Comparative pharmacokinetics of yohimbine in steers, horses and dogs.

In steers, horses and dogs, the comparative pharmacokinetics of yohimbine were determined using model-independent analysis. The intravenous dose of yohimbine was 0.25 mg/kg of body weight in steers, 0.075 or 0.15 mg/kg in horses, and 0.4 mg/kg in dogs. The mean residence time (+/- SD) of yohimbine was 86.7 +/- 46.2 min in steers, 106.2 +/- 72.1 to 118.7 +/- 35.0 min in horses, and 163.6 +/- 49.7 min in dogs. The mean apparent volume of distribution of yohimbine at steady state was 4.9 +/- 1.4 L/kg for steers, 2.7 +/- 1.0 to 4.6 +/- 1.9 L/kg for horses, and 4.5 +/- 1.8 L/kg for dogs. The total body clearance of yohimbine was 69.6 +/- 35.1 mL/min/kg for steers, 34.0 +/- 19.4 to 39.6 +/- 16.6 mL/min/kg for horses, and 29.6 +/- 14.7 mL/min/kg for dogs. Between-species comparisons indicated that the mean area under the serum concentration versus time curve was significantly greater (P less than 0.05) in dogs than in horses. There were no significant differences (P greater than 0.05) between the means for the apparent volume of distribution, clearance, mean residence time, terminal rate constant, and area under the curve between horses given the two doses of yohimbine. The harmonic mean effective half-life (+/- pseudo standard deviation) of yohimbine was 46.7 +/- 24.4 min in steers, 52.8 +/- 27.8 to 76.1 +/- 23.1 min in horses, and 104.1 +/- 32.1 min in dogs. The data may explain why steers, horses, and dogs given certain sedatives and anesthetics do not relapse when aroused by an intravenous injection of yohimbine hydrochloride.

Quipazine-metoclopramide inhibition of CB-154-induced prolactin suppression in rats: neurotransmitter-metabolite correlations.

The ability of quipazine and metoclopramide to protect rats from CB-154-induced suppression of serum prolactin concentrations was studied. These drugs affect whole brain concentrations of dopamine and serotonin, and their major metabolites dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid. Serum prolactin concentrations have been correlated with the concentrations of the neurotransmitters and their respective metabolites. Differences in the metabolite/precursor ratios have been used to compare turnover rates of the neurotransmitters dopamine and serotonin. Increased turnover of dopamine and decreased turnover of serotonin correlate with elevated prolactin concentrations for quipazine and metoclopramide administered together. The combination of quipazine and metoclopramide protects rats against CB-154-induced prolactin suppression better than either of the drugs given alone. This study suggests that a quipazine-metoclopramide regimen may have therapeutic potential for combating ergotlike fescue and other similar toxicities observed in cattle grazing on endophyte-infected pasture grasses.

Effect of clonidine, quipazine, and LY 53857 on the prolactin-suppressant action of bromocriptine in rats.

The alpha 2-adrenergic agonist clonidine hydrochloride, the serotonin agonist quipazine maleate, and the serotonin (5-HT2) antagonist LY 53857 were tested alone and in various combinations for their capabilities to increase mean serum prolactin (MSP) concentrations in rats given the synthetic ergot alkaloid CB-154 (2-bromo-alpha-ergocriptine), a known prolactin suppressor. The LY 53857 and the combination of clonidine, quipazine, and LY 53857 significantly decreased MSP concentrations. Quipazine given alone (10 mg/kg of body weight) was best able to increase MSP concentration and has potential to antagonize prolactin-depressant effects of ergot alkaloids.

Prompt arousal from fentanyl-droperidol-pentobarbital anesthesia in dogs: a preliminary study.

Groups of fentanyl-droperidol-pentobarbital-anesthetized dogs (n = 6 dogs/group) were given IV saline solution (control group), graded doses of naloxone (0.01, 0.1, 1.0, 10.0 mg/kg) or fixed doses of 4-aminopyridine (0.5 mg/kg), yohimbine (0.4 mg/kg), or doxapram (5.0 mg/kg) alone or in combination with a fixed dose of naloxone (1.0 mg/kg). The purpose was to determine which drug or drug combination would produce arousal most quickly without producing obvious undesirable side effects. Control group mean arousal time, mean walk time and mean duration of postarousal sedation were 66.1 minutes, 112.4 minutes and 5.6 hours, respectively. Naloxone (1.0 mg/kg) decreased mean arousal time to 10.8 minutes without significantly decreasing mean walk time or mean duration of postarousal sedation. The combination of naloxone + doxapram decreased mean arousal time and mean walk time to 1.0 minute and 57.1 minutes, respectively, without decreasing mean duration of postarousal sedation. In all groups, emergence from anesthesia was smooth. Relapses or undesirable side effects were not observed. Naloxone + doxapram is superior to naloxone alone for arousal of fentanyl-droperidol-pentobarbital-anesthetized dogs.

Effect of yohimbine hydrochloride on serum prolactin concentration in the rat: possible antagonist for fescue toxicosis.

Yohimbine hydrochloride is an indole alkaloid which blocks alpha 2-adrenergic and dopamine receptors and stimulates serotonergic receptors. Yohimbine was selected for testing as a possible antagonist in fescue toxicosis. Reduced body weight gains in cattle with chronic fescue toxicosis may be due to ergot alkaloids produced by fungi which infect the fescue grass. Ergot alkaloids stimulate dopamine receptors, antagonize serotonin, and lower serum prolactin concentrations. It was hypothesized that yohimbine may reverse or counteract the effects of the toxic fescue. Investigation was made of the treatment effects of multiple doses of yohimbine given in rats by intraperitoneal and oral routes. Given intraperitoneally once a day for 8 days, yohimbine hydrochloride increased serum prolactin concentrations. When given orally in feed for 7 days, the drug decreased the serum prolactin concentration. The effects of yohimbine on prolactin concentrations were dependent on the dosages and routes of administration. The inability of yohimbine, when given orally, to increase serum prolactin levels decreased its potential usefulness for prolonged treatment of fescue toxicosis.

Antagonism of xylazine sedation in steers by doxapram and 4-aminopyridine.

Five groups of 6 fasted crossbred steers were injected IM with standard dosages of xylazine hydrochloride (0.3 to 0.5 mg/kg). At maximal sedation, the steers were injected IV with the antagonists' doxapram (1.0 mg/kg), doxapram + yohimbine (0.125 mg of yohimbine/kg), doxapram + 4-aminopyridine (4-AP; 0.3 mg of 4-AP/kg), or 4-AP + yohimbine. One group was given 1.0 ml of saline solution IV instead of antagonists. Doxapram, doxapram + yohimbine, doxapram + 4-AP, and 4-AP + yohimbine decreased mean standing time (time from antagonist injection until animal could stand unaided) to 17.0, 4.3, 3.3, and 4.5 minutes, respectively--significantly (P less than 0.05) down from a control value of 49.8 minutes. Mean total recovery time (time from xylazine injection until animal resumed eating) was decreased to 78 minutes by doxapram and 81.6 minutes by doxapram + 4-AP--significantly (P less than 0.05) down from the control value of 142.9 minutes. Respiratory character was improved (depth of respiration was increased) only by doxapram + 4-AP. Relapses to recumbency and marked sedation were not seen in steers given doxapram + 4-AP or the saline solution. One steer given doxapram, 2 given doxapram + yohimbine, and 1 given 4-AP + yohimbine relapsed to recumbency and sedation. Recovery was relatively smooth in steers given doxapram + 4-AP or 4-AP + yohimbine. Animals given doxapram or doxapram + yohimbine had difficult recoveries.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversal of pentobarbital anesthesia with 4-aminopyridine and yohimbine in cats pretreated with acepromazine and xylazine.

In 2 separate experiments, groups of atropinized cats (6 cats/group) were given acepromazine (0.25 mg/kg of body weight) or xylazine (2.2 mg/kg) IM and anesthetized with pentobarbital. The mean dose of pentobarbital was decreased approximately 36% by acepromazine, and approximately 80% by xylazine, compared with published doses. Anesthetized cats were given IV saline solution (control groups) or were given the antagonists 4-aminopyridine (4-AP; 0.5 mg/kg), yohimbine (0.4 mg/kg), or 4-AP + yohimbine (0.5 mg/kg and 0.4 mg/kg, respectively). In acepromazine-treated cats, 4-AP + yohimbine was the most effective antagonist; arousal and walking occurred in an average of 10.4 minutes and 91.7 minutes, respectively. Yohimbine enhanced the antagonistic effects of 4-AP. In xylazine-treated cats, yohimbine was an effective antagonist; arousal and walking occurred in an average of 2.8 minutes and 12.8 minutes, respectively. Yohimbine did not enhance the antagonistic effects of 4-AP. Mean respiratory rates were decreased by acepromazine, but were increased by xylazine. Thus, respiratory rate depression by pentobarbital was not as marked with xylazine as it was with acepromazine. Changes in mean heart rate were not remarkable with either sedative, and cardiac irregularities were not palpated or auscultated. In healthy cats, the duration of pentobarbital anesthesia can be controlled by 4-AP + yohimbine (acepromazine-pretreated cats) or by yohimbine alone (xylazine-pretreated cats).

Pharmacokinetics of 4-aminopyridine in cattle.

Concentrations of 4-aminopyridine hydrochloride in plasma of cattle were measured over an 8-hour period following a bolus IV injection (0.3 mg/kg). The drug was assayed by a gas-liquid chromatographic method using a nitrogen-phosphorus detector. Plasma 4-aminopyridine hydrochloride vs time data best fit a 2-compartment pharmacokinetic model. Distribution half-life was 12.08 minutes; elimination half-life, 128.96 minutes; volume of the central compartment, 1.48 L/kg; volume of distribution based on total area, 3.07 L/kg; volume of distribution at steady state, 2.75 L/kg; and body clearance, 16.57 ml/min/kg.

Meperidine-acepromazine-pentobarbital anesthesia in cats: reversal by 4-aminopyridine and yohimbine.

Groups of atropinized cats (6/group) were given IM meperidine (5.5 mg/kg of body weight) plus acepromazine (0.25 mg/kg). Forty minutes later, the cats were anesthetized to disappearance of pedal reflexes with 1% pentobarbital IV. Volume of anesthetic was recorded. Five minutes later, the cats were given IV saline solution (2 ml; control group), the antagonists 4-aminopyridine (4-AP; 0.5 mg/kg), yohimbine (0.4 mg/kg), or a combination of 0.5 mg of 4-AP/kg plus 0.4 mg of yohimbine/kg. Mean arousal time (MAT), walk time (MWT), respiratory rate, and heart rate were measured. Emergence phenomena also were recorded. Meperidine plus acepromazine caused mydriasis and mild sedation without ataxia or marked protrusion of the 3rd eyelid. The cats did not resist restraint for venipuncture. The pooled mean dosage level of pentobarbital required for anesthesia was 12.3 mg/kg. Control group MAT and MWT were 66.2 minutes and 126 minutes, respectively. Marked residual sedation lasted several hours. In cats given 4-AP plus yohimbine, MAT and MWT were decreased to 4.4 minutes and 36.5 minutes, respectively. These values were not significantly shorter than those same values in cats given 4-AP or yohimbine alone (P greater than 0.05), but the combination of 4-AP plus yohimbine produced a qualitatively better reversal of anesthesia than did 4-AP or yohimbine alone. Emergence was smooth in all 4 groups; mild-to-moderate residual sedation lasted 2 to 4 hours in the principals. Relapses, drug side effects, and behavioral aberrations were not observed. Mean respiratory rates and heart rates decreased during anesthesia but these values were not excessively depressed or stimulated at any time. Cardiac irregularities were not detected by palpation or auscultation.(ABSTRACT TRUNCATED AT 250 WORDS)

Antagonism of xylazine and ketamine anesthesia by 4-aminopyridine and yohimbine in geldings.

Thirty-six fasted, mixed horse breed geldings (6 groups of 6 animals each) were anesthetized with xylazine and ketamine, and when maximally sedated, were given 1 of the following antagonists: saline solution, 4-aminopyridine (4-AP), small-dose yohimbine, large-dose yohimbine, 4-AP plus low-dose yohimbine, or 4-AP plus high-dose yohimbine. Measured data included mean standing time (MST), heart rate, respiratory rate, rectal temperature, and mean total recovery time ( MTRT ). Emergence phenomena were also observed and recorded as smooth, fairly smooth, fairly rough, or rough. Groups given 4-AP alone, small-dose yohimbine alone, or large-dose yohimbine alone produced a significant (P less than 0.05) decrease in MST (9.9 +/- 1.6 minutes, 11.3 +/- 1.7 minutes, and 10.6 +/- 2.3 minutes, respectively) compared with that in the saline control group (24.3 +/- 9.2 minutes). The MTRT were not significantly (P greater than 0.05) different (47.2 +/- 10 minutes, 90.4 +/- 15.1 minutes, and 83.2 +/- 23 minutes, respectively) from control values (66.2 +/- 13.4 minutes). When the antagonists were combined, 4-AP plus small-dose yohimbine and 4-AP plus large-dose yohimbine produced significant (P less than 0.05) decreases (10.3 +/- 2 minutes and 8.3 +/- 2.6 minutes, respectively) in MST compared with that of saline controls. The MTRT was significantly longer in the combined antagonist group (4-AP + small-dose yohimbine--131.8 +/- 28.9 minutes; 4-AP + large-dose yohimbine--131.3 +/- 19.4 minutes) compared with that of control or any antagonist alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of 4-aminopyridine in horses.

The pharmacokinetics of 4-aminopyridine (4-AP), a drug capable of antagonizing nondepolarizing neuromuscular blocking drugs, as well as several classes of injectable sedative and anesthetic agents, were studied in 6 intact, awake horses. Plasma samples were assayed for 4-AP over a frequent sampling schedule for 8 hours after IV administration. The plasma 4-AP vs time data best fit a 2-compartment pharmacokinetic model. Distribution half-life was 7.4 minutes, elimination half-life was 259 minutes, volume of the central compartment was 0.89 L/kg, volume of distribution (area) was 1.98 L/kg, volume of distribution at steady state was 1.9 L/kg, and total clearance was 5.3 ml min(-1) kg(-1). The 259-minute elimination halflife observed in the present study is consistent with prolonged clinical effectiveness observed in a previous study of antagonism of xylazine/ketamine anesthesia by 4-AP in horses.

Comparison of five preanesthetic medicaments in pentobarbital-anesthetized dogs: antagonism by 4-aminopyridine, yohimbine, and naloxone.

Effects of saline solution (groups 1, 2, and 3), xylazine (2.2 mg/kg of body weight, groups 4 and 5), acepromazine (0.1 mg/kg, groups 6 and 7), diazepam (1.0 mg/kg, groups 8 and 9), morphine (1.0 mg/kg, groups 10 and 11), or fentanyl-droperidol (0.055 ml/kg, groups 12 and 13), IM were compared in groups of atropinized dogs. Treated dogs were anesthetized to stage III, plane 2 with pentobarbital, IV. After stabilization of anesthesia, the dogs were given IV 0.5 mg of 4-aminopyridine (4-AP)/kg + 0.25 mg of yohimbine/kg (groups 2, 5, 7, and 9), or 4-AP + yohimbine + 0.04 mg of naloxone/kg (groups 3, 11, and 13). Groups 1, 4, 6, 8, 10, and 12 were given saline solution instead of test antagonists. Required dosage of pentobarbital, arousal and walk times (measured from injection of antagonists), respiratory rate, and heart rate were measured. Emergence phenomena were recorded and graded as smooth, fairly smooth, smooth in some dogs to rough in other dogs, rough, or very rough. In group 1 dogs, mean arousal time (MAT) was 279.5 minutes, mean walk time (MWT) was 583.3 minutes, and emergence was rough. In groups 4, 6, 8, 10, and 12, MAT was decreased by the sedatives to the range of 52 to 115.3 minutes and MWT was decreased to the range of 82.3 to 188.5 minutes. Emergence was smooth (groups 4 and 6), fairly smooth (groups 10 and 12), or smooth to rough (group 8).(ABSTRACT TRUNCATED AT 250 WORDS)

Acepromazine-xylazine combination in dogs: antagonism with 4-aminopyridine and yohimbine.

Groups of fasted atropinized crossbred dogs of both sexes were injected IM with a standard dosage of a xylazine-acepromazine combination (2.2 mg/kg and 0.5 mg/kg, respectively). Righting reflex was uniformly lost and considered to be the point of maximum sedation. After maximal sedation, dogs were injected IV with 4-amino-pyridine (4-AP, 0.5 mg/kg), yohimbine (0.25 mg/kg), or a combination of 4-AP and yohimbine. Controls were given (IV) 1 ml of saline solution. The 4-AP, yohimbine, and 4-AP + yohimbine significantly reduced walk times (time to arousal and ability to walk on a leash) from a control value of 43.1 minutes to 7.6, 4.4, and 1.9 minutes, respectively (P less than 0.05). Relapse to unconsciousness did not occur with any antagonist regimen and recovery was uneventful. In 3 dogs sedated with the xylazine-acepromazine combination supplemented with halothane having surgically placed cannulas and electrodes for measurement of electroencephalo-, electrocardio-, and electromyographic (EEG, ECG, and EMG) responses, arterial blood pressure, and respiratory rates and depth, IV injection of 4-AP + yohimbine caused transient femoral arterial hypotension with tachycardia, increases in respiratory rate, depth, and minute volume, increased EMG and EEG activities preceding and accompanying gross movements, slight speeding of ECG, and behavioral arousal within 3 minutes. Increased heart rate also was observed in intact dogs given yohimbine. Increased rate and depth of respiration also was seen in all intact dogs given antagonists. Curiously, the xylazine-acepromazine combination did not induce arterial hypotension as expected from the product literature. To what extent pretreatment with atropine sulfate may have counteracted this effect is unknown.(ABSTRACT TRUNCATED AT 250 WORDS)

Antagonism of xylazine sedation by 4-aminopyridine and yohimbine in cattle.

Twenty-four crossbred steers (4 groups of 6 steers each) were injected IM with a standard dosage range of xylazine hydrochloride (0.2 to 0.3 mg/kg of body weight). When the steers were maximally sedated, group I (control group) were given isotonic saline solution (1 ml, IV), group II were given 4-aminopyridine (4-AP, 0.3 mg/kg) IV, group III were given yohimbine hydrochloride (0.125 mg/kg) IV, and group IV were given 4-AP (0.3 mg/kg) plus yohimbine hydrochloride (0.125 mg/kg) IV. The 4-AP decreased mean standing time (MST; time until animal could stand unaided) from 94.3 minutes (control) to 13.4 minutes. Yohimbine decreased MST to 27 minutes. The combination of 4-AP + yohimbine decreased MST to 7.4 minutes. Mean total recovery time (MTRT; time from xylazine injection until normal behavior, including eating and drinking) was not significantly (P = greater than 0.05) decreased from control values by any of the antagonists tested. The combination of 4-AP + yohimbine decreased MST in animals given a 3X overdose of xylazine (0.6 mg/kg) from 124 minutes (control) to 30.3 min. The MTRT was not significantly (P greater than 0.05) decreased from control values. Two animals given a 5X overdose of xylazine (1 mg/kg) and then given 4-AP + yohimbine had a MST of 32.5 minutes and a MTRT of 3.7 hours. The combination of 4-AP + yohimbine produced marked antagonism of xylazine sedation in cattle. The combination of antagonists may prove to be useful for the arousal of animals sedated with xylazine alone or with a combination of sedatives including xylazine.