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Azaperone, acepromazine, xylazine and diazepam were tested for mutagenic activity. To screen these veterinary drugs we used the Salmonella/microsome test on 5 histidine-auxotrophic strains, with and without metabolic activation. Azaperone and xylazine were found to be weakly mutagenic.
In two experiments, the effect of intensive housing on behavior and adrenocortical reactivity was studied in 68 castrated male German Landrace pigs. In both experiments, half of the pigs were tethered on a partially slatted floor without straw and half were kept, as controls, in groups on straw. Prior to the study, 32 of the pigs used in the first experiment were selected according to their reaction to halothane anesthesia; for the second experiment, 36 pigs were selected according to their adrenocortical response to azaperone-metomidate anesthesia. During the 4- to 6-wk experimental period, behavioral activity was observed and adrenocortical reactivity was analyzed after stimulation with synthetic ACTH(1-24), azaperone-metomidate anesthesia, insulin-induced hypoglycemia and neostigmine-atropine. Although no difference was found in general activity between groups, tethered pigs revealed a significantly higher cortisol increase after stimulation with ACTH(1-24) in both experiments and after insulin stimulation in the second experiment. Similarly, the area below the cortisol response curve after ACTH stimulation was significantly larger in tethered pigs in the second experiment. The individual reaction pattern was positively correlated between tests, indicating this pattern is a relatively constant, individual characteristic. In contrast, no correlation was found between behavior or adrenocortical reaction pattern and sensitivity to halothane. The results suggest that tethering on a partially slatted floor constitutes a chronic stressor which changes the adrenocortical response to an additional acute stressor. This increased reactivity is revealed most clearly after stimulation with ACTH(1-24) when individual responsiveness is taken into consideration.
When pigs were fed small amounts at regular short intervals (5-10 min), drinking followed each ingestion. This resulted in a greatly increased total water intake (schedule-induced polydipsia: s.i.p.). Injection of angiotensin II into the lateral cerebral ventricle of water-replete pigs on normal feeding also produced a significant increase in water intake. Prior administration of the angiotensin II antagonist, saralasin, attenuated the dipsogenic effect of angiotensin II, but did not modify s.i.p. The tranquilizing drug, azaperone, had no effect on normal water intake and did not modify the response to angiotensin II. However, azaperone reduced the water intake of animals on scheduled feeding. From this, it was concluded that the increased drinking due to scheduled feeding did not involve the renin-angiotensin system but it is tentatively suggested that it may involve central dopaminergic neuronal systems.
The reactions of pigs to the vibration and noise components of transport were examined with the use of an apparatus which simulated these factors. The pigs were trained to switch off the apparatus by pressing a switch panel with their snouts. It was found that vibration was aversive but that noise was not. The pigs switched off the apparatus more frequently when the vibration was fast and when they had been fed a large meal before the test. Although the sedative tranquillizing drug azaperone decreased the number of times the apparatus was switched off, the effect appeared to be non-specific because azaperone also reduced the number of responses that pigs would make in order to receive food.
White rhinoceros anaesthetised with etorphine and azaperone combination develop adverse physiological changes including hypoxia, hypercapnia, acidosis, tachycardia and hypertension. These changes are more marked in field-anaesthetised rhinoceros. This study was designed to develop a technique to improve safety for field-anaesthetised white rhinoceros by tracheal intubation and oxygen insufflation. Twenty-five free-ranging white rhinoceros were anaesthetised with an etorphine and azaperone combination for translocation or placing microchips in their horns. Once anaesthetised the rhinoceros were monitored prior to crating for transportation or during microchip placement. Physiological measurements included heart and respiratory rate, blood pressure and arterial blood gas samples. Eighteen rhinoceros were intubated using an equine nasogastric tube passed nasally into the trachea and monitored before and after tracheal insufflation with oxygen. Seven rhinoceros were not intubated or insufflated with oxygen and served as controls. All anaesthetised rhinoceros were initially hypoxaemic (percentage arterial haemoglobin oxygen saturation (%O2Sa) = 49% +/- 16 (mean +/- SD) and PaO2 = 4.666 +/- 1.200 kPa (35 +/- 9 mm Hg)), hypercapnic (PaCO2 = 8.265 +/- 1.600 kPa (62 +/- 12 mm Hg)) and acidaemic (pHa = 7.171 +/- 0.073 ). Base excess was -6.7 +/- 3.9 mmol/l, indicating a mild to moderate metabolic acidosis. The rhinoceros were also hypertensive (systolic blood pressure = 21.861 +/- 5.465 kPa (164 +/- 41 mm Hg)) and tachycardic (HR = 107 +/- 31/min). Following nasal tracheal intubation and insufflation, the %O2Sa and PaO2 increased while blood pHa and PaCO2 remained unchanged. Tracheal intubation via the nose is not difficult, and when oxygen is insufflated, the PaO2 and the %O2Sa increases, markedly improving the safety of anaesthesia, but this technique does not correct the hypercapnoea or acidosis. After regaining their feet following reversal of the anaesthesia, the animals' blood gas values return towards normality.
A fluorometric method is described for direct and sensitive determinations of azaperone, haloperidol and bromoperidol in pharmaceutical preparations. These compounds can be converted into strongly fluorescing derivatives by the action of potassium permanganate on their alcoholic solutions in acid medium, the limits of detection being respectively 8.10(-3), 5.10(-2) microgram/ml. The fluorescence phenomenon is very stable. Preliminary results are reported on the isolation and structure determination of one of the main fluorophors, produced in the case of azaperone.
A multi-residue method for the determination of tranquiliser residues in animal tissue is described. The procedure may be used to determine residues of the tranquilisers acepromazine, azaperone, chlorpromazine, haloperidol, propionylpromazine, xylazine, the metabolite of azaperone, azaperol, and the beta-adrenoreceptor blocking agent carazolol. Existing methods of analysis for tranquilisers are based on ultraviolet and fluorescence detection and have been used for pig kidney analysis. Determination in this method was by high-performance liquid chromatography with electrochemical detection in the screen mode. The enhanced selectivity offered by the electrochemical detector allowed determination in liver extracts, which often give rise to more interferences on chromatographic traces when using conventional methods of detection. The method offers up to a ten-fold improvement in limits of determination over methods using ultraviolet and fluorescence detection. Recoveries and coefficients of variation have been determined in the range 2-25 micrograms/kg in pig kidney and liver. This electrochemical detection method has been used to measure residues in routine surveillance programmes.
Many drugs contain the arylpiperazine moiety in the side-chain of their molecules. A common metabolic pathway of such drugs is cleavage of the side-chain with the formation of 1-arylpiperazines. This has been verified by combined gas chromatography-mass spectrometry of biological samples from rats given orally a series of heterocyclic derivatives bearing a 4-aryl(phenyl, pyrimidinyl, pyridyl or thiazolyl)-1-piperazinylalkyl moiety (oxypertine, zolertine, millipertine, empiprazole, dapiprazole, antrafenine, piribedil, azaperone). A sensitive and selective electron-capture gas-liquid chromatographic procedure for 1-arylpiperazines in rat plasma and brain is described. The overall recovery from plasma and brain was 70-90%. The limit of detection for substituted (halogenated) phenylpiperazines was 10-25 ng/ml or ng/g and 25-100 ng/ml or ng/g for other derivatives. Preliminary data are reported on the time course of the production and elimination of 1-arylpiperazines after oral administration of representative compounds with the arylpiperazine moiety (oxypertine, azaperone and S-3608).
BACKGROUND AND OBJECTIVES: Benzodiazepine agonists and azaperone derivatives are used clinically as anxiolytics but have different neuroreceptor mechanisms of action. This study evaluated clinical pharmacodynamic approaches to distinguishing these two classes of compounds. METHODS: Healthy volunteers received single oral doses of placebo, the benzodiazepine agonist triazolam (0.25 mg) or the azaperone anxiolytic buspirone (20 mg), in a double-blind, three-way crossover study. Ratings of mood and sedation, performance on the digit symbol substitution test (DSST), and quantitative measures of electroencephalographic (EEG) beta activity (13 to 31.75 cycles/sec) determined by fast-Fourier transform were obtained at multiple times after dosage. RESULTS: Triazolam significantly increased self- and observer-rated sedation, impaired DSST performance, impaired recall, and increased EEG beta activity. Pharmacodynamic changes were significantly intercorrelated; all effects were maximal 1 to 2 hours after dosage but were indistinguishable from placebo by 8 hours. Buspirone did not alter the EEG or DSST performance but did increase self-ratings of sedation and feeling "spacey" and impaired memory function; these effects generally were quantitatively less than with triazolam. Peak plasma triazolam concentrations preceded maximum pharmacodynamic effects; the mean plasma effect site equilibration half-life was 9.4 minutes. Kinetic-dynamic modeling procedures yielded significant relationships between hypothetical effect site triazolam concentrations and pharmacodynamic changes. CONCLUSIONS: Quantitative analysis of the EEG clearly distinguishes a typical benzodiazepine agonist from a nonagonist anxiolytic, in clinically relevant dosage, whose pharmacodynamic actions do not involve benzodiazepine receptor occupancy. EEG effects associated with triazolam are intercorrelated with other pharmacodynamic measures.
A rapid and sensitive multi-residue method was developed to attempt to confirm the presence of the beta-blocker carazolol and the tranquillizers acepromazine, azaperone, chlorpromazine, propionylpromazine and xylazine in pig muscle tissues. The procedure involves determination by liquid chromatography coupled with tandem mass spectrometry. The liquid chromatographic separation was performed on a Symmetry C18 column with gradient elution. A mixture of aqueous buffer, containing 0.01% m/v trifluoroacetic acid (pH 3.5), and acetonitrile at a flow rate of 0.4 ml min-1 was used as the mobile phase. The abundant parent ions [M+ H+] produced by positive electrospray ionisation were selected for collisional dissociation with argon. Fragment ions were recorded with daughter ion scan and multiple reaction monitoring. The analytes were identified unambiguously by assessing retention times and diagnostic ions in meat samples spiked from 50 micrograms kg-1 [maximum residue limit (MRL) for azaperone and azaperol] to 5 micrograms kg-1 (MRL for carazolol).
Six 1-year-old farmed red deer were used to compare physiological and behavioural responses to a range of doses of 5% xylazine with or without the addition of 0.4 mg of fentanyl citrate and 3.2 mg of azaperone per ml. Each deer was randomly assigned to one of six treatments: xylazine alone at 0.4 and 0.6 mg/kg, the xylazinelfentanyl citrate/azaperone combination containing 0.2, 0.4 and 0.6 mg/kg of xylazine, or a sterile water control. Injections were given intramuscularly in the anterior neck, operator blind, on each of 6 sampling days between October and January, such that each deer received all treatments with 9-28 days between each treatment. Measurements included heart rate and respiration rate. A 0-3 scoring system (normal to nil response, respectively) was devised to record sedative responses (body stance, head position, degree of eye closure, palpebral reflex, resistance to movement of the head, response to noise) and analgesic responses to touch and pinching of the ear, and response to a needle prick in the gluteal region. Scores were added to produce a sedation score and analgesia score, respectively, for each treatment. Records were taken immediately prior to injection and thereafter at 5, 14, 25, 35, 60, 90, 120, 150, 180, 210, 240 and 300 minutes. All deer given each dose rate of the xylazine and the xylazine/fentanyl citrate/azaperone combination became recumbent. There was a tendency for the time to recumbency and variation of time to recumbency to be shorter at higher dose rates and with the addition of fentanyl citrate and azaperone to xylazine, particularly with xylazine at 0.4 mg/kg. These trends were not statistically significant (p>0.05). The duration of recumbency was shorter with the low dose of the xylazine/fentanyl trateiazaperone combination (0.2 mg/kg of xylazine) than for the higher doses of xylazine alone or the combination of drugs (p<0.05). There were no significant differences in heart rates or respiration rates between treatments, although all treatments significantly reduced both heart and respiration rates (p<0.01). The sedation scores showed similar peak responses and timing to peak responses (14-25 min) to both drug treatments and all dose rates, but the responses were less persistent for lower doses. The analgesia scores showed a similar pattern, with peak responses 14-35 minutes after administration and more persistence at higher dose rates of both xylazine alone and the xylazine/fentanyl citrate/azaperone combination. This study has shown that most physiological and behavioural responses to a range of doses of xylazine or the xylazine/fentanyl citrate/azaperone combination were statistically similar. However, there was a tendency for recumbency to occur more rapidly and with less variation in timing when the mid-range dose of the drug combination was used, supporting the observation by practitioners that the drug combination results in a more rapid and reliable state of recumbency at a lower dose rate of xylazine.
Göttingen mini-pigs were given atropine and anaesthetized with one of the following drug combinations: 1) azaperone + metomidate, 2) acepromazine + thiopentone for endotracheal intubation, followed by halothane + methoxyflurane in oxygen. Respiration rate, arterial O2 and CO2 tensions, arterial pH, mean arterial blood pressure and heart rate were recorded at 15 min. intervals from 30 to 120 min. after the induction of anaesthesia. The azaperone-metomidate combination, which requires continuous intravenous access, caused a mild respiratory acidosis, but acid-base status was stable, whereas blood pressure and heart rate rose steadily throughout the observation period. The second combination depressed respiratory and cardiovascular function, but the condition of the animals did not deteriorate further during 2 hrs of surgical anaesthesia. Endotracheal intubation for inhalation anaesthesia should, however, be performed after a single injection of metomidate, as thiopentone tended to cause respiratory arrest.
Anaesthesia of 2 five-year-old female African elephants (Loxodonta africana) was required for dental surgery. The animals were each premedicated with 120 mg of azaperone 60 min before transportation to the hospital. Before offloading, 1 mg etorphine was administered intramuscularly (i.m.) to each elephant to facilitate walking them to the equine induction/recovery room. For induction, 2 mg etorphine was administered i.m. to each animal. Induction was complete within 6 min. Surgical anaesthesia was induced with halothane-in-oxygen after intubation of the trunk. During surgery the mean heart rate was 61 and 45 beats/min respectively. Systolic blood pressures increased to 27.5 and 25.6 kPa respectively, and were treated with intravenous azaperone. Blood pressure decreased thereafter to a mean systolic pressure of 18.1 and 19.8 kPa, respectively. Rectal temperature was 35.6 and 33.9 degrees C at the onset of surgery, and decreased to 35.3 and 33.5 degrees C, respectively, at the end of anaesthesia. Etorphine anaesthesia was reversed with 5 mg diprenorphine at the completion of 90 min of surgery.
In a clinical study alfentanil/etomidat-short-active anaesthesia was used in 150 cats. The anaesthesia progress was compared to usual steroid anaesthesia by using clinical parameters as respiratory and pulse frequency as well as reflexes. Surgical tolerance in both anaesthesia was 6 minutes without and 7 minutes with azaperon premedication. In both anaesthesia excitations occur during waking time. They can be prevented by using a calm waking room or by premedication with azaperon (in subclinical dose of 0.25 mg/kg BW) or diazepam (in the usual dose of 0,2-1 mg/kg BW). Premedication with diazepam is preferred because it has no influence on respiration and circulation and does not intensify the anaesthesia. Indications for alfentanil/etomidat short-active anaesthesia are minor surgery, diagnostic measures and teeth treatment. In addition, alfentanil/etomidat was shown to be suitable for introducing inhalation anaesthesia particularly in old and sick animals.
Previous studies have reported significant radiobiological and hemodynamic effects associated with sodium pentobarbital (PB) anesthetization. The present work contrasts the effects of PB with azaperone-ketamine (AZ) in RIF-1 and KHT tumors while animal body core temperature is maintained at 37 degrees C. The primary aims were to evaluate both agents in terms of: (i) duration of anesthetic; (ii) effect on absolute levels of 31P NMR phosphocreatine (PCr) + beta-nucleoside triphosphate (beta-NTP)/inorganic phosphate (Pi) ratios; and (iii) effect on temporal variability of PCr + beta-NTP/Pi ratios. In terms of overall duration, AZ was the clear preference. Although the maintenance of 37 degrees C core temperature significantly reduced overall durations for both anesthetics, AZ animals invariably remained immobile for a minimum of 80 min. For PB, durations were highly unpredictable. With AZ, mean PCr + beta-NTP/Pi ratios were constant over the entire 80 min period for both lines. With PB, PCr + beta-NTP/Pi ratios were lower in relation to AZ for KHT at select timepoints, but highly variable among RIF-1 tumours. Since ratios under PB varied substantially with time for RIF-1 lines, measurements taken with PB are clearly not representative of the control state. Furthermore, in light of the consistent and reproducible results obtained with AZ, this anesthetic is considered a marked improvement over PB for animal studies of this nature.
The effect of cocaine, over a dose range of 2--60 mg/kg, i.p., on self-stimulation (SS) behavior was studied in rats with electrodes either in the posterior hypothalamus (PH, monoaminergic) or the area ventralis tegmentum (A10, dopaminergic). The drug increased SS behavior with peak effects at 30 mg/kg in PH rats and 20 mg/kg in A10 rats. Azaperone (an alpha-adrenergic blocker) and haloperidol (an antidopaminergic neuroleptic) given at doses that did not affect baseline SS responses reduced cocaine-induced enhancement of SS in both PH and A10 rats, showing the involvement of both noradrenergic and dopaminergic mechanisms in SS behavior. A scopolamine dose that itself facilitated SS responding enhanced the effect of cocaine on this behavior, thus suggesting an additional involvement of cholinergic mechanisms in cocaine effect.
A method is described for the analytical determination of the neuroleptics azaperone (plus its metabolite azaperol), acetylpromazine, propionylpromazine, chlorpromazine and the beta-blocking agent carazolol in pork kidneys. These compounds may be used illegally to calm pigs during their transport to the abattoir. The kidney samples (plus atosil as an internal standard) are incubated with NaOH (90 degrees C, 60 min); the rather fluid samples are extracted with diethylether. The separation of interfering compounds in the extracts is achieved on a silica gel column. The remaining interfering compounds are removed with ether after acidification of the eluted material. After alkalization of the aqueous solution, the drugs are extracted with either and applied to a Symmetry RP18 column (mobile phase: acetate buffer solution pH 4.5/acetonitrile/tetrahydrofurane, 65/30/10 by volume by HPLC. Recovery in spiked samples of pork kidneys (recovery of 50 micrograms/kg, carazolol 5 micrograms/kg) was between 71.5% (for propionylpromazine) and 88% (for azaperol). The method was verified on samples of treated pigs.
The dose-response relationship for d-amphetamine (0.125-2 mg/kg, IP) and its l-isomer (0.125-3 mg/kg, IP) was studied in self-stimulation behavior of rats each with an electrode at posterior hypothalamus (PH, mainly monoaminergic) or area ventralis tegmentum (A10, dopaminergic). The drug effects increased with the dose reaching a peak (at 0.5 mg/kg with d-amphetamine and at 1.0 mg/kg with 1-amphetamine) and then decreased. The d-isomer was approximately twice as potent as the l-isomer in enhancing intracranial self-stimulation (ICSS) rate with electrodes at either site. Azaperone (mainly an alpha-adrenergic blocker) and haloperidol (an antidopaminergic neuroleptic) used in small doses (0.05 and 0.008 mg/kg respectively) which did not affect the baseline responding, blocked amphetamine-induced enhancement of ICSS in both groups of rats. Thus, amphetamine-induced facilitation of ICSS at both PH and A10 areas and its blockade by an alpha-adrenergic blocker as well as an antidopaminergic neuroleptic show the involvement of both noradrenergic and dopaminergic mechanisms in self-stimulation behavior.