Midazolam Research Articles

Differential expression and activities of cytochrome P450 3A in the rat brain microsomes and mitochondria.

Midazolam (MDZ), a benzodiazepine derivative, is metabolized to 1'- and 4-hydroxylated metabolites (1'-OH-MDZ and 4-OH-MDZ, respectively) by cytochrome P450 3A (CYP3A). The purpose of this study was to investigate the CYP3A-mediated hydroxylation of MDZ in the rat brain mitochondria (MT). Brain microsomes (MC) and MT fractions were prepared from rats (n = 8) using differential and density gradient centrifugations, and the purity of the fractions was evaluated using VDAC1 and calreticulin as markers of MT and MC, respectively. The formation rates of 1'-OH-MDZ and 4-OH-MDZ in the rat brain MC and MT samples were determined using an LC-MS/MS method after validation. Subsequently, Michaelis-Menten kinetics of 1'- and 4-hydroxylation of MDZ were estimated. Western blot (WB) analysis was used to determine the protein expression of CYP3A in the rat brain MC and MT. The MC fractions had 5.93% ± 3.01% mitochondrial impurity, and the MT fractions had 19.3% ± 7.8% microsomal impurity (mean ± SD). The maximum velocity (Vmax ) values of the formation of the hydroxylated metabolites in the brain MT were 2.4-9-fold higher than those in MC. Further, the Vmax values of 4-OH-MDZ in both MC and MT fractions were substantially higher than those of 1'-OH-MDZ. The WB analysis showed that the intensity of the CYP3A immunoreactive band in MT was more than twofold higher than that in MC. It is concluded that compared with MC, rat brain MT contains substantial CYP3A, which may affect the pharmacology or toxicology of centrally acting xenobiotic and endogenous substrates of this enzyme.

Design And Optimization of Midazolam Loaded Microemulsion Using Quality by Design (Qbd) Assisted Statistical Modelling

Introduction: More emphasize was given in the present work is application of QbD tools and DoE approach. The existing study was aimed towards development and characterization of Midazolam (MZM) loaded microemulsion (ME) for brain delivery through nasal route.Methods: Different QTPP and CQAs were identified initially and REM was prepared. Further D optimal design was employed with concentration of Oil (X1), concentration of Smix (X2) and concentration of water (X3) as significant independent variables (IVs). Globule size (Y1), %Transmittance (Y2) and Viscosity (Y3) were kept as important CQAs.Results: MLR models revealed that selected IVs have great impact on Y1 and Y3, especially main and interactive effect. The results were supported by contour plots (2D and3D) and predicated Vs actual plot. % PE values for check point batches were found less than 5% indicating accuracy of evolved MLR models. Further, control space was mapped from design space of overlay plot and out of control space, one batch was optimized and revised REM was prepared. Revised REM showed low risk potential of various IVs on selected CQAs. Optimized batch was tested for zeta potential, conductivity, Polydispersity index, viscosity, refractive index, isotropic number. Moreover, ex vivo permeation using sheep nasal mucosa in simulated nasal fluid (SNF). The study revealed that superior permeation than Midazolam suspension which is attributed to the incorporation of MZM into ME carrier.Conclusion: So, in a nutshell, it can be concluded that application of QbD approach and DoE concepts in MZM loaded ME yielded design space which will be useful for error free scale up plan implementation.

A Comparative Evaluation of the Anxiolytic Effect of Oral Midazolam and a Homeopathic Remedy in Children During Dental Treatment.

Background Midazolam is recommended by many health standards. However, there is no compelling evidence that midazolam has anti-anxiety effects in children. Homeopathy can be one of the mainstays for effective child management while reducing negative side effects. The aim of the study was to evaluate the anxiolytic efficacy of midazolam (oral) and homeopathic remedies in children during dental treatments. Methodology The current ex-vivo study was conducted in the department of Pedodontics and Preventive Dentistry department of a private dental institution. A total of 48 children aged four to 14 years were selected based on the inclusion and exclusion criteria. The participants were evenly and randomly divided into groups A and B using the lottery method. Group A: 20 minutes previous to the treatment, a right blend of an equal volume of 0.5mg/kg injectable solution of midazolam hydrochloride. Group B: Received Aconite napellus (homeopathic remedy). Results During anxiety, the hypothalamic pituitary adrenal axis gets activated which causes a release of body fluids including salivary cortisol levels. Salivary amylase also responds quickly during stress and anxiety by increasing its levels. Midazolam is used in Dentistry to reduce anxiety as it is able to reduce salivary cortisol and amylase levels.Aconite napellus being homeopathic remedy is useful in Dentistry to reduce salivary cortisol and amylase levels which is observed in the present study. There was a decrease in salivary cortisol and amylase concentrations following midazolam (8.51 ± 6.7) (41.48 ± 23.8) and Aconite napellus (homeopathic remedy) (7.53 ± 5.2) (37.08± 22.8) administration, as well as a decrease in heart rate, systolic and diastolic blood pressure. Furthermore, all of the differences were statistically significant (p<0.05). Conclusion In children with behavioral difficulties, homeopathic remedy was marginally more successful than oral midazolam in lowering anxiety during dental treatment.

Influence of Zhuanggu Guanjie Pill on Seven Cytochrome P450 Enzymes Based on Probe Cocktail and Pharmacokinetics Approaches.

The use of herbal medicines has tremendously increased over the past few decades. Case reports and controlled clinical investigations of herbal-drug interactions have been reported. Since Cytochrome P450 (CYP) enzymes play an important role in drug interactions. The evaluation of the influence of herbal medicines on the activities of CYPs is beneficial to promote scientific and rational clinical use of herbal medicines. Herein, we aimed to develop and validate a method to simultaneously quantify seven CYP cocktail probe drugs consisting of phenacetin (PNC), bupropion (BPP), losartan potassium (LK), omeprazole (OMP), dextromethorphan (DM), chlorzoxazone (CZZ) and midazolam (MDZ) and their respective metabolites in a single acquisition run and use this method to evaluate the influence of Zhuanggu Guanjie Pill (ZGGJP) on seven CYPs. A cost-effective and simple UHPLC-(±)ESI-MS/MS method for simultaneous determination of seven probe drugs and metabolites in rat plasma was developed and validated. Male and female rats were randomly divided into three groups and treated with 1.2 g/kg/d ZGGJP, 5 g/kg/d ZGGJP and 0.5% CMC-Na for 14 consecutive days. After 24 h of the last administration, all rats were administrated orally with probe drugs. The influence of ZGGJP on the CYPs was carried out by comparing the metabolic ratio (Cmax, AUC0-t) of metabolites/probe drugs in rats. The calibration curves were linear, with correlation coefficient > 0.99 for seven probe drugs and their corresponding metabolites. Intra- and inter-day precisions were not greater than 15% RSD and the accuracies were within ± 15% of nominal concentrations. The ZGGJP showed significant inductive effect on CYP1A2, CYP2B6, CYP2C9 and CYP3A in male and female rats. ZGGJP had inductive effects on CYP1A2, CYP2B6, CYP2C9 and CYP3A in male and female rats.

Midazolam versus Dexmedetomidine in Patients at Risk of Obstructive Sleep Apnea during Urology Procedures: A Randomized Controlled Trial.

Benzodiazepines are the most commonly used sedatives for the reduction of patient anxiety. However, they have adverse intraoperative effects, especially in obstructive sleep apnea (OSA) patients. This study aimed to compare dexmedetomidine (DEX) and midazolam (MDZ) sedation considering intraoperative complications during transurethral resections of the bladder and prostate regarding the risk for OSA. This study was a blinded randomized clinical trial, which included 115 adult patients with a mean age of 65 undergoing urological procedures. Patients were divided into four groups regarding OSA risk (low to medium and high) and choice of either MDZ or DEX. The doses were titrated to reach a Ramsay sedation scale score of 4/5. The intraoperative complications were recorded. Incidence rates of desaturations (44% vs. 12.7%, p = 0.0001), snoring (76% vs. 49%, p = 0.0008), restlessness (26.7% vs. 1.8%, p = 0.0044), and coughing (42.1% vs. 14.5%, p = 0.0001) were higher in the MDZ group compared with DEX, independently of OSA risk. Having a high risk for OSA increased the incidence rates of desaturation (51.2% vs. 15.7%, p < 0.0001) and snoring (90% vs. 47.1%, p < 0.0001), regardless of the sedative choice. DEX produced fewer intraoperative complications over MDZ during sedation in both low to medium risk and high-risk OSA patients.

The Reversal of Empathy-Induced Hypernociception in Male Mice by Intra-Amygdala Administration of Midazolam and Cannabidiol Depends on 5-HT3 Receptors.

Introduction: Empathy is a fundamental prosocial behavior. It has been defined as perception, awareness, and understanding of others' emotional states, including painful processes. Mice living in pairs with conspecific chronic suffering from constriction injury exhibit pain hypersensitivity mediated by the amygdaloid complex. Nevertheless, the underlying mechanisms in the amygdala responsible for this response remain to be determined. This study investigated if the anxiolytic benzodiazepine midazolam (MDZ) and cannabidiol (CBD), a phytocannabinoid with multiple molecular targets, would attenuate this behavioral change. We also investigated if serotonergic and γ-aminobutyric acid (GABA)ergic mechanisms in the amygdala are involved in this effect. Materials and Methods: Male Swiss mice were housed in pairs for 28 days. The pairs were divided into two groups on the 14th day: cagemate nerve constriction and cagemate sham. On the 24th day, cagemates underwent a stereotaxic surgery and, on the 28th day, were evaluated on the writhing test. Results: The results showed that living with chronic pain leads to hypernociception in the cagemate and increases the expression of 5-HT3 receptor (5-HT3R) and glutamic acid decarboxylase 67 within the amygdala. MDZ (3.0 and 30 nmol) and CBD (30 and 60 nmol) attenuated the hypernociceptive behavior. The 5-HT3R antagonist ondansetron (0.3 nmol) prevented the antinociceptive effects of MDZ and CBD. Conclusion: These findings indicate that 5-HT3R and GABAergic mechanisms within the amygdala are involved in the pain hypersensitivity induced by the empathy for pain model. They also suggest that MDZ and CBD could be a new potential therapy to alleviate emotional pain disorders.

Effect of Dexmedetomidine on Intestinal Barrier inPatients Undergoing Gastrointestinal Surgery-A Single-Center Randomized ClinicalTrial.

Gastrointestinal failure results in death in critically ill patients. This study aimed to explore the effect of dexmedetomidine (DEX) on intestinal barrier function and its mechanism in critically ill patients undergoing gastrointestinal surgery. Patients undergoing gastrointestinal surgery were randomized into the DEX group (n=21) or midazolam (MID) group (n=21). Sufentanil was used for analgesia in both groups. In the DEX group, DEX was loaded (1μg/kg) before sedation and infused (0.7μg/kg/h) during sedation. In the MID group, MID was loaded (0.05mg/kg) before sedation and infused (0.1mg/kg/h) during sedation. The mean arterial pressure , heart rate , borborygmus resumption time , first defecation time, length of intensive care unit stay, and length of hospital stay were observed. The diamine oxidase (DAO), D-lactate , TNF-α, IL-6, and α7nAChR levels in plasma or hemocytes were detected before the start of sedation (0h) and after sedation (24h). No significant differences in age, sex, body mass index, Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were noted (P>0.05). The mean arterial pressure between 0h and 24h showed no significant difference between the groups (P>0.05), but the heart rate was significantly lower in the DEX group (P=0.042). The borborygmus resumption time was significantly earlier in the DEX group (P=0.034). The lengths of intensive care unit stay (P=0.016) and hospital stay (P=0.031) were significantly shorter in the DEX group. The TNF-α level in the DEX group was lower at 24h than 0h. The D-lactate level was significantly lower in the DEX group than the MID group at 24h(P=0.016). The expression of α7nAChR in the DEX group was significantly higher at 24h than 0h(P<0.05). DEX maintained intestinal barrier integrity in patients undergoing gastrointestinal surgery through the cholinergic anti-inflammatory pathway.

Unravelling the pharmacokinetics of aflatoxin B1: In vitro determination of Michaelis-Menten constants, intrinsic clearance and the metabolic contribution of CYP1A2 and CYP3A4 in pooled human liver microsomes.

Mycotoxins, fungal secondary metabolites, are ubiquitously present in food commodities. Acute exposure to high levels or chronic exposure to low levels has an impact on the human body. The phase I metabolism in the human liver, performed by cytochrome P450 (CYP450) enzymes, is accountable for more than 80% of the overall metabolism of exogenous and endogenous compounds. Mycotoxins are (partially) metabolized by CYP450 enzymes. In this study, in vitro research was performed on CYP450 probes and aflatoxin B1 (AFB1), a carcinogenic mycotoxin, to obtain pharmacokinetic data on AFB1, required for further experimental work. The CYP450 probes of choice were a CYP3A4 substrate, midazolam (MDZ) and a CYP1A2 substrate, phenacetin (PH) since these are the main metabolizing phase I enzymes of AFB1. Linearity experiments were performed on the three substrates indicating that linear conditions were achieved at a microsomal protein concentration and incubation time of 0.25 mg/ml and 5 min, 0.50 mg/ml and 20 min and 0.25 mg/ml and 5 min for MDZ, PH and AFB1, respectively. The Km was determined in human liver microsomes and was estimated at 2.15 μM for MDZ, 40.0 μM for PH and 40.9 μM for AFB1. The associated Vmax values were 956 pmol/(mg.min) (MDZ), 856 pmol/(mg.min) (PH) and 11,536 pmol/(mg.min) (AFB1). Recombinant CYP systems were used to determine CYP450-specific Michaelis–Menten values for AFB1, leading to a CYP3A4 Km of 49.6 μM and an intersystem extrapolation factor (ISEF) corrected Vmax of 43.6 pmol/min/pmol P450 and a CYP1A2 Km of 58.2 μM and an ISEF corrected Vmax of 283 pmol/min/pmol P450. An activity adjustment factor (AAF) was calculated to account for differences between microsome batches and was used as a correction factor in the determination of the human in vivo hepatic clearance for MDZ, PH and AFB1. The hepatic blood clearance corrected for the AAF CLH,B,MDZ,AAF, CLH,B,PH,AAF CLH,B,AFB1,AAF(CYP3A4) and CLH,B,AFB1,AAF(CYP1A2) were determined in HLM at 44.1 L/h, 21.7 L/h, 40.0 L/h and 38.5 L/h. Finally, inhibition assays in HLM showed that 45% of the AFB1 metabolism was performed by CYP3A4/3A5 enzymes and 49% by CYP1A2 enzymes.

Dexmedetomidine for sedation during epicardial ablation for ventricular tachycardia: a single-center experience.

Epicardial approach to ventricular tachycardia (VT) ablation is mainly performed under general anesthesia (GA). Although catheter manipulation and ablation in the epicardial space could be painful, GA lowers blood pressure and may interfere with arrhythmia induction and mapping, and the use of muscle relaxants precludes identification of the phrenic nerve (PN). Moreover, an anesthesiologist's presence is required during GA for the whole procedure, which may not always be possible. Therefore, we evaluated the feasibility and safety of epicardial VT ablations performed under conscious sedation using dexmedetomidine in our center. Between January 2018 and January 2022, all patients who underwent epicardial VT ablation under continuous dexmedetomidine infusion were prospectively included in the study. All patients received premedication 30min before the epicardial puncture with paracetamol (acetaminophen 10mg/ml) 1000mg and ketorolac 30mg. Sedation protocol included an intravenous bolus of midazolam hydrochloride (0.03-0.05mg/kg) followed by continuous infusion of dexmedetomidine (0.2-0.7 mcg/kg/h). In addition, an intravenous fentanyl citrate bolus (0.7-1.4 mcg/kg) was given for short-term analgesia, followed by a second dose repeated after 30 to 45min. Sedation-related complications were defined in case of respiratory failure, severe hypotension, and bradycardia requiring treatment. Sixty-nine patients underwent epicardial or endo-epi VT ablation under conscious sedation and were included in the analysis. The mean age was 65.4 ± 12.1years; forty-six patients were males (66.6%). All patients had drug-refractory recurrent VT. Forty-seven patients (68.1%) had non-ischemic cardiomyopathy (NICM), 13 patients (18.9%) had ischemic-cardiomyopathy (ICM), and 9 patients (13%) had myocarditis. Standard percutaneous sub-xiphoid access was attempted in all patients. Non-inducibility of any VT was achieved in 82.6% (9/9 myocarditis, 10/13 ICM, 38/47 NICM, n = 57/69 patients), inducibility of non-clinical VT in 13% (3/13 ICM, 6/38 NICM, n = 9/69 patients), and failure in 4.3% (3/38 NICM, n = 3/69 patients). Although we observed procedural-related complications in five patients (7.2%), one transient PN palsy, two pericarditis, and two vascular complications, those were not related to the conscious sedation protocol. No respiratory failure, severe hypotension, or bradycardia requiring treatment has been observed among the patients. Prompt availability of anesthesiology support remains crucial for complex procedures such as epicardial VT ablation. Continuous infusion of dexmedetomidine and administration of midazolam and fentanyl seem to be a safe and effective sedation protocol in patients undergoing epicardial VT ablation.

Virtual Reality Glasses versus Midazolam in Alleviation of Child’s Anxiety during Dental Rehabilitation: Randomized Controlled Clinical Trial

Objective: To evaluate virtual reality glasses versus premedication with oral midazolam, and their effect on separation anxiety and postoperative behavioural changes in children experiencing dental rehabilitation under general anaesthesia. Introduction: Several children suffer anxiety when experiencing dental rehabilitation under general anaesthesia, which may be caused by separation from parents, and negative anticipation of surgical procedures. Midazolam (MDZ) is a generation of Benzodiazepines that have been widely used as a premedication. Whereas distraction is a common technique used to reduce pain and anxiety during short invasive procedures. Methodology: This was a randomized clinical trial; children aged 4-6 years who were healthy, uncooperative, and planned to be treated using general anaesthesia were randomly distributed between two groups (Group I), using the Virtual glasses and (Group II), given oral midazolam. The baseline heart rate (HR) was recorded twice. Ease of separation was assessed for all the participants using the Parental Separation Anxiety Scale (PSAS). The Postoperative behavioural changes were scored using (PHBQ) Questionnaire after 24 hours and 14 days after the operation. Results: Regression analysis showed that the type of intervention was non-significantly associated with the acceptability of separation. Males showed significantly less acceptable separation than females. There was a statistically significant increase in the heart rate readings in both groups when compared before and after separation. The parent-reported child morbidity following the surgery showed no significant difference except when regarding the children “who were upset at mentioning doctors, dentists or hospitals” where (P=0.000). Conclusion: VR and premedication with oral midazolam were both effective strategies for controlling preoperative anxiety in children during parental separation, with lots of advantages when using the VR distraction approach.

Advances in Research and Treatment on Patients with Alzheimer's disease Induced by Sleep disorders

Alzheimer's disease (AD) is a disease characterized by memory impairment, loss of words and inability in emotional control that occurs in the early and intermediate stage of the end of our lives. A number of studies have shown that the incidence and severity of AD is higher in patients with sleep disorders than in healthy people. The pathogenic mechanism of AD is still inconclusive, while several hypotheses have been proposed according to its etiological characteristics: Some studies suggest that the β-amyloid protein hypothesis and the mechanism of abnormal phosphorylation of protein tau induced by sleep disorders may be the key factors leading to AD. This paper will summarize the mechanisms of AD induced by sleep disorders and discuss the current therapies approaches to it, which included pharmacological therapy, using Trazodone, Midazolam Maleate tablets, Gardenia Citrusaurantium capsules as well as non-pharmacological therapy, which use aerobic exercise and light therapy, promoting the idea of relieving sleep disorders as an adjunctive treatment for AD. The contents summarized in this paper have some significance of reference to the direction of treatment of AD sleep disorders.

Antiseizure and Neuroprotective Efficacy of Midazolam in Comparison with Tezampanel (LY293558) against Soman-Induced Status Epilepticus.

Acute exposure to nerve agents induces status epilepticus (SE), which can cause death or long-term brain damage. Diazepam is approved by the FDA for the treatment of nerve agent-induced SE, and midazolam (MDZ) is currently under consideration to replace diazepam. However, animal studies have raised questions about the neuroprotective efficacy of benzodiazepines. Here, we compared the antiseizure and neuroprotective efficacy of MDZ (5 mg/kg) with that of tezampanel (LY293558; 10 mg/kg), an AMPA/GluK1 receptor antagonist, administered 1 h after injection of the nerve agent, soman (1.2 × LD50), in adult male rats. Both of the anticonvulsants promptly stopped SE, with MDZ having a more rapid effect. However, SE reoccurred to a greater extent in the MDZ-treated group, resulting in a significantly longer total duration of SE within 24 h post-exposure compared with the LY293558-treated group. The neuroprotective efficacy of the two drugs was studied in the basolateral amygdala, 30 days post-exposure. Significant neuronal and inter-neuronal loss, reduced ratio of interneurons to the total number of neurons, and reduction in spontaneous inhibitory postsynaptic currents accompanied by increased anxiety were found in the MDZ-treated group. The rats treated with LY293558 did not differ from the control rats (not exposed to soman) in any of these measurements. Thus, LY293558 has significantly greater efficacy than midazolam in protecting against prolonged seizures and brain damage caused by acute nerve agent exposure.

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 (<30ng/mL) were enrolled in a 2-phase study. In phase 1 (suboptimal), subjects were administered a single oral dose of VitD3 (5000IU) and MDZ (2mg). 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.

Systematic review and meta-analysis comparing the efficacy of dexmedetomidine to midazolam as premedication and a sedative agent in pediatric patients undergoing dental procedures.

Pediatric dental surgeries are associated with the emotions of fear, anxiety, and other behavioral disturbances of children that need to be managed. Sedation using drugs like dexmedetomidine (DEX) and midazolam (MID) is a common pharmacological behavior managing technique. We conducted this meta-analysis to evaluate the efficacy of both these drugs in current literature. A thorough literature search was conducted on PubMed, MEDLINE, Google Scholar, and Cochrane's database for randomized studies that compared sedative efficacy of dexmedetomidine with midazolam in children of 0-15 years of age undergoing dental surgeries. Sedation in children during dental procedure, when used as a premedication, at the time of separation from parents and at the time of mask induction, onset time, duration of anesthesia, and surgery were evaluated. The mean differences (MDs), odds ratio (OR), and their 95% confidence intervals (CIs) were calculated both for continuous and dichotomous outcome data using random-effects model. Seven studies met out inclusion criteria and were analyzed. Results of premedication with DEX was associated with more anxiolysis (OR=0.29, 95% CI: 0.17-0.52, p=0.0001; I2=0%) and at the time of separation from parents (OR=0.36, 95% CI: 0.19-0.69, p=0.002; I2=52%) in comparison to MID. No significant differences in results were seen at mask induction (OR=0.63, 95% CI: 0.34-1.18, p=0.15; I2=47%) and for sedation in children during dental procedures (OR=0.52, 95% CI: 0.07-3.70, p=0.51; I2=72%). Also, there were no significant differences in onset time, duration of anesthesia, and surgery between the two agents. DEX proved to be a better premedicant than MID for pediatric patients. No significant difference in efficacy of both sedative agents was observed in children undergoing dental treatment. More clinical trials need to be conducted to see its efficacy in dental surgeries in children of standardized ages and with standard doses.

Midazolam as a Probe for Heterotropic Drug-Drug Interactions Mediated by CYP3A4.

Human cytochrome P450 CYP3A4 is involved in the processing of more than 35% of current pharmaceuticals and therefore is responsible for multiple drug-drug interactions (DDI). In order to develop a method for the detection and prediction of the possible involvement of new drug candidates in CYP3A4-mediated DDI, we evaluated the application of midazolam (MDZ) as a probe substrate. MDZ is hydroxylated by CYP3A4 in two positions: 1-hydroxy MDZ formed at lower substrate concentrations, and up to 35% of 4-hydroxy MDZ at high concentrations. The ratio of the formation rates of these two products (the site of metabolism ratio, SOM) was used as a measure of allosteric heterotropic interactions caused by effector molecules using CYP3A4 incorporated in lipid nanodiscs. The extent of the changes in the SOM in the presence of effectors is determined by chemical structure and is concentration-dependent. MD simulations of CYP3A4 in the lipid bilayer suggest that experimental results can be explained by the movement of the F-F’ loop and concomitant changes in the shape and volume of the substrate-binding pocket. As a result of PGS binding at the allosteric site, several residues directly contacting MDZ move away from the substrate molecule, enabling the repositioning of the latter for minor product formation.

Comparison of two Intranasal Sedatives, Midazolam versus Dexmedetomidine, in Children with High Dental Fear: a Randomized Clinical Trial.

Statement of the Problem: Pharmacologic management of uncooperative behavior is a growing trend in dentistry. Determining the most appropriate drug, route of administration, and proper candidate for sedation have been the goal of several investigations.Purpose: The aim of this study was to compare the sedative effect of intranasal (IN) sedation of midazolam (MDZ) in compare to dexmedetomidine (DEX) while taking into consideration the effect of dental fear, and psychological status on sedation success.Materials and Method: This double-blind randomized clinical trial included 92 uncooperative dental patients aged 4-6. Study participants were randomly assigned to receive either 0.2mg/kg IN MDZ or 1µg/kg DEX. Sedation was evaluated using the Houpt sedation rating scale. Vital signs were recorded before and during sedation. Prior to sedation, the level of dental fear was determined through children's fear survey schedule-dental subscale (CFSS-DS). Psychological characteristics were screened using the strengths and difficulties questionnaire (SDQ). Data were analyzed using T-test, Mann-Whitney, Chi-square, and repeated-measures analysis of variance (ANOVA).Results: Overall ratings of sedation and subscales of sleep, crying, and movement were comparable between groups (p> 0.05); however, more acceptable behavior (overall scores (4+5+6) was observed in MDZ group compared to DEX group (64% vs. 47.7%) (p= 0.007). All participants were found to have abnormal levels of dental fear (CFSS-DS≥38). However, according to SDQ, the study participants have mainly shown normal behavioral status. A significant association was found between dental fear and sedation success (MDZ, p= 0.001, DEX, p= 0.03), while similar findings were not observed for psychological characteristics (MDZ, p= 0.09 and p= 0.41; DEX, p= 0.71 and p= 0.53). Physiological parameters remained within normal limits in both groups.Conclusion: Sedation with IN MDZ resulted in overall behaviors, which were more satisfactory in highly fearful pediatric dental patients. Despite baseline uncooperative behaviors, the psychological status of study participants were close to average and were not associated with sedation failure.

Simultaneous detection of a panel of nine sedatives and metabolites in plasma from critically ill pediatric patients via UPLC-MS/MS

Sedative use can result in adverse drug reactions. Intensive care unit patients are especially at risk and pharmacokinetic modeling of drug concentrations is an approach to develop precision dosing strategies. However, limited blood sampling availability in critically ill children and need for multiple assays to quantify a variety of commonly used sedatives creates logistical challenges. The goal of this project was to develop a sensitive and selective assay for the simultaneous quantification of a panel of sedatives comprised of midazolam (MDZ), alpha hydroxymidazolam (1- OH MDZ), dexmedetomidine (DEX), morphine (MOR), morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), fentanyl (FEN), norfentanyl (NF), and hydromorphone (HM) in small volume pediatric plasma samples. A sensitive and efficient ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method was developed following FDA guidance for bioanalytical validation. Minimal sample preparation consisting of simple protein precipitation extraction using acetonitrile with internal standards was utilized. Analyte separation was achieved using a gradient mixture of (A: 0.15% formic acid in water and B: Acetonitrile) and a Waters Acquity C18, 1.7 µm (2.1 × 100 mm) column. Assays were linear over the clinical concentration ranges: MDZ, MOR, HM: 0.5–125 ng/mL; 1-OH MDZ, M3G, M6G: 5–500 ng/mL; and DEX, FEN, NF: 0.05–7.5 ng/mL (R2 > 0.99 for all). Assay run time was 10 min and required only 100 μL of plasma. Initial testing of samples from pediatric patients demonstrates adequacy of assay to measure sedatives and metabolites at clinical concentrations confidently in low volumes of plasma. This novel highly-sensitive and specific method to measure a total of nine different analytes (five sedatives, four metabolites) simultaneously enables comprehensive analysis of a panel of sedatives in small volumes such as in pediatric ICU patients.

Usefulness of Continuous Low-Dose Fentanyl in Combination with Dexmedetomidine and Midazolam for Intravenous Sedation: A Randomised Controlled Trial.

Intravenous dexmedetomidine (DEX) and midazolam (MZ) are currently used to achieve sedation in dental surgery under local anaesthesia. However, the efficacy of low-dose fentanyl (FEN) in combination with DEX and MZ sedation remains unclear. Therefore, we implemented a prospective randomised controlled trial to investigate the intra- and postoperative analgesic effects, intraoperative respiratory and circulatory dynamics, and frequency of intra- and postoperative adverse events of continuous low-dose fentanyl administration with DEX and MZ sedation. Patients aged 20–64 years scheduled for dental surgery under sedation were randomly assigned to the DEX+MZ (DM) or DEX+MZ+FEN (DMF) group. DEX was administered at 4 μg/kg/h for 10 min and then reduced to 0.7 μg/kg/h until the end of surgery. MZ was administered at 0.04 mg/kg upon the initial administration of DEX and 0.02 mg/kg every hour thereafter. In the DMF group, FEN infusion was administered at 2 μg/kg/h during the initial administration of DEX and then reduced to 1 μg/kg/h after 10 min until the end of surgery. Primary outcomes were intra- and postoperative analgesic efficacies, whereas secondary outcomes were intraoperative respiratory and circulatory dynamics. The total amount of intraoperative local anaesthetic administered and the heart rate were significantly lower in the DMF group than in the DM group (P = 0.044 and P < 0.01, respectively). No significant difference was observed in the frequency of postoperative administration of analgesics and intra- and postoperative adverse events. These findings demonstrated that low-dose FEN infusion in combination with DEX and MZ sedation in dental surgery provides intraoperative analgesia and suppresses tachycardia with little effect on blood pressure and respiratory dynamics and without effect on postoperative analgesia.

Recycling Unused Midazolam Drug as Efficient Corrosion Inhibitor for Copper in Nitric Acid Solution.

The current work explores the potential for recycling unused or expired Midazolam (MID) drug, a benzodiazepine derivative, as an efficient corrosion inhibitor for copper in nitric acid solution. The technical advantage of recycling expired MID drug relates to the avoidance of organic inhibitor production costs and the reduction of disposal costs of the expired medication. A combination of electrochemical methods (potentiodynamic polarization and electrochemical impedance spectroscopy), weight loss, and quantum chemical calculation were used to assess the inhibition mechanism and efficiency of MID. It was found that inhibition efficiency increases with inhibitor concentration, reaching a highest value of 92.9% for a concentration of 10−4 M MID. MID was classified as a mixed-type inhibitor, showing a preferential cathodic suppression mechanism. The obtained values of −45.89 kJ mol−1 for the standard free energy of adsorption indicate that the inhibition mechanism is based on chemisorption of MID molecules on the copper surface, which obeys the Langmuir isotherm. Surface analysis using scanning electronic microscopy revealed that MID offers high protection against corrosion during both immersion and polarization tests. Molecular modelling and quantum chemical calculations indicated chemical interactions between MID molecules and the copper surface, as well as electrostatic interactions. The results obtained using the different techniques were in good agreement and highlight the effectiveness of MID in the corrosion inhibition of copper.

Comparison of intravenous sedation using midazolam versus dexmedetomidine in elderly patients with dementia: a randomized cross-over trial

Differences between the effects of intravenous sedation with midazolam (MID) and dexmedetomidine (DEX) on the cerebral function of elderly patients with severe dementia are unclear. This study aimed to compare the effects of intravenous sedation with MID or DEX on parameters such as brain waves and cerebral blood flow (CBF). This cross-over study analyzed 12 patients with severe dementia, with each patient receiving both drug treatments. Each drug was administered until a Modified Observer’s Assessment of Alertness/Sedation (OAA/S) score of 2 was reached. Bispectral index (BIS) and normalized tissue hemoglobin index (nTHI), which reflects CBF using near-infrared spectroscopy, were measured. Mann–Whitney U, Wilcoxon signed-rank, and Friedman tests, and multiple regression analysis were performed. While a similar decline in BIS values was observed in both groups (P < 0.030), there was a significant decrease in nTHI up to 11% in the MID group (P = 0.005). In the DEX group, nTHI values did not differ from baseline. When an OAA/S score of 2 was just achieved, CBF in the MID group (− 5%) was significantly lower than in the DEX group (± 0%). In dementia patients, sedation with MID resulted in a decrease in CBF, while the CBF value was maintained during sedation with DEX.