Oral Administration Of Midazolam Research Articles

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

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. 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. 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. 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. This trial (NCT05480488) was registered on 29 July, 2022.

Preoperative Midazolam and Patient-Centered Outcomes of Older Patients

The effect of oral midazolam premedication on patient satisfaction in older patients undergoing surgery is unclear, despite its widespread use. To determine the differences in global perioperative satisfaction in patients with preoperative administration of oral midazolam compared with placebo. 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. Patients were randomized to receive oral midazolam, 3.75 mg (n = 309), or placebo (n = 307) 30 to 45 minutes prior to anesthesia induction. 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. 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. 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. ClinicalTrials.gov Identifier: NCT03052660.

The Effect of Computer Tablets on the Need for Medical Anxiolysis in Children in an Ambulatory Surgical Center.

Background Preoperative anxiety is common in children undergoing surgery. When anxiety is identified or suspected, there are several strategies typically used to manage it. Perhaps the most common is anxiolytic premedication or parental presence at induction. Medications such as midazolam have been associated with adverse effects, such as a slower wakeup, and require timing of administration, while parental presence can be disturbing to the parent and divert the attention of the operating room team. A more recent option is distraction via electronic tablets. The purpose of this study was to retrospectively investigate and quantify any change in the use of midazolam, the most common anxiolytic approach at our institution, and any change in the length of time in the post-anesthesia care unit (PACU) following the introduction of tablet computers to a pediatric ambulatory surgical center. Methods We conducted an IRB-approved retrospective chart review of 13,790 pediatric patients ages one to 18 undergoing outpatient elective surgeries at the University of Florida (UF) Children's Surgical Center over a five-year period. A univariate analysis was conducted using the Fisher's Exact test and interrupted time series analysis to determine differences between midazolam administration and PACU times, with interruption occurring at tablet implementation. A multivariable analysis and sensitivity analyses were performed to confirm the findings of the univariate analysis. Results On univariate analysis, tablet availability was associated with both a decreased preoperative oral midazolam administration (odds ratio (OR) 0.158, 95% confidence interval (CI): 0.140 to 0.179, P-value <0.001) and a decreased PACU length of stay (-17.4 min, 95% CI: -19.6 to -15.3 min, P-value <0.001). The association with decreased preoperative midazolam administration held after multivariable analysis (adjusted OR 0.207, 95% CI: 0.154 to 0.278, P-value <0.001), but PACU length of stay was not statistically significant (-9.1 min, 95% CI: -20.6 to 2.4, P-value = 0.12). These results were confirmed on sensitivity analysis, with tablet availability continuing to be associated with decreased preoperative oral midazolam administration but not with reduced PACU length of stay. Conclusion Our results demonstrate that computer tablets were associated with a significant decrease in the frequency of midazolam administration and consequently may reduce preoperative pediatric anxiety.We did not find an associated change in PACU length of stay following the introduction of tablets. Tablets present a unique distraction alternative to chemical anxiolysis for institutions seeking to reduce medication use in pediatric patients.

Randomized Controlled Clinical Trial to Examine the Efficacy of Oral Midazolam in Post Operative Pain Reduction in Patients Undergoing Laparoscopic Cholecystectomy

Background: Stressful conditions like surgery and anesthesia trigger neuroendocrine pathway activation, which can have dangerous hemodynamic effects on the patient. One method for minimizing these hemodynamic consequences is maintaining an optimum level of anesthesia. Another option is giving patients a pharmaceutical formulation that modifies how anesthetic agents react. Objective: The current study sought to determine if preoperative oral midazolam could reduce postoperative pain scores and the occurrence of Rescue Analgesia in patients undergoing laparoscopic cholecystectomy. Methods: This is a single-blinded randomized controlled study conducted at the Surgery department of Jinnah Medical College Hospital, Korangi Karachi, on patients undergoing laparoscopic cholecystectomy. Through simple random sampling, participants were divided into two study groups, control (n=32) and 7.5mg receiving preoperative oral midazolam-intervention group. After surgery, the VAS pain score in both group participants was measured at 2, 8, 12, and 24 hours. The frequency of rescue analgesia and duration of hospital stay was also observed. Standard deviation, mean, chi-square test, and T-test was performed to determine the variation in both groups by using SPSS version 26. The P value ≤0.005 was measured significant. Results: No significant difference in the postoperative pain score after oral administration of midazolam in the intervention group compared to the control group at 2, 12, and 24 hrs intervals. Except at 8-hour intervals, a significant change of 0.004 was observed in both study groups. A significant variation of 0.008 was observed in the duration of hospital stay in the intervention group when compared with the control group. Lastly, in the present study, no significant difference in the frequency of rescue analgesics was observed in both study groups. Practical implication: This study will help out to determine the right dosage of oral midazolam which might effectively be used in managing post-operative pain in laparoscopic cholecystectomy patients. Conclusion: Orally administeredmidazolam was not efficient in lowering the pain score in patients undergoing laparoscopic cholecystectomy. Keywords: Midazolam, Post-operative pain, Laparoscopic cholecystectomy, Local anesthetics

Effects of Chronic Oral Administration of Midazolam on Memory and Circadian Rhythms in Rats.

Studies have shown the ability of benzodiazepine drugs to cause memory loss in animals and humans. Midazolam is a benzodiazepine commonly administered intravenously during surgical procedures because it reacts rapidly, causes anterograde amnesia, and has few side effects. It has also been used in palliative medicine where, among others, an oral route has been employed for chronic administration of the drug. The current study evaluated the effects of chronic orally administered midazolam on spatial working memory and procedural memory in control and experimental female rats over a three-week experimental period utilizing the Morris water maze. Sample and test run times to a submerged platform in the maze were recorded daily. In addition, activity wheels attached to each cage were employed to monitor daily circadian activity of the animals. Spatial working memory was not impaired in either group. However, procedural memory amnesia occurred in animals receiving the drug indicative of a consolidation or retrieval problem. Concerning circadian rhythms, a phase-shift was noted in experimental animals possibly indicating that time of day of drug administration is important. The findings of the present study could shed insight into altered reactions observed in humans who have received midazolam as a component of treatment in palliative medicine.

The Efficacy and Complications of Deep Sedation in Pediatric Dental Patients: A Retrospective Cohort Study.

Background Dental anxiety in children is a common problem. Currently, many of dental procedures are performed under sedation. Different methods of sedation have been employed for this purpose. Compared to adults, children usually need a deeper sedation level. The aim of this retrospective study is to assess the efficacy and complication of deep sedation in pediatric dental patients. Method This study was performed on 250 ASA (American Society of Anesthesiologists) I, II children undergoing deep sedation during the dental procedures. After the administration of oral midazolam as premedication, the monitoring process started. The patients that received the sedation dose of propofol and oxygen through nasal cannula during the procedure were carefully monitored for the purpose of evaluating hemodynamic and respiratory complications. The mean procedure and recovery time, postoperative nausea and vomiting (PONV), and success rate were further studied. Result The average age of the patients was 3.7. 32% of the patients were females, and 68% of them were males. Laryngospasm that occurred in 5 cases was resolved immediately by using positive pressure ventilation. Mild hypoxia was observed in 17 cases which were immediately managed by a bag-valve-mask ventilation. No cases of hemodynamic complications and PONV were reported. The mean length of the procedure was 57 minutes, and the mean length of recovery was 16 minutes. The success rate of this method was estimated to be 99.6%. Conclusion Deep sedation with propofol is a suitable technique with a high success rate for dental procedures in children. It was also concluded that in pediatric dental procedures, the presence of a skilled anesthetist and the implementation of a close monitoring process are required.

A comparison of midazolam, dexmedetomidine 2µg/kg and dexmedetomidine 4µg/kg as oral premedication in children, a randomized double-blinded clinical triall

Background: The objective of this study was to analyze an oral administration of midazolam with two different doses of dexmedetomidine for premedication in paediatric patients. Methods: A prospective, randomized, double blind study. Three hundred patients, aged 1-7 years, undergoing elective surgery under general anesthesia were recruited for the study. Patients were randomized into three groups to receive oral midazolam 0.5mg/kg (group M), oral dexmedetomidine 2 µg/kg (group D2) and oral dexmedetomidine 4 µg/kg (group D4) for premedication. An observer blinded to the patient group allocation assessed level of sedation at 30 minutes after giving the premedication, ease of parental separation was assessed while shifting the patients to the operating room, mask acceptance during induction and postoperative agitation scores in post anesthesia care unit. Results: The sedation score of group D4 was significantly higher than group D2 and group M [ group D4- 4 (4,3), group D2- 2(2,2) and group M -2(3,2), H statistics = 80.4718, p &lt; 0.00001]. The parental separation score, mask acceptance score and postoperative was also significantly better for group D4 compared to the other two group. Conclusion: These results suggest that oral dexmedetomidine 4 µg/kg is more effective than oral midazolam 0.5mg/kg and oral dexmedetomidine 2 µg/kg for premedication in children.

Predictable sedation: Safe administration of oral Midazolam and nitrous oxide gas for paediatric patients in the general dental practice

Behaviour management for anxious paediatric dental patients is challenging. Solutions include education and sedation. Various drugs have been used to effectively sedate paediatric patients during treatment. The aim of this study was to review literature on the sedation of paediatric patients. The study specifically looked at those reviews covering the combination of two sedation methods in case of more challenging paediatric patients. The study undertook a literature review focused on studies using nitrous oxide, Midazolam, or a combination of the two substances. An electronic search was done on EBSCOhost to source articles published from 1979 to 2019. A deeper form of sedation can be achieved for paediatric patients when using a combination of nitrous oxide, oxygen and a hypnotic agent such as Midazolam. Dealing with the anxiety levels of paediatric patients is a challenge for dental health providers. Two of the main strategies used to deal with anxious children are behaviour management and sedation. A critical review of journal articles on the use of nitrous oxide and oxygen in combination with Midazolam was therefore undertaken. The findings suggest that, in order to achieve a deeper form of sedation, the combination of nitrous oxide, oxygen and Midazolam works well to reduce discomfort, anxiety and/or pain in paediatric patients.

Sedative effect of midazolam in different vehicles for oral administration.

Oral administration of midazolam is one of the most important protocols for producing adequate conscious sedation; however, it has an unpleasant taste and is poorly tolerated by pediatric patients. The aim of this study was to evaluate the sedative effect of diluted midazolam in different vehicles used to mask its unpleasant taste. A total of 30 male mice (BALB-c) were randomly distributed in five groups. They were administered diluted midazolam in different vehicles (saline solution, paracetamol syrup, diclofenac suspension, multi-vitamin syrup, and boxed juice). All suspensions were administered orally (0.6 mg/Kg). The pH variation was evaluated with a digital pH meter, and the quality of sedation was evaluated in three tests: hole board test, grip strength test, and forced swimming test. The paracetamol syrup vehicle was found to be the only vehicle which did not change its pH over time after dilution of midazolam. When evaluating the perforated platform, the greatest sedative effect was observed in the midazolam group with the paracetamol syrup (P > 0.05). Regarding grip strength, a difference was evident in all study groups at 45 minutes (P = 0.006); the midazolam group with the multi-vitamin syrup was less effective. Regarding the response time to forced swimming, the midazolam group with the paracetamol syrup presented the longest time at 15 and 30 minutes (5.39 ± 0.93 and 6.29 ± 0.83, respectively). The suspension of midazolam diluted in the paracetamol syrup is the most suitable for performing conscious sedation efficiently.

Safety of Oral Midazolam as a Perioperative Anxiolytic for Outpatient Dermatologic Procedures.

Perioperative anxiety can negatively impact patient satisfaction and can complicate outpatient dermatologic procedures. Evaluate adverse events associated with oral midazolam as a perioperative anxiolytic during dermatologic surgery and assess whether an enhanced monitoring approach is associated with an increased detection rate. Five hundred cases (250 before and after change in monitoring) where patients were administered oral midazolam between July 2015 and May 2017 were retrospectively reviewed. The number of procedures, type of procedures, dose in milligrams, number of doses, major and minor adverse events, and vital signs were recorded. The difference in number of treatment sites, types of procedures, and total dose administered was not significant. There were minor but significant differences in the mean change in blood pressure, heart rate, respiratory rate, and Richmond Agitation and Sedation Scale score before and after the procedure but not oxygen saturation. These vital sign changes were not clinically significant. There were zero major adverse events in both groups. There were 2 patients who became transiently hypoxic. Oral midazolam administration was not associated with major adverse events including in the more intensively monitored group. This supports its use as an anxiolytic for outpatient dermatologic procedures.

Efficacy of oral midazolam for minimal and moderate sedation in pediatric patients: A systematic review.

One of the most widely used options for minimal/moderate sedation in pediatric patients is oral midazolam, as it presents an alternative to less well‐accepted routes of administration (eg, intravenous or intranasal) of this well‐known efficacious and well‐tolerated short‐acting benzodiazepine. A systematic review of the literature was conducted in order to identify clinical studies evaluating the effectiveness of oral midazolam for sedation in pediatric patients in the context of premedication before anesthesia or during diagnostic/treatment procedures. The percentage of responders (response rate) after single administration of oral midazolam was evaluated and compared versus placebo in a subset of placebo‐controlled studies. The range of oral midazolam doses providing effective sedation in the different pediatric age subsets was analyzed in order to assess optimum dosing strategies. A total of 25 pediatric clinical studies, utilizing a variety of measures of sedation effectiveness, were selected. These studies included a total of 1472 patients (aged 4 months‐18 years) treated with midazolam (0.25‐1.5 mg/kg) and 138 patients treated with placebo. The response rates [95% confidence interval] with oral midazolam ranged from 36.7% [21.6%, 54.9%] to 97.8% [86.1%, 99.7%], while with placebo response rates ranged from 4.0% [0.6%, 23.5%] to 41.0% [29.4%, 53.6%]. When considering the 4 placebo‐controlled studies, the odds ratios [95% confidence interval] for the comparison of midazolam vs. placebo ranged from 13.4 [5.0, 36.0] to 25.9 [6.7, 100.6]. The analysis of subgroups by context of sedation showed response rates [95% confidence interval] with oral midazolam ranging from 36.7% [21.6%, 54.9%] to 97.0% [94.8%, 98.3%] for anesthetic premedication and from 56.1% [43.1%, 68.4] to 97.8% [86.1%, 99.7%] for medical procedures. The efficacy of midazolam for pediatric minimal/moderate sedation from a dose of 0.25 mg/kg and above was demonstrated. The probability of occurrence of adverse events and over‐sedation increases with increasing doses.

Evaluation of the effect of pre-operative oral midazolam on post-operative oral fluid intake after tonsillectomy

IntroductionThe objective of this study was to determine if pre-operative oral midazolam administration decreased postoperative oral fluid intake after tonsillectomy with or without adenoidectomy. MethodsA retrospective chart review identified 104 patients who were undergoing tonsillectomy with and without adenoidectomy who were not given midazolam preoperatively and 182 who were given midazolam preoperatively. Indications for tonsillectomy with or without adenoidectomy included obstructive sleep apnea, recurrent acute streptococcal pharyngotonsillitis, and, in selected cases, periodic fever with aphthous stomatitis, pharyngitis and adenopathy. All patients were evaluated in the pre-operative area by the attending anesthesiologist, who then determined whether or not he/she felt the patient would benefit from premedication with oral midazolam prior to surgery. Patients whom the attending anesthesiologist judged would benefit from midazolam were then given a 0.12–1.06 mg/kg dose (mean 0.35 mg/kg, STD 0.12), at the discretion of the anesthesiologist. Various methods were used to perform tonsillectomy, such as coblation and electrocautery, at the discretion of the otolaryngologist. Results were not stratified by surgical technique. Oral fluid intake was calculated by establishing the time of return to the floor from surgery and determining the documented oral fluid intake for the next 12 h. Oral fluid intake per kg per hour was then calculated. The amount of midazolam given was documented. ResultsThere was no significant difference in oral fluid intake by group when adjusting for age and weight, F(1, 282) = 0.383, p = 0.537. Also, there was no significant difference in ml/kg/hr by group when adjusting for age and weight, F(1, 282) = 2.813, p = 0.095. ConclusionsThere was no significant difference in oral fluid intake between the no midazolam and midazolam groups, indicating that clinicians can continue to use their judgement in administering midazolam to select anxious patients prior to tonsillectomy with or without adenoidectomy. Future work could include multi-center retrospective reviews or a randomized placebo-controlled trial to examine more carefully the effects of midazolam on postoperative oral fluid intake. Level of evidenceLevel IV.

Analysis of the effect of oral midazolam and triazolam premedication before general anesthesia in patients with disabilities with difficulty in cooperation.

BackgroundWhen performing dental treatment under general anesthesia in adult patients who have difficulty cooperating due to intellectual disabilities, anesthesia induction may be difficult as well. In particular, patients who refuse to come into the dental office or sit in the dental chair may have to be forced to do so. However, for adult patients with a large physique, physical restraint may be difficult, while oral sedatives as premedication may be helpful. Here, a retrospective analysis was performed to investigate the effect of oral sedatives.MethodsA hospital-based medical information database was searched for patients who were prescribed oral midazolam or triazolam between January 2009 and December 2017. Pre-anesthesia evaluation, anesthesia, and anesthesia recovery records of all patients were analyzed, and information on disability type, reason for prescribing oral sedatives, prescribed medication and dose, cooperation level during anesthesia induction, anesthesia duration, length of recovery room stay, and complications was retrieved.ResultsA total of 97 patients were identified, of whom 50 and 47 received midazolam and triazolam, respectively. The major types of disability were intellectual disabilities, autism, Down syndrome, blindness, cerebral palsy, and epilepsy. Analyses of changes in cooperation levels after drug administration showed that anesthesia induction without physical restraint was possible in 56.0% of patients in the midazolam group and in 46.8% of patients in the triazolam group (P = 0.312).ConclusionsWith administration of oral midazolam or triazolam, general anesthesia induction without any physical restraint was possible in approximately 50% of patients, with no difference between the drugs.

Intranasal sedation using ketamine and midazolam for pediatric dental treatment (NASO): study protocol for a randomized controlled trial

BackgroundUncooperative children may need to receive dental treatment under sedation, which is indicated when nonpharmacological behavior guidance is unsuccessful. There are randomized controlled trials (RCTs) comparing different sedative protocols for dental procedures; however, the evidence for superiority of one form over another is weak. The primary aim of this study is to investigate the efficacy of intranasally administered ketamine plus midazolam for the dental treatment of children.MethodsWe have designed a three-armed, parallel RCT to assess intranasal sedation using ketamine/midazolam in terms of the following measures: efficacy, safety, and cost-effectiveness. Two- to 6-year-old healthy children, referred for dental treatment in a dental sedation center in Brazil due to uncooperative behavior and requiring restorative dental procedures, will be recruited. Each child will be randomly assigned to one of the three groups: A – Intranasal administration of ketamine (4.0 mg/kg, maximum 100 mg) and midazolam (0.2 mg/kg, maximum 5.0 mg); B – Oral administration of ketamine (4.0 mg/kg, maximum 100 mg) and midazolam (0.5 mg/kg, maximum 20 mg); and C – Oral administration of midazolam (1.0 mg/kg, maximum 20 mg). The primary outcome is the child’s behavior assessed through an observational scale using digital videos of the restorative dental treatment under sedation. The secondary outcomes are as follows: acceptance of sedative administration; memory of intraoperative events; the child’s stress; adverse events; the child’s pain during the procedure; the parent’s, dentists’, and child’s perceptions of sedation; and economic analysis. Measures will be taken at baseline and drug administration and during and after the dental procedure. The necessary sample size was estimated to be 84 children after a blinded interim analysis of the first 30 cases.DiscussionThis study will provide data that can substantially add to science and pediatric dentistry as it examines the effect of sedative regimes from different perspectives (outcomes).Trial registrationClinicalTrials.gov, identifier: NCT02447289. Registered on 11 May 2015, named “Midazolam and Ketamine Effect Administered Through the Nose for Sedation of Children for Dental Treatment (NASO).”

Inhibitory Effect of Oxethazaine on Midazolam Metabolism in Rats.

There have been few reports concerning to the drug-drug interactions (DDIs) with OTC drugs although an increase in the use of OTC drugs in recent years. This current study was conducted to clarify the DDIs through CYP3A inhibition by oxethazaine (OXZ), an antacid available as an OTC drug. Midazolam (MDZ) was used as a probe drug for CYP3A activity. In an in vivo study, a single oral dose of OXZ (50 mg/kg) was administered to rats 30, 60, or 120 min before oral MDZ administration (15 mg/kg). Serum concentrations of MDZ were analyzed by HPLC, and its pharmacokinetic parameters were compared with a water-treated control group. The inhibitory effect of OXZ on MDZ 1'-hydroxylation (MDZ 1'-OH) activity was investigated in vitro using rat liver and intestinal microsomes. Pretreatment of OXZ 120 min before MDZ administration significantly increased the area under the serum concentration-time curve (AUC0-∞) of MDZ six-fold compared to the control group without a change in elimination half-life (t1/2). In contrast, OXZ pretreatment 30 or 60 min before MDZ administration did not show any remarkable change in MDZ pharmacokinetic parameters. The in vitro study showed that OXZ inhibited MDZ 1'-OH activity in a concentration-dependent manner both in liver and intestinal microsomes. These results suggested that OXZ increases serum MDZ concentration presumably by the inhibition of liver and/or intestinal CYP3A activity. OXZ was predicted to cause the DDIs mediated by CYP3A inhibition, although this effect depended on the dose interval.

The effect of play distraction on anxiety before premedication administration: a randomized trial

Study objectiveThe majority of children scheduled to undergo surgery experience substantial anxiety in the preoperative holding area before induction of anesthesia. Pharmacological interventions aimed at reducing perioperative anxiety are paradoxically a source of stress for children themselves. Midazolam is frequently used as premedication, and the formula of this drug in Turkey is bitter. We aimed to assess the role of distraction in the form of playing with play dough (Play-Doh) on reducing premedication anxiety in children. DesignProspective randomized clinical trial. SettingPreoperative holding area. PatientsOne hundred four healthy children aged 3 to 7 years scheduled to undergo elective surgery were enrolled into the study. InterventionsAll children routinely receive sedative premedication (oral midazolam) before anesthesia. Children were randomized to 2 groups to receive either play dough (group PD) (n=52) or not (group C) (n=52) before administration of oral premedication. MeasurementsChildren's premedication anxiety was determined by the modified Yale Preoperative Anxiety Scale (mYPAS). Main resultsThe difference in mYPAS scores between groups at T0 (immediately after entering the preoperative holding area) was not significant (P=.876). Compared with group C, group PD was associated with lower mYPAS scores at T1 and T2 (P<.001). In group PD, mYPAS scores were significantly lower at both T1 and T2 as compared with the scores at T0 (P<.001); they were similar between T1 and T2 (P>.001). ConclusionThis study showed that distraction in the form of playing with play dough facilitated administration of oral midazolam in young children.

The Effect of Ticagrelor on the Metabolism of Midazolam in Healthy Volunteers

BackgroundIn vitro studies have demonstrated that ticagrelor, an oral antiplatelet agent, is a substrate, activator, and inhibitor of cytochrome P450 (CYP) 3A. Thus, potential CYP3A-mediated drug–drug interactions may occur. ObjectivesThe goal of this article was to report study results on the effect of ticagrelor on the pharmacokinetics of oral midazolam (oral midazolam study) and oral versus intravenous (IV) midazolam (oral/IV midazolam study). Secondary objectives included assessing the effect of midazolam on ticagrelor pharmacokinetic parameters, and the safety and tolerability of ticagrelor/midazolam coadministration. MethodsTwo randomized crossover studies were conducted in healthy volunteers (n = 28 in each) with ticagrelor and midazolam. In the first study, volunteers received oral ticagrelor (400 mg daily) or placebo for 6 days, then oral midazolam (7.5 mg). The second study regimen was a single dose of ticagrelor 270 mg, then ticagrelor 180 mg BID for 6 days with a single oral (7.5 mg) or IV (2.5 mg) dose of midazolam. ResultsAfter oral midazolam administration, ticagrelor significantly reduced the AUC0–∞ of midazolam (30%–32%) and 4-hydroxymidazolam (42%–47%) but not 1-hydroxymidazolam. After administration of IV midazolam, ticagrelor reduced the AUC0–∞ of midazolam (12%) and 4-hydroxymidazolam (23%) but not 1-hydroxymidazolam. ConclusionsThese results indicate that ticagrelor can weakly activate the metabolism of midazolam to its major 1′-hydroxy metabolite, and at the same time, seems to weakly inhibit midazolam 4′-hydroxylation. Furthermore, ticagrelor affects both hepatic and intestinal CYP3A activity.

A Phase I Study Evaluating the Effect of Everolimus on the Pharmacokinetics of Midazolam in Healthy Subjects

The selective mammalian target of rapamycin (mTOR) inhibitor everolimus has demonstrated competitive inhibition of cytochrome P450 enzyme (CYP) 3A4 in vitro; however, its influence on CYP3A4 activity in humans is unknown. This study examined the influence of everolimus on the pharmacokinetics of midazolam, a sensitive CYP3A4/5 substrate, and its 1-hydroxy metabolite in 25 healthy male subjects. Compared with administration of oral midazolam 4 mg/day alone, coadministration with everolimus 10 mg/day increased the midazolam maximum plasma concentration (C(max)) by 25% and the area under the plasma concentration-time curve (AUC) by 30%. The C(max) and AUC of 1-hydroxymidazolam increased by 20% and 25%, respectively. Concomitant administration of everolimus with midazolam did not change the midazolam metabolic ratio (i.e., the ratio of 1-hydroxymidazolam AUC to midazolam AUC) or the midazolam or 1-hydroxymidazolam terminal half-lives (geometric mean ratios for midazolam + everolimus vs. midazolam alone of 0.96, 1.03, and 1.06, respectively). These results suggest everolimus may affect the bioavailability, but not the systemic clearance, of orally coadministered CYP3A4 substrate drugs.

Prolonged sedation following administration of oral midazolam

Prolonged sedation following administration of oral midazolam

Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers.

Turmeric extract derived curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) are currently being evaluated for the treatment of cancer and Alzheimer's dementia. Previous in vitro studies indicate that curcuminoids and piperine (a black pepper derivative that enhances curcuminoid bioavailability) could inhibit human CYP3A, CYP2C9, UGT and SULT dependent drug metabolism. The aim of this study was to determine whether a commercially available curcuminoid/piperine extract alters the pharmacokinetic disposition of probe drugs for these enzymes in human volunteers. A randomized placebo-controlled six way crossover study was conducted in eight healthy volunteers. A standardized curcuminoid/piperine preparation (4 g curcuminoids plus 24 mg piperine) or matched placebo was given orally four times over 2 days before oral administration of midazolam (CYP3A probe), flurbiprofen (CYP2C9 probe) or paracetamol (acetaminophen) (dual UGT and SULT probe). Plasma and urine concentrations of drugs, metabolites and herbals were measured by HPLC. Subject sedation and electroencephalograph effects were also measured following midazolam dosing. Compared with placebo, the curcuminoid/piperine treatment produced no meaningful changes in plasma C(max), AUC, clearance, elimination half-life or metabolite levels of midazolam, flurbiprofen or paracetamol (α = 0.05, paired t-tests). There was also no effect of curcuminoid/piperine treatment on the pharmacodynamics of midazolam. Although curcuminoid and piperine concentrations were readily measured in plasma following glucuronidase/sulfatase treatment, unconjugated concentrations were consistently below the assay thresholds (0.05-0.08 μM and 0.6 μM, respectively). The results indicate that short term use of this piperine-enhanced curcuminoid preparation is unlikely to result in a clinically significant interaction involving CYP3A, CYP2C9 or the paracetamol conjugation enzymes.