Effects of the selective AMPA modulator NBI-1065845 on the pharmacokinetics of midazolam or ethinyl estradiol-levonorgestrel in healthy adults.

This parallel-arm, phase I study investigated the potential cytochrome P450 (CYP)3A induction effect of NBI-1065845 (TAK-653), an investigational α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiator in phase II development for major depressive disorder. The midazolam treatment arm received the sensitive CYP3A substrate midazolam on Day 1, followed by NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with midazolam, then NBI-1065845 alone on Day 15. The oral contraceptive treatment arm received ethinyl estradiol-levonorgestrel on Day 1, then NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with ethinyl estradiol-levonorgestrel, then NBI-1065845 alone on Days 15-17. Blood samples were collected for pharmacokinetic analyses. The midazolam treatment arm comprised 14 men and 4 women, of whom 16 completed the study. Sixteen of the 17 healthy women completed the oral contraceptive treatment arm. After multiple daily doses of NBI-1065845, the geometric mean ratios (GMRs) (90% confidence interval) for maximum observed concentration were: midazolam, 0.94 (0.79-1.13); ethinyl estradiol, 1.00 (0.87-1.15); and levonorgestrel, 0.99 (0.87-1.13). For area under the plasma concentration-time curve (AUC) from time 0 to infinity, the GMRs were as follows: midazolam, 0.88 (0.78-0.98); and ethinyl estradiol, 1.01 (0.88-1.15). For levonorgestrel, the GMR for AUC from time 0 to the last quantifiable concentration was 0.87 (0.78-0.96). These findings indicate that NBI-1065845 is not a CYP3A inducer and support its administration with CYP3A substrates. NBI-1065845 was generally well tolerated, with no new safety signals observed after coadministration of midazolam, ethinyl estradiol, or levonorgestrel.

Acute Dissociation and Ketamine's Antidepressant and Anti-Suicidal Ideation Effects in a Midazolam-Controlled Trial.

OBJECTIVE: We sought to explore relationships of acute dissociative effects of intravenous ketamine with change in depression and suicidal ideation and with plasma metabolite levels in a randomized, midazolam-controlled trial. METHODS: Data from a completed trial in suicidal, depressed participants (n = 40) randomly assigned to ketamine was used to examine relationships between ketamine treatment-emergent dissociative and psychotomimetic symptoms with pre/post-infusion changes in suicidal ideation and depression severity. Nonparametric correlational statistics were used. These methods were also used to explore associations between dissociative or psychotomimetic symptoms and blood levels of ketamine and metabolites in a subset of participants (n = 28) who provided blood samples immediately post-infusion. RESULTS: Neither acute dissociative nor psychotomimetic effects of ketamine were associated with changes in suicidal ideation or depressive symptoms from pre- to post-infusion. Norketamine had a trend-level, moderate inverse correlation with dissociative symptoms on Day 1 post-injection (P = .064; P =.013 removing 1 outlier). Dehydronorketamine correlated with Clinician-Administered Dissociative States Scale scores at 40 minutes (P = .034), 230 minutes (P = .014), and Day 1 (P = .012). CONCLUSION: We did not find evidence that ketamine's acute, transient dissociative, or psychotomimetic effects are associated with its antidepressant or anti-suicidal ideation actions. The correlation of higher plasma norketamine with lower dissociative symptoms on Day 1 post-treatment suggests dissociation may be more an effect of the parent drug.

Impact of Viloxazine Extended-Release Capsules (Qelbree®) on Select Cytochrome P450 Enzyme Activity and Evaluation of CYP2D6 Genetic Polymorphisms on Viloxazine Pharmacokinetics.

BACKGROUND AND OBJECTIVE: Viloxazine extended-release (ER) [Qelbree®] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for viloxazine to inhibit cytochrome 450 (CYP) enzymes 1A2, 2B6, 2D6 and 3A4. This clinical study therefore evaluated viloxazine ER effects on index substrates for CYP1A2, 2D6, and 3A4, and secondarily evaluated the impact of CYP2D6 polymorphisms on viloxazine pharmacokinetics. METHODS: Thirty-seven healthy subjects received a modified Cooperstown cocktail (MCC; caffeine 200 mg, dextromethorphan 30 mg, midazolam 0.025 mg/kg) on Day 1, viloxazine ER 900 mg/day on Days 3-5, and a combination of viloxazine ER 900 mg and MCC on Day 6. Viloxazine ER effects on MCC substrates were evaluated using analysis of variance. The impact of CYP2D6 genetic polymorphisms on steady-state viloxazine plasma concentrations was evaluated using Student's t test assessing pharmacokinetic parameter differences between poor versus extensive metabolizers. RESULTS: The least squares geometric mean ratio [GMR%] (90% CI) of MCC substrate + viloxazine ER/MCC substrate alone for caffeine maximum concentration (Cmax), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUCt), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC∞) was 99.11 (95.84-102.49), 436.15 (398.87-476.92), and 583.35 (262.41-1296.80), respectively; 150.76 (126.03-180.35), 185.76 (155.01-222.61), and 189.71 (160.37-224.42) for dextromethorphan Cmax, AUCt, and AUC∞, respectively; and 112.81 (104.71-121.54), 167.56 (153.05-183.45), and 168.91 (154.38-184.80) for midazolam Cmax, AUCt, and AUC∞, respectively. At steady state, viloxazine least squares GMR (90% CI) for poor/extensive CYP2D6 metabolizers were Cmax 120.70 (102.33-142.37) and area under the plasme concentration-time curve from time 0 to 24 hours (AUC0-24 125.66 (105.36-149.87)). CONCLUSION: Viloxazine ER is a strong CYP1A2 inhibitor and a weak CYP2D6 and CYP3A4 inhibitor. CYP2D6 polymorphisms did not meaningfully alter the viloxazine ER pharmacokinetic profile.

Association of midazolam route of administration and need for recurrent dosing among children with seizures cared for by emergency medical services.

OBJECTIVE: National guidelines in the United States recommend the intramuscular and intranasal routes for midazolam for the management of seizures in the prehospital setting. We evaluated the association of route of midazolam administration with the use of additional benzodiazepine doses for children with seizures cared for by emergency medical services (EMS). METHODS: We conducted a retrospective cohort study from a US multiagency EMS dataset for the years 2018-2022, including children transported to the hospital with a clinician impression of seizures, convulsions, or status epilepticus, and who received an initial correct weight-based dose of midazolam (.2 mg/kg intramuscular, .1 mg/kg intravenous, .2 mg/kg intranasal). We evaluated the association of route of initial midazolam administration with provision of additional benzodiazepine dose in logistic regression models adjusted for age, vital signs, pulse oximetry, level of consciousness, and time spent with the patient. RESULTS: We included 2923 encounters with patients who received an appropriate weight-based dose of midazolam for seizures (46.3% intramuscular, 21.8% intranasal, 31.9% intravenous). The median time to the first dose of midazolam from EMS arrival was similar between children who received intramuscular (7.3 min, interquartile range [IQR] = 4.6-12.5) and intranasal midazolam (7.8 min, IQR = 4.5-13.4) and longer for intravenous midazolam (13.1 min, IQR = 8.2-19.4). At least one additional dose of midazolam was given to 21.4%. In multivariable models, intranasal midazolam was associated with higher odds (odds ratio [OR] = 1.39, 95% confidence interval [CI] = 1.10-1.76) and intravenous midazolam was associated with similar odds (OR = 1.00, 95% CI = .80-1.26) of requiring additional doses of benzodiazepines relative to intramuscular midazolam. SIGNIFICANCE: Intranasal midazolam was associated with greater odds of repeated benzodiazepine dosing relative to initial intramuscular administration, but confounding factors could have affected this finding. Further study of the dosing and/or the prioritization of the intranasal route for pediatric seizures by EMS clinicians is warranted.

Characterization of Pediatric Rectal Absorption, Drug Disposition, and Sedation Level for Midazolam Gel Using Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling.

This study aims to explore and characterize the role of pediatric sedation via rectal route. A pediatric physiologically based pharmacokinetic-pharmacodynamic (PBPK/PD) model of midazolam gel was built and validated to support dose selection for pediatric clinical trials. Before developing the rectal PBPK model, an intravenous PBPK model was developed to determine drug disposition, specifically by describing the ontogeny model of the metabolic enzyme. Pediatric rectal absorption was developed based on the rectal PBPK model of adults. The improved Weibull function with permeability, surface area, and fluid volume parameters was used to extrapolate pediatric rectal absorption. A logistic regression model was used to characterize the relationship between the free concentrations of midazolam and the probability of sedation. All models successfully described the PK profiles with absolute average fold error (AAFE) < 2, especially our intravenous PBPK model that extended the predicted age to preterm. The simulation results of the PD model showed that when the free concentrations of midazolam ranged from 3.9 to 18.4 ng/mL, the probability of "Sedation" was greater than that of "Not-sedation" states. Combined with the rectal PBPK model, the recommended sedation doses were in the ranges of 0.44-2.08 mg/kg for children aged 2-3 years, 0.35-1.65 mg/kg for children aged 4-7 years, 0.24-1.27 mg/kg for children aged 8-12 years, and 0.20-1.10 mg/kg for adolescents aged 13-18 years. Overall, this model mechanistically quantified drug disposition and effect of midazolam gel in the pediatric population, accurately predicted the observed clinical data, and simulated the drug exposure for sedation that will inform dose selection for following pediatric clinical trials.

Effect of Daridorexant on the Pharmacokinetics of Midazolam, and on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Male Subjects.

BACKGROUND AND OBJECTIVES: Daridorexant, a dual orexin receptor antagonist was recently approved for the treatment of insomnia at doses up to 50 mg once per night. This study investigated the effect of single-dose and multiple-dose daridorexant 50 mg at steady state on the pharmacokinetics (PK) of the cytochrome P450 (CYP) 3A4-sensitive substrate midazolam, and the effect of single-dose daridorexant 50 mg on the PK and pharmacodynamics (PD) of the CYP2C9-sensitive substrate warfarin. METHODS: In this prospective, single-center, open-label, fixed-sequence, phase I, drug-drug interaction study, 18 healthy male subjects sequentially received Treatment A, B, and C in three periods. Treatment A consisted of a single oral concomitant administration of midazolam 2 mg and warfarin 25 mg on day 1 of the first period. Treatment B consisted of one oral administration of daridorexant 50 mg followed 1 h later by a single oral dose of midazolam 2 mg concomitantly with a single oral dose of warfarin 25 mg on day 1 and a once-daily oral administration of daridorexant 50 mg for 6 days of the second period. Treatment C consisted of a single oral administration of daridorexant 50 mg at steady state followed 1 h later by a single oral administration of midazolam 2 mg on day 1 of the third period. Blood samples were assessed for midazolam and S-warfarin PK, and PD (international normalized ratio and factor VII). Noncompartmental  PK parameters and PD variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment B/A versus C/A for midazolam, and treatment B/A for warfarin. Safety and tolerability of each treatment were also assessed. RESULTS: Midazolam maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) were 1.13- and 1.42-fold higher, respectively, after single-dose administration of daridorexant 50 mg compared to administration of midazolam alone, while Cmax and AUC0-24 were 1.12- and 1.35-fold higher, respectively, after administration of daridorexant 50 mg once daily at steady state. Terminal half-life and time to maximum plasma concentration were comparable between treatments. Daridorexant had no influence on the PK and PD of warfarin. All treatments were safe and well tolerated. CONCLUSIONS: Daridorexant at 50 mg is classified as a weak CYP3A4 inhibitor after single- and multiple-dose administration once daily at steady state. Daridorexant 50 mg did not induce CYP3A4 activity or inhibit CYP2C9 activity. CLINICAL TRIAL REGISTRATION: This trial (NCT05480488) was registered on 29 July, 2022.

Time Course of the Interaction Between Oral Short-Term Ritonavir Therapy with Three Factor Xa Inhibitors and the Activity of CYP2D6, CYP2C19, and CYP3A4 in Healthy Volunteers.

BACKGROUND: We investigated the effect of a 5-day low-dose ritonavir therapy, as it is used in the treatment of COVID-19 with nirmatrelvir/ritonavir, on the pharmacokinetics of three factor Xa inhibitors (FXaI). Concurrently, the time course of the activities of the cytochromes P450 (CYP) 3A4, 2C19, and 2D6 was assessed. METHODS: In an open-label, fixed sequence clinical trial, the effect and duration of a 5-day oral ritonavir (100 mg twice daily) treatment on the pharmacokinetics of three oral microdosed FXaI (rivaroxaban 25 µg, apixaban 25 µg, and edoxaban 50 µg) and microdosed probe drugs (midazolam 25 µg, yohimbine 50 µg, and omeprazole 100 µg) was evaluated in eight healthy volunteers. The plasma concentrations of all drugs were quantified using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods and pharmacokinetics were analysed using non-compartmental analyses. RESULTS: Ritonavir increased the exposure of apixaban, edoxaban, and rivaroxaban, but to a different extent the observed area under the plasma concentration-time curve (geometric mean ratio 1.29, 1.46, and 1.87, respectively). A strong CYP3A4 inhibition (geometric mean ratio > 10), a moderate CYP2C19 induction 2 days after ritonavir (0.64), and no alteration of CYP2D6 were observed. A CYP3A4 recovery half-life of 2.3 days was determined. CONCLUSION: This trial with three microdosed FXaI suggests that at most the rivaroxaban dose should be reduced during short-term ritonavir, and only in patients receiving high maintenance doses. Thorough time series analyses demonstrated differential effects on three different drug-metabolising enzymes over time with immediate profound inhibition of CYP3A4 and only slow recovery after discontinuation. CLINICAL TRIAL REGISTRATION: EudraCT number: 2021-006643-39.

Effects of Midazolam/Dexmedetomidine with Buprenorphine or Extended-release Buprenorphine Anesthesia in C57BL/6 Mice.

The effects of commonly used injectable combinations of anesthetics such as ketamine and xylazine, with or without acepromazine, vary widely across individuals, have a shallow-dose response curve, and do not provide long-term analgesia. These drawbacks indicate the importance of continuing efforts to develop safe and effective injectable anesthetic combinations for mice. In this study, a series of experiments was designed to validate the use of dexmedetomidine and midazolam to provide chemical restraint for nonpainful procedures and the addition of buprenorphine or extended-release buprenorphine to reliably provide a surgical plane of anesthesia in C57BL/6J mice. Loss of consciousness was defined as the loss of the righting reflex (LORR); a surgical plane of anesthesia was defined as the LORR and loss of pedal withdrawal after application of a 300 g noxious stimulus to a hind paw. The combination of intraperitoneal 0.25 mg/kg dexmedetomidine and 6 mg/kg midazolam produced LORR, sufficient for nonpainful or noninvasive procedures, without achieving a surgical plane in 19 of 20 mice tested. With the addition of subcutaneous 0.1 mg/kg buprenorphine or 1 mg/kg buprenorphine-ER, 29 of 30 mice achieved a surgical plane of anesthesia. The safety and efficacy of the regimen was then tested by successfully performing a laparotomy in 6 mice. No deaths occurred in any trial, and, when administered 1 mg/kg atipamezole IP, all mice recovered their righting reflex within 11 min. The anesthetic regimen developed in this study is safe, is reversible, and includes analgesics that previous studies have shown provide analgesia beyond the immediate postsurgical period. Buprenorphine-ER can be safely substituted for buprenorphine for longer-lasting analgesia.

Patient-Reported Quality of Recovery after Sedation for Endoscopy in the Elderly.

INTRODUCTION: Although sedation is critical in minimizing discomforts in patients, conflicting data regarding the safety of sedation among the elderly population exist. This prospective study aimed to compare the quality of recovery (QoR) from gastrointestinal endoscopy performed under sedation between elderly and younger patients. METHODS: We included 177 patients aged 40-64 (group 1, n = 66), 65-79 (group 2, n = 76), and ≥80 (group 3, n = 35) years. QoR was assessed 1 day after the procedure using the quality of recovery 15 (QoR-15) questionnaire, which is a 15-item questionnaire with scores ranging from 0 to 150. Patient demographic, procedural, and sedation data were collected, and neurocognitive function was assessed before and a day after sedation. RESULTS: Groups 1 and 3 differed according to the Mini-Cog test and 3-word memory test performed before the procedure (p < 0.001). QoR-15 scores between groups were not different (139 ± 19 group 1, 141 ± 17 group 2, and 147 ± 26 group 3; p > 0.05). Patients in groups 3 and 2 were administered lower doses of propofol and midazolam than those in group 1. The incidence of oxygen desaturation (SaO2 <90% for >30 s) was lower in groups 1 and 2 than in group 3 (p = 0.01). CONCLUSIONS: As indicated by the QoR-15 questionnaire, the QoR from sedation was not significantly different between the study groups.

Pharmacokinetic Evaluation of the CYP3A4 and CYP2C9 Drug-Drug Interaction of Avacopan in 2 Open-Label Studies in Healthy Participants.

Avacopan, a complement 5a receptor (C5aR) antagonist approved for treating severe active antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, was evaluated in 2 clinical drug-drug interaction studies. The studies assessed the impact of avacopan on the pharmacokinetics (PK) of CYP3A4 substrates midazolam and simvastatin and CYP2C9 substrate celecoxib, and the influence of CYP3A4 inhibitor itraconazole and inducer rifampin on the PKs of avacopan. The results indicated that twice-daily oral administration of 30 mg of avacopan increased the area under the curve (AUC) of midazolam by 1.81-fold and celecoxib by 1.15-fold when administered without food, and twice-daily oral administration of 30 or 60 mg of avacopan increased the AUC of simvastatin by approximately 2.6-3.5-fold and the AUC of the active metabolite ß-hydroxy-simvastatin acid by approximately 1.4-1.7-fold when co-administered with food. Furthermore, the AUC of avacopan increased by approximately 2.19-fold when co-administered with itraconazole and decreased by approximately 13.5-fold when co-administered with rifampin. These findings provide critical insights into the potential drug-drug interactions involving avacopan, which could have significant implications for patient care and treatment planning. (NCT06207682).

Midostaurin drug interaction profile: a comprehensive assessment of CYP3A, CYP2B6, and CYP2C8 drug substrates, and oral contraceptives in healthy participants.

PURPOSE: Midostaurin, approved for treating FLT-3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is metabolized by cytochrome P450 (CYP) 3A4 to two major metabolites, and may inhibit and/or induce CYP3A, CYP2B6, and CYP2C8. Two studies investigated the impact of midostaurin on CYP substrate drugs and oral contraceptives in healthy participants. METHODS: Using sentinel dosing for participants' safety, the effects of midostaurin at steady state following 25-day (Study 1) or 24-day (Study 2) dosing with 50 mg twice daily were evaluated on CYP substrates, midazolam (CYP3A4), bupropion (CYP2B6), and pioglitazone (CYP2C8) in Study 1; and monophasic oral contraceptives (containing ethinylestradiol [EES] and levonorgestrel [LVG]) in Study 2. RESULTS: In Study 1, midostaurin resulted in a 10% increase in midazolam peak plasma concentrations (Cmax), and 3-4% decrease in total exposures (AUC). Bupropion showed a 55% decrease in Cmax and 48-49% decrease in AUCs. Pioglitazone showed a 10% decrease in Cmax and 6% decrease in AUC. In Study 2, midostaurin resulted in a 26% increase in Cmax and 7-10% increase in AUC of EES; and a 19% increase in Cmax and 29-42% increase in AUC of LVG. Midostaurin 50 mg twice daily for 28 days ensured that steady-state concentrations of midostaurin and the active metabolites were achieved by the time of CYP substrate drugs or oral contraceptive dosing. No safety concerns were reported. CONCLUSION: Midostaurin neither inhibits nor induces CYP3A4 and CYP2C8, and weakly induces CYP2B6. Midostaurin at steady state has no clinically relevant PK interaction on hormonal contraceptives. All treatments were well tolerated.

Subhypnotic Intravenous Ketamine Improves Patient Satisfaction With Burn Wound Care: A Quality Improvement Project.

Despite advancements in pain management for burn injuries, analgesia often fails to meet our patients' needs. We hypothesized that low doses of intravenous (IV) ketamine as an adjunct to our current protocol would be safe, improving both nurse and patient satisfaction with analgesia during hydrotherapy. Burn patients admitted who underwent hydrotherapy from June 1, 2021, to June 30, 2023 were surveyed. Ketamine was administered with the standard opioid-midazolam regimen. Demographics, oral morphine equivalents, midazolam, ketamine doses and time of administration, and adverse events were collected. Patient and nurse satisfaction scores were collected. The ketamine and no-ketamine groups were compared. P < .05 was considered significant. Eighty-five hydrotherapies were surveyed, 47 without ketamine, and 38 with ketamine. Demographics, comorbidities, %TBSA, and hospital length of stay were not different. The median amount of ketamine given was 0.79 mg/kg [0.59-1.06]. Patients who received ketamine were more likely to receive midazolam (100% vs 61.7%; P < .001), and both oral and IV opioids (94.7% vs 68.1%; P = .002) prior to hydrotherapy and less likely to receive rescue opioids or midazolam during hydrotherapy. Two patients in the ketamine group had hypertension (defined as SBP > 180) that did not require treatment. Nurses tended to be more satisfied with patient pain control when ketamine was used (10 [8-10] vs 9 [7-10], P = .072). Patient satisfaction was higher in the ketamine group (10 [8.8-10] vs 9 [7-10], P = .006). Utilizing subhypnotic dose of IV ketamine for hydrotherapy is safe and associated with increased patient satisfaction.

A Comparison of Three Anesthetic Drug Combinations for Use in Inducing Surgical Anesthesia in Female Guinea Pigs (Cavia porcellus).

Guinea pigs are often used in translational research, but providing them with safe and effective anesthesia is a challenge. Common methods like inhalant anesthesia and injectable ketamine/xylazine induce surgical anesthesia but can negatively affect cardiovascular, respiratory, and thermoregulatory systems and complicate the interpretation of research outcomes. Several alternative anesthetic regimens have been investigated, but none have consistently achieved a surgical plane of anesthesia. Therefore, identifying an anesthetic regimen that achieves a stable state of the surgical plane of anesthesia while preserving cardiorespiratory function would be a valuable contribution. To address this issue, we compared the efficacy of 3 anesthetic combinations in female Dunkin-Hartley guinea pigs: 1) alfaxalone, dexmedetomidine, and fentanyl (ADF); 2) alfaxalone, midazolam, and fentanyl (AMF); and 3) alfaxalone, midazolam, fentanyl, and isoflurane (AMFIso). We monitored anesthetic depth, heart rate, oxygenation, respiratory rate, respiratory effort, blood pressure, and body temperature every 15 min from injection to recovery. We also recorded the time to loss of righting reflex, duration of anesthesia, and time to achieve a surgical plane. The results showed no statistically significant differences in induction and recovery times among the groups. In the AMFIso group, 100% of the animals achieved a surgical plane of anesthesia, whereas only 10% of the animals in the AMF group reached that level. None of the animals in ADF group reached a surgical plane of anesthesia. Respiratory rate was significantly lower in the AMFIso as compared with the ADF group (P < 0.001) but was not different between the AMF and ADF groups. Temperature was significantly lower in the AMFIso group as compared with both the ADF and AMF groups (P < 0.001). In conclusion, both combinations of solely injectable anesthetics assessed in this study can be used for short, nonpainful procedures without significant cardiorespiratory depression. However, for mildly to moderately painful surgical procedures, the addition of an inhalant anesthetic like isoflurane is necessary for female guinea pigs.

Validation of the anesthetic effect of a mixture of remimazolam, medetomidine, and butorphanol in three mouse strains.

Proper administration of anesthesia is indispensable for the ethical treatment of lab animals in biomedical research. Therefore, selecting an effective anesthesia protocol is pivotal for the design and success of experiments. Hence, continuous development and refinement of anesthetic agents are imperative to improve research outcomes and elevate animal welfare. "Balanced anesthesia" involves using multiple drugs to optimize efficacy while minimizing side effects. The medetomidine, midazolam, and butorphanol, called MMB, and medetomidine, alfaxalone, and butorphanol, called MAB, are popular in Japan. However, the drawbacks of midazolam, including its extended recovery time, and the narrow safety margin of MAB, have prompted research for suitable alternatives. This study replaced midazolam in the MMB combination with remimazolam (RMZ), which is noted for its ultra-short half-life. The resulting combination, called MRB, was effective in providing a wider safety margin compared to MAB while maintaining an anesthesia depth equivalent level to that of MMB in mice. Notably, MRB consistently exhibited better recovery scores after antagonist administration in contrast to MMB. Furthermore, the re-sedation phenomenon observed with MMB was not observed with MRB. The rapid metabolism of RMZ enables reliable anesthesia induction, circumventing the complications linked to MAB. Overall, MRB excelled in providing extended surgical anesthesia and swift post-antagonist recovery. These results highlight the potential of RMZ for broader animal research applications.

Anestesia balanceada em gato palheiro (Leopardus braccatus) para realização de gastrotomia e enterotomia ­ relato de caso / Balanced anesthesia in pamps cat (Leopardus braccatus) for gastrotomy and enterotomy ­ case report / Anestesia balanceada en gato palheiro (Leopardus braccatus) para gastrotomía y enterotomía ­ reporte de caso

Foi atendido no Hospital Veterinária da Universidade Federal de Mato Grosso (HOVET-UFMT) - Campus Cuiabá, um gato palheiro (Leopardus braccatus), macho, filhote e pesando 1,8kg. Após avaliação clínica e exames complementares diagnosticou-se presença de corpo estranho solido gástrico e intestinal. Como medicação pré-anestésica optou-se pela associação de cetamina (1mg/kg) e midazolam (0,2mg/kg), seguiu-se com a indução com propofol (à efeito) e manutenção anestésica por meio do fornecimento de isofluorano. Como técnica adicional utilizou-se epidural, com uma associação de lidocaína (4,5mg/kg) e morfina (0,1mg/kg). Durante o procedimento anestésico notou-se estabilidade das variáveis cardiovasculares e respiratórias, além de recuperação satisfatória ao final do procedimento.

Was attended to in the Veterinary Hospital of the Federal University of Mato Grosso (HOVET-UFMT) - Campus Cuiabá, a pantanal cat (Leopardus braccatus), male, puppy and weighing 1.8 kg. After clinical evaluation and complementary exams, the presence of a solid gastric and intestinal foreign body was diagnosed. As pre-anesthetic medication, the association of ketamine (1mg/kg) and midazolam (0.2mg/kg) was chosen, followed by induction with propofol (for effect) and anesthetic maintenance by supplying isoflurane. As an additional technique, an epidural was used, with an association of lidocaine (4.5mg/kg) and morphine (0.1mg/kg). During the anesthetic procedure, stability of cardiovascular and respiratory variables was observed, in addition to satisfactory recovery at the end of the procedure.

Ingresó en el Hospital Veterinario de la Universidad Federal de Mato Grosso (HOVET-UFMT) · Campus Cuiabá, un gato palheiro (Leopardus braccatus), macho, cachorro y con un peso de 1,8 kg. Luego de evaluación clínica y exámenes complementarios se diagnosticó la presencia de cuerpo extraño sólido gástrico e intestinal. Como medicación preanestésica se optó por la asociación de ketamina (1 mg/kg) y midazolam (0,2 mg/kg), seguida de inducción con propofol (por efecto) y mantenimiento anestésico mediante suministro de isoflurano. Como técnica adicional se utilizó epidural, con asociación de lidocaína (4,5 mg/kg) y morfina (0,1 mg/kg). Durante el procedimiento anestésico se observó estabilidad de variables cardiovasculares y respiratorias, además de recuperación satisfactoria al final del procedimiento.

Preoperative Midazolam and Patient-Centered Outcomes of Older Patients: The I-PROMOTE Randomized Clinical Trial.

Importance: The effect of oral midazolam premedication on patient satisfaction in older patients undergoing surgery is unclear, despite its widespread use. Objective: To determine the differences in global perioperative satisfaction in patients with preoperative administration of oral midazolam compared with placebo. Design, Setting, and Participants: This double-blind, parallel-group, placebo-controlled randomized clinical trial was conducted in 9 German hospitals between October 2017 and May 2019 (last follow-up, June 24, 2019). Eligible patients aged 65 to 80 years who were scheduled for elective inpatient surgery for at least 30 minutes under general anesthesia and with planned extubation were enrolled. Data were analyzed from November 2019 to December 2020. Interventions: Patients were randomized to receive oral midazolam, 3.75 mg (n = 309), or placebo (n = 307) 30 to 45 minutes prior to anesthesia induction. Main Outcomes and Measures: The primary outcome was global patient satisfaction evaluated using the self-reported Evaluation du Vécu de l'Anesthésie Generale (EVAN-G) questionnaire on the first postoperative day. Key secondary outcomes included sensitivity and subgroup analyses of the primary outcome, perioperative patient vital data, adverse events, serious complications, and cognitive and functional recovery up to 30 days postoperatively. Results: Among 616 randomized patients, 607 were included in the primary analysis. Of these, 377 (62.1%) were male, and the mean (SD) age was 71.9 (4.4) years. The mean (SD) global index of patient satisfaction did not differ between the midazolam and placebo groups (69.5 [10.7] vs 69.6 [10.8], respectively; mean difference, -0.2; 95% CI, -1.9 to 1.6; P = .85). Sensitivity (per-protocol population, multiple imputation) and subgroup analyses (anxiety, frailty, sex, and previous surgical experience) did not alter the primary results. Secondary outcomes did not differ, except for a higher proportion of patients with hypertension (systolic blood pressure ≥160 mm Hg) at anesthesia induction in the placebo group. Conclusion and Relevance: A single low dose of oral midazolam premedication did not alter the global perioperative patient satisfaction of older patients undergoing surgery or that of patients with anxiety. These results may be affected by the low dose of oral midazolam. Further trials-including a wider population with commonplace low-dose intravenous midazolam and plasma level measurements-are needed. Trial Registration: ClinicalTrials.gov Identifier: NCT03052660.

Comparison of Caudal Dexmedetomidine and Midazolam as an Adjuvant to Ropivacaine for Postoperative Pain Relief in Children Undergoing Infra-Umbilical Surgeries: A Randomized Controlled Trial.

BACKGROUND: We explored the analgesic efficacy of two non-opioid adjuvants (midazolam and dexmedetomidine) with ropivacaine in children undergoing infraumbilical surgeries. METHODS: In this parallel group randomized controlled trial, 135 children aged between 2 and 8 years were recruited. Children were randomly allocated to one of three groups: RD received 1 mL/kg of ropivacaine (0.2%) with dexmedetomidine 1 µg/kg, RM received 1 mL/kg of ropivacaine (0.2%) with midazolam 30 µg/kg, and R received 1 mL/kg of ropivacaine (0.2%) with 1 mL normal saline. The primary outcome of the present study was to determine the duration of postoperative analgesia. Secondary outcomes were assessing postoperative face, leg, activity, cry, consolability (FLACC) pain score, rescue analgesics, hemodynamics, sedation scores, and adverse effects. RESULTS: The analgesia duration was significantly prolonged in the RD and RM group (600.0 [480.0-720.0] minutes and 600.0 [480.0-720.0] minutes, respectively) compared to the R group 360.0 (300.0-480.0) minutes (P < 0.001). The FLACC score was comparatively higher in the R group compared to the RD and RM groups postoperatively. Time for the first rescue analgesia was more prolonged in RD and RM groups when compared with the R group. Postoperative sedation was higher in the RM group up to 120 minutes postoperatively compared to the RD and R groups. CONCLUSION: The combination of dexmedetomidine or midazolam with local anesthetics significantly increases the analgesia duration while minimizing adverse effects.

Prospective, randomised comparison of two intravenous sedation methods for magnetic resonance imaging in children.

BACKGROUND: Children usually need sedation or even anaesthesia for magnetic resonance imaging (MRI) studies. As there is no universally accepted method for this purpose we undertook a prospective, randomised comparison of propofol and dexmedetomidine in children aged 1 to 10 years. METHODS: After Institutional Board approval and parents' informed consent 64 ASA status I or II children scheduled for MRI scan were enrolled. Patients were premedicated with intravenous (IV) midazolam (0.1 mg kg -1 ) and ketamine (1 mg kg -1 ) and randomised to propofol (P) or dexmedetomidine (D) group. A propofol bolus of 1 mg kg -1 followed by infusion of 4 mg kg -1 h -1 , or dexmedetomidine 1 µg kg -1 followed by 2 µg kg -1 h-1 infusion were used. Heart rate, SpO 2 and non-invasive blood pressure were monitored and recorded at 5 min intervals. Results were compared by means of standard statistical methods. RESULTS: Both dexmedetomidine and propofol after premedication with ketamine and midazolam are suitable for MRI sedation, although propofol use results in shorter recovery time. Less interventions are needed when dexmedetomidine is used.

Comparison of intranasal dexmedetomidine-midazolam, dexmedetomidine-ketamine, and midazolam-ketamine for premedication in paediatric patients: a double-blinded randomized trial.

BACKGROUND: Paediatric patients are a population with a high level of anxiety. The prevention of perioperative stress in a frightened child is important to render the child calm and cooperative for smoother induction. Intranasal premedication is easy and safe, and the drug is rapidly absorbed into the systemic circulation, ensuring early onset of sedation in children and good effectiveness. METHODS: 150 patients in the age group 2-4 years, ASA class I, undergoing elective surgical procedures were enrolled. The patients were randomly divided into 3 groups: a DM group (receiving intranasal dexmedetomidine 1 µg kg -1 and midazolam 0.12 mg kg -1 ), a DK group (receiving intranasal dexmedetomidine 1 µg kg -1 and keta-mine 2 mg kg -1 ), and an MK group (receiving intranasal midazolam 0.12 mg kg -1 and ketamine 2 mg kg -1 ). After 30 minutes of administration of the drugs, the patients were assessed for parent separation anxiety, sedation, ease of IV cannulation, and mask acceptance. RESULTS: The comparison among the 3 groups showed a statistically significant difference for ease of IV cannulation and mask acceptance at 30 minutes, with a P -value of 0.010 with CI of 0.0-0.02, and P -value 0.007 with CI 0.0-0.02, respectively. The parent separation anxiety and sedation score at 30 minutes was statistically insignificant with a P -value of 0.82 with CI of 0.03-0.14 and P -value 0.631 with CI of 0.38-0.58, respectively. CONCLUSIONS: The combination of midazolam and ketamine had a better clinical profile for premedication as compared to other combination drugs used in our study in terms of IV cannulation and acceptance of masks with a comparable decrease in separation anxiety from parents and adequate sedation.