Sustained Mood Improvement with Laughing Gas Exposure (SMILE): Study protocol for a randomized placebo-controlled pilot trial of nitrous oxide for treatment-resistant depression.

BACKGROUND: Nitrous oxide has shown potentially as an efficacious intervention for treatment-resistant depression, yet there remains insufficient evidence pertaining to repeated administration of nitrous oxide over time and active placebo-controlled studies with optimal blinding. Thus, we aim to examine the feasibility and preliminary efficacy of a six-week follow up study examining the effects of a 4 week course of weekly administered nitrous oxide as compared to the active placebo, midazolam. METHODS: In this randomized, active placebo-controlled, pilot trial, 40 participants with treatment-resistant depression will receive either inhaled nitrous oxide (1 hour at 50% concentration) plus intravenous saline (100mL) or inhaled oxygen (1 hour at 50% concentration) plus intravenous midazolam (0.02 mg/kg in 100mL, up to 2mg) once per week, for 4 consecutive weeks. Participants will be followed up for 6 weeks starting from the first treatment visit. Primary feasibility outcomes include recruitment rate, withdrawal rate, adherence, missing data, and adverse events. The primary exploratory clinical outcome is change in Montgomery-Åsberg Depression Rating Scale (MADRS) score at day 42 of the study. Other exploratory clinical outcomes include remission (defined as MADRS score <10), response (defined as ≥ 50% reduction in MADRS score), and adverse side effects. DISCUSSION: This pilot study will provide valuable information regarding the feasibility and preliminary efficacy of repeated nitrous oxide administration over time for treatment-resistant depression. If feasible, this study will inform the design of a future definitive trial of nitrous oxide as an efficacious and fast-acting treatment for treatment-resistant depression. TRIAL REGISTRATION: ClinicalTrials.gov NCT04957368. Registered on July 12, 2021.

Vascular effects of midazolam, flumazenil, and a novel imidazobenzodiazepine MP-III-058 on isolated rat aorta.

Hypotensive influences of benzodiazepines and other GABAA receptor ligands, recognized in clinical practice, seem to stem from the existence of "vascular" GABAA receptors in peripheral blood vessels, besides any mechanisms in the central and peripheral nervous systems. We aimed to further elucidate the vasodilatatory effects of ligands acting through GABAA receptors. Using immunohistochemistry, the rat aortic smooth muscle layer was found to express GABAA γ2 and α1-5 subunit proteins. To confirm the role of "vascular" GABAA receptors, we investigated the vascular effects of standard benzodiazepines, midazolam, and flumazenil, as well as the novel compound MP-III-058. Using two-electrode voltage clamp electrophysiology and radioligand binding assays, MP-III-058 was found to have modest binding but substantial functional selectivity for α5ß3γ2 over other αxß3γ2 GABAA receptors. Tissue bath assays revealed comparable vasodilatory effects of MP-III-058 and midazolam, both of which at 100 µmol/L concentrations had efficacy similar to prazosin. Flumazenil exhibited weak vasoactivity per se, but significantly prevented the relaxant effects of midazolam and MP-III-058. These studies indicate the existence of functional GABAA receptors in the rat aorta, where ligands exert vasodilatory effects by positive modulation of the benzodiazepine binding site, suggesting the potential for further quest for leads with optimized pharmacokinetic properties as prospective adjuvant vasodilators.

Evaluating Patient Tolerability for Urological Procedures Under Conscious Sedation: A Prospective Study.

OBJECTIVE: To prospectively evaluate patient-reported tolerability and surgical outcomes of urologic procedures with conscious sedation with or without local anesthesia. Administration of general or spinal anesthesia is associated with anesthetic-related complications, long wait times, and high costs. Using intravenous conscious sedation and/or local anesthesia is an emerging alternative for a myriad of urologic procedures. METHODS: Patients were enrolled from June-August 2021 at a tertiary care hospital. All procedures were completed using fentanyl, midazolam, or both with patient and procedural data recorded upon completion. Patients were telephoned 4-6 weeks post-procedure with a standardized patient tolerability questionnaire. A multivariable adjusted logistic regression analysis was performed to evaluate whether a patient would opt for conscious sedation again as opposed to general anesthesia. RESULTS: A total of 196 procedures were performed by 6 attending urologists with an overall success rate of 98.5% and 0% intraoperative complication rate. At 4-6 weeks follow-up, 85.6% of patients reported they would opt for conscious sedation as opposed to general anesthesia. Predictors of opting for conscious sedation in the future were older age (Odds Ratio (OR): 1.049; P = .017) and surgeon perceived level of patient tolerability (OR: 2.124; P <.001, scored 1-10). CONCLUSION: Physician directed, nursing administered IV conscious sedation is a viable alternative for various urologic procedures and has minimal risk of perioperative complications.

Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis.

Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.

A Comparative Analysis of Prehospital Emergency Treatments: Midazolam Intramuscularly, Diazepam Enema, and Chloral Hydrate Enema for Pediatric Convulsions.

Objective: This study aimed to compare the effectiveness of prehospital emergency treatments using midazolam (MDL) intramuscularly, diazepam (DZP) enema, and chloral hydrate (CH) enema in managing pediatric convulsions. Methods: A comparative observational study was conducted, and a total of 140 children with acute convulsions treated with prehospital anti-convulsions at Qinhuangdao First Hospital's emergency department between June 2015 and May 2019 were included in this study. The children were categorized based on the prehospital anti-convulsion measures received: group M (n = 48) received MDL intramuscularly, group D (n = 46) received DZP enema, and group C (n = 46) received CH enema. The emergency effects of the three treatment groups were compared. Results: 1. Group M showed significantly shorter treatment preparation time and total rescue time compared to groups C and D (both P < .05); no significant difference was observed between groups C and D (both P > .05), including convulsion control time in the effective cases (45 in group M, 42 in group C, and 43 in group D) (all P > .05 Group M had effective rates of 93.75%, while group C and group D had rates of 91.3% and 93.48%, respectively (all P > .05); Group M had more controlled cases at 1 min, 3 min, 5 min, and 10 min than group C and group D (all P > .05). Group M had significantly fewer relapses, cases requiring intravenous maintenance treatment, and faster convulsion control after intravenous maintenance compared to groups C and D (P < .05), with no significant differences between groups C and D in time to recovery of consciousness and length of hospitalization (P > .05). 4. Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), respiratory (R) frequency, and peripheral oxygen saturation (SpO2) showed no significant differences before and 10 minutes after medication in all three groups (P > .05); SBP and DBP levels fluctuated within the normal range, while HR decreased, R frequency decreased, and SpO2 increased significantly 10 minutes after medication compared to before treatment (P < .05). 5. No significant adverse effects were observed in the three patient groups. Conclusions: MDL intramuscular injection, DZP enema, and CH enema were effective prehospital treatments for pediatric acute convulsions. MDL intramuscular injection demonstrated advantages such as fast onset, reliable efficacy, ease of use, and high safety, making it more suitable for the prehospital treatment of pediatric convulsions.

The Exploration of Cannabis and Cannabinoid Therapies for Migraine.

PURPOSE OF REVIEW: There is increasing interest in the use of cannabis and cannabinoid therapies (CCT) by the general population and among people with headache disorders, which results in a need for healthcare professionals to be well versed with the efficacy and safety data. In this manuscript, we review cannabis and cannabinoid terminology, the endocannabinoid system and its role in the central nervous system (CNS), the data on efficacy, safety, tolerability, and potential pitfalls associated with use in people with migraine and headache disorders. We also propose possible mechanisms of action in headache disorders and debunk commonly held myths about its use. RECENT FINDINGS: Preliminary studies show that CCT have evidence for the management of migraine. While this evidence exists, further randomized, controlled studies are needed to better support its clinical use. CCT can be considered an integrative treatment added to mainstream medicine for people with migraine who are refractory to treatment and/or exhibit disability and/or interest in trying these therapies. Further studies are warranted to specify appropriate formulation, dosage, and indication(s). Although not included in guidelines or the AHS 2021 Consensus Statement on migraine therapies, with the legalization of CCT for medical or unrestricted use across the USA, recent systematic reviews highlighting the preliminary evidence for its use in migraine, it is vital for clinicians to be well versed in the efficacy, safety, and clinical considerations for their use. This review provides information which can help people with migraine and clinicians who care for them make mutual, well-informed decisions on the use of cannabis and cannabinoid therapies for migraine based on the existing data.

Comparative review of airway anesthesia and sedation methods for awake intubation.

PURPOSE OF REVIEW: Successful awake intubation hinges upon adequate airway anesthesia and sedation for patient comfort. This review will summarize relevant anatomy and regional anesthesia techniques to achieve airway anesthesia, and compare various airway anesthesia and sedation regimens. RECENT FINDINGS: Overall, nerve blocks consistently provided superior airway anesthesia, shorter time to intubation, higher patient comfort, and higher postintubation patient satisfaction. Additionally, ultrasound guidance can further provide benefit by reducing the amount of local anesthetic administered, leading to denser blockade, and proving invaluable in challenging clinical situations. Regarding sedation methods, numerous studies supported the use of dexmedetomidine, with or without the addition of supplemental sedation, such as midazolam, ketamine, or opioids. SUMMARY: Emerging evidence has indicated that nerve blocks for airway anesthesia may be superior to other methods of topicalization. Additionally, dexmedetomidine can be useful, both as monotherapy and with supplemental sedatives, to safely provide anxiolysis for the patient and increase success. However, it is crucial to note that the method of airway anesthesia and sedation regimen should be adapted to each patient and clinical situation, and knowledge of multiple techniques and sedation regimens can best equip anesthesiologists to do so.

Evaluation of Cytochrome P450-Mediated Cannabinoid-Drug Interactions in Healthy Adult Participants.

Understanding cannabis-drug interactions is critical given regulatory changes that have increased access to and use of cannabis. Cannabidiol (CBD) and Δ-9-tetrahydrocannabinol (Δ9-THC), the most abundant phytocannabinoids, are in vitro reversible and time-dependent (CBD only) inhibitors of several cytochrome P450 (CYP) enzymes. Cannabis extracts were used to evaluate quantitatively potential pharmacokinetic cannabinoid-drug interactions in 18 healthy adults. Participant received, in a randomized cross-over manner (separated by ≥ 1 week), a brownie containing (i) no cannabis extract (ethanol/placebo), (ii) CBD-dominant cannabis extract (640 mg CBD + 20 mg Δ9-THC), or (iii) Δ9-THC-dominant cannabis extract (20 mg Δ9-THC and no CBD). After 30 minutes, participants consumed a cytochrome P450 (CYP) drug cocktail consisting of caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A). Plasma and urine samples were collected (0-24 hours). The CBD + Δ9-THC brownie inhibited CYP2C19 > CYP2C9 > CYP3A > CYP1A2 (but not CYP2D6) activity, as evidenced by an increase in the geometric mean ratio of probe drug area under the plasma concentration-time curve (AUC) relative to placebo (AUCGMR ) of omeprazole, losartan, midazolam, and caffeine by 207%, 77%, 56%, and 39%, respectively. In contrast, the Δ9-THC brownie did not inhibit any of the CYPs. The CBD + Δ9-THC brownie increased Δ9-THC AUCGMR by 161%, consistent with CBD inhibiting CYP2C9-mediated oral Δ9-THC clearance. Except for caffeine, these interactions were well-predicted by our physiologically-based pharmacokinetic model (within 26% of observed interactions). Results can be used to help guide dose adjustment of drugs co-consumed with cannabis products and the dose of CBD in cannabis products to reduce interaction risk with Δ9-THC.

Ketamine versus midazolam as an adjuvant to peribulbar block using a single inferonasal injection in patients undergoing vitreoretinal surgery: A randomized controlled trial.

INTRODUCTION AND OBJECTIVES: This study aimed to assess the safety and efficacy of midazolam and ketamine as adjuvants to the peribulbar block in vitreoretinal surgeries. PATIENTS AND METHODS: This randomized controlled trial included 93 adult patients undergoing vitreoretinal surgeries performed with peribulbar anaesthesia. Patients were randomly allocated to 3 groups (31 participants each): control (standard anaesthetic mixture), midazolam (standard mixture + midazolam), and ketamine (standard mixture + ketamine). The primary outcomes were onset of globe akinesia and duration of analgesia. Secondary outcomes were duration of motor blockade, onset of corneal anaesthesia and lid akinesia, and changes in vital data (blood pressure, oxygen saturation, and pulse rate). RESULTS: The ketamine group vs. the control and midazolam groups showed the most rapid onset of lid and globe akinesia (p < 0.001) and corneal anaesthesia (0.7 ± 0.2 vs. 1.5 ± 0.5 and 1.2 ± 0.4, respectively; p < 0.001) and the longest duration of both analgesia (3.7 ± 0.6 vs. 2.3 ± 0.4 and 3.1 ± 0.6, respectively; p < 0.001) and akinesia (3.8 ± 0.5 vs. 3.0 ± 0.4, and 3.7 ± 0.5, respectively; p < 0.001). The midazolam group showed better outcomes than controls, but the drug was less effective than ketamine. There were no significant differences in vital data among groups (p > 0.05). CONCLUSIONS: Ketamine is an effective adjuvant for peribulbar blockade. It enhances both motor and sensory blockade by hastening onset and prolonging duration. These effects are desirable in lengthier ophthalmic procedures such as vitreoretinal surgeries. The effects of ketamine were superior to those of midazolam.

Treatment of cholinergic-induced status epilepticus with polytherapy targeting GABA and glutamate receptors.

Despite new antiseizure medications, the development of cholinergic-induced refractory status epilepticus (RSE) continues to be a therapeutic challenge as pharmacoresistance to benzodiazepines and other antiseizure medications quickly develops. Studies conducted by Epilepsia. 2005;46:142 demonstrated that the initiation and maintenance of cholinergic-induced RSE are associated with trafficking and inactivation of gamma-aminobutyric acid A receptors (GABAA R) thought to contribute to the development of benzodiazepine pharmacoresistance. In addition, Dr. Wasterlain's laboratory reported that increased N-methyl-d-aspartate receptors (NMDAR) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) contribute to enhanced glutamatergic excitation (Neurobiol Dis. 2013;54:225; Epilepsia. 2013;54:78). Thus, Dr. Wasterlain postulated that targeting both maladaptive responses of reduced inhibition and increased excitation that is associated with cholinergic-induced RSE should improve therapeutic outcome. We currently review studies in several animal models of cholinergic-induced RSE that demonstrate that benzodiazepine monotherapy has reduced efficacy when treatment is delayed and that polytherapy with drugs that include a benzodiazepine (eg midazolam and diazepam) to counter loss of inhibition, concurrent with an NMDA antagonist (eg ketamine) to reduce excitation provide improved efficacy. Improved efficacy with polytherapy against cholinergic-induced seizure is demonstrated by reduction in (1) seizure severity, (2) epileptogenesis, and (3) neurodegeneration compared with monotherapy. Animal models reviewed include pilocarpine-induced seizure in rats, organophosphorus nerve agent (OPNA)-induced seizure in rats, and OPNA-induced seizure in two mouse models: (1) carboxylesterase knockout (Es1-/- ) mice which, similarly to humans, lack plasma carboxylesterase and (2) human acetylcholinesterase knock-in carboxylesterase knockout (KIKO) mice. We also review studies showing that supplementing midazolam and ketamine with a third antiseizure medication (valproate or phenobarbital) that targets a nonbenzodiazepine site rapidly terminates RSE and provides further protection against cholinergic-induced SE. Finally, we review studies on the benefits of simultaneous compared with sequential drug treatments and the clinical implications that lead us to predict improved efficacy of early combination drug therapies. The data generated from seminal rodent studies of efficacious treatment of cholinergic-induced RSE conducted under Dr. Wasterlain's guidance suggest that future clinical trials should treat the inadequate inhibition and temper the excess excitation that characterize RSE and that early combination therapies may provide improved outcome over benzodiazepine monotherapy.

The effect of lavender aromatherapy on the level of intraoperative anxiety in caesarean case under spinal anesthesia: A randomized controlled trial.

BACKGROUND: Preoperative anxiety can be reduced by aromatherapy. This study aimed to evaluate the effect of lavender aromatherapy in reducing intraoperative anxiety in patients undergoing caesarean section (CS) under spinal anesthesia. METHODS: This study was two-armed and randomized controlled trial. A total of 96 patients who were scheduled for CS were randomly divided into two groups: the aromatherapy (A) group (n=48), comprising patients who were randomized to receive lavender aromatherapy with mask oxygen after the birth of the baby, and the control (C) group (n=48), comprising patients who inhaled carrier oil. During the preoperative period, baseline anxiety levels and Visual Analog Scale (VAS) pain scores were recorded using the State-Trait Anxiety Inventory (STAI-I) scale. After birth, two drops of oil were inhaled in an oxygen mask for 5 min. After 5 min, the Ramsey Sedation Scale was evaluated, and patients with a score of 1 received 2 mg of intravenous midazolam for sedation. The STAI-I and VAS pain scores were re-evaluated at the third postoperative hour. RESULTS: The primary outcome was the significant reduction in the need for midazolam brought about by lavender aromatherapy, and the secondary outcomes included postoperative third-hour STAI-I scores, intraoperative complications and patient satisfaction. CONCLUSION: The effectiveness of lavender aromatherapy, which reduced the need for intraoperative anxiolytics, can be offered as an alternative for pregnant women who undergo CS under spinal anesthesia.

Breast augmentation under local anesthesia with intercostal blocks and light sedation.

INTRODUCTION: This study of breast augmentations performed under local anesthesia with intercostal blocks and light sedation describes the outcomes and evaluates benefits and complications. METHOD: From December 2005 until August 2019, 335 women consecutively underwent bilateral breast augmentation procedures. The anesthetic protocol consisted of an initial intravenous bolus of 1 mg midazolam and 0.25 mg alfentanil preoperatively. In 2017, this was changed to 2-4 mg midazolam intramuscularly, 1 mg midazolam intravenously, and 2.5 µg sufentanil intravenously. Intercostal blocks were injected at the midaxillary line into the intercostal spaces two to seven. The operating field was infiltrated with tumescent local anesthesia. Retrospective data extraction from patients' medical charts was done, registering demographics, dosage of anesthesia, surgical characteristics, complications, and reoperation rates. RESULTS: Two hundred and eighty-one women underwent primary augmentation and 54 had implant replacement. The most common complications included suboptimal cosmetic results, asymmetry, and healing-related problems. The overall rate of reoperation was 16.1% within an average follow-up period of 2 years, ranging from 0 to 12.5 years. The majority of the reoperations were due to cosmetic reasons. The change in anesthetic regime was associated with a significantly (p < 0.0001) decreased need for supplementary medication with no increased risk of complications. CONCLUSION: Breast augmentations in local anesthesia with intercostal blocks and light sedation can be performed safely and can serve as an alternative to procedures in general anesthesia.

Physical compatibility of remimazolam with opioid analgesics, sedatives, and muscle relaxants during simulated Y-site administration.

PURPOSE: There is a lack of information on the compatibility of remimazolam with opioid analgesics, muscle relaxants, and other sedatives. This study aimed to evaluate the physical compatibility of remimazolam with these drug classes. METHODS: Remimazolam was combined with 1 or 2 target drugs (remifentanil, fentanyl, rocuronium, vecuronium, dexmedetomidine, and midazolam). Ten physical compatibility tests were conducted, including four 3-drug compatibility tests. Remimazolam was dissolved in 0.9% sodium chloride injection to a final concentration of 5 mg/mL. Other medications were diluted in 0.9% sodium chloride injection to obtain clinically relevant concentrations. Compatibility tests were conducted with 3 test solutions, wherein remimazolam and the target drugs were compounded at equal volume ratios (1:1 or 1:1:1). Visual appearance was assessed and testing of Tyndall effect, turbidity, and pH was performed immediately after mixing and then again 1 hour and 4 hours after mixing. Appearance and turbidity were evaluated by comparison with the control solution of each target drug diluted with 0.9% sodium chloride injection to the same concentration as the test solution. RESULTS: All drugs tested were determined to be compatible with remimazolam. The drug combination with the highest change of turbidity was remimazolam and vecuronium (a mean increase of 0.16 NTU relative to the remimazolam control solution), 4 hours after mixing. The combination with the highest pH was remimazolam, fentanyl, and vecuronium (mean [SD], 3.76 [0.01]), 4 hours after mixing. The combination of remimazolam and fentanyl showed a larger change in pH at 4 hours after mixing (a mean increase of 2.6%) than immediately after mixing. CONCLUSION: Remifentanil, fentanyl, rocuronium, vecuronium, dexmedetomidine, and midazolam are physically compatible with remimazolam during simulated Y-site administration.

Sedative Effect of Ketamin-Midazolam Administered at Acupoint GV20 Compared to Intramuscular Route in Blue-Fronted Amazon (Amazona aestiva): a Pilot Study.

Background: The growth of exotic pet medicine is leading to fast developments in clinical investigations on birds. Acupuncture, specifically pharmacopuncture, offers safe chemical restraint options. Objectives: To investigate pharmacopuncture at acupoint GV20 in blue-fronted Amazon parrots (Amazona aestiva) using ketamine and midazolam. Methods: Sixteen healthy birds were distributed into four groups (C: intramuscular control; 1/2 C: 1/2 dose intramuscular control; 1/2 GV20: 1/2 dose at acupoint GV20; 1/5 GV20: 1/5 dose at acupoint GV20). Degree of sedation, latency, recuperation time, heart and respiratory rate, and body temperature were measured. Quantitative data were analyzed by a Student's t-test. Results: The C, 1/2 C, and 1/2 GV20 groups showed the same degree of sedation. The 1/2 GV20 group showed longer latency times (6 ± 2.1) than the 1/2 C (2.5 ± 0.5) group. Sedation time did not differ between the C (28 ± 9.8), 1/2 C (30.5 ± 8.6), and 1/2 GV20 (41 ± 22.24) groups. The 1/2 GV20 group recuperated faster (13.7 ± 3.7) than the C group (64.2 ± 3.5). The C and 1/2 C groups showed tremors and slow and unstable recovery. Two animals in the C group showed mild hypothermia (38°C). Conclusion: The use of 1/2 GV20 was effective and safe to sedate blue-fronted Amazon parrots without side effects, providing easy, stable, and fast recovery. The use of 1/5 GV20 had a shorter sedation time. These findings show that the combination of acupuncture and drugs provides new possibilities for efficient anesthetic protocols with fewer side effects in birds.

Comparison of the effects of cranial electrotherapy stimulation and midazolam as preoperative treatment in geriatric patients: A CONSORT-compliant randomized controlled trial.

BACKGROUND: Although midazolam is widely administered as an anxiolytic premedication, it may cause over-sedation and hypoxia in geriatric patients. Cranial electrotherapy stimulation (CES) is a nonpharmacological device with anxiolytic effect. This study compared the effects of CES and midazolam as a preoperative treatment in geriatric patients. METHODS: Eighty patients, under the age of 65 to 79 years, undergoing general anesthesia were randomly assigned into midazolam premedication group (M group, n = 40) or CES pretreatment group (CES group, n = 40). The patients in the M group were intramuscularly injected with midazolam (0.07 mg/kg) 30 minutes before receiving general anesthesia. The patients in the CES group received 20 minutes of CES pretreatment on the day before and on the morning of the surgery. RESULTS: In the preoperative holding area, the anxiety score (P = .02) and the sedation score (P < .001) were significantly lower in the CES group compared with those in the M group. The oxygen saturations at the preoperative holding area and the operating room were significantly higher in the CES group than those in the M group (P < .001). CONCLUSION: CES pretreatment relieved preoperative anxiety with less risk of over-sedation and respiratory depression than midazolam premedication in geriatric patients.

Molecular dynamics simulation and in vitro evaluation of herb-drug interactions involving dietary polyphenols and CDK inhibitors in breast cancer chemotherapy.

Dietary polyphenols such as quercetin and curcumin have been extensively administered to patients with cancer in the form of herbal supplements. They may have a synergistic anticancer effect; however, a risk of pharmacokinetic interactions with selective CDK-4/6 inhibitors that are metabolized by the CYP3A4 enzyme exists. Considering these pharmacokinetic aspects, the current study examined the effects of curcumin and quercetin on human CYP3A4 to ascertain CYP3A4-mediated herb-drug interactions with CDK inhibitors. In this study, using in silico methods and CYP3A4 inhibition kinetics in human liver microsomes and recombinant CYP3A4 enzymes, the effects of concentration-dependent inhibition of CYP3A4 by quercetin and curcumin on CDK inhibitors metabolism were examined. Based on our in-silico docking findings, curcumin and quercetin were considerably bound to CYP3A4 protein and displace CDK inhibitors from the CYP3A4 substrate binding domain. The IC50 values of curcumin and quercetin were 16.10 and 0.05 µM, respectively, for CYP3A4-mediated 1'-hydroxylation of midazolam. The dietary polyphenols prolonged the in vitro half-life of palbociclib and ribociclib by 6.4-fold and decreased their intrinsic microsomal clearance by approximately 4.6 times. Our findings indicate that curcumin and quercetin effectively cause herb-drug interactions and should be cautiously used to avoid therapeutic failure.

Safety of Dexmedetomidine as an Alternative Pediatric Magnetic Resonance Imaging (MRI) Sedative: A Retrospective Single-Center Study.

BACKGROUND Dexmedetomidine provides anxiolysis, sedation, dose-dependent hypnosis, and mild analgesia with minimal respiratory function effects. The aim of this study was to assess the efficacy and safety of dexmedetomidine for pediatric patients during MRI. MATERIAL AND METHODS We retrospectively analyzed 87 cases of pediatric sedations for MRI. Dexmedetomidine and a single dose of midazolam were used in all the cases, according to the in-house pediatric sedation protocol for MRI. The patients were divided in to 2 groups: group 1, who reached adequate sedation up to 10 min of induction and group 2, who achieved proper sedation after 10 min. RESULTS The median age was 3 years (0-17). The median duration of procedure was 75 min (40-150). The induction of standardized sedation was performed without additional sedatives and proper depth of sedation was reached in the majority of cases (94.3%). Five patients (5.7%) received additional sedative after 10 min of induction. The median time of adequate sedation was 8 min (3-13) after induction, and 51% of patients achieved RASS-4 in 8 min. There was no significant difference between groups 1 and 2. Ten patients (11.5%) experienced bradycardia, regardless of the usage of additional drugs, dexmedetomidine boluses, duration of the procedure, or induction time. CONCLUSIONS High-dose dexmedetomidine with a single dose of midazolam might be an effective combination at the induction stage for pediatric sedation for MRI, with very few adverse events. Over 50% of enrolled patients achieved an adequate level of sedation before 10 min. We conclude that induction of dexmedetomidine infusion can be shortened up to 8 min.

Effect of music intervention in colonoscopy-naïve adults: a randomised controlled trial.

BACKGROUND: Previous studies have evaluated music interventions before and during a colonoscopy, but the results are contradictory and inconclusive. AIMS: The aims of the present study were to evaluate the effect of a music intervention with MusiCure music, both before and during colonoscopy. METHODS: The study was a two-armed, prospective, randomised, controlled trial and 337 patients undergoing colonoscopy were included. Patients were allocated to receive relaxing music (MusiCure) before and during the colonoscopy or standard care (no music). Outcome measures included pain intensity, duration of the colonoscopy, consumption of alfentanil and midazolam, vital signs, patient satisfaction and caecal intubation rates (CIR). FINDINGS: Men in the music group had a lower middle arterial blood pressure compared with men in the no music group. The majority of patients in the music group would prefer to listen to music if they need a colonoscopy in the future. No differences were found between groups regarding pain intensity, duration of the colonoscopy, consumption of alfentanil and midazolam, vital signs, patient satisfaction and CIR. CONCLUSION: The researchers were unable to show an effect on the primary endpoints. However, a high patient satisfaction was found in the music group and a decrease in the blood pressure during the colonoscopy, indicating a reduced stress level. Music before and during a colonoscopy may improve the patient experience.

The Impact of Suboptimal 25-Hydroxyvitamin D Levels and Cholecalciferol Replacement on the Pharmacokinetics of Oral Midazolam in Control Subjects and Patients With Chronic Kidney Disease.

The aim of this study was to investigate the impact of suboptimal 25-hydroxyvitamin D (25-VitD) and cholecalciferol (VitD3 ) supplementation on the pharmacokinetics of oral midazolam (MDZ) in control subjects and subjects with chronic kidney disease (CKD). Subjects with CKD (n = 14) and controls (n = 5) with suboptimal 25-VitD levels (<30 ng/mL) were enrolled in a 2-phase study. In phase 1 (suboptimal), subjects were administered a single oral dose of VitD3 (5000 IU) and MDZ (2 mg). In phase 2 (replete) subjects who achieved 25-VitD repletion after receiving up to 16 weeks of daily cholecalciferol were given the identical single oral doses of VitD3 and MDZ as in phase 1. Concentrations of MDZ and metabolites, 1'-hydroxymidazolam (1'-OHMDZ), and 1'-OHMDZ glucuronide (1'-OHMDZ-G) were measured by liquid chromatography-tandem mass spectrometry and pharmacokinetic analysis was performed. Under suboptimal 25-VitD, reductions in MDZ clearance and renal clearance of 47% and 87%, respectively, and a 72% reduction in renal clearance of 1'-OHMDZ-G were observed in CKD vs controls. In phase 1 versus phase 2, MDZ clearance increased in all control subjects, with a median (interquartile range) increase of 10.5 (0.62-16.7) L/h. No changes in MDZ pharmacokinetics were observed in subjects with CKD between phases 1 and 2. The effects of 25-VitD repletion on MDZ disposition was largely observed in subjects without kidney disease. Impaired MDZ metabolism and/or excretion alterations due to CKD in a suboptimal 25-VitD state may not be reversed by cholecalciferol therapy. Suboptimal 25-VitD may augment the reductions in MDZ and 1'-OHMDZ-G clearance values observed in patients with CKD.

Midazolam premedication in ileocolic intussusception: a retrospective multicenter study.

Ileocolic intussusception is a common cause of bowel obstruction. When spontaneous reduction does not occur, non-operative management through enema reduction is necessary. Despite the evidence indicating that sedatives favor success in the reduction, their use is still not a common practice. To determine if midazolam (MDZ) before enema improves the rate of procedure success, we retrospectively reviewed charts of patients admitted to two Italian pediatric emergency departments. Outcome measures were the success rate of the enema, recurrence, and need for surgery. Patients were grouped according to the use of MDZ or not, before hydrostatic reduction attempt. We included 69 and 37 patients in the MDZ and non-MDZ groups, respectively. The two groups did not differ in demographics, clinical characteristics, and ultrasound findings. Intussusception reduction after the first enema attempt occurred in 75% (MDZ group) and 32.4% (non-MDZ group) of patients (P < .001); 27.9% (MDZ group) and 77.8% (non-MDZ group) of patients underwent surgery (P < .001). Among them, spontaneous reduction of intussusception during the induction of general anesthesia occurred in 31.6% and 42.9% of patients, respectively (P .43). Multivariate logistic regression analysis showed that only MDZ had a positive effect on the result of the enema (OR 7.602, 95%CI 2.669-21.652, P < .001). CONCLUSION: Procedural sedation with MDZ for enema reduction of intussusception can increase the success rate and lead to a better management of patients. WHAT IS KNOWN: • Despite the evidence of the usefulness of sedatives in the reduction of intussusception, their use is still not a common practice. WHAT IS NEW: • Midazolam during enema reduction of intussusception can increase the success rate and consequently lead to better management of patients.