4 inhibitor ZL-n-91 on LPS-induced acute lung injury (ALI) in mice and its mechanism. ALI was induced in ICR mice by instilling intratracheally with LPS, and mice were divided into seven groups: control (Saline), LPS group, ZL-n-91 (3 microg, 10 microg, and 30 microg kg(-1), ip), Rolipram (1.0 mg kg(-1), ip) and dexamethasone (0.5 mg kg(-1), ip). After the 6h of instilling intratracheally with LPS in mice, total leukocyte number, neutrophil number and protein content in BALF increased rapidly, a large number of neutrophil infiltration around the pulmonary vessel and airway, the lung wet weight/dry weight (w/d)ratio raised significantly. MPO activity, TNF-alpha level and cAMP-PDE, PDE4 activity in lung homogenate raised significantly. P(a)O(2), P(a)CO(2) and PH value in peripheral arterial blood also changed obviously, P(a)O(2) and PH value dropped slightly and P(a)CO(2) increased significantly in LPS group. ZL-n-91 (3 microg, 10 microg, 30 microg kg(-1)) dose-dependently reduced the total leukocyte number, neutrophil number and total protein content in BALF, MPO activity, TNF-alpha level and cAMP-PDE, PDE4 activity in lung homogenate, but the effect of ZL-n-91 in pathological changes and lung wet w/d ratio is slight; Rol and Dex significantly reduced lung wet w/d ratio and improved pathological changes, neutrophil around the pulmonary vessel and airway significantly reduced, symptoms of lung edema relieved; The PH value, P(a)O(2) and P(a)CO(2) in ZL-n-91 high dosage group and Rol group had changes, but there was no significant difference compared with LPS group or saline group; After the administration, the righting reflex recovery time significantly shorten in every group of ZL-n-91. the righting reflex recovery time of Rol group was similar with ZL-n-91 30 microg kg(-1) group, while Dex group was similar with saline group. The present study confirms that the inhibitory effect of ZL-n-91(30 microg kg(-1)) on the inflammatory reactivity, including inhibition of inflammatory cell and protein exudation, MPO and PDE4 activity, improvement of the blood gas, those effects were equivalent with rolipram 1 mg kg(-1), and suggested that ZL-n-91 was stronger than rolipram in PDE4 inhibition. So we speculated that ZL-n-91 may have stronger therapeutic potential for treatment of inflammatory disease than rolipram, meantime have stronger nervous system effect than rolipram.

Involvement of ATP-sensitive K(+) channels in the peripheral antinociceptive effect induced by the alpha(2)-adrenoceptor agonist xylazine.

Xylazine is an alpha(2)-adrenergic agonist extensively used in veterinary medicine and animal experimentation for producing antinociception, sedation, and muscle relaxation. The nitric oxide (NO) / cGMP / ATP-sensitive K(+) (K(ATP)) channel pathway has been proposed as the action mechanism of peripheral antinociception of several groups of drugs, including opioids and nonsteroidal analgesics. Considering the lack of knowledge regarding the mechanisms involved in xylazine effects, the present study investigated the contribution of K(+) channels on peripheral antinociception induced by xylazine using the rat paw pressure test, in which hyperalgesia was induced by intraplantar injection of prostaglandin E(2). Xylazine administered into the right hind paw elicited a local antinociceptive effect, since only much higher doses produced a systemic effect in the contralateral paw. The peripheral antinociceptive effect induced by xylazine was antagonized by glibenclamide, a specific blocker of K(ATP) channels. In another experiment, tetraethylammonium, a voltage-dependent K(+)-channel blocker, and paxilline and dequalinium, which are selective blockers for the large- and small-conductance Ca(2+)-activated K(+) channels, respectively, were ineffective at blocking xylazine antinociception. These results provide evidence that the peripheral antinociceptive effect of xylazine probably results from K(ATP)-channel activation, while the voltage-dependent K(+) channels, small- and large-conductance Ca(2+)-activated K(+) channels, appear not to be involved in this mechanism.

Reversal of ketamine/xylazine combination anesthesia by atipamezole in olive baboons (Papio anubis).

BACKGROUND: The potential of Atipamezole (ATI) to reverse Ketamine/Xylazine (KET/XYL) anesthesia in the Olive baboon (Papio anubis) was studied. METHODS: Anesthesia was induced with 10 mg/kg KET and 0.5 mg/kg XYL intramuscularly. Mean arousal time (MAT), heart rate (HR), systolic arterial blood pressure (SAP), rectal temperature, respiratory rate (RR), and hemoglobin oxygen saturation (SpO(2)) were monitored. Baboons were treated with: KET/XYL only, KET/XYL followed by 100 microg/kg ATI or by 200 microg/kg ATI administered 25 minutes after KET/XYL. RESULTS: Atipamezole rapidly reversed depressed HR and SAP (10 +/- 5.2 minutes), RR (5 +/- 2 minutes) and SpO(2) (3 +/- 6 minutes) and significantly decreased MAT (13 +/- 2.2 minutes) vs. KET/XYL alone (35 +/- 5 minutes). Emesis was absent and salivation was observed after administration of 200 microg/kg ATI only. CONCLUSIONS: Atipamezole at 100 microg/kg is sufficient for rapid and smooth reversal of KET/XYL anesthesia in the Olive baboon with minimal side effects.

Sedative and cardiopulmonary effects of medetomidine hydrochloride and xylazine hydrochloride and their reversal with atipamezole hydrochloride in calves.

OBJECTIVE: To assess the sedative and cardiopulmonary effects of medetomidine and xylazine and their reversal with atipamezole in calves. ANIMALS: 25 calves. PROCEDURES: A 2-phase (7-day interval) study was performed. Sedative characteristics (phase I) and cardiopulmonary effects (phase II) of medetomidine hydrochloride and xylazine hydrochloride administration followed by atipamezole hydrochloride administration were evaluated. In both phases, calves were randomly allocated to receive 1 of 4 treatments IV: medetomidine (0.03 mg/kg) followed by atipamezole (0.1 mg/kg; n = 6), xylazine (0.3 mg/kg) followed by atipamezole (0.04 mg/kg; 7), medetomidine (0.03 mg/kg) followed by saline (0.9% NaCl; 6) solution (10 mL), and xylazine (0.3 mg/kg) followed by saline solution (10 mL; 6). Atipamezole or saline solution was administered 20 minutes after the first injection. Cardiopulmonary variables were recorded at intervals for 35 minutes after medetomidine or xylazine administration. RESULTS: At the doses evaluated, xylazine and medetomidine induced a similar degree of sedation in calves; however, the duration of medetomidine-associated sedation was longer. Compared with pretreatment values, heart rate, cardiac index, and PaO(2) decreased, whereas central venous pressure, PaCO(2), and pulmonary artery pressures increased with medetomidine or xylazine. Systemic arterial blood pressures and vascular resistance increased with medetomidine and decreased with xylazine. Atipamezole reversed the sedative and most of the cardiopulmonary effects of both drugs. CONCLUSIONS AND CLINICAL RELEVANCE: At these doses, xylazine and medetomidine induced similar degrees of sedation and cardiopulmonary depression in calves, although medetomidine administration resulted in increases in systemic arterial blood pressures. Atipamezole effectively reversed medetomidine- and xylazine-associated sedative and cardiopulmonary effects in calves.

A comparison of two combinations of xylazine-ketamine administered intramuscularly to alpacas and of reversal with tolazoline.

OBJECTIVE: To evaluate the anesthetic and cardiorespiratory effects of two doses of intramuscular (IM) xylazine/ketamine in alpacas, and to determine if tolazoline would reduce the anesthetic recovery time. STUDY DESIGN: Prospective randomized crossover study. ANIMALS: Six castrated male alpacas. METHODS: Each alpaca received a low dose (LD) (0.8 mg kg(-1) xylazine and 8 mg kg(-1) ketamine IM) and high dose (HD) (1.2 mg kg(-1) xylazine and 12 mg kg(-1) ketamine IM) with a minimum of one week between trials. Time to sedation, duration of lateral recumbency and analgesia, pulse rate, respiratory rate, hemoglobin oxygen saturation, arterial blood pressure, blood-gases, and the electrocardiogram were monitored and recorded during anesthesia. With each treatment three alpacas were randomly selected to receive tolazoline (2 mg kg(-1) IM) after 30 minutes of lateral recumbency. RESULTS: Onset of sedation, lateral recumbency and analgesia was rapid with both treatments. The HD was able to provide > or =30 minutes of anesthesia in five of six alpacas. The LD provided > or =30 minutes of anesthesia in three of six alpacas. Respiratory depression and hypoxemia occurred with the HD treatment during the first 10 minutes of lateral recumbency: two animals were severely hypoxemic and received nasal oxygen for 5 minutes. Heart rate decreased, but there were no significant changes in arterial blood pressure. Tolazoline significantly shortened the duration of recumbency with the HD. CONCLUSIONS: The HD provided more consistent clinical effects in alpacas than the LD. Intramuscular tolazoline shortened the duration of lateral recumbency in alpacas anesthetized with the HD combination. CLINICAL RELEVANCE: Both doses of the combination were effective in providing restraint in alpacas and the duration of restraint was dose dependent. Supplemental oxygen should be available if using the HD and IM administration of tolazoline will shorten the recovery time.

Strategies for refinement of abdominal device implantation in mice: strain, carboxymethylcellulose, thermal support, and atipamezole.

A widely used in vivo technique in mice and other species is the surgical implantation of transmitters for telemetric monitoring of core body temperature, locomotor activity, and other variables. However, these devices are quite large relative to the size of the mouse abdomen. We report here on the results of several related studies that we conducted to evaluate refinement strategies relevant to implantation of abdominal devices in mice. First, we evaluated survival from surgery as a function of strain and body weight and found that both parameters influence the proportion of mice that survive. Second, we assessed the effect of several interventions on postsurgical recovery of food and water intakes, core temperature, and locomotor activity. Some of the interventions were associated with increased mortality (atipamezole) or were otherwise detrimental (the abdominal lubricant carboxymethylcellulose), whereas others had little or no effect on recovery (thermal support). These findings indicate that interventions presumed to promote recovery from surgery that are based on data from other species may not always have the anticipated positive effect in mice. This study therefore underscores the need to carefully assess the effect of modifications in experimental procedures to avoid causing unexpected complications in mice.

Sedative effects of midazolam and xylazine with or without ketamine and detomidine alone following intranasal administration in Ring-necked Parakeets.

OBJECTIVE: To evaluate the effects of intranasal administration of midazolam and xylazine (with or without ketamine) and detomidine and their specific antagonists in parakeets. DESIGN: Prospective study. ANIMALS: 17 healthy adult Ring-necked Parakeets (Psittacula krameri) of both sexes (mean weight, 128.83+/-10.46 g [0.28+/-0.02 lb]). PROCEDURE: The dose of each drug or ketamine-drug combination administered intranasally that resulted in adequate sedation (ie, unrestrained dorsal recumbency maintained for >or=5 minutes) was determined; the onset of action, duration of dorsal recumbency, and duration of sedation associated with these treatments were evaluated. The efficacy of the reversal agents flumazenil, yohimbine, and atipamezole was also evaluated. RESULTS: In parakeets, intranasal administration of midazolam (7.3 mg/kg [3.32 mg/lb]) or detomidine (12 mg/kg [5.45 mg/lb]) caused adequate sedation within 2.7 and 3.5 minutes, respectively. Combinations of midazolam (3.65 mg/kg [1.66 mg/lb]) and xylazine (10 mg/kg [4.55 mg/lb]) with ketamine (40 to 50 mg/kg [18.2 to 22.7 mg/lb]) also achieved adequate sedation. Compared with detomidine, duration of dorsal recumbency was significantly longer with midazolam. Intranasal administration of flumazenil (0.13 mg/kg [0.06 mg/lb]) significantly decreased midazolam-associated recumbency time. Compared with the xylazineketamine combination, duration of dorsal recumbency was longer after midazolam-ketamine administration. Intranasal administration of flumazenil, yohimbine, or atipamezole significantly decreased the duration of sedation induced by midazolam, xylazine, or detomidine, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Intranasal administration of sedative drugs appears to be an acceptable method of drug delivery in Ring-necked Parakeets. Reversal agents are also effective when administered via this route.

Determination and evaluation of an optimal dosage of carfentanil and xylazine for the immobilization of white-tailed deer (Odocoileus virginianus).

Using an iteration method, optimal hand-injected immobilization dosages of carfentanil/xylazine (CAR/XYL) were determined for 13 adult white-tailed deer (Odocoileus virginianus). Deer were temporarily restrained in a squeeze chute and were repeatedly immobilized one to four times at 2-5-wk intervals from December 2002 to March 2003. A fixed ratio of 1 mg CAR:10 mg XYL intramuscularly was used, increasing or decreasing the dosage until the optimal dosage (defined by an induction time < 3 min and PaCO(2)< 60 mmHg) was reached for each animal. Inductions were video-recorded and reviewed by observers blinded to drugs and dosages, who rated qualitative aspects of each induction. There were significant (P < 0.05) dosage-dependent decreases in induction time, time to first effect, PaO(2), SaO(2), and arterial pH, and significant dosage-dependent increases in PaCO(2) and quality ratings. The median optimal dosage (mOD) was 0.03 (range, 0.015-0.06) mg/kg CAR+0.3 (range, 0.15-0.6) mg/kg XYL. Induction times using the mOD were rapid (median 3.0 min [range, 1.8-10.0]), but quality ratings were considered undesirable for nine of 13 deer. Increased rectal body temperatures of 40.6+/-0.5 C (mean +/- SD) were noted in all deer and hyperthermia (T > 41 C) was noted in three. There was a positive correlation between body temperature and induction time (r=0.44). Heart rates significantly decreased from 5 to 15 min postinduction and remained decreased at the 20-min reading; there was occasional bradycardia. There was a significant increase in pH from 10 to 20 min postinduction, but metabolic acidemia (pH<7.3) persisted throughout the immobilization periods for all deer. Possible hypoxemia (SaO(2) and SpO(2)<90 mmHg but PaO(2)>60 mmHg) was present after induction, while hypercapnea (PaCO(2) > 60 mmHg) did not occur. Reversal times with naltrexone and yohimbine were rapid (mean 3.7+/-1.5 min) and uneventful, with no evidence of renarcotization. Although the median optimal dosage produced rapid inductions, no respiratory depression, complete reversal after antagonist administration, and no renarcotization, negative attributes included elevated body temperatures, acidemia, and undesirable induction qualities.

The analgesic effects of intrathecal xylazine and detomidine in sheep and their antagonism with systemic atipamezole.

OBJECTIVE: To evaluate the analgesic and adverse side effects of intrathecal (IT) xylazine (XYL) and detomidine (DET) and the subsequent effects of two doses of intravenous (IV) atipamezole (ATI). STUDY DESIGN: Prospective, randomized, cross-over. ANIMALS: Five adult healthy female sheep with mean body mass of 55 +/- 2.3 kg. Material and methods Each sheep underwent four treatments: 1) 50 microg kg(-1) XYL IT and 5 microg kg(-1) ATI IV, 2) 50 microg kg(-1) XYL IT and 2.5 microg kg(-1) ATI IV, 3) 10 microg kg(-1) DET IT and 5 microg kg(-1) ATI IV, 4) 10 microg kg(-1) DET IT and 2.5 microg kg(-1) ATI IV. Pain threshold (TH) was tested by applying pulsed and stepwise incremental direct current to the skin overlying the pastern. The current at the point of foot lift was recorded as the TH. Heart rate (HR), mean arterial pressure, arterial oxygen (PO(2)) and carbon dioxide (PCO(2)) tensions were monitored. Outcomes were derived as differences between baseline assessment and measurements after treatment. Two-way anova was used to analyse drug effects, treatment differences between groups were examined with an F-test or Wilcoxon's rank sum test in case of non-parametric data distribution. p was set at 0.05. RESULTS: Both drugs increased the pain TH, caused small increases in PCO(2), and small decreases in HR, the latter was only significant for XYL recipients. Xylazine produced a significantly higher TH, more rapidly and for longer than DET. Atipamezole only significantly affected PaCO(2) in the XYL group 2. The pain TH was not affected in either group after IV ATI. CONCLUSIONS: At the doses used, IT XYL, and to a lesser extent DET, induced pastern analgesia. Atipamezole 5 microg kg(-1) IV antagonized some side effects without affecting analgesia. CLINICAL RELEVANCE: Intrathecal XYL may be useful as an analgesic in sheep. Its safety is increased because IV ATI antagonizes side effects, but not analgesia.

Effectiveness of antagonists for tiletamine-zolazepam/xylazine immobilization in female white-tailed deer.

A combination of tiletamine-zolazepam/xylazine (TZ/X) is effective in the chemical immobilization of white-tailed deer (Odocoileus virginianus); however, the lengthy duration of immobilization may limit its usefulness. From October to November 2002, 21 captive female deer were assigned randomly to an alpha(2) antagonist treatment to reverse xylazine-induced sedation (seven does per group). All deer were given 220 mg of TZ (4.5+/-0.4 mg/kg) and 110 mg of X (2.2+/-0.2 mg/kg) intramuscularly (IM). Antagonist treatments were either 200 mg of tolazoline (4.0+/-0.4 mg/kg), 11 mg of atipamezole (0.23+/-0.02 mg/kg), or 15 mg of yohimbine (0.30+/-0.02 mg/kg) injected, half intravenously and half subcutaneously, 45 min after the IM TZ/X injection. In addition, 10 other deer (five per group) were immobilized as before and then given tolazoline (200 mg) after 45 min, with either a carrier (dimethyl sulfoxide [DMSO]) or carrier (DMSO) plus flumazenil (5 mg) to reverse the zolazepam portion of TZ. Mean times from antagonist injection until a deer raised its head were different for alpha(2) antagonist treatments (P=0.02). Times were longer for yohimbine (62.3+/-42.7 min) than for either atipamezole (24.3+/-17.1 min) or tolazoline (21.3+/-14.3 min). Mean times from antagonist injection until standing were not different (P=0.15) among yohimbine (112.0+/-56.4 min), atipamezole (89.7+/-62.8 min), or tolazoline (52.6+/-37.2 min). A sedation score based on behavioral criteria was assigned to each deer every 30 min for 5 hr. On the basis of sedation scores, tolazoline resulted in a faster and more complete reversal of immobilization. Flumazenil treatment did not affect recovery.

Intranasal administration of xylazine to reduce stress in elk captured by net gun.

Forty free-ranging elk (Cervus elaphus manitobensis) were captured by net gun in Riding Mountain National Park (Manitoba, Canada) during February 2002 and were administered either saline (control) or xylazine by the intranasal route, to evaluate the efficacy and benefit of intranasal xylazine to reduce stress. Elk that received xylazine had higher relaxation scores than control elk, and the onset of sedation occurred quickly, often <1 min. Serum concentrations of cortisol, creatine kinase, and gamma-glutamyltransferase were lower in elk that received xylazine than in control elk. At the conclusion of handling, the intravenous administration of yohimbine quickly abolished the sedative effect of xylazine, which allowed elk to be released without concern of physical injury due to ataxia. The intranasal administration of xylazine can be used to reduce stress in wild animals under situations where they are being handled while physically restrained.

Comparative immobilization of wild felids in Thailand.

We immobilized individuals of four free-ranging felid species, leopard cat (Prionailurus bengalensis), clouded leopard (Neofelis nebulosa), Asiatic golden cat (Catopuma temminckii), and marbled cat (Pardofelis marmorata) with ketamine hydrochloride and xylazine hydrochloride (KH-XH) and with tiletamine hydrochloride and zolazepam hydrochloride (TH-ZH) between March 1998 and July 2002. Mean (+/-SD) dose of KH and XH was 26.51+/-5.71 mg/kg and 1.89+/-0.43 mg/kg, respectively (n=25), and mean dose of TH-ZH was 11.61+/-3.39 mg/kg (n=28). Dose was significantly correlated with induction time (P<0.001) and duration of anesthesia (P<0.05), but not with recovery time. There were significant differences between the drug combinations in time to induction (P<0.03) and time to anesthesia (P<0.01); recovery times were not significantly different. We conclude that immobilization of these felids with TH-ZH and KH-XH is effective and safe, but TH-ZH is preferred because of the smaller volume of drug necessary for sedation, faster time to induction, and absence of prolonged muscle rigidity during anesthesia.

Immobilization of mule deer with thiafentanil (A-3080) or thiafentanil plus xylazine.

We evaluated thiafentanil oxalate (A-3080) for the immobilization of mule deer (Odocoileus hemionus) under laboratory and field conditions. In a crossover experiment comparing recommended (0.1 mg/kg) and 2x recommended thiafentanil doses in captive deer, both produced rapid induction and immobilization. Mean induction was shorter (P = 0.013) for the 2x group (1.9 vs. 3 min); mean reversals for both groups were rapid (recommended = 0.9 min after naltrexone injection; 2x = 1 min) and did not differ (P = 0.29). Six free-ranging mule deer were immobilized with 7 mg thiafentanil and four with 10 mg; mean induction was 2.3 min for both groups (95% confidence interval [CI]: 7 mg, 1.2-3.4; 10 mg, 1.9-2.8), and mean reversal was <1 min for both groups. Of 165 free-ranging deer darted with various combinations of thiafentanil and xylazine, we successfully immobilized 148 (90%). Mean induction ranged from 2.1 to 4.9 min for different drug combinations. Reversals were not compared because naltrexone and yohimbine doses varied, but overall mean reversal was 1.9 min (95% CI, 1.7-2.1 min) after injection of naltrexone and yohimbine intravenously (i.v.); naltrexone:thiafentanil ratios ranging from 10:1 to 43:1 provided mean recoveries ranging from 1.5 to 2.3 min. All 25 deer fitted with radio collars were alive at 30 days postcapture. On the basis of overall reliability and effectiveness, drug volumes, and ease of handling drugged animals, we recommend using a combination of 10-12 mg thiafentanil (0.15-0.2 mg/kg) and 100 mg xylazine to immobilize mule deer; immobilization can be effectively reversed with 100 mg naltrexone or more and 15 mg yohimbine or more i.v. Where feasible, we also recommend the use of transmitter darts when immobilizing mule deer with opioids in order to maximize recovery of darted deer and to ensure that missed darts are found.

Synthesis of 3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles, displaying combined 5-HT uptake inhibiting and alpha(2)-adrenoceptor antagonistic activities: a novel series of potential antidepressants.

The synthesis of a series of novel 3-piperazinylmethyl-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles as novel dual 5-HT reuptake inhibitors and alpha(2)-adrenoceptor antagonists is described. Their affinity at the three different human alpha(2)-adrenoceptor subtypes and the 5-HT transporter site is reported. The in vivo activity of the compounds was measured in two different assays: (1). inhibition of pCA-induced excitation, which evaluates the ability to block the central 5-HT transporter, and (2). inhibition of xylazine-induced loss of righting, which evaluates the ability to block central alpha(2)-adrenoceptors.

A comparison of carfentanil/xylazine and Telazol/xylazine for immobilization of white-tailed deer.

October 2001 to January 2002, captive free-ranging white-tailed deer (Odocoileus virginianus) were immobilized with a combination of carfentanil citrate and xylazine hydrochloride. From this study, we selected a dose of carfentanil/xylazine for the purpose of comparing immobilization parameters and physiologic effects with those of a combination of tiletamine and zolazepam (Telazol) and xylazine. Animals were initially given intramuscular injections of 10 mg xylazine and one of four doses of carfentanil (i.e., 0.5, 1.0, 1.5, and 2.0 mg). A carfentanil dose of 1.2 mg (x +/- SD = 23.5 +/- 3.2 microg/kg) and 10 mg xylazine (0.2 +/- 0.03 mg/kg) were selected, based on induction times and previously published reports, to compare with a combination of 230 mg of Telazol (4.5 +/- 0.6 mg/kg) and 120 mg xylazine (2.3 +/- 0.3 mg/kg). Time to first observable drug effects and to induction were significantly longer for deer treated with carfentanil/xylazine than with Telazol/xylazine (P < 0.01). Hyperthermia was common in deer immobilized with carfentanil/xylazine, but heart rate, respiration rate, and hemoglobin saturation were within acceptable levels. Degree of anesthesia of deer immobilized with Telazol/xylazine was superior to deer immobilized with carfentanil/xylazine. The combination of 120 mg of naltrexone hydrochloride and 6.5 mg of yohimbine hydrochloride provided rapid and complete reversal (1.9 +/- 1.1 min) of carfentanil/xylazine immobilization. Animals immobilized with Telazol/xylazine had long recovery times with occasional resedation after antagonism with 6.5 mg of yohimbine. The combination of carfentanil and xylazine at the doses tested did not provide reliable induction or immobilization of white-tailel (leer even though drug reversal was rapid and safe using naltrexone and yohimbine.

Tiletamine-zolazepam, ketamine, and xylazine anesthesia of captive cheetah (Acinonyx jubatus).

Thirty-two anesthetic episodes used a combination of tiletamine-zolezepam (50 mg/ml each), ketamine (80 mg/ml), and xylazine (20 mg/ml) at various dosages for routine diagnostic and minor surgical procedures in 13 captive cheetahs (Acinonyx jubatus). The mean dosage (0.023 +/- 0.003 ml/kg) provided rapid induction with a single i.m. injection along with safe predictable working time, good muscle relaxation, and analgesia. Yohimbine administration subsequently accelerated smooth and rapid recovery.

The reversal of xylazine hydrochloride by yohimbine and 4-aminopyridine in goats.

Yohimbine, 4-aminopyridine, and a combination of the 2 drugs were studied to assess their potential as antagonists to xylazine in goats. Twenty-four small East African goats were divided randomly into 4 groups of 6 goats each in a placebo-controlled study. They were all treated with intramuscular xylazine at 0.44 mg/kg. At the time of maximum sedation, sterile water was administered intravenously to the control group, 0.15% 4-aminopyridine at 0.4mg/kg to Group 2, 0.1% yohimbine at 0.25 mg/kg to Group 3, and the combination of the 2 drugs at the same dose rates to Group 4. The yohimbine/4-aminopyridine combination was also used to antagonise xylazine at 0.88mg/kg in 6 goats. The heart rate, respiratory rate and rate of ruminal movements, the pedal and palpebral reflexes as well as the reaction to noxious stimuli, the standing time and the total recovery time were established and evaluated to assess the effects of the treatments. The drugs reversed the xylazine-induced decrease in the heart rate, respiratory rate and rate of ruminal movements, and also rapidly restored the reflexes as well as the reaction to noxious stimulation. In addition, they significantly (P < 0.05) decreased the mean standing time. The mean total recovery time was decreased significantly (P < 0.05) by 4-aminopyridine and the yohimbine/4-aminopyridine combination, but non-significantly (P > 0.05) by yohimbine. No relapse in sedation occurred. Overall, the combination of yohimbine and 4-aminopyridine produced better responses than the individual drugs, and may therefore be used for rapid reversal of xylazine-induced sedation in goats. Yohimbine or 4-aminopyridine may also be useful for this purpose but recovery may be prolonged.