Fentanyl and xylazine crisis:Crafting coherent strategies for opioid overdose prevention

The United States is in the throes of a severe opioid overdose epidemic,primarily fueled by the pervasive use of fentanyl and the emerging threat of xylazine,a veterinary sedative often mixed with fentanyl.The high potency and long duration of fentanyl is compounded by the added risks from xylazine,heightening the lethal danger faced by opioid users.Measures such as enhanced surveillance,public awareness campaigns,and the distribution of fentanylxylazine test kits,and naloxone have been undertaken to mitigate this crisis.Fentanyl-related overdose deaths persist despite these efforts,partly due to inconsistent policies across states and resistance towards adopting harm reduction strategies.A multifaceted approach is imperative in effectively combating the opioid overdose epidemic.This approach should include expansion of treatment access,broadening the availability of medications for opioid use disorder,implementation of harm reduction strategies,and enaction of legislative reforms and diminishing stigma associated with opioid use disorder.

Pharmacokinetic Characterization of Xylazine in Goats with Simultaneous Anesthesia Studies

The aim was to study the pharmacokinetics of xylazine as a stable anesthetic in goats.In this study,goats were injected with xylazine at the rate of 0.3 mL·kg-1 intramusculally,and blood samples were collected at 1,3,5,10,20,30,45,60,90,120,180,and 240 min after administration,respectively.Xylazine was extracted by liquid-liquid extraction and separation method,and blood concentration was determined by high performance liquid chromatography(HPLC).The pharmacokinetic characteristics of xylazine in healthy goats were analyzed by pharmacokinetic software.The results showed that the chromatographic peak time of xylazine chromatography was 9-11 min.The specificity of the method was good.The linear correlation coefficient R2 of the standard curve was 0.9982 when the concentration of xylazine was in the range of 10-1×1000 ng.The pharmacokinetic model of xylazine in goats was a one-chamber model with first-order rate absorption,distribution half-life t1/2Ka was(0.49±0.041)min,elimination half-life t1/2Ke was(23.3±2.5)min,and the peak time(Tp)of the highest concentration was(2.8±0.2)min.The total drug clearance CL/F was(0.00016±0.000016)mg·kg-1·min-1(ng·mL-1),and the minimum effective blood concentration was 56.6 ng·mL-1,which was consistent with the clinical anesthetic effect.The results showed that xylazine had the characteristics of rapid absorption,wide distribution,short peak time,slow clearance rate,and long anesthetic time in goats,which could be used as the basic drug for the development of goat complex anesthetic preparation.

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 usefulfor characterizing the cardiovascular system. To achieve this, it is necessary to know thedetailed characteristics of APWs in different states of an organism, which would allowAPW 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 ofisoflurane (ISO) and Zoletil/xylazine (ZO/XY) anesthesia and to study the effect of rootextract from Acanthopanax senticosus (ASRE) in these anesthetic conditions.Methods : The right jugular vein of anesthetized rats was cannulated for the administrationof ASRE and the left carotid artery for the detection of APWs from which 35APW- 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 insystolic and diastolic blood pressure (BP) and heart rate or increases in pulse BP, d P /d t max , and systolic and diastolic areas. Whereas the transient effects of ASRE weresimilar, the extract had prolonged disturbing effects on the cardiovascular system inrats under ZO/XY but not under ISO anesthesia. This negative effect can result fromthe disturbance caused by ZO/XY anesthesia on the cardiovascular system.Conclusions : We characterized 35 APW- Ps of rats under ISO and ZO/XY anesthesiaand found that ASRE contains compounds that can modulate the properties of thecardiovascular system, which significantly depended on the status of the cardiovascularsystem. This should be considered when using ASRE as a nutritional supplementby individuals with cardiovascular problems.

Effect of Xylazine Anesthesia on Glu and GABA Amino Acid Neurotransmitters in Rat

Neurotransmitters of the central nervous system were the important way to study the mechanism of anesthesia. The effect of different doses of xylazine anesthetic on the glutamate(Glu) and γ-aminobutyric-acid(GABA) were investigated and the mechanism of xylazine anesthetic on the central nervous system were explored in this study. A total of 88 rats were randomly divided into three groups, including normal saline control group, group with low dose of xylazine and group with high dose of xylazine.Cerebrum, cerebellum, hippocampus, thalamus and brainstem were collected. The results showed that the concentration of Glu in the hippocampus, thalamus and brainstem decreased first and then increased, but it increased first and then decreased in the cerebrum and cerebellum during the period of anesthesia. The concentration of GABA in the cerebrum, thalamus, brainstem and hippocampus increased first and then decreased. The results showed that xylazine inhibited Glu and promoted GABA with different dose dependence. The results and methods could provide guides for the clinical use of xylazine.

Effect of different anesthetic mixtures——ketamine-xylazine, ketamine-acepromazine and tiletamine-zolazepam——on the physiological and blood biochemistry parameters of male rhesus monkeys(Macaca mulatta) at different ages

Background: Anesthetic agents are commonly utilized in the handling of non‐human primates for prevent the stress caused in physical exploration or physical restrain. For this reason, the objective of this work was to describe the effect of age and dissociative anesthetics (ketamine and tiletamine), and their combinations with acepromazine, xylazine and zolazepam, on the physiological and blood biochemical parameters in Macaca mulatta. Methods: Eighty male Macaca mulatta were divided into four experimental groups depending on the anesthetic mixture applied. Each group of 20 males was divided into five sub‐groups according to age. Physiological parameters were recorded every five minutes during a 30‐minute period. A blood sample was drawn to analyze blood biochemistry. Results: Statistical analyses revealed significant differences in the physiological parameters between the ketamine‐acepromazine and ketamine‐xylazine groups compared to the control group. The analysis of blood biochemistry found significant differences by age and by anesthetic mixture among all groups. Conclusion: These findings contribute to standardizing this animal model in biological research.

Effect of Atipamzole on Fos Protein Expression Induced by Telazol/ Xylazine in Rat Cerebral Cortex and Thalamencephal

The aim of the study was to assess effect of the atipamezolc on talezol/xylazine induced expression of c-fos in rat brain. Rats were injected with the mixture of 13.81 mg· kg^-1 telazol and 5.21 mg· kg^-1 xylazine, following 10 min later 0.522 mg· kg^-1 atipamezole injected, and then the cerebral cortex and thalamencephal were removed at 1 h after injected. Level of Fos protein was measured in the brain tissue by westem-blot. The results revealed that telazol/xylazine induction Fos protein expression in the thalamencephal and cerebral cortex during the period of anesthesia, atipamezole attenuated tclazol/ xylazine induction Fos protein expression in the thalamencephal and cerebral cortex. The results indicated that atipamezolc could inhibite telazol/xylazine-induced c-los expression in the rat brain, and played a protective role of neuronal injury.

Anesthesia protocol for ear surgery in Wistar rats(animal research)

Objective:To formulate an anesthesia protocol for safe and satisfactory anesthesia for ear surgery in rats.Methods:The rats were anesthetized with xylazine(10 mg/kg body weight)and keta-mine at doses of 80,50,40,and 30 mg/kg body weight or with isoflurane anesthesia(2%-3.5%in 100%oxygen;maintenance dose 1.5%-3.5%).The anesthesia induction,surgery,and recovery time were recorded.Results:In total,17 rats were induced by varying doses of ketamine-xylazine and 28 rats with isoflurane.Mean induction time with ketamine-xylazine was 6±2.9 min compared with 3.8±1.1 min with isoflurane.Mean recovery time with ketamine-xylazine was 142.6±49.3 min compared with 4.1±1.2 min with isoflurane.A mortal-ity of 4 animals after developing dyspnea was recorded with ketamine-xylazine.Conclusion:Isoflurane anesthesia offers appropriate induction and recovery times and low mortality rates for the surgeries performed.Isoflurane anesthesia offers reli-able results for ear surgery in rats.However,more equipment and technical skills are needed.

Effect of anesthetics on gastric damage using two models of portal hypertension

AIM:To investigate the effect of sodium pentobarbitone(SP) or ketamine/xylazine(KX) anesthetics on acute gastric injury.METHODS:Portal hypertension was induced by bile duct ligation(BDL) or portal vein stenosis(PVS).Ethanol(EtOH)-induced gastric damage was assessed using ex vivo gastric chamber experiments.Gastric blood flow(GBF) was also measured by laser doppler flowmetry.RESULTS:EtOH-induced gastric damage was reduced in BDL rats under KX anesthesia in comparison to those under SP anesthesia.GBF dysfunction in fasted BDL rats was partially restored under KX anesthesia.In contrast,in fasted PVS rats,EtOH-induced gastric damage was increased under KX anesthesia while GBF was reduced.CONCLUSION:The use of KX anesthesia in experimental procedures involving cirrhotic rats(but not those with pure portal hypertension) is preferable to SP anesthesia.