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Trials Nov 2023Preoperative anxiety management is gaining particular attention in paediatric anaesthesia. Pharmacological and non-pharmacological resorts can be implemented to address...
Comparison of S-ketamine and midazolam for intravenous preoperative sedative and anxiolytic effects in preschool children: study protocol for a randomized controlled clinical trial.
BACKGROUND
Preoperative anxiety management is gaining particular attention in paediatric anaesthesia. Pharmacological and non-pharmacological resorts can be implemented to address this special issue. Despite the various approaches currently used for preoperative sedation in children, the different sedative and anti-anxiety effects between the newly marketed anaesthetic, S-ketamine, and the traditional sedative, midazolam, are still unclear.
METHODS
This is a patient- and assessor-blinded randomized controlled clinical trial. Participants (n = 110) will receive S-ketamine (0.5 mg/kg) or midazolam (0.08 mg/kg) intravenously administrated at a ratio of 1:1 in the anaesthesia holding area. The primary outcome of this study is the sedative effect evaluated via the change in the modified Yale preoperative anxiety scale. It will be performed at two timepoints: in the pre-anaesthetic holding area before premedication (baseline, marked as T0) and about 5 min after premedication in the operating room without the existence of their guardians (marked as T1). Our secondary objectives include the parent separation anxiety score, postoperative agitation, caregivers' and anaesthesia care providers' satisfaction, and mask compliance.
DISCUSSION
This randomized controlled trial is the first study to compare the anti-anxiety effect of intravenous S-ketamine and midazolam. We will provide a new approach for the clinical management of preoperative anxiety in preschool children posted for elective surgery.
TRIAL REGISTRATION
ChiCTR2300069998. Registered on 30 March 2023.
Topics: Child, Preschool; Humans; Hypnotics and Sedatives; Midazolam; Anti-Anxiety Agents; Anesthetics; Double-Blind Method; Randomized Controlled Trials as Topic
PubMed: 37957769
DOI: 10.1186/s13063-023-07767-2 -
BMC Anesthesiology Jun 2024Dexmedetomidine and midazolam are commonly used sedatives in children. We conducted a systematic review and meta-analysis to compare the safety and effectiveness of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Dexmedetomidine and midazolam are commonly used sedatives in children. We conducted a systematic review and meta-analysis to compare the safety and effectiveness of sedation provided by dexmedetomidine combined with midazolam versus other sedatives including chloral hydrate, midazolam and other sedatives in pediatric sedation.
METHODS
The Embase, Web of Science, Cochrane Library, and PubMed databases, and Clinicaltrials.gov register of controlled trials were searched from inception to June 2022. All randomized controlled trials used dexmedetomidine-midazolam in pediatric sedation were enrolled. The articles search, data extraction, and quality assessment of included studies were performed independently by two researchers. The success rate of sedation was considered as the primary outcome. The secondary outcomes included onset time of sedation, recovery time of sedation and occurrence of adverse events.
RESULTS
A total of 522 studies were screened and 6 RCTs were identified; 859 patients were analyzed. The administration of dexmedetomidine combined with midazolam was associated with a higher sedation success rate and a lower incidence of nausea and vomiting in computed tomography, magnetic resonance imaging, Auditory Brainstem Response test or fiberoptic bronchoscopy examinations than the other sedatives did (OR = 2.92; 95% CI: 1.39-6.13, P = 0.005, I = 51%; OR = 0.23, 95% CI: 0.07-0.68, P = 0.008, I = 0%, respectively). Two groups did not differ significantly in recovery time and the occurrence of adverse reactions (WMD = - 0.27, 95% CI: - 0.93 to - 0.39, P = 0.42; OR 0.70; 95% CI: 0.48-1.02, P = 0.06, I = 45%. respectively). However, the results of the subgroup analysis of ASA I-II children showed a quicker onset time in dexmedetomidine-midazolam group than the other sedatives (WMD=-3.08; 95% CI: -4.66 to - 1.49, P = 0.0001, I = 30%).
CONCLUSIONS
This meta-analysis showed that compared with the control group, dexmedetomidine combined with midazolam group provided higher sedation success rates and caused a lower incidence of nausea and vomiting in completing examinations, indicating a prospective outpatient clinical application for procedural sedation.
Topics: Dexmedetomidine; Humans; Hypnotics and Sedatives; Midazolam; Child; Drug Therapy, Combination; Randomized Controlled Trials as Topic
PubMed: 38907338
DOI: 10.1186/s12871-024-02570-1 -
BMC Psychiatry Nov 2023Depression is a common psychiatric disorder and a leading cause of disability worldwide. Conventional monoaminergic antidepressants have limited efficacy and take weeks...
BACKGROUND
Depression is a common psychiatric disorder and a leading cause of disability worldwide. Conventional monoaminergic antidepressants have limited efficacy and take weeks to exert a therapeutic effect. Single infusions of subanaesthetic doses of ketamine exhibit rapid antidepressant action but effects are transient and relapse is common. One potential strategy for increasing ketamine's antidepressant efficacy and/or prolonging its therapeutic benefit may be serial infusions. There is limited evidence on the efficacy and safety of repeated ketamine infusions against an active comparator.
METHODS
This protocol describes an ongoing pragmatic, randomised, controlled, parallel-group, patient- and rater-blind, superiority trial. Eligible adult inpatients with a confirmed DSM-5 diagnosis of a major depressive episode (unipolar or bipolar) are randomly allocated in a 1:1 ratio to a course of up to eight infusions of ketamine or midazolam twice-weekly over four weeks. The primary objective is to assess the efficacy of serial adjunctive ketamine infusions versus active comparator midazolam by measuring Montgomery-Åsberg Depression Rating Scale score difference between arms from before the first infusion to 24 h after the final infusion, supplemented by a 95% confidence interval. To facilitate generalisability of results, the trial takes place under "real world" conditions with both groups continuing to receive regular inpatient care including treatment-as-usual pharmacotherapy, nursing care, and psychological and other therapies during the randomised treatment phase and regular outpatient care thereafter. Participants are monitored for relapse during a 24-week follow-up after the end of the randomised phase. Secondary objectives of the trial are to assess: response and remission rates at the end of randomised phase; relapse status during the 24-week follow-up after the end of the randomised phase; the safety and tolerability of repeated ketamine infusions regarding psychotomimetic and other psychiatric side effects, cognitive side effects, as well as withdrawal symptoms, haemodynamic stability, neurological, urological, and other physical side effects; and quality of life and cost-effectiveness.
DISCUSSION
There is an unmet clinical need for rapidly-acting novel antidepressants. This trial will provide efficacy, safety and health economic data on serial ketamine infusions and thus help inform clinical practice on the potential role of this treatment in the management of depression.
TRIAL REGISTRATION
EudraCT 2019-003109-92. Registered 2 October 2019.
CLINICALTRIALS
gov NCT04939649. Registered 25 June 2021.
Topics: Adult; Humans; Depressive Disorder, Major; Ketamine; Depression; Midazolam; Quality of Life; Antidepressive Agents; Recurrence; Treatment Outcome; Randomized Controlled Trials as Topic
PubMed: 37974160
DOI: 10.1186/s12888-023-05365-9 -
Drug Metabolism and Disposition: the... Jun 2024Arsenite is an important heavy metal. Some Chinese traditional medicines contain significant amounts of arsenite. The aim of this study was to investigate subacute...
Arsenite is an important heavy metal. Some Chinese traditional medicines contain significant amounts of arsenite. The aim of this study was to investigate subacute exposure of arsenite on activities of cytochrome P450 enzymes and pharmacokinetic behaviors of drugs in rats. Midazolam, tolbutamide, metoprolol, omeprazole, caffeine, and chlorzoxazone, the probe substrates for CYPs3A2, 2C6, 2D2, 2C11, 1A2, and 2E1, were selected as model drugs for the pharmacokinetic study. Significant decreases in AUCs of probe substrates were observed in rats after consecutive 30 day exposure at 12 mg/kg. Microsomal incubation study showed that the subacute exposure to arsenite resulted in little changes in effects on the activities of P450 enzymes examined. However, everted gut sac study demonstrated that such exposure induced significant decreases in intestinal absorption of these drugs by both passive diffusion and carrier-mediated transport. In addition, study showed that the arsenite exposure decreased the rate of peristaltic propulsion. The decreases in intestinal permeability of the probe drugs and peristaltic propulsion rate most likely resulted in the observed decreases in the internal exposure of the probe drugs. Exposure to arsenite may lead to the reduction of the efficiencies of pharmaceutical agents co-administered resulting from the observed drug-drug interactions. Exposure to arsenite may lead to the reduction of the efficiencies of pharmaceutical agents co-administered resulting from the observed drug-drug interactions. In this study, we found that P450 enzyme probe drug exposure was reduced in arsenic-exposed animals (AUCs) and the intestinal absorption of the drug was reduced in the animals. Subacute arsenic exposure tends to cause damage to intestinal function, which leads to reduced drug absorption.
PubMed: 38849209
DOI: 10.1124/dmd.124.001772 -
BMJ Supportive & Palliative Care Dec 2023While clinical wisdom has long provided suggested guidance around caring for people who use illicit drugs (referred to as PWUD) at the end of life, there is striking...
BACKGROUND
While clinical wisdom has long provided suggested guidance around caring for people who use illicit drugs (referred to as PWUD) at the end of life, there is striking paucity of empirical evidence underpinning these practices. Understanding medications and doses required to manage symptoms at the end of life is essential to provide effective end-of-life care for these patients. This study aimed to examine the type and dose of medications prescribed to hospitalised patients who use illicit drugs at the end of life, compared with patients without previous or current illicit drug use.
METHOD
A retrospective medical record review was conducted on consecutive patient deaths between 2012 and 2017 at a metropolitan hospital. PWUD were identified using the International Classification of Diseases 10th Revision codes for illicit drug use. Daily dosage of opioids, benzodiazepines and antipsychotics was documented for the last 3 days of life and compared with a matched comparator group.
RESULTS
PWUD patients (n=55) received higher doses of opioids, midazolam and antipsychotics than comparator patients (n=55) for each day, significant for opioids in the last 24 hours (p=0.01). PWUD patients received a significantly higher total opioid dose (median=480.0 mg vs 255.0 mg) and midazolam (median=15.0 mg vs 5.0 mg) (both p<0.05). Rates of dose escalation did not differ.
CONCLUSIONS
Results suggest that PWUD require greater doses of symptom-controlling medications, particularly opioids and midazolam, at the end of life but that rates of dose escalation do not differ greatly. This study provides a foundation for future research to inform clinical guidelines for this cohort of palliative care patients.
Topics: Humans; Illicit Drugs; Midazolam; Retrospective Studies; Terminal Care; Analgesics, Opioid; Substance-Related Disorders; Death
PubMed: 34001548
DOI: 10.1136/bmjspcare-2021-002906 -
Biochemical and Biophysical Research... Feb 2024Highly cytotoxic maytansine derivatives are widely used in targeted tumor delivery. Structure-activity studies published earlier suggested the C9 carbinol to be a key...
Highly cytotoxic maytansine derivatives are widely used in targeted tumor delivery. Structure-activity studies published earlier suggested the C9 carbinol to be a key element necessary to retain the potency. However, in 1984 a patent was published by Takeda in which the synthesis of 9-thioansamitocyn (AP3SH) was described and its activity in xenograft models was shown. In this article we summarize the results of an extended study of the anti-tumor properties of AP3SH. Like other maytansinoids, it induces apoptosis and arrests the cell cycle in the G2/M phase. It is metabolized in liver microsomes predominately by C3A4 isoform and doesn't inhibit any CYP isoforms except CYP3A4 (midazolam, IC50 7.84 μM). No hERG inhibition, CYP induction or mutagenicity in Ames tests were observed. AP3SH demonstrates high antiproliferative activity against 25 tumor cell lines and tumor growth inhibition in U937 xenograft model. Application of AP3SH as a cytotoxic payload in drug delivery system was demonstrated by us earlier.
Topics: Humans; Antineoplastic Agents; Maytansine; Cell Line, Tumor; Cell Cycle; Cell Division
PubMed: 38219484
DOI: 10.1016/j.bbrc.2024.149483 -
Annals of Emergency Medicine Aug 2023
Topics: Humans; Dexmedetomidine; Hypnotics and Sedatives; Midazolam; Administration, Intranasal; Emergency Service, Hospital
PubMed: 37055283
DOI: 10.1016/j.annemergmed.2023.02.022 -
Resuscitation Aug 2023To understand the serum and cerebrospinal fluid (CSF) distribution of midazolam is important for proper timing of neurological prognostication of targeted temperature... (Observational Study)
Observational Study
Time-course relationship between cerebrospinal fluid and serum concentrations of midazolam and albumin in patients with cardiac arrest undergoing targeted temperature management.
AIM
To understand the serum and cerebrospinal fluid (CSF) distribution of midazolam is important for proper timing of neurological prognostication of targeted temperature management(TTM) patients. Midazolam binds extensively to albumin in serum although non protein bound form exist in CSF. We investigated the time-course of CSF, serum concentrations of midazolam and albumin in patients with cardiac arrest who underwent TTM.
METHODS
This prospective, single-center, observational study was conducted between May 2020 and April 2022. Midazolam and albumin concentrations in CSF and serum were quantified 0, 24, 48, and 72 h after the return of spontaneous circulation for comparison between the good (Cerebral Performance Category (CPC) 1 and 2) and poor (CPC 3, 4, and 5) neurologic outcome groups. The CSF/serum (C/S) ratios of midazolam and albumin concentrations were determined, along with their correlation coefficients.
RESULTS
Of the 19 enrolled patients, 13 experienced poor outcomes. At 0 h, serum midazolam concentrations were the lowest, whereas serum albumin levels were the highest; in the CSF, the concentrations of both peaked at 24 h. There were no significant inter-group differences in midazolam concentrations in CSF or serum. The C/S ratios of midazolam and albumin significantly differed between the groups. Moderate to strong positive correlations were observed between the midazolam and albumin C/S ratios.
CONCLUSION
In CSF, midazolam and albumin concentrations peaked 24 h post-cardiac arrest. Midazolam and albumin C/S ratios were significantly higher in the poor outcome group and positively correlated with each other, suggesting blood-brain barrier disruption 24 h post-cardiac arrest.
Topics: Humans; Midazolam; Out-of-Hospital Cardiac Arrest; Prospective Studies; Albumins; Hypothermia, Induced
PubMed: 37302686
DOI: 10.1016/j.resuscitation.2023.109867 -
Cancer Chemotherapy and Pharmacology Sep 2023Adavosertib may alter exposure to substrates of the cytochrome P450 (CYP) family of enzymes. This study assessed its effect on the pharmacokinetics of a cocktail of...
PURPOSE
Adavosertib may alter exposure to substrates of the cytochrome P450 (CYP) family of enzymes. This study assessed its effect on the pharmacokinetics of a cocktail of probe substrates for CYP3A (midazolam), CYP2C19 (omeprazole), and CYP1A2 (caffeine).
METHODS
Period 1: patients with locally advanced or metastatic solid tumors received 'cocktail': caffeine 200 mg, omeprazole 20 mg, and midazolam 2 mg (single dose); period 2: after 7- to 14-day washout, patients received adavosertib 225 mg twice daily on days 1-3 (five doses), with cocktail on day 3. After cocktail alone or in combination with adavosertib administration, 24-h pharmacokinetic sampling occurred for probe substrates and their respective metabolites paraxanthine, 5-hydroxyomeprazole (5-HO), and 1'-hydroxymidazolam (1'-HM). Safety was assessed throughout.
RESULTS
Of 33 patients (median age 60.0 years, range 41-83) receiving cocktail, 30 received adavosertib. Adavosertib co-administration increased caffeine, omeprazole, and midazolam exposure by 49%, 80%, and 55% (AUC), respectively; AUC increased by 61%, 98%, and 55%. Maximum plasma drug concentration (C) increased by 4%, 46%, and 39%. Adavosertib co-administration increased 5-HO and 1'-HM exposure by 43% and 54% (AUC) and 49% and 58% (AUC0-t), respectively; paraxanthine exposure was unchanged. Adavosertib co-administration decreased C for paraxanthine and 5-HO by 19% and 7%; C increased by 33% for 1'-HM. After receiving adavosertib, 19 (63%) patients had treatment-related adverse events (six [20%] grade ≥ 3).
CONCLUSION
Adavosertib (225 mg bid) is a weak inhibitor of CYP1A2, CYP2C19, and CYP3A.
CLINICALTRIALS
GOV: NCT03333824.
Topics: Humans; Adult; Middle Aged; Aged; Aged, 80 and over; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP3A; Midazolam; Caffeine; Cytochrome P-450 CYP2C19; Drug Interactions; Cytochrome P-450 Enzyme System; Omeprazole; Neoplasms
PubMed: 37394627
DOI: 10.1007/s00280-023-04554-3 -
PloS One 2023The use of dexmedetomidine rather than midazolam may improve ICU outcomes. We summarized the available recent evidence to further verify this conclusion. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The use of dexmedetomidine rather than midazolam may improve ICU outcomes. We summarized the available recent evidence to further verify this conclusion.
METHODS
An electronic search of PubMed, Medline, Embase, Cochrane Library, and Web of Science was conducted. Risk ratios (RR) were used for binary categorical variables, and for continuous variables, weighted mean differences (WMD) were calculated, the effect sizes are expressed as 95% confidence intervals (CI), and trial sequential analysis was performed.
RESULTS
16 randomized controlled trials were enrolled 2035 patients in the study. Dexmedetomidine as opposed to midazolam achieved a shorter length of stay in ICU (MD = -2.25, 95%CI = -2.94, -1.57, p<0.0001), lower risk of delirium (RR = 0.63, 95%CI = 0.50, 0.81, p = 0.0002), and shorter duration of mechanical ventilation (MD = -0.83, 95%CI = -1.24, -0.43, p<0.0001). The association between dexmedetomidine and bradycardia was also found to be significant (RR 2.21, 95%CI 1.31, 3.73, p = 0.003). We found no difference in hypotension (RR = 1.44, 95%CI = 0.87, 2.38, P = 0.16), mortality (RR = 1.02, 95%CI = 0.83, 1.25, P = 0.87), neither in terms of adverse effects requiring intervention, hospital length of stay, or sedation effects.
CONCLUSIONS
Combined with recent evidence, compared with midazolam, dexmedetomidine decreased the risk of delirium, mechanical ventilation, length of stay in the ICU, as well as reduced patient costs. But dexmedetomidine could not reduce mortality and increased the risk of bradycardia.
Topics: Humans; Midazolam; Dexmedetomidine; Respiration, Artificial; Bradycardia; Intensive Care Units; Hypnotics and Sedatives; Delirium
PubMed: 37963140
DOI: 10.1371/journal.pone.0294292