A Retrospective Comparison of Electrocardiographic Parameters in Ketamine and Tiletamine-Zolazepam Anesthetized Indian Rhesus Monkeys (Macaca mulatta).

Electrocardiographic evaluation is performed in rhesus monkeys to establish the cardiovascular safety of candidate molecules before progressing to clinical trials. These animals are usually immobilized chemically by ketamine (KTM) and tiletamine-zolazepam (TZ) to obtain a steady-state heart rate and to ensure adequate human safety. The present study aimed to evaluate the effect of these anesthetic regimens on different electrocardiographic parameters. Statistically significant lower HR and higher P-wave duration, RR, QRS, and QT intervals were observed in the KTM-anesthetized group in comparison to TZ-anesthetized animals. No significant changes were noticed in the PR interval and p-wave amplitude. Sex-based significance amongst these parameters was observed in male and female animals of TZ- and KTM-anesthetized groups. Regression analysis of four QTc formulas in TZ-anesthetized rhesus monkeys revealed that QTcNAK (Nakayama) better corrected the QT interval than QTcHAS (Hassimoto), QTcBZT (Bazett), and QTcFRD (Fridericia) formulas. QTcNAK exhibited the least correlation with the RR interval (slope closest to zero and r = .01) and displayed no statistical significance between male and female animals. These data will prove useful in the selection of anesthetic regimens for chemical restraint of rhesus monkeys in nonclinical safety evaluation studies.

Movement disorder caused by abuse of veterinary anesthesia containing tiletamine.

Zoletil (Telazol) is a fixed-ratio combination of the tranquilizer zolazepam, with the dissociative anesthetic tiletamine, used for injection anesthesia in dogs, cats, wild, and zoo animals. We report a veterinarian who developed movement disorder after abuse of Zoletil for a 2-week period. Phencyclidine derivatives, that is, tiletamine can induce movement disorder in human. Tiletamine/zolazepam can be abused for recreational purpose, especially by those people with easy access to veterinary medications. Emergency physicians should have high alert to the diverse presentations of drug abuse. This case again highlights that the association between accessibility of scheduled drugs and health care professionals.

Clinical and pathologic features of cynomolgus macaques (Macaca fascicularis) infected with aerosolized Yersinia pestis.

Since the anthrax attacks of 2001, the emphasis on developing animal models of aerosolized select agent pathogens has increased. Many scientists believe that nonhuman primate models are the most appropriate to evaluate pulmonary response to, vaccines for, and treatments for select agents such as Yersinia pestis (Y. pestis), the causative agent of plague. A recent symposium concluded that the cynomolgus macaque (Macaca fascicularis) plague model should be characterized more fully. To date, a well-characterized cynomolgus macaque model of pneumonic plague using reproducible bioaerosols of viable Y. pestis has not been published. In the current study, methods for creating reproducible bioaerosols of viable Y. pestis strain CO92 (YpCO92) and pneumonic plague models were evaluated in 22 Indonesian-origin cynomolgus macaques. Five macaques exposed to doses lower than 250 CFU remained free of any indication of plague infection. Fifteen macaques developed fever, lethargy, and anorexia indicative of clinical plague. The 2 remaining macaques died without overt clinical signs but were plague-positive on culture and demonstrated pathology consistent with plague. The lethal dose of plague in humans is reputedly less than 100 organisms; in this study, 66 CFU was the dose at which half of the macaques developed fever and clinical signs (ED(50)), The Indonesian cynomolgus macaque reproduces many aspects of human pneumonic plague and likely will provide an excellent model for studies that require a macaque model.

Comparison of cardiovascular effects of tiletamine-zolazepam, pentobarbital, and ketamine-xylazine in male rats.

We allocated 35 male Sprague-Dawley rats into 7 groups and anesthetized each by using one of the following regimens: ketamine 50 mg+xylaxine 5 mg; ketamine 75 mg+xylazine 5 mg; pentobarbital 45 mg; and Telazol 30, 40, 50, and 60 mg/kg; supplemental doses were used as required. Respiratory rate, heart rate, mean arterial pressure, cardiac index, and stroke index were measured every 30 min for 4 h. The Telazol groups showed a dose-dependent increase in duration of anesthesia. Duration of anesthesia was significantly shorter for the ketamine and pentobarbital groups than for any of the Telazol doses. Heart rate showed a dose-dependent decrease among the Telazol groups, but overall heart rate in these groups was higher than in the ketamine and pentobarbital groups. Mean arterial pressure in the Telazol 40 and 50 groups was significantly higher than the pentobarbital and higher ketamine groups yet lower than that of the Telazol 60 group. Overall animals anesthetized with Telazol showed the highest cardiac index, ketamine intermediate, and pentobarbital the lowest; cardiac index was higher in the Telazol 50 group than in either the Telazol 30 or pentobarbital groups. The pentobarbital group exhibited the lowest stroke index, whereas ketamine-treated animals had an intermediate stroke index. These differing effects of anesthetics on cardiovascular parameters must be considered when choosing an anesthesia regimen or comparing data from different studies. In our model, the Telazol 40 and 50 groups appeared to exhibit the fewest adverse cardiovascular effects.

Optimization of intraperitoneal injection anesthesia in mice: drugs, dosages, adverse effects, and anesthesia depth.

PURPOSE: The goals of the study were to find a safe intraperitoneal injection anesthesia protocol for medium-duration surgery in mice (e.g., embryo transfer/vasectomy) coupled with a simple method to assess anesthesia depth under routine laboratory conditions. METHODS: Eight anesthetic protocols consisting of combinations of dissociative anesthetics (ketamine, tiletamine), alpha2-agonists (xylazine, medetomidine), and/or sedatives (acepromazine, azaperone, zolazepam) were compared for their safety and efficacy (death rate, surgical tolerance), using observations and reflex tests. The four best protocols were further evaluated during vasectomy: physiologic measurements (respiratory rate, electrocardiogram, arterial blood pressure, body temperature, blood gas tensions, and acid-base balance) were used to characterize the quality of anesthesia. The reactions of physiologic parameters to surgical stimuli were used to determine anesthesia depth, and were correlated with reflex test results. RESULTS: The protocol with the highest safety margin and the longest time of surgical tolerance (54 min) was ketamine/ xylazine/acepromazine. Three further anesthetic combinations were associated with surgical tolerance: ketamine/ xylazine, ketamine/xylazinelazaperone, and tiletamine/xylazine/zolazepam (Telazol/xylazine). The protocols consisting of ketamine/medetomidine and ketamine/azaperone were not associated with clearly detectable surgical tolerance. The most reliable parameter of surgical tolerance under routine laboratory conditions was the pedal withdrawal reflex. CONCLUSIONS: The best intraperitoneal injection anesthesia regimen consisted of ketamine/xylazine/acepromazine. The dose must be adapted to the particulars of each experimental design (mouse strain, sex, age, mutation). This is best done by measuring surgical tolerance, using the pedal withdrawal reflex.

A fatality related to the veterinary anesthetic telazol.

A 45-year-old male veterinarian was found dead in bed. Police investigation showed no evidence of trauma or other suspicious circumstances. Autopsy was unremarkable except for cardiomegaly and hepatosplenomegaly. Toxicological analysis revealed the presence of Telazol and ketamine. Telazol is a veterinary anesthetic agent that is composed of equal parts of tiletamine and zolazepam. Tiletamine is a disassociative anesthetic similar to ketamine and phencyclidine, and zolazepam is a diazepine derivative tranquilizer used to minimize the muscle hypertonicity and seizures associated with tiletamine. Quantitation of tiletamine and zolazepam was performed using gas chromatography-mass spectrometry in the selected ion monitoring mode following a solid-phase extraction. Postmortem blood, urine, and liver concentrations of tiletamine were 295 ng/mL, 682 ng/mL, and 196 ng/g, respectively, whereas postmortem concentrations of zolazepam for the same tissues were 1.71 microg/mL, 1.33 microg/mL, and 15.5 microg/g, respectively. Blood and urine ketamine levels were 37 ng/mL and 381 ng/mL, respectively. The cause of death was ruled an acute mixed drug intoxication of tiletamine, zolazepam, and ketamine with the manner of death ruled as unclassified.

Evaluation of Telazol-xylazine as an anesthetic combination for use in Syrian hamsters.

The availability of safe parenteral anesthetics for use in Syrian hamsters is limited. We evaluated the effects of Telazol-xylazine (TZX) combinations with respect to anesthetic efficacy and potential for tissue damage. Two dose levels of the combination were administered by both the intraperitoneal (IP) and intramuscular (IM) routes. TZX by the IM route failed to consistently produce anesthesia and caused gross and histopathologic muscle lesions. IP administration of 20 mg/kg Telazol combined with 10 mg/kg xylazine was adequate for restraint purposes. IP administration of 30 mg/kg Telazol combined with 10 mg/kg xylazine produced a safe, reliable level of surgical anesthesia without evidence of gross or histopathologic lesions. There was no nephrotoxicity at either concentration of the anesthetic. A dose level of TZX that provides safe parenteral anesthesia in Syrian hamsters was determined.

Anesthetic and nephrotoxic effects of Telazol in New Zealand white rabbits.

Telazol was evaluated as an anesthetic for rabbits. Two groups of five rabbits each were injected intramuscularly with 32 or 64 mg/kg of Telazol, and the depth and duration of anesthesia period monitored. At both doses, the righting reflex was lost within 2 minutes postinjection. Animals in both groups responded to noxious stimuli for the duration of the anesthesia. Hematology and urinalyses were performed daily for 7 days postinjection. Hematologic parameters remained unchanged in both groups. In the high-dose group, blood urea nitrogen and serum creatinine levels increased 1 day postinjection and continued steadily throughout the week. Elevations in urine protein and the presence of casts correlated with this increase. In the low-dose group, blood urea nitrogen and creatinine levels increased and protein was present in the urine of four of five rabbits beginning approximately 5 days postinjection. Histologically, severe renal tubular necrosis was evident 7 days postinjection in all high-dose rabbits and in three rabbits in the low-dose group. Our results indicate that Telazol does not produce analgesia in rabbits and is nephrotoxic at both 32 and 64 mg/kg. We conclude that Telazol is contraindicated for use in rabbits.