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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 -
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 -
Journal of Wildlife Diseases Oct 2023The aim of this study was to compare the effects of two anesthetic induction protocols for long procedures carried out in the field in Tapiridae. Sixteen tapirs were...
EFFECTS OF DETOMIDINE AND DEXMEDETOMIDINE ON PHYSIOLOGICAL PARAMETERS AND ANESTHETIC RECOVERY IN TAPIRUS TERRESTRIS ANESTHETIZED WITH KETAMINE, GLYCERYL GUAIACOL ETHER, AND MIDAZOLAM.
The aim of this study was to compare the effects of two anesthetic induction protocols for long procedures carried out in the field in Tapiridae. Sixteen tapirs were divided into two groups (n=8) receiving either detomidine (DET) or dexmedetomidine (DEX) for anesthetic induction. All animals were anesthetized by intramuscular administration of a combination of ketamine (1.5 mg/kg), midazolam (0.2 mg/kg), plus either DET (0.04 mg/kg) or DEX (0.007 mg/kg). Anesthetic maintenance was by continuous infusion of ketamine, midazolam, and glyceryl guaiacol ether at 2 mg/kg per hour, 0.1 mg/kg per hour, and 100 mg/kg per hour, respectively). The animals were kept anesthetized for a total of 50 min to allow physical examination and collection of biological material as part of a research program, and physiological variables (heart rate [HR], respiratory rate, oxyhemoglobin saturation [SpO2], rectal temperature [RT], mean arterial pressure [MAP], blood glucose [GLI], and cortisol) and electrocardiogram were recorded during anesthesia. Anesthetic recovery was monitored by two researchers who were not informed of the induction protocol group. The recorded results were statistically evaluated. In both groups there was an initial increase in MAP, which subsequently decreased; RT gradually decreased during anesthesia; HR and GLI increased throughout the procedure; SpO2 was below normal throughout the procedure. Cortisol levels were significantly higher in the DEX group than in the DET group. Also, the animals in the DEX group had a longer recovery time than those in the DET group. On the basis of the results, we conclude that the combination of alpha-2 agonists and midazolam, ketamine, and glyceryl guaicol ether is an appropriate protocol for the anesthesia of tapirs in the field. However, in moderately extended procedures oxygen supplementation is recommended. Additionally, DEX resulted in fewer cardiovascular effects and longer-lasting sedation than DET.
Topics: Animals; Midazolam; Ketamine; Dexmedetomidine; Hydrocortisone; Anesthetics; Ethers; Hypnotics and Sedatives
PubMed: 37846913
DOI: 10.7589/JWD-D-22-00136 -
The British Journal of Oral &... Apr 2024The aim of this study was to determine what is considered a long oral surgery and conduct a cost-effective analysis of sedative agents used for intravenous sedation... (Review)
Review
The aim of this study was to determine what is considered a long oral surgery and conduct a cost-effective analysis of sedative agents used for intravenous sedation (IVS) and sedation protocols for such procedures. Pubmed and Google Scholar databases were used to identify human studies employing IVS for extractions and implant-related surgeries, between 2003 and July/2023. Sedation protocols and procedure lengths were documented. Sedative satisfaction, operator satisfaction, and sedation assessment were also recorded. Cost estimation was based on The British National Formulary (BNF). To assess bias, the Cochrane Risk of Bias tools were employed. This review identified 29 randomised control trials (RCT), six cohorts, 14 case-series, and one case-control study. The study defined long procedures with an average duration of 31.33 minutes for extractions and 79.37 minutes for implant-related surgeries. Sedative agents identified were midazolam, dexmedetomidine, propofol, and remimazolam. Cost analysis revealed midazolam as the most cost-effective option (<10 pence per procedure per patient) and propofol the most expensive option (approximately £46.39). Bias analysis indicated varying degrees of bias in the included studies. Due to diverse outcome reporting, a comparative network approach was employed and revealed benefits of using dexmedetomidine, propofol, and remimazolam over midazolam. Midazolam, dexmedetomidine, propofol, and remimazolam demonstrated safety and efficacy as sedative agents for conscious IVS in extended procedures like extractions or implant-related surgeries. While midazolam is the most cost-effective option, dexmedetomidine, propofol, and remimazolam offer subjective and clinical benefits. The relatively higher cost of propofol may impede its widespread use. Dexmedetomidine and remimazolam stand out as closely priced options, necessitating further clinical investigations for comparative efficacy assessment.
PubMed: 38797651
DOI: 10.1016/j.bjoms.2024.04.006 -
Cureus Oct 2023Background and aims MRI sedation in paediatrics includes challenges like respiratory depression, maintaining haemodynamic stability and use of neuroprotective drugs,...
Background and aims MRI sedation in paediatrics includes challenges like respiratory depression, maintaining haemodynamic stability and use of neuroprotective drugs, since MRI is performed in remote places outside the operating room with a lack of support staff and nonavailability of choice of medications and equipments. The primary aim was to use a combination of the drugs to encounter the above challenges and look for its efficacy. The secondary aim of the study was to determine the rate of successful completion of MRI in children using a combination of intranasal dexmedetomidine and intravenous midazolam - without the need for rescue sedatives. Methods This is an observational study involving 60 children in the age group between two months and six years undergoing an MRI. Children belonging to the American Society of Anesthesiology (ASA) 1 and 2 were given intranasal dexmedetomidine 3µg/kg, time to onset of sedation was noted and injection of midazolam 0.1 mg/kg was given intravenously. MRI was started once the child was asleep. Children who woke up during the MRI were supplemented with inj. propofol 0.5-1mg/kg and were documented. Results The median time duration for MRI was 38.7 min and the onset of sedation after intranasal dexmedetomidine was 18.7 min. The scan was successfully completed with a combination of intranasal dexmedetomidine and intravenous midazolam in 86.7% and only 13.3% of the children woke up either at the start or in between the scan and required the addition of propofol. Conclusion Drugs used for sedation during MRI should not cause respiratory depression and be safe for the developing brain. The above study has shown that a combination of intranasal dexmedetomidine and intravenous midazolam is effective and safe in performing MRIs in paediatrics.
PubMed: 37954765
DOI: 10.7759/cureus.46787 -
Acta Anaesthesiologica Scandinavica Nov 2023Procedural sedation aims to facilitate a successful diagnostic or therapeutic procedure. The pharmacokinetic properties and pharmacodynamic effects need to be taken into... (Review)
Review
BACKGROUND
Procedural sedation aims to facilitate a successful diagnostic or therapeutic procedure. The pharmacokinetic properties and pharmacodynamic effects need to be taken into consideration when choosing the ideal sedative. Midazolam and propofol are frequently employed. However, they are associated with respiratory depression with increasing dosage. Also, midazolam has a potentially unpredictable pharmacodynamic response and propofol may cause hypotension and injection site pain. Remimazolam may provide a superior alternative due to its rapid pharmacodynamic profile and insignificant circulatory effects.
METHODS
This protocol employs the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The review aims to assess the beneficial and harmful clinical effects of remimazolam versus placebo or other sedatives in adult patients requiring sedation in relation to a diagnostic or therapeutic procedure, or due to other circumstances. Three primary outcomes are identified: Sedation success rate, respiratory complications, and hemodynamic complications. Six secondary outcomes are identified: among these are quality of recovery and serious adverse events. All randomized trials are included. The search strategy includes six major biomedical databases. Literature screening and data extraction will be performed independently by two authors. Risk of systemic error will be assessed with Risk of Bias 2 Tool. Risk of random error will be assessed with trial sequential analysis. Heterogeneity will be evaluated by appropriate statistical tests. The certainty of the evidence will be judged using Grading of Recommendations Assessment, Development, and Evaluation. Meta-analysis will be carried out with Rstudio. A "Summary of Findings" table will be presented with our primary and secondary outcome results.
DISCUSSION
The systematic review with up-to-date methodology outlined in this protocol investigates the clinical effects of remimazolam in relation to procedural sedation. The results may guide clinicians in the clinical use of remimazolam.
PubMed: 37580880
DOI: 10.1111/aas.14316