Cardiovascular effects of intravenous vatinoxan (MK-467) in medetomidine-tiletamine-zolazepam anaesthetised red deer (Cervus elaphus).

OBJECTIVE: To determine the effect of intravenous vatinoxan administration on bradycardia, hypertension and level of anaesthesia induced by medetomidine-tiletamine-zolazepam in red deer (Cervus elaphus). STUDY DESIGN AND ANIMALS: A total of 10 healthy red deer were included in a randomised, controlled, experimental, crossover study. METHODS: Deer were administered a combination of 0.1 mg kg-1 medetomidine hydrochloride and 2.5 mg kg-1 tiletamine-zolazepam intramuscularly, followed by 0.1 mg kg-1 vatinoxan hydrochloride or equivalent volume of saline intravenously (IV) 35 minutes after anaesthetic induction. Heart rate (HR), mean arterial blood pressure (MAP), respiration rate (fR), end-tidal CO2 (Pe'CO2), arterial oxygen saturation (SpO2), rectal temperature (RT) and level of anaesthesia were assessed before saline/vatinoxan administration (baseline) and at intervals for 25 minutes thereafter. Differences within treatments (change from baseline) and between treatments were analysed with linear mixed effect models (p < 0.05). RESULTS: Maximal (81 ± 10 beats minute-1) HR occurred 90 seconds after vatinoxan injection and remained significantly above baseline (42 ± 4 beats minute-1) for 15 minutes. MAP significantly decreased from baseline (122 ± 10 mmHg) to a minimum MAP of 83 ± 6 mmHg 60 seconds after vatinoxan and remained below baseline until end of anaesthesia. HR remained unchanged from baseline (43 ± 5 beats minute-1) with the saline treatment, whereas MAP decreased significantly (112 ± 16 mmHg) from baseline after 20 minutes. Pe'CO2, fR and SpO2 showed no significant differences between treatments, whereas RT decreased significantly 25 minutes after vatinoxan. Level of anaesthesia was not significantly influenced by vatinoxan. CONCLUSIONS AND CLINICAL RELEVANCE: Vatinoxan reversed hypertension and bradycardia induced by medetomidine without causing hypotension or affecting the level of anaesthesia in red deer. However, the effect on HR subsided 15 minutes after vatinoxan IV administration. Vatinoxan has the potential to reduce anaesthetic side effects in non-domestic ruminants immobilised with medetomidine-tiletamine-zolazepam.

Arterial pH and blood gas values in rats under three types of general anesthesia: a chronobiological study.

The aim of study was to review the status of arterial pH, pO(2) and pCO(2) under general anesthesias in dependence on the light-dark (LD) cycle in spontaneously breathing rats. The experiments were performed using three- to four-month-old pentobarbital(P)-, ketamine/xylazine(K/X)- and zoletil(Z)-anesthetized female Wistar rats after a four-week adaptation to an LD cycle (12 h light:12 h dark). The animals were divided into three experimental groups according to the anesthetic agent used: P (light n=11; dark n=8); K/X (light n=13; dark n=11); and Z (light n=18; dark n=26). pH and blood gases from arterial blood were analyzed. In P anesthesia, LD differences in pH, pO(2), and pCO(2) were eliminated. In K/X anesthesia, parameters showed significant LD differences. In Z anesthesia, LD differences were detected for pH and pO(2) only. Acidosis, hypoxia, and hypercapnia have been reported for all types of anesthesia during the light period. In the dark period, except for P anesthesia, the environment was more stable and values fluctuated within normal ranges. From a chronobiological perspective, P anesthesia was not the most appropriate type of anesthesia in these rat experiments. It eliminated LD differences, and also produced a more acidic environment and more pronounced hypercapnia than K/X and Z anesthesias.

The abuse liability of the NMDA receptor antagonist-benzodiazepine (tiletamine-zolazepam) combination: evidence from clinical case reports and preclinical studies.

The tiletamine-zolazepam (TZ) combination is an anaesthetic drug commonly used in veterinary medicine. It is an equal amount combination of tiletamine, a dissociative anaesthetic pharmacologically classified as an N-methyl-D-aspartate (NMDA) receptor antagonist, and zolazepam, a benzodiazepine tranquilizer. There are concerns regarding the safety profile of this drug combination due to incidents of human misuse/abuse. In this paper, we discuss the abuse liability of this drug combination based on currently available scientific evidence. We performed an in-depth search of medical and scientific literature and found seven reported cases of human abuse of the TZ combination, two of which resulted in fatal outcomes. In most of these cases, drug administration was intentional indicating that the TZ combination was abused by humans. This finding is bolstered by the results of preclinical studies showing that the TZ combination produces rewarding effects in rats, although manifested only in pretreated subjects. Further studies revealed that the addictive effects of the TZ combination are influenced by pre-exposure to other psychoactive drugs. Pre-exposure to ketamine, diazepam, propofol, or ethanol facilitated the expression of the rewarding effects of the TZ combination. These findings support the hypothesis that the TZ combination was and can be used as a substitute or replacement drug. Altogether, the compiled evidence indicates that the TZ combination can potentially be abused by humans. Thus, careful use, dispensation, and monitoring of the TZ combination and associated substances are strongly advocated. Copyright © 2016 John Wiley & Sons, Ltd.

Pre-exposure to related substances induced place preference and self-administration of the NMDA receptor antagonist-benzodiazepine combination, zoletil.

Previously, we have reported that the N-methyl-D-aspartate (NMDA) receptor antagonist-benzodiazepine veterinary anesthetic combination, zoletil, produced reward and reinforcement, but only in rats repeatedly pretreated with the drug and not in drug-naïve rats. Therefore, we hypothesized that previous drug exposure plays an important role in the abuse of zoletil. In the present study, we examined whether pre-exposure to related substances, NMDA receptor antagonists (tiletamine, ketamine), and benzodiazepines (zolazepam, diazepam) predisposes animals to abuse zoletil. We examined whether animals repeatedly pretreated with tiletamine, ketamine, zolazepam, or diazepam, for 14 days, would show locomotor activation, place preference, and self-administration in response to zoletil. Place preference was observed in groups pretreated with either an NMDA receptor antagonist (ketamine) or a benzodiazepine (diazepam). However, locomotor activation and self-administration were only observed in rats pretreated with NMDA receptor antagonists (tiletamine and ketamine). These results show that pre-exposure to related substances might have induced neurobiological changes that consequently led to the expression of the rewarding and reinforcing effects of zoletil. This provides evidence that zoletil may be used as a substitute drug by abusers of NMDA receptor antagonists or benzodiazepines.

Capture, anesthesia, and disturbance of free-ranging brown bears (Ursus arctos) during hibernation.

We conducted thirteen immobilizations of previously collared hibernating two- to four-year-old brown bears (Ursus arctos) weighing 21-66 kg in central Sweden in winter 2010 and 2011 for comparative physiology research. Here we report, for the first time, an effective protocol for the capture and anesthesia of free-ranging brown bears during hibernation and an assessment of the disturbance the captures caused. Bears were darted in anthill, soil, or uprooted tree dens on eleven occasions, but two bears in rock dens fled and were darted outside the den. We used medetomidine at 0.02-0.06 mg/kg and zolazepam-tiletamine at 0.9-2.8 mg/kg for anesthesia. In addition, ketamine at 1.5 mg/kg was hand-injected intramuscularly in four bears and in six it was included in the dart at 1.1-3.0 mg/kg. Once anesthetized, bears were removed from the dens. In nine bears, arterial blood samples were analyzed immediately with a portable blood gas analyzer. We corrected hypoxemia in seven bears (PaO(2) 57-74 mmHg) with supplemental oxygen. We placed the bears back into the dens and antagonized the effect of medetomidine with atipamezole. Capturing bears in the den significantly increased the risk of den abandonment. One of twelve collared bears that were captured remained at the original den until spring, and eleven, left their dens (mean ± standard deviation) 3.2±3.6 (range 0.5-10.5) days after capture. They used 1.9±0.9 intermediate resting sites, during 6.2±7.8 days before entering a new permanent den. The eleven new permanent dens were located 730±589 m from the original dens. We documented that it was feasible and safe to capture hibernating brown bears, although they behaved differently than black bears. When doing so, researchers should use 25% of the doses used for helicopter darting during the active period and should consider increased energetic costs associated with den abandonment.

[Features of anesthesia in rats at abdominal operations].

Nowadays, in Russia, diethyl ether is the most popular narcosis for rodent and particular rats. We had tested the new methods based on Zoletil 100 + XylaVet (15 mg/kg and 15-10-5 mg/kg) respectively. 6 conventional female rats were treated with this narcosis. The rats, early have narcotized by diethyl ether were investigated as control group. All of 6 treated with new narcosis animals died in early post-operative time. Interestingly enough, that organ toxicity, except neurologic toxicity, was not described in literature and manuals. We assume that this new narcosis is the cause of portal thromboses.

Physiologic evaluation of capture and anesthesia with medetomidine-zolazepam-tiletamine in brown bears (Ursus arctos).

Physiologic variables during anesthesia with medetomidine-zolazepam-tiletamine were evaluated in 52 free-ranging brown bears (Ursus arctos) darted from a helicopter and in six captive brown bears darted at a zoo. During anesthesia, rectal temperature, respiratory rate, heart rate, and pulse oximetry derived hemoglobin oxygen saturation were recorded. Arterial blood samples were collected and immediately analyzed for evaluation of pulmonary gas exchange, acid-base status, and selected hematologic and plasma variables. At the end of anesthesia, atipamezole was administered intramuscularly at five times the medetomidine dose. Capture-induced hyperthermia and lactic acidemia were documented in free-ranging bears. Hypoxemia during anesthesia was documented in both free-ranging and captive bears. In free-ranging bears, rectal temperature, heart rate, lactate, hematocrit, and hemoglobin decreased significantly during anesthesia, whereas partial pressure of arterial carbon dioxide, pH, potassium, and glucose increased. Yearlings had a significantly higher heart rate, pH, base excess, bicarbonate, and glucose, and had a significantly lower rectal temperature, sodium, hematocrit, and hemoglobin when compared with subadult and adult brown bears. In conclusion, alterations in pulmonary gas exchange and acid-base status in brown bears during anesthesia with medetomidine-zolazepam-tiletamine with the doses and capture methods used in this study were identified. Oxygen supplementation is recommended to counteract hypoxemia during anesthesia.

Urinary cortisol responses to unusual events in captive chimpanzees (Pan troglodytes).

This study investigated the urinary cortisol stress response to one known stressor (anaesthesia) and three unusual events hypothesized to result in increases in cortisol (confinement to one half of an enclosure for several days due to a hurricane, an enrichment exercise, and a change in group composition) in young chimpanzees (Pan troglodytes). Although a cortisol stress response to a variety of laboratory experiences has been documented in captive animals, it is unclear whether other types of atypical events are stressful, including those that are not necessarily negative. Cortisol was measured in 519 urine samples collected from 20 awake, unrestrained chimpanzees; individuals were compared against their own baseline values. A significant increase in urinary cortisol concentration was found as a result of the stress of anaesthesia, but no significant change in urinary cortisol resulted from the three other potential stressors. A lack of a urinary cortisol response to these events may indicate that the events were not actually stressful for the chimpanzees, but may have resulted from the limited temporal resolution of measuring cortisol excretion as an indicator of integrated secretion, or from changes in rates of agonistic behaviors.

Contenção farmacológica do gato-do-mato-pequeno, Leopardus tigrinus, para colheita de sêmen, pela associação de tiletamina zolazepam e xilazina / Chemical restraint of tigrinas, Leopardus tigrinus, for semen collection with allometrically scaled doses of tiletamine, zolazepam, and xylazine

Foram avaliados os efeitos anestésicos da associação de cloridrato de tiletamina, cloridrato de zolazepam e cloridrato de xilazina para contenção farmacológica de gatos-do-mato-pequenos, Leopardus tigrinus Schreber, 1775 (Felidae), submetidos à colheita de sêmen por eletroejaculação. Formularam-se três diferentes protocolos, sendo as doses calculadas individualmente, por meio de extrapolação alométrica interespecífica, com base nas indicações posológicas usuais para o cão doméstico com massa de 10,0 kg. No Protocolo 1 (n=10) a base para o cálculo alométrico foi 5,0mg/kg para tiletamina + zolazepam e 0,5mg/kg para xilazina; no Protocolo 2 (n=12,) foi 5,0mg/kg para tiletamina + zolazepam e 0,75mg/kg para xilazina; e no Protocolo 3 (n=11), foi 5,0mg/ kg para tiletamina + zolazepam e 1,0mg/kg para xilazina. Os animais foram anestesiados em três ocasiões, com intervalo mínimo de 30 dias. Após a administração dos fármacos, monitorizaram-se durante 120 minutos freqüência cardíaca, freqüência respiratória, temperatura retal, miorrelaxamento e nocicepção. Também foram avaliados período de latência, período anestésico hábil e contaminação do ejaculado por urina. De um total de 32 colheitas, houve contaminação por urina em 10 colheitas (31,2 por cento) e em 18 alíquotas (0,07 por cento), as quais foram desprezadas, não inviabilizando a análise e o processamento do sêmen. Observou-se pequeno aumento da temperatura retal durante a eletroejaculação, justificado pela contração muscular, ocorrendo redução da temperatura após o procedimento. As freqüências cardíaca e respiratória oscilaram durante o experimento, porém se mantiveram dentro dos padrões fisiológicos para a espécie. Nos três protocolos analisados não houve diferença significativa de sensibilidade de membros torácicos entre momentos antes e durante a eletroejaculação (pe"0,10), caracterizando assim a eficácia dos protocolos em propiciar analgesia e anestesia durante a colheita de sêmen por tal método.

This paper reports the anesthetic effects of the combination of tiletamine HCl, zolazepam HCl, and xylazine HCl in tigrinas, Leopardus tigrinus Schreber, 1775 (Fam. Felidae), submitted to semen collection by electroejaculation. Three different protocols and the individual anesthetic doses were calculated by interspecific allometric scaling, based on the usual recommendations for a 10.0 kg domestic dog: On Protocol 1 (n=10) the basis for calculation was 5.0mg/kg for tiletamine + zolazepam and 0.5mg/kg for xylazine; on Protocol 2 (n=12) 5.0mg/kg for tiletamine + zolazepam and 0.75mg/kg for xylazine; and on Protocol 3 (n=11) 5.0mg/kg for tiletamine + zolazepam and 1.0mg/kg for xylazine. The tigrinas were anesthetized on three different occasions with a minimum interval of 30 days. During 120 minutes after the drug administration cardiac and respiratory frequencies, rectal temperature, limb myorelaxation and sensitivity to deep pain were monitored. Latency period, anesthetic period, and contamination of the semen with urine were also monitored. From a total of 32 collections, 10 samples (31.2 percent) and 18 aliquots (0.07 percent) were contaminated and rejected, but this episodes were not detrimental for semen analysis and processing. A discrete increase in rectal temperature during electroejaculation caused by muscle contraction, followed by temperature decrease, was observed. Cardiac and respiratory frequency varied during the experiment, but remained within physiological standards for the species. The three tested protocols showed to be safe and effective to produce analgesia and anesthesia in L. tigrinus during semen collection by electroejaculation.

Avaliação do uso de Tiletamina e Zolapezam por via epidural em cães / Assessment of the epidural use of tiletamine and zolazepam in dogs / Evaluación del uso de tiletamina y zolazepam por vía epidural en perros

Dez cães receberam administração epidural da associação de cloridrato de tiletamina e zolazepam, entre as vértebras L7 e S1, avaliando-se a analgesia pela observação dos padrões respiratório e comportamental, e pela aplicação dos filamentos de von Frey nos coxins plantares e ao redor do esfíncter anal externo. Não foram observadas as manifestações sistêmicas características da administração parenteral de anestésicos dissociativos, e todos os animais manifestaram completa analgesia, sendo que o emprego dos filamentos de von Frey permitiu testes de sensibilidade cutânea sem causar lesões teciduais. A técnica empregada promoveu ataxia e paresia, que perduraram por 41,25 (± 2,18) minutos, acompanhadas por relaxamento do esfíncter anal externo dos cães. Outros estudos sobre os efeitos da administração epidural da associação de cloridrato de tiletamina e zolazepam deverão ser efetuados, no que diz respeito a quantificar e qualificar a analgesia nesse período, bem como avaliar a possibilidade de realização de intervenções cirúrgicas cruentas, com essa técnica.

Ten dogs received an epidural administration of tiletamine HCl and zolazepam, between vertebrae L7 and S1. The analgesia was evaluated by observation breathing and behavioral patterns, and by the use of von Frey filaments applied to the external anal sphincter and footpads. Systemic manifestations from parenteral administration of dissociative anesthetics were not observed, and all the animals showed complete analgesia. The technique promoted ataxia and paresis which persisted for 41.25 (±2.18) minutes, followed by external anal sphincter myorelaxation. The von Frey filaments allowed cutaneous sensibility tests without causing any tissue lesion. Other investigations searching the tiletamine HCL and zolazepam effects should be performed in order to quantify and qualify the analgesia in that period, as well as to evaluate the possibility of accomplishment of painful surgical procedures with this technique.

Diez perros recibieron administración epidural de la asociación de clorhidrato de tiletamina y zolazepam, entre las vértebras L7 y S1, evaluándose la analgesia por observación de los estándares respiratorio y de comportamiento, y por la aplicación de los filamentos de von Frey en los asientos plantares y alrededor del esfínter anal externo. No fueron observadas las manifestaciones sistémicas características de la administración parenteral de anestésicos disociativos, y todos los animales manifestaron completa analgesia, siendo que el empleo de filamentos de von Frey permitió testes de sensibilidad cutánea sin causar lesiones en tejidos. La técnica empleada promovió ataxia y paresia, que perduraron por 41,25 (±2,18) minutos, acompañadas por relajamiento del esfínter anal externo de los perros. Otros estudios sobre los efectos de la administración epidural de la asociación de clorhidrato de tiletamina y zolazepam deberán ser efectuados, por lo que respecta a cuantificar y calificar la analgesia en ese período, bien como evaluar la posibilidad de realización de procedimientos quirúrgicos cruentos, con esa técnica.

Tiletamine-zolazepam and xylazine is a potent cardiodepressive combination: a case report.

Intramuscular injection of tiletamine-zolazepam and xylazine is commonly used as a preanesthetic for veterinary surgical procedures and for short-term restraint. However, this combination can have marked cardiodepressive and hypothermic effects that persist for hours to days. Here we present a case report of these effects in a swine heart failure model.

Efficacy of immobilizing free-ranging elk with Telazol and xylazine hydrochloride using transmitter-equipped darts.

From January 1999 to April 2002, 14 free-ranging elk were darted with a mixture of Telazol reconstituted with xylazine hydrochloride (HCl) in a forested habitat in southwestern Oklahoma and north-central Arkansas. Elk were darted from ground blinds, tree stands, or a vehicle at distances of 14-46 m and were recovered 37-274 m from the dart site. Elk were located using radiotelemetry with 3-cc disposable Pneu-dart transmitter darts. Mean+/-SD dose of Telazol and xylazine HCl was 590+/-192 mg/ml and 276+/-153 mg/ml, respectively, and mean time to standing after injection of reversal agent was 27 min (range: 1-65 min). The combination of Telazol and xylazine HCl successfully immobilized free-ranging elk, and transmitter-equipped darts permitted successful location of sedated elk by two people in areas of dense forest cover. The dose required to sedate elk appeared to vary depending on physiology and behavior, but no drug-induced mortality occurred despite the wide variance in the doses administered. We recommend 500 mg Telazol reconstituted with 300 mg xylazine HCl as an initial dose for a >or=200 kg elk. If needed to achieve full sedation, up to 3 additional ml of the mixture may be administered without adverse effects.

Chemical immobilization of crested porcupines with tiletamine HCl and zolazepam HCl (Zoletil) under field conditions.

The combination of tiletamine HCl and zolazepam HCl has been used on many species of wild mammals. Short induction time, low dosage, satisfactory safety margins, relatively constant immobilization time, and smooth recovery are benefits reported. This combination (Zoletil 100) was used during a study on behavioural ecology of the crested porcupine (Hystrix cristata) in a Mediterranean coastal area (Maremma Regional Park, Tuscany, Italy). We used this mixture 42 times on 31 individuals. Mean adult dose was (+/- SE) 7.24 +/- 0.37 mg/kg (74.0 +/- 3.0 mg/individual). Average adult induction time was 5.3 min (+/- 1.1) and average adult immobilization time was 22.6 min (+/- 6.0). One adult male porcupine died after chemical restraints. The use of tiletamine-zolazepam seems adequate for chemical immobilization of crested porcupines under field conditions, mainly because of its short induction time, small volume to be injected and wide safety margin.

Response of wild subantarctic fur seal (Arctocephalus tropicalis) females to ketamine and tiletamine-zolazepam anesthesia.

This study is the first to compare the anesthetic effects of two cyclohexamines on free-ranging subantarctic fur seal (Arctocephalus tropicalis) females. From April to July 1999, 107 females were immobilized for tooth extraction and blood sampling, using either ketamine (Ketalar, n = 58) alone or tiletamine-zolazepam (Zoletil 100, n = 49) mixture. Animals were injected intramuscularly at mean doses of 2.1 mg/kg for ketamine and 1.1 mg/kg for tiletamine-zolazepam mixture. Individual response to both drugs was highly variable. The dosage required to achieve a satisfactory level of anesthesia was smaller for subantarctic fur seals than for most other species of seals and was less for animals in better body condition. Few side effects were observed during the trials, aside from mild tremors caused by ketamine, and respiratory depression or prolonged apnea caused by tiletamine-zolazepam. We recommend use of ketamine, especially by those with little experience in anesthesia of fur seals. However, precautionary measures should be taken, such as using low doses for animals in good body condition and being prepared for anesthetic emergencies to avoid any casualties.

Treatment of hypoxemia during xylazine-tiletamine-zolazepam immobilization of wapiti.

Hypoxemia is a commonly observed complication during the chemical immobilization of wild ruminants. If severe and left untreated, it can predispose animals to arrhythmias, organ failure, and capture myopathy. The following prospective study was designed to measure the degree of hypoxemia in wapiti that were immobilized with a combination of xylazine and tiletamine-zolazepam and to assess the response to nasal oxygen therapy. Pulse oximetry and arterial blood gas analysis were used to assess the degree of hypoxemia prior to nasal insufflation of oxygen and to demonstrate any beneficial effects of this intervention. All wapiti exhibited mild to marked hypoxemia (PaO2 = 43 +/- 11.8 mmHg) prior to treatment and showed marked improvement after 5 minutes of nasal insufflation of oxygen at 10 L/min (PaO2 = 207 +/- 60 mmHg). This inexpensive, noninvasive technique has great benefit in treating clinical hypoxemia under field conditions, and we recommend that nasal insufflation of oxygen be implemented during xylazine-tiletamine-zolazepam-induced immobilization of wapiti and other wild ruminants.

Efeitos cardiorrespiratórios da tiletamina-zolazepam em cäes hipovolêmicos / Cardiorespiratory effects of tiletamine-zolazepan in hypovolemic dogs

O objetivo deste estudo foi avaliar os efeitos da associaçäo tiletamina-zolazepam em cäes hipovolêmicos. Estudaram-se as alteraçöes cardiovasculares em 14 cäes, divididos em grupo A (controle, n=7) e grupo B (experimental, n=7). Os cäes foram anestesiados com sevoflurano (1,5 concentraçäo alveolar mínima - CAM) para a implantaçäo dos cateteres venosos, arteriais e da termodiluiçäo. A concentraçäo do sevoflurano foi reduzida (0,5 CAM) e nos cäes do grupo B, induziu-se hipovolemia retirando-se sangue na proporçäo de 30ml/kg de peso corpóreo. Subseqüentemente, registraram-se as freqüências cardíaca (FC) e respiratória (FR), a pressäo arterial (PAM) e o débito cardíaco (DC), e aplicaram-se 10 mg/kg de tiletamina-zolazepam, pela via intravenosa. Aos cäes do grupo A aplicou-se igual tratamento. Os cäes foram observados por 120 minutos. A associaçäo tiletamina-zolazepam produziu apnéia transitória e manteve estável a FC, PAM e DC. Os resultados permitem concluir que a associaçäo manteve estáveis as pressöes arteriais sistólica, diastólica e média, e näo alterou o débito cardíaco, podendo vir a ser usada com segurança na anestesia de cäes com hipovolemia