Pharmacokinetics and metabolism of fenbendazole in channel catfish.

Fenbendazole (FBZ) was administered intravenously (1 mg/kg) and orally (5 mg/kg) to catheterized, confined channel catfish. Blood samples were collected for 72 h, and resulting FBZ plasma concentrations were pharmacokinetically modelled. Following intravenous administration t 1/2 alpha was 0.51 h, t 1/2 beta was 16.8 h, body clearance (C1B) was 0.0598 L/kg/h, and Vd (area) was 1.45 L/kg. After oral administration the t 1/2 (abs) was 1.47 h, the t 1/2 beta was 20.1 h, and the tlag was 0.1 h. Following oral administration of 5 mg FBZ/kg body weight, the following tissues and body fluids were sampled for concentrations of FBZ, oxfendazole (FBZ-SO), sulphone metabolite (FBZ-SO2) and hydroxy metabolite (FBZ-OH): liver, posterior kidney, fat, muscle, bowel contents and urine. Fenbendazole was detected in the highest concentrations in abdominal fat, whereas oxfendazole was found primarily in the kidney, liver and abdominal fat. The sulphone metabolite was detected only in urine and bowel contents, while the hydroxy metabolite was found most often in the liver and abdominal fat samples.

Pharmacokinetics of doxycycline in dogs.

Six adult dogs were given doxycycline hyclate at a dosage of 5 mg/kg of body weight intravenously so that pharmacokinetic parameters could be evaluated. Serum doxycycline concentrations were determined over a 48 h period using a modified agar well bioassay. Compartmental pharmacokinetic evaluation of the serum concentration time data indicated that doxycycline has a half-life of 10.36 h, a body clearance of 1.68 +/- 0.44 mL/min/kg, and a volume of distribution at steady state of 1.468 +/- 0.237 L/kg. Doxycycline pharmacokinetics are favorable for therapeutic use in the dog.

Compartmental and noncompartmental pharmacokinetic analyses of minocycline hydrochloride in the dog.

Six adult dogs were given 5 mg of minocycline hydrochloride/kg of body weight IV. Pharmacokinetic evaluation of the serum drug concentration versus time data was performed, using the 2-compartment open model, the 3-compartment open model, and a noncompartmental model involving use of the statistical moment theory. All pharmacokinetic values except clearance were model independent. Minocycline half-life ranged between 6.48 and 7.24 hours; volume of distribution at steady state, between 1.859 +/- 0.368 and 2.001 +/- 0.468 L/kg; and clearance, between 3.195 +/- 0.618 and 3.424 +/- 0.684 ml/min/kg. These data are similar to those reported for oxytetracycline and indicate that the frequency of administration of the 2 tetracyclines should be the same. Three of the 6 dogs developed an adverse response to the IV injection of minocycline. Dog 1 developed urticaria and had initial serum drug concentrations of approximately 2 times the mean concentrations for the other dogs; values were not included in the pharmacokinetic analysis. Two other dogs had transient signs indicating cardiovascular depression or hypotension; their data were included. Due to the frequency of the unexpected reactions found in this study, it was concluded that dogs should not be given minocycline rapidly IV.

Antagonism of xylazine sedation with yohimbine, 4-aminopyridine, and doxapram in dogs.

Groups of atropinized dogs (6 dogs/group) were sedated with xylazine (2.2 mg/kg of body weight, IM). At recumbency, the dogs were given IV saline solution (control groups), yohimbine (0.05, 0.1, and 0.2 mg/kg), 4-aminopyridine (4-AP; 0.3, 0.6, and 0.9 mg/kg), doxapram (0.5, 1.0, 2.0, and 4.0 mg/kg), or the smallest dose of these antagonists in dual combinations or in triple combination. Two additional groups were sedated with an overdose of xylazine (11 mg/kg, IM). At recumbency, 1 of these groups was given saline solution IV and the other group was given yohimbine IV (0.4 mg/kg) as the antagonist. With the 2.2 mg/kg dose of xylazine, control mean arousal time (MAT) and mean walk time (MWT) were 15.5 minutes and 24.8 minutes, respectively. These values were decreased by the individual antagonists to 0.5 to 2.5 minutes and 0.9 to 7.4 minutes, respectively. Approximate equipotent doses of antagonists (mg/kg) were: yohimbine, 0.2; 4-AP, 0.6; and doxapram, 0.5. Relapses did not occur after yohimbine or 4-AP. With doxapram, muscle tremors and spasms, abnormal postures, or aggressive behavior occurred in several dogs and several dogs had partial or complete relapses. The small doses of individual antagonists were synergistic with regard to MAT, MWT, and duration of residual sedation, but the various combinations of antagonists were not more effective in these regards than were larger doses of the single antagonists. With the overdose of xylazine, control MAT and MWT were 41.5 minutes and 144.5 minutes, respectively. Yohimbine decreased these values to 2.2 minutes and 2.5 minutes, respectively. Relapses did not occur.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Comparison of five preanesthetic medicaments in thiopental-anesthetized cats: antagonism by selected compounds.

Effects of IM injections of saline solution (groups 1, 2, 3, and 4), xylazine (2.2 mg/kg of body weight, groups 5 and 6), acepromazine (0.11 mg/kg, groups 7 and 8), ketamine (11 mg/kg, groups 9 and 10), meperidine (4.4 mg/kg, groups 11 and 12), and diazepam (1 mg/kg, groups 13 and 14) were compared in atropinized cats. Treated cats were anesthetized to loss of palpebral reflex with thiopental, IV. Within 2 minutes, the cats were given IV injections of 0.15 mg of 4-aminopyridine (4-AP) with 0.125 mg of yohimbine/kg (groups 2, 6, 8, and 10), 0.04 mg of naloxone/kg (groups 3 and 12), or 5 mg of the benzodiazepine antagonist Ro 15-1788/kg (groups 4 and 14). Groups 1, 5, 7, 9, 11, and 13 were given saline solution instead of the test antagonists. Required doses of thiopental, arousal time, walk time (measured from injection of antagonists), respiratory rate, and heart rate were recorded. Induction phenomena were also recorded. Emergence was graded as smooth, fairly smooth, fairly smooth in some cats to fairly rough in other cats, rough, or very rough. In group 1 cats, mean arousal time (MAT) was 20.1 minutes, mean walk time (MWT) was 50 minutes, and emergence was rough. In groups given saline solution as the antagonist, the MAT, MWT (both expressed in minutes), and emergence, respectively, were: group 5 = 52.5, 65.5, smooth; group 7 = 15.6, 36.2, fairly smooth; group 9 = 22.5, 58.1, rough; group 11 = 31.3, 52.7, fairly smooth to fairly rough; and group 13 = 91.8, 427, very rough.(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)

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.

The effects of halothane-and-oxygen anesthesia, and of halothane-nitrous oxide-and-oxygen anesthesia on tympanograms in the dog.

Electroacoustic tympanograms were recorded from both ears of 20 dogs of either sex, aged 6 mo to 12 yrs, prior to anesthesia, at 10 min after halothane- and-oxygen (HO) anesthesia, and at 5 min after nitrous oxide was added to the HO mixture (HNO). Both HO and HNO anesthesia significantly increased compliance and peak pressure values from pre-anesthetic (own control) values. In addition, HNO anesthesia significantly increased peak pressure values above HO anesthesia levels. HNO compliance values were not significantly different from HO values. These results suggest that tympanograms recorded during either HO or HNO anesthesia in the dog will be altered and that interpretation of the tympanograms should include consideration of the state of consciousness of the animal during recording.

Cardiovascular effects of intravenous administration of propylene glycol and of oxytetracycline in propylene glycol in calves.

Comparisons were made of the acute cardiovascular effects of oxytetracycline, oxytetracycline in propylene glycol, and propylene glycol alone given to conscious dairy calves. The calves were chronically instrumented with intravascular catheters and electromagnetic flowmeter transducers in and on the pulmonary and renal arteries. Injection (IV) of aqueous preparations of oxytetracycline produced no statistically significant (P greater than 0.05) cardiocirculatory changes in these calves. Oxytetracycline in propylene glycol and propylene glycol alone both produced transient (1 to 4 minute) periods of cardiovascular depression characterized by cardiac asystole, systemic hypotension, and decreased pulmonary and renal arterial blood flow. The two preparations, in equivalent doses and volumes, produced statistically similar hemodynamic changes in the calves. The data from this study support the conclusion that the monitored cardiovascular effects of the commercially available oxytetracycline in propylene glycol in the intact, awake calves were due to the solvent propylene glycol. This conclusion is consistent with reports of other injectable products containing the same solvent.