USE OF A PETHIDINE AND MIDAZOLAM COMBINATION FOR THE REVERSIBLE SEDATION OF CRABEATER SEALS (LOBODON CARCINOPHAGUS)

Between October and December of 1996–1999, off eastern Antarctica (60°-150°E), we darted 31 crabeater seals with midazolam and pethidine at estimated dose rates of 0.15–0.4 mg/kg and 1–3 mg/kg, respectively. Maximum sedation was reached at 23 ± 9 min (n = 18) and first signs of recovery were noted at 54 ± 24 min (n = 4). Seals greater than 250 kg body-mass were sedated by administration of approximately 90–100 mg midazolam and 600 mg pethidine, but the degree of sedation was unpredictable and did not permit invasive procedures in some cases. Behavior of the seal and adjacent conspecifics affected the success of procedures and our ability to monitor vital signs. Naloxone and flumazenil reversed sedation, making this combination attractive for use in animals adjacent to water. Additional ketamine was administered to two seals, resulting in improved restraint.     

Anesthetic Effects of a Mixture of Medetomidine,Midazolam and Butorphanol in Two Strains of Mice

The combination of ketamine and xylazine is a widely used anesthetic for laboratory animals. However, due to an abuse problem in Japan, ketamine has been specified as a narcotic since 2007. Instead of using ketamine, Kawai et al. reported an injectable formula with an equivalent effect to the mixture of ketamine and xylazine [11]. The mixture of 0.3 mg/kg body weight (b.w.) medetomidine (Med.), 4.0 mg/kg b.w. midazoram (Mid.), and 5.0 mg/kg b.w. butorphanol (But.) produced an anesthetic duration of around 40 min in outbred ICR mice. However, the anesthetic effect of the mixture for inbred mice strains remains unknown. Therefore, we examined anesthetic effects of the mixture of Med., Mid., and But. in the BALB/c and C57BL/6J strains. After intraperitoneal injection into mice, right front paw, left hind paw, and tail pinch reflexes as well as corneal and righting reflexes were observed. Every 5 min, we scored each reflex category as 0 for reaction or 1 for no reaction. As long as the total score was at least 4 out of 5, we considered the mixture as putting a mouse in a surgical anesthetic state. The mixture produced an anesthetic duration of more than 45 min in both strains of mice. These results indicate that the mixture of Med., Mid., and But. can be a useful and effective anesthesia for the BALB/c and C57BL/6J strains of inbred mice as well as outbred ICR mice.     

Effectiveness of Partial Sedation to Reduce Stress in Captured Mule Deer

Information garnered from the capture and handling of free-ranging animals helps advance understanding of wildlife ecology and can aid in decisions on wildlife management. Unfortunately, animals may experience increased levels of stress, injuries, and death resulting from captures (e.g., exertional myopathy, trauma). Partial sedation is a technique proposed to alleviate stress in animals during capture, yet efficacy of partial sedation for reducing stress and promoting survival post-capture remains unclear. We evaluated the effects of partial sedation on physiological, biochemical, and behavioral indicators of acute stress and probability of survival post-capture for mule deer (Odocoileus hemionus) that were captured via helicopter net-gunning in the eastern Greater Yellowstone Ecosystem, Wyoming, USA. We administered 10–30 mg of midazolam and 15 mg of azaperone intramuscularly (IM) to 32 mule deer in 2016 and 53 mule deer in 2017, and maintained a control group (captured but not sedated) of 38 mule deer in 2016 and 54 mule deer in 2017. To evaluate indicators of acute stress, we measured heart rate, blood-oxygen saturation, body temperature, respiration rate, and levels of serum cortisol. We recorded number of kicks and vocalizations of deer during handling and evaluated behavior during release. We also measured levels of fecal glucocorticoids as an indicator of baseline stress. Midazolam and azaperone did not reduce physiological, biochemical, or behavioral indicators of acute stress or influence probability of survival post-capture. Mule deer that were administered midazolam and azaperone, however, were more likely to hesitate, stumble or fall, and walk during release compared with individuals in the control group, which were more likely to trot, stot, or run without stumbling or falling. Our findings suggest that midazolam (10–30 mg IM) and azaperone (15 mg IM) may not yield physiological or demographic benefits for captured mule deer as previously assumed and may pose adverse effects that can complicate safety for captured animals, including drug-induced lethargy. Although we failed to find efficacy of midazolam and azaperone as a method for reducing stress in captured mule deer, the efficacy of midazolam and azaperone or other combinations of partial sedatives in reducing stress may depend on the dose of tranquilizer, study animal, capture setting, and how stress is defined. © 2020 The Wildlife Society.     

USE OF MIDAZOLAM/PETHIDINE AND TILETAMINE/ZOLAZEPAM COMBINATIONS FOR THE CHEMICAL RESTRAINT OF LEOPARD SEALS (HYDRURGA LEPTONYX)

We immobilized 200–550-kg leopard seals ( Hydrurga leptonyx ) on sea ice in Prydz Bay, Antarctica (68°25'S, 77°10'E) between November 1997 and February 2000. Midazolam (0.18–0.27 mg/kg)/ pethidine (1.0–1.5 mg/kg) was administered by dart to 16 leopard seals. Unpredictable immobilization, poor airway maintenance, and our inability to fully assess the suitability of flumazenil (0.003–0.01 mg/kg), naloxone (0.01–0.013 mg/kg), and naltrexone (0.05–0.12 mg/kg) as reversal agents limited suitability of midazolam/pethidine. Tiletamine/zolazepam 1:1 (0.5–1.5 mg/kg) was, therefore, administered to 19 leopard seals. It produced faster induction (19 ± 3 min), more effective and reliable response to dose (rank correlation: r _s= 0.88, n = 18), and better pulmonary ventilation and faster return of cognitive function upon recovery, in comparison to midazolam/pethidine. Best results were achieved with tiletamine/zolazepam (1.2–1.4 mg/kg) which safely immobilized seven of nine seals for 20–30 min. Entry to the water upon darting was minimized, but not eliminated, by the use of lightweight air-pressurized darts and a thorough knowledge of leopard seal behavior.     

舒芬太尼复合小剂量咪达唑仑在下肢骨折椎管内麻醉前的应用观察

目的观察舒芬太尼复合小剂量咪达唑仑在下肢骨折椎管内麻醉前的应用效果。方法选取我院收治的下肢骨折患者450例,采取数字随机法分为观察组和对照组。对照组在椎管内麻醉前给予小剂量咪达唑仑,观察组在对照组的基础上于椎管麻醉前加用舒芬太尼,比较两组的应用效果。结果观察组给药后收缩压(SBP)、舒张压(DBP)、心率(HR)水平均低于入室时(P0.05),而且也明显低于对照组(P0.05)。两组血氧饱和度(SpO2)水平在入室时、给药后比较,差异无统计学意义(P0.05)。观察组给药后30、45min的镇静、镇痛效果评分均高于对照组(P0.05),而且观察组给药后45min的镇静、镇痛效果评分低于给药后30min(P0.05)。结论舒芬太尼复合小剂量咪达唑仑在下肢骨折椎管内麻醉前的应用效果显著,可达到镇静、止痛作用。     

Vital signs monitoring during injectable and inhalant anesthesia in mice

Selecting the appropriate anesthetic protocol for the individual animal is an essential part of laboratory animal experimentation. The present study compared the characteristics of four anesthetic protocols in mice, focusing on the vital signs. Thirty-two male ddY mice were divided into four groups and administered anesthesia as follows: pentobarbital sodium monoanaesthesia; ketamine and xylazine combined (K/X); medetomidine, midazolam, and butorphanol combined (M/M/B); and isoflurane. In each group, rectal temperature, heart rate, respiratory rate, and O₂ saturation (SPO₂) were measured, and the changes over time and instability in these signs were compared. The anesthetic depth was also evaluated in each mouse, and the percentage of mice achieving surgical anesthesia was calculated. K/X anesthesia caused remarkable bradycardia, while the respiratory rate and SPO₂ were higher than with the others, suggesting a relatively strong cardiac influence and less respiratory depression. The M/M/B group showed a relatively lower heart rate and SPO₂, but these abnormalities were rapidly reversed by atipamezole administration. The pentobarbital group showed a lower SPO₂, and 62.5% of mice did not reach a surgical anesthetic depth. The isoflurane group showed a marked decrease in respiratory rate compared with the injectable anesthetic groups. However, it had the most stable SPO₂ among the groups, suggesting a higher tidal volume. The isoflurane group also showed the highest heart rate during anesthesia. In conclusion, the present study showed the cardiorespiratory characteristics of various anesthetic protocols, providing basic information for selecting an appropriate anesthetic for individual animals during experimentation.     

Effects of midazolam on the contraction and relaxation of segments of thoracic aorta stripped of endothelium and stimulated by adrenaline – experimental study in rabbits

To evaluate the effects of midazolam on the angiokinesis of segments of rabbits' thoracic aorta stripped of endothelium and stimulated by adrenaline.Two groups of aortic rings removed from albinic rabbits anesthetized with thiopental were used (Group I – 6 animals; Group II – 12 animals), stripped of endothelium, studied in an organ chamber, perfused by Krebs-Henseleit solution. The groups were stimulated by adrenaline, recording the maximum contraction and dT/dt at 12, 36, 60 and 120. When the plateau phase was reached, the vessel was washed with perfusion solution, recording relaxation at 2, 4 and 6. When the base values were reached, Group I underwent a new adrenergic stimulus; and Group II was stimulated with midazolam and then with adrenaline, and the same values were recorded. T test was applied as a statistical analysis when two variables were studied. When studying more than two variables the Anova test was used, supplemented by the Tuckey test.Group I did not show any significant difference between the two stimuli. Group II – the midazolam significantly reduced the maximum contraction induced by adrenaline (83.01 ± 4.11%) (p < 0.01). The dT/dt was reduced at 12 (57.06 ± 8.47%), and also at 36 (70.59 ± 5.26%). There was no significance at 60 and 120 (p < 0.01).The relaxation increased significantly at all measurements – at 2-adrenaline 39.31 ± 9.60%; adrenaline/midazolam: 44.06 ± 9.62% (p < 0.05). At 4-adrenaline: 53.08 ± 8.3%; adrenaline/midazolam: 61.68 ± 8.50% (p < 0.01). At 6-adrenaline: 76.26 ± 5.45%; adrenaline/midazolam: 84.20 ± 7.96% (p < 0.01).Midazolam significantly reduced the maximum contraction obtained by the adrenergic stimulus as well as the dT/dt in the initial phases of contraction. The relaxation speed also increased.     

In vitro and in vivo effects of some benzodiazepine drugs on human and rabbit erythrocyte carbonic anhydrase enzymes

Carbonic anhydrase inhibitors (CAIs) are a class of pharmaceuticals used as antiglaucoma agents, diuretics and antiepileptics. Thus, discovery of novel CAIs has become of great importance in the recent years. In the current study, in vitro and in vivo inhibition effects of benzodiazepine drugs, diazepam and midazolam, on human erythrocytes carbonic anhydrase I and II isozymes were investigated. After purification of the isoenzymes, in vitro inhibition assays were performed and K_i values were determined to be of 141.5 μM and 40.7 μM for hCA I and of 5.11 μM and 0.58 μM against hCA II by the esterase activity assay, respectively. The drugs showed strong inhibitory effects on hCA II, in the same range as the clinically used sulphonamide acetazolamide. For in vivo studies, five adult male New Zealand White rabbits (3–4.2?kg) were selected for intravenous administrations of the drugs (2?mg/kg and 0.2?mg/kg body weight, respectively). The enzyme was significantly inhibited by 2?mg/kg diazepam (p?<?0.05), and 0.2?mg/kg midazolam (p?<?0.05) for up to 30?min following intravenous administration.     

Liposome-encapsulated midazolam for oral administration

The oral administration of midazolam has often been used for sedation in pediatric patients. However, oral administration of an intravenous formulation of midazolam is difficult for younger pediatric patients because of its bitter taste. Liposomes have been developed as vesicles encapsulating various kinds of drugs to serve as a medical drug-delivery system. Thus, the aim of the present study was to produce pH-sensitive liposomes encapsulating midazolam and to evaluate its pharmacokinetics on rabbits. Liposome-encapsulated midazolam was produced from hydrogenated L-α-phosphatidylcholine, cholesterol, dipalmitoylphosphatidic acid, and midazolam. The capacity of liposomes to encapsulate midazolam (encapsulation efficiency), stability of encapsulation, and release efficiency were evaluated in vitro. Further, the produced liposome-encapsulated midazolam solution was orally administered to rabbits in vivo. As a result, midazolam was encapsulated by liposomes with a high encapsulation efficiency and was stably encapsulated in a physiological medium. Further, the produced liposomes rapidly and effectively released midazolam in an acidic medium in vitro. When the liposome-encapsulated midazolam solution was orally administered to rabbits, the time to achieve the maximum plasma concentration of midazolam after administration was slightly longer, but both the maximum plasma concentration and area under the concentration-time curve were higher than those receiving midazolam solution. In conclusion, we produced pH-sensitive liposome-encapsulated midazolam, which remained stable in a physiological medium and showed efficient release in an acidic environment. The results suggest that it is possible to clinically use liposome-encapsulated midazolam for oral administration as a useful drug-delivery vehicle.     

Safety and physiologic effects of intranasal midazolam and nitrous oxide inhalation based sedation in children visiting Saveetha Dental College and Hospitals,India

A large number of patients avoid dental care due to anxiety. Various techniques are available for behaviour related management. Therefore, safety and physiologic effects of intranasal midazolam and nitrous oxide inhalation based sedation in children aged 4 to 8 years visiting Saveetha Dental College and Hospitals, India is of interest. 35 anxious patients aged 4 to 8 years were included in the study. The patient received either intranasal midazolam/nitrous oxide in the first visit and vice versa at the second visit. The onset of sedation, recovery time and procedure duration were recorded using a timer. Physiological parameters were recorded using a monitor. Safety scale was used for assessing prevalence of adverse reactions. There was no significant difference between the groups in safety scale scores, recovery time and procedure duration. Midazolam group showed a statistically significant faster onset of sedation and a statistically significant increase in heart rate at four recorded time-points. All the vitals were within the physiological limits. Thus, intranasal midazolamis a safe alternative to nitrous-oxide sedation in completing the intended dental treatment while managing the anxious children in dental clinic.