Evaluation of a hapten conjugate vaccine against the "zombie drug" xylazine.

Xylazine has emerged as a primary adulterant in fentanyl, exacerbating the complexity of the opioid crisis. Yet, there is no approved drug that can reverse xylazine's pathophysiology. As a prelude to monoclonal antibodies being assessed as a viable therapeutic, a vaccine inquiry was conducted evaluating the immune response in reversing xylazine induced behavior effects.

Comparison of two pharmacological protocols for inducing ex copula ejaculation in donkeys.

This study aimed to compare the efficacy of two pharmacological protocols for inducing ex copula ejaculation in donkeys. Seven healthy jacks (male donkeys) aged 4 to 20 years (median 8 years) and weighing 136.2±4.17 kg (mean±SE) were enrolled. Using a crossover design, each jack was subjected in a random order to two treatment protocols (IX and IDO) with an interval of 7 days between the two protocols. Each jack was orally administered 3 mg/kg imipramine hydrochloride followed 2 hours later by intravenous (IV) administration of 1.1 mg/kg xylazine hydrochloride (IX protocol) or 0.02 mg/kg detomidine hydrochloride and 20 IU total dose oxytocin (IDO protocol). The jacks were monitored for behavioral changes and ejaculation up to 3 hours from the beginning of each protocol. A total of 22 ex copula ejaculation replicates were attempted. Both protocols resulted in deep sedation and partial to complete penile protrusion in all jacks. There was no difference in the efficacy with the IX protocol inducing ejaculation in 1 of the 11 replicates and the IDO protocol inducing ejaculation in none of the 11 replicates. The results suggest that neither of the two tested pharmacological protocols were effective in inducing ex copula ejaculation in donkeys.

The effects of anesthetic drug choice on heart rate variability and echocardiography parameters in cats.

Heart rate variability (HRV) is one of the assessments of cardiovascular risk during general anesthesia. This study aimed to assess the effects of an anesthetic drug on HRV in cats and to provide information for clinical applications. Twenty-four healthy client-owned cats of various breeds, 12 females and 12 males scheduled for elective surgery, were enrolled in this study. The cats were premedicated and induced with 4 protocols: protocol 1, diazepam (0.3 mg/kg) and propofol (2-4 mg/kg) IV; protocol 2, diazepam (0.3 mg/kg) and alfaxalone (1-3 mg/kg) IV; protocol 3, diazepam (0.3 mg/kg) and ketamine (3-5 mg/kg) IV; and protocol 4, xylazine (1 mg/kg) and tiletamine/zolazepam (Zoletil) (5 mg/kg) IM. The heart rate and HRV of the 24 cats were collected before and at least 1 h after administering the anesthetic drugs. Echocardiography was performed to evaluate heart function. Oscillometric blood pressure monitoring was used to obtain the mean blood pressure. After anesthetic drug administration, higher heart rates were found in cats premedicated and induced with alfaxalone (p = 0.045) than in the other protocols. The lowest heart rate (HR) values were found in cats in protocol 4 using xylazine and Zoletil. The HRV low frequency (LF) and high frequency (HF) power ratios increased in all protocols except for cats premedicated and intubated with propofol. The standard deviation of the regular sinus beats (SDNN) was higher in cats premedicated and induced with ketamine than in other anesthetic protocols (p = 0.015). An increase in sympathetic activity and reduced HRV is associated with high blood pressure and left atrial dimension. The percentage of fractional shortening (FS) decreased in cats premedicated with ketamine. The results showed that the anesthesia method using diazepam and propofol caused the least disturbance of HRV compared with other anesthesia methods that were used in this study.

Subcutaneous Alfaxalone-XylazineBuprenorphine for Surgical Anesthesia and Echocardiographic Evaluation of Mice (Mus musculus).

Alfaxalone is a commonly used injectable anesthetic in dogs and cats due to its minimal cardiovascular side effects. Data for its use in mice are limited and demonstrate strain- and sex-associated differences in dose-response relationships. We performed a dose-comparison study of alfaxalone-xylazine-buprenorphine (AXB) in Crl: CFW (SW) mice. Subcutaneous injection of 50 mg/kg alfaxalone-10 mg/kg xylazine-0.1 mg/kg buprenorphine HCl consistently achieved a surgical plane of anesthesia (loss of toe pinch) for 48.6 ± 4.7 and 60.8 ± 9.6 min in females and males, respectively. The same dose and route of AXB induced a surgical plane of anesthesia in C57Bl/6NCrl (females: 42.3 ± 11.2 min; males: 51.6 ± 12.3 min), NCr-Foxn1nu (females: 76.8 ± 32.5 min; males: 80.0 ± 1.2 min), and NOD. Cg-Prkdc SCID Il2rg tm1Wjl /SzJCr (females: 56.0 ± 37.2 min and males: 61.2 ± 10.2 min) mice. We found no significant difference in the duration of the surgical plane of anesthesia between males and females within the mouse strains Crl: CFW (SW), C57Bl/6NCrl, NCr-Foxn1nu, and NOD. Cg-PrkdcSCID Il2rgtm1Wjl /SzJCr. We next performed an echocardiography study (n = 5 per group) of Crl: CFW (SW) mice ( n = 5 per group) to compare subcutaneous AXB anesthesia with that produced by intraperitoneal injection of 100 mg/kg ketamine and 10 mg/kg xylazine (KX). AXB induced significantly less bradycardia (295.4 ± 29 bpm) than KX (185.8 ± 38.9 bpm) did, with no significant differences in cardiac output, ejection fraction, end-diastolic volume, end-systolic volume, or fractional shortening. These results suggest that subcutaneous administration of AXB is a viable alternative to KX for inducing a surgical plane of anesthesia in Crl: CFW (SW), C57Bl/6NCrl, NCr-Foxn1nu, and NOD. Cg-PrkdcSCID Il2rgtm1Wjl /SzJCr mice, regardless of sex. AXB may also be a better injectable anesthetic option as compared with KX for avoiding adverse cardiac effects in mice.

Evaluation of the use of intranasal atipamezole to reverse the sedative effects of xylazine in dogs.

OBJECTIVE: To assess the ability of intranasal atipamezole to reverse sedative effects of xylazine in dogs. DESIGN: Prospective proof-of-concept study. SETTING: University research laboratory. ANIMAL: Six healthy, staff-owned dogs. INTERVENTIONS: Dogs were sedated with 1.1 mg/kg of xylazine intravenously. The sedation score of each dog was recorded every 5 minutes until they achieved a sedation score of >13/21 for 3 readings. Once achieved, 0.3 mg/kg of atipamezole was administered intranasally using a mucosal atomization device. Sedation scores continued to be recorded every 5 minutes until successful reversal was achieved (<4/21). MEASUREMENTS AND MAIN RESULTS: Average times to standing and normal wakefulness after administration of intranasal atipamezole were 6 minutes, 30 seconds and 7 minutes, 20 seconds, respectively. CONCLUSIONS: Intranasal atipamezole successfully reversed the sedation effects of xylazine. The findings of this study provide justification for future controlled prospective studies into the potential use of intranasal atipamezole in a variety of settings including exposure to xylazine in operational canines as well as bioavailability studies for optimal dosing.

Comparison of lidocaine and lidocaine-xylazine for distal paravertebral anesthesia in dairy cattle.

OBJECTIVE: To determine the time of onset and duration of action of distal paravertebral blocks (DPB) in dairy cattle using lidocaine and lidocaine plus xylazine (LX). ANIMALS: 10 healthy adult Holstein cows. METHODS: Unilateral DPB were performed in 6 cows at L1, L2, and L4. They received 2 treatments (lidocaine and LX) in a blinded random crossover design. Due to treatment failure, 4 additional cows were enrolled. The lidocaine treatment received 1,800 mg (90 mL) of lidocaine, and treatment LX received 1,784 mg (89.2 mL) of lidocaine and 16 mg (0.8 mL) of xylazine. Anesthesia was assessed by response (rapid movements of the tail, directed movements of the feet, or turning of the head towards the site of the needle pricks) to 6 approximately 1-cm deep needle pricks to the paralumbar fossa with a 22-gauge hypodermic needle. The time of onset, duration of action, maximum sedation score, and average heart rate (HR) were compared between treatments. RESULTS: Duration of anesthesia was significantly prolonged after DPB in cows treated with LX (251.6 ± 96.94 minutes) compared to lidocaine (105.8 ± 35.9 minutes; P = .01). Treatment with LX was associated with significantly lower average heart rate (56 ± 3 beats/min) compared to cows treated with lidocaine (59 ± 3 beats/min; P = .045). The LX treatment was associated with mild sedation but was not significant (P = .063). CLINICAL RELEVANCE: The addition of xylazine to a lidocaine DPB provides a longer duration of anesthesia, is inexpensive and practical, and can be implemented with ease.

Comparison of Ketamine-Xylazine, Butorphanol-Azaperone-Medetomidine, and Nalbuphine-Medetomidine-Azaperone for Raccoon (Procyon lotor) Immobilization.

Raccoons (Procyon lotor) are frequently handled using chemical immobilization in North America for management and research. In a controlled environment, we compared three drug combinations: ketamine-xylazine (KX), butorphanol-azaperone-medetomidine (BAM), and nalbuphine-medetomidine-azaperone (NalMed-A) for raccoon immobilization. In crossover comparisons, raccoons received a mean of the following: 8.66 mg/kg ketamine and 1.74 mg/kg xylazine (0.104 mL/kg KX); 0.464 mg/kg butorphanol, 0.155 mg/kg azaperone, and 0.185 mg/kg medetomidine (0.017 mL/kg BAM); and 0.800 mg/kg nalbuphine, 0.200 mg/kg azaperone, and 0.200 mg/kg medetomidine (0.020 mL/kg NalMed-A). Induction time was shortest with KX (mean±SE, 10.0±0.7 min) and longest with NalMed-A (13.0±1.3 min). A sampling procedure was completed on 89% (16/18), 72% (13/18), and 89% (16/18) of the raccoons administered KX, BAM, and NalMed-A, respectively. Reasons for incomplete sampling included inadequate immobilization (one KX and one NalMed-A), responsive behaviors (one each with KX, BAM, NalMed-A), or animal safety (four BAM). Mean recovery time for KX was 32.8±7.1 min without antagonizing and 28.6±5.2 min following delivery of an antagonist. Mean recovery time was 6.2±0.8 min for BAM and 5.1±0.5 min for NalMed-A after antagonizing. Only with KX were raccoons observed to recover without use of an antagonist. Supplemental oxygen was provided to 23% (3/13), 72% (13/18), and 71% (12/17) of raccoons immobilized with KX, BAM, and NalMed-A, respectively. Hypoxemia at <80% oxygen saturation occurred in 0% (0/17), 27% (4/15), and 6% (1/16) of the raccoons administered KX, BAM, and NalMed-A, respectively; all raccoons fully recovered from chemical immobilization. All combinations could be used for raccoon immobilization; however, the need for delivery of supplemental oxygen to a majority of raccoons immobilized with BAM and NalMed-A may limit broader use of these agents for certain field studies involving capture, sample, and release of free-ranging animals from a practical standpoint.

Optimal clinical dose of medetomidine for sedation of young cows during dehorning surgery.

The present paper reports on the clinical efficacy and optimal clinical dose of medetomidine for sedation of young cows during dehorning surgery. Medical records of 24 female Holstein cows that underwent dehorning surgery were used in this study. In four groups, the sedation of animals was carried out by one of the four intravenous treatments: 0.1 mg kg-1 xylazine (Xyl group, n = 6), 5.0 µg kg-1 medetomidine (5.0 Med group, n = 6), 10.0 µg kg-1 medetomidine (10.0 Med group, n = 6) or 20.0 µg kg-1 medetomidine (20.0 Med group, n = 6). The clinical sedation score (CSS) and heart rate (HR) were recorded. The CSSs after intravenous administration of each α2-adrenergic receptor agonist increased rapidly and peaked at 12.5 (10.0-16.0) at t = 20 min in the Xyl group, 11.5 (10.0-15.0) at t = 10 min in the 5.0 Med group, 16.0 (14.0-16.0) at t = 20 min in the 10.0 Med group and 16.0 (14.0 - 16.0) at t = 20 min in the 20.0 Med group. A similar degree of bradycardia was observed after every sedative treatment. We conclude that the intravenous administration of 10.0-20.0 µg kg-1 medetomidine is appropriate for sedation of young cows without severe side effects.

Impacts of xylazine on fentanyl demand, body weight, and acute withdrawal in rats: A comparison to lofexidine.

The opioid use landscape has recently shifted to include xylazine, a veterinary anesthetic, as an adulterant in the fentanyl supply. The health impacts of xylazine as an emerging fentanyl adulterant has raised alarm regarding xylazine as a public health threat, warranting research on the impacts of xylazine on fentanyl's behavioral effects. No prior studies have evaluated the effects of xylazine on fentanyl consumption at various unit doses, fentanyl demand, or withdrawal as compared to the Food and Drug Administration-approved opioid withdrawal medication, lofexidine (Lucemyra®). This is important because lofexidine and xylazine are both adrenergic α2a (A2aR) agonists, however, lofexidine is not a noted fentanyl adulterant. Here we evaluated xylazine and lofexidine combined with self-administered fentanyl doses in male and female rats and evaluated fentanyl demand, body weight, and acute withdrawal. Consumption of fentanyl alone increased at various unit doses compared to saline. Xylazine but not lofexidine shifted fentanyl consumption downward at a number of unit doses, however, both lofexidine and xylazine suppressed fentanyl demand intensity as compared to a fentanyl alone control group. Further, both fentanyl + lofexidine and fentanyl + xylazine reduced behavioral signs of fentanyl withdrawal immediately following SA, but signs increased by 12 h only in the xylazine co-exposed group. Weight loss occurred throughout fentanyl SA and withdrawal regardless of group, although the xylazine group lost significantly more weight during the first 24 h of withdrawal than the other two groups. Severity of weight loss during the first 24 h of withdrawal was also correlated with severity of somatic signs of fentanyl withdrawal. Together, these results suggest that body weight loss may be an important indicator of withdrawal severity during acute withdrawal from the xylazine/fentanyl combination, warranting further translational evaluation.

The dilutional volume of morphine and xylazine administered via caudal epidural catheter affects cranial spread of analgesia in healthy standing horses.

OBJECTIVE: To test the influence of increasing injectate volumes on the regional effects of xylazine and morphine epidural analgesia, with the hypothesis that increasing volume produces more cranial spread of analgesia as determined by thermal threshold (TT) testing. ANIMALS: 6 university-owned research/teaching horses (2 mares, 4 geldings) deemed healthy on physical examination and basic lameness evaluation, aged 6-19 years and weighing 420-560 kg, were used in this prospective, randomized, blinded, cross-over experimental study. METHODS: After routine placement of a caudal epidural catheter, all animals were subsequently instrumented with a TT testing system at the withers (Location A), the cranial (Location B), and caudal (Location C) abdominal area, over the tuber coxae (Location D), and the hind limb dorsal pasterns (Location E). All horses underwent five testing cycles with 0.2 mg/kg morphine and 0.2 mg/kg xylazine diluted to 20, 35, 50, 75, and 100 mL. TT testing was performed at 2, 4, 6, 8, and 10 hours by blinded investigators. RESULTS: With increased epidural volume, significantly greater cranial spread of analgesic effect was noted. All epidural volumes caused significant changes in TT testing at location E but only the largest volume resulted in a significant TT testing change at location A. CLINICAL RELEVANCE: Volume influences the regional effects of caudal epidural analgesia in horses but might affect analgesic reliability.

Commonly used anesthetics modify alcohol and (-)-trans-delta9-tetrahydrocannabinol in vivo effects on rat cerebral arterioles.

BACKGROUND: Ethyl alcohol and cannabis are widely used recreational substances with distinct effects on the brain. These drugs increase accidental injuries requiring treatment under anesthesia. Moreover, alcohol and cannabis are often used in anesthetized rodents for biomedical research. Here, we compared the influence of commonly used forms of anesthesia, injectable ketamine/xylazine (KX) versus inhalant isoflurane, on alcohol- and (-)-trans-delta9-tetrahydrocannabinol (THC) effects on cerebral arteriole diameter evaluated in vivo. METHODS: Studies were performed on male and female Sprague-Dawley rats subjected to intracarotid catheter placement for drug infusion, and cranial window surgery for monitoring pial arteriole diameter. Depth of anesthesia was monitored every 10-15 min by toe-pinch. Under KX, the number of toe-pinch responders was maximal after the first dose of anesthesia and diminished over time in both males and females. In contrast, the number of toe-pinch responders under isoflurane slowly raised over time, leading to increase in isoflurane percentage until deep anesthesia was re-established. Rectal temperature under KX remained stable in males while dropping in females. As expected for gaseous anesthesia, both males and females exhibited rectal temperature drops under isoflurane. RESULTS: Infusion of 50 mM alcohol (ethanol, EtOH) into the cerebral circulation rendered robust constriction in males under KX anesthesia, this alcohol action being significantly smaller, but still present under isoflurane anesthesia. In females, EtOH did not cause measurable changes in pial arteriole diameter regardless of the anesthetic. These findings indicate a strong sex bias with regards to EtOH induced vasoconstriction. Infusion of 42 nM THC in males and females under isoflurane tended to constrict cerebral arterioles in both males and females when compared to isovolumic infusion of THC vehicle (dimethyl sulfoxide in saline). Moreover, THC-driven changes in arteriole diameter significantly differed in magnitude depending on the anesthetic used. Simultaneous administration of 50 mM alcohol and 42 nM THC to males constricted cerebral arterioles regardless of the anesthetic used. In females, constriction by the combined drugs was also observed, with limited influence by anesthetic presence. CONCLUSIONS: We demonstrate that two commonly used anesthetic formulations differentially influence the level of vasoconstriction caused by alcohol and THC actions in cerebral arterioles.

The effects of repeated doses of xylazine-ketamine and medetomidineketamine anesthesia on DNA damage in the liver and kidney.

PURPOSE: This study evaluated the DNA damage caused by repeated doses of xylazine-ketamine and medetomidine-ketamine anesthesia in the liver and kidneys. METHODS: In this study, 60 rats were used. The rats were divided into group 1 (xylazine-ketamine), and group 2 (medetomidine-ketamine), and these anesthetic combinations were administered to the rats at repeated doses with 30-min intervals. The effects of these anesthetic agents on the tumor necrosis factor-alpha gene for DNA damage were investigated. RESULTS: According to the gene expression results, it was observed that a single dose of xylazine-ketamine was 2.9-fold expressed, while first and second repeat doses did not show significant changes in expression levels. However, in the case of the third repetition, it was observed to be 3.8-fold overexpressed. In the case of medetomidine-ketamine administration, it was observed that a single-dose application resulted in a 1.04-fold expression, while the first and the third repeat doses showed a significant down expression. The samples from the second repeat dose administration group were found to have insignificant levels of expression. CONCLUSIONS: This study can contribute to understanding the safe anesthetic combination in research and operations in which xylazine-ketamine and medetomidine-ketamine combinations are used.

RETROSPECTIVE COMPARISON OF FIVE DRUG PROTOCOLS FOR IMMOBILIZATION OF CAPTIVE SABLE ANTELOPE (HIPPOTRAGUS NIGER).

Sable antelope (Hippotragus niger), a large, dominant species, often require chemical immobilization for captive management. Despite several recorded protocols, limited objective or subjective data are available to guide chemical immobilization of this species. This study retrospectively compared immobilization drug combinations of carfentanil-xylazine (CX), thiafentanil-xylazine (TX), etorphine-xylazine (EX), carfentanil-acepromazine (CA), and butorphanol-azaperone-medetomidine (BAM) for healthy sable antelope at one institution. Clinically applicable physiologic measures, subjective ratings, and timing of anesthetic milestones of 161 events for 107 individuals revealed the following statistically significant findings (P < 0.05). Induction ratings were best for TX, highest degree of muscle relaxation occurred with BAM and TX, and anesthetic ratings were best for TX and EX. Time to recovery was longest and complications 2.56 times more likely with CX. Time to recumbency was shortest in TX. Heart rate was highest in CA and lowest in BAM. For immobilization procedures, this study suggests TX would be the preferred combination for H. niger. However, all drug combinations evaluated can be used successfully to immobilize H. niger, and certain combinations may be situationally preferred based on desired muscle relaxation, expected induction or recovery times, or anticipated procedure length.

Xylazine potentiates the lethal but not the rewarding effects of fentanyl in mice.

BACKGROUND: Fentanyl is commonly laced with xylazine. People who use this combination report heightened effects, but it also increases death risk. Although no medication has been approved to counteract overdoses produced by fentanyl and xylazine, naloxone is frequently used. This paper studies the preclinical rewarding and lethal effects of fentanyl combined with xylazine and the efficacy of yohimbine or naloxone to prevent death. METHODS: Male Swiss Webster mice were treated with (in mg/kg, i.p.) xylazine (0.3, 1, 3, or 5.6), fentanyl (0.01, 0.3, or 0.1), or 1 xylazine plus 0.01 (non-effective) or 0.1 (effective) fentanyl doses during the conditioned-place preference (CPP) test. In addition, independent groups received (in mg/kg, i.p.): xylazine (31.6, 60, 74.2, or 100), fentanyl (3.1 or 10), or both substances at two doses: 31.6 xylazine + 3.1 fentanyl, or 60 xylazine + 10 fentanyl to analyze lethal effects. We determined whether yohimbine or naloxone (each medication tested at 10 or 30mg/kg) could prevent the lethality produced by fentanyl/xylazine combinations. Female mice were also tested in key experiments. RESULTS: Xylazine neither induced CPP nor altered fentanyl's rewarding effects. In contrast, lethality was potentiated when fentanyl was combined with xylazine. Naloxone, but not yohimbine, effectively prevented the lethality of the fentanyl/xylazine combinations. CONCLUSIONS: At the doses tested, xylazine does not increase the rewarding effect of fentanyl on the CPP in male mice but potentiates the risk of fatal overdose in male and female mice. A high naloxone dose prevents death induced by coadministration of fentanyl and xylazine in both sexes.

Use of a rat model to characterize 35 arterial pulse wave parameters in a comparative study of isoflurane and Zoletil/xylazine anesthesia and the effect of Acanthopanax senticosus extract.

BACKGROUND: Information obtained from arterial pulse waveforms (APW) can be useful for characterizing the cardiovascular system. To achieve this, it is necessary to know the detailed characteristics of APWs in different states of an organism, which would allow APW parameters (APW-Ps) to be assigned to particular (patho)physiological conditions. Therefore, our work aimed to characterize 35 APW-Ps in rats under the influence of isoflurane (ISO) and Zoletil/xylazine (ZO/XY) anesthesia and to study the effect of root extract from Acanthopanax senticosus (ASRE) in these anesthetic conditions. METHODS: The right jugular vein of anesthetized rats was cannulated for the administration of ASRE and the left carotid artery for the detection of APWs from which 35 APW-Ps were evaluated. RESULTS: We obtained data on 35 APW-Ps, which significantly depended on the anesthesia, and thus, they characterized the cardiovascular system under these two conditions. ASRE transiently modulated all 35 APW-Ps, including a transient decrease in systolic and diastolic blood pressure (BP) and heart rate or increases in pulse BP, dP/dtmax , and systolic and diastolic areas. Whereas the transient effects of ASRE were similar, the extract had prolonged disturbing effects on the cardiovascular system in rats under ZO/XY but not under ISO anesthesia. This negative effect can result from the disturbance caused by ZO/XY anesthesia on the cardiovascular system. CONCLUSIONS: We characterized 35 APW-Ps of rats under ISO and ZO/XY anesthesia and found that ASRE contains compounds that can modulate the properties of the cardiovascular system, which significantly depended on the status of the cardiovascular system. This should be considered when using ASRE as a nutritional supplement by individuals with cardiovascular problems.

Immunomodulatory and pro-oncologic effects of ketamine and isoflurane anesthetics in a murine model.

INTRODUCTION: Volatile and intravenous anesthetics may worsen oncologic outcomes in basic science animal models. These effects may be related to suppressed innate and adaptive immunity, decreased immunosurveillance, and disrupted cellular signaling. We hypothesized that anesthetics would promote lung tumor growth via altered immune function in a murine model and tested this using an immunological control group of immunodeficient mice. METHODS: Lewis lung carcinoma cells were injected via tail vein into C57BL/6 immunocompetent and NSG immunodeficient mice during exposure to isoflurane and ketamine versus controls without anesthesia. Mice were imaged on days 0, 3, 10, and 14 post-tumor cell injection. On day 14, mice were euthanized and organs fixed for metastasis quantification and immunohistochemistry staining. We compared growth of tumors measured from bioluminescent imaging and tumor metastasis in ex vivo bioluminescent imaging of lung and liver. RESULTS: Metastases were significantly greater for immunocompromised NSG mice than immunocompetent C57BL/6 mice over the 14-day experiment (partial η2 = 0.67, 95% CI = 0.54, 0.76). Among immunocompetent mice, metastases were greatest for mice receiving ketamine, intermediate for those receiving isoflurane, and least for control mice (partial η2 = 0.88, 95% CI = 0.82, 0.91). In immunocompetent mice, significantly decreased T lymphocyte (partial η2 = 0.83, 95% CI = 0.29, 0.93) and monocyte (partial η2 = 0.90, 95% CI = 0.52, 0.96) infiltration was observed in anesthetic-treated mice versus controls. CONCLUSIONS: The immune system appears central to the pro-metastatic effects of isoflurane and ketamine in a murine model, with decreased T lymphocytes and monocytes likely playing a role.

Pharmacology and toxicology of xylazine: quid novum?

The current opioid overdose crisis is characterized by the presence of unknown psychoactive adulterants. Xylazine is an alpha-2 receptor agonist that is not approved for human use but is commonly used in veterinary medicine due to its sedative and muscle-relaxant properties. Cases of human intoxication due to accidental or voluntary use have been reported since the 1980s. However, reports of adulteration of illicit opioids (heroin and illicit fentanyl) with xylazine have been increasing all over Western countries. In humans, xylazine causes respiratory depression, bradycardia, and hypotension-posing individuals, using xylazine-adulterated opioids. We present a narrative review of the latest intoxication cases related to xylazine, to bring awareness to readers and also to help pathologists to detect and deal with xylazine cases.

Comparison of two ratios of xylazine:ketamine for the anesthesia of free-ranging North American beavers (Castor canadensis) in a remote setting.

The objective of this study was to evaluate and compare 2 different xylazine:ketamine combination anesthetic protocols in free-ranging beavers (Castor canadensis). Twenty-two beavers (weighing 2.5 to 18.5 kg) were equally assigned to one of the following protocols: 1:10 xylazine:ketamine ratio and 3:10 xylazine:ketamine ratio. Using standard metabolic scaling, the following ranges of dosages were calculated and used: for the 1:10 xylazine:ketamine group 1.08 to 2.25 mg/kg (median = 1.2 mg/kg) of xylazine + 10.8 to 22.5 mg/kg (median = 12 mg/kg) of ketamine IM; andfor the 3:10 xylazine:ketamine group 2.04 to 3.67 mg/kg (median = 2.7 mg/kg) of xylazine + 6.81 to 12.25 mg/kg (median = 8.8 mg/kg) ketamine IM. Measured cardiorespiratory parameters and anesthetic event intervals were compared between protocols. Both protocols rapidly induced levels of anesthesia adequate for minimally invasive procedures of short duration. Durations of immobility ranged from 15 to 35 min and were not significantly different between the protocols (P = 0.64). Recovery phases, following the IM administration of 0.2 mg/kg of atipamezole 30 to 65 min post-induction, were usually faster with the 3:10 xylazine:ketamine protocol, but this was not statistically significant (P = 0.40). Heart rates were significantly lower with the 3:10 xylazine:ketamine protocol (P = 0.0002). PETCO2 values, measured with a nasal cannula, were similar between protocols and suggestive of hypoventilation. Despite the fact that the 3:10 xylazine:ketamine protocol was associated with a greater cardiac depression, the apparent, even if not statistically significant, faster recovery time with that protocol is definitively an asset for projects occurring in remote locations relying on helicopter transportation.

Le but de cette étude était d'évaluer et de comparer 2 protocoles anesthétiques différents combinant xylazine et kétamine chez des castors sauvages (Castor canadensis). Vingt-deux castors (2,5­18,5 kg) ont été assignés de manière égale à l'un des protocoles suivants : xylazine:kétamine à un ratio de 1:10 et xylazine:kétamine à un ratio de 3:10. À l'aide d'une échelle métabolique standard, les dosages calculés et utilisés ont été les suivants : 1,08 à 2,25 (médiane = 1,2) mg/kg de xylazine + 10,8 à 22,5 (médiane = 12) mg/kg de kétamine IM pour le groupe xylazine:kétamine à un ratio de 1:10; et2,04 à 3,67 (médiane = 2,7) mg/kg de xylazine + 6,81 à 12,25 (médiane = 8,8) mg/kg de kétamine IM pour le groupe xylazine:kétamine à un ratio de 3:10.Les paramètres cardiorespiratoires et les intervalles anesthésiques mesurés ont été comparés entre les protocoles. Les deux protocoles ont permis d'induire rapidement tous les castors à un niveau d'anesthésie adéquat pour une procédure minimalement invasive de courte durée. Les durées d'immobilité variaient de 15 à 35 minutes et n'étaient pas significativement différentes entre les protocoles (P = 0,64). Les phases de récupération, après l'administration IM de 0,2 mg/kg d'atipamézole 30 à 65 minutes après l'induction, étaient généralement plus rapides avec le protocole xylazine:kétamine à un ratio de 3:10, mais cela n'était pas statistiquement significatif (P = 0,40). Les fréquences cardiaques étaient significativement plus basses avec le protocole xylazine:kétamine à un ratio de 3:10 (P = 0,0002). Les valeurs de PETCO2, mesurées avec une canule nasale, étaient similaires entre les protocoles et suggéraient une hypoventilation. Malgré le fait que le protocole xylazine:kétamine à un ratio de 3:10 était associé à une dépression cardiaque plus importante, le temps de récupération apparemment plus rapide, même si ce n'était pas statistiquement significatif, avec ce protocole est définitivement un atout pour les projets se déroulant dans des endroits éloignés accessibles uniquement par hélicoptère.(Traduit par les auteurs).