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Purpose The objective of this study was to assess the bioavailability and the sedative effect of a single-dose administration of an innovative oral solution of midazolam containing γ-cyclodextrins (ADV6209). Methods A bioavailability study with a standard two-sequences, two-periods, and crossover design was conducted. Subjects randomly received 15 mg of ADV6209 by oral route followed by 5 mg of the reference drug (midazolam hydrochloride intravenous solution (Hypnovel®, Roche) by intravenous route or vice versa. Blood samples were drawn at different time points to measure midazolam and its metabolite α-hydroxymidazolam concentrations. Non-compartmental pharmacokinetic methods were used to calculate main pharmacokinetic parameters and absolute bioavailability. Results Caucasian healthy subjects ( n  = 12) were included in the study. ADV6209 had a bioavailability of 39.6%. The oral elimination half-life with ADV6209 was slightly shorter than with the reference i.v. form (2.66 h versus 2.99 h). The sedative effect was observed 27.5 ± 15.5 min after oral administration for a duration of 48.5 ± 35.4 min. Double peak phenomenon was observed in 5 patients. Conclusions Cyclodextrins have little impact on midazolam oral bioavailability and the pharmacokinetics parameters of midazolam formulation ADV6209 are close to those reported previously.

Daily interruption of sedative therapy and limitation of deep sedation have been shown in several randomized trials to reduce the duration of mechanical ventilation and hospital length of stay, and to improve the outcome of critically ill patients. However, patients with severe acute brain injury (ABI; including subjects with coma after traumatic brain injury, ischaemic/haemorrhagic stroke, cardiac arrest, status epilepticus) were excluded from these studies. Therefore, whether the new paradigm of minimal sedation can be translated to the neuro-ICU (NICU) is unclear. In patients with ABI, sedation has ‘general’ indications (control of anxiety, pain, discomfort, agitation, facilitation of mechanical ventilation) and ‘neuro-specific’ indications (reduction of cerebral metabolic demand, improved brain tolerance to ischaemia). Sedation also is an essential therapeutic component of intracranial pressure therapy, targeted temperature management and seizure control. Given the lack of large trials which have evaluated clinically relevant endpoints, sedative selection depends on the effect of each agent on cerebral and systemic haemodynamics. Titration and withdrawal of sedation in the NICU setting has to be balanced between the risk that interrupting sedation might exacerbate brain injury (e.g. intracranial pressure elevation) and the potential benefits of enhanced neurological function and reduced complications. In this review, we provide a concise summary of cerebral physiologic effects of sedatives and analgesics, the advantages/disadvantages of each agent, the comparative effects of standard sedatives (propofol and midazolam) and the emerging role of alternative drugs (ketamine). We suggest a pragmatic approach for the use of sedation-analgesia in the NICU, focusing on some practical aspects, including optimal titration and management of sedation withdrawal according to ABI severity.

This systematic review synthesized literature evidence and compared midazolam’s risks and clinical outcomes with other sedatives in critically ill mechanically ventilated patients. We included randomized controlled trials (RCTs) from databases of PubMed, Embase, Cochrane Library, Web of Science, and CINAHL without language restrictions. We used relative risk (RR) for binary outcomes and standardized mean difference (SMD) for continuous outcomes, with corresponding 95% confidence interval (CI). 17 RCTs involving 1509 patients were included. Compared to other sedatives, midazolam significantly increased the incidence of delirium (RR 2.39, 95 % CI, 1.75 to 3.26), the time up to extubation (SMD 1.99, 95 % CI, 0.81 to 3.16) and ICU length of stay (SMD 0.63, 95 % CI, 0.20 to 1.08), but significantly reduced the incidence of bradycardia (RR 0.52, 95 % CI, 0.36 to 0.76). No differences were identified in hypotension incidence (RR 0.69, 95 % CI, 0.37 to 1.31) or duration of mechanical ventilation (SMD 0.28, 95 % CI, −0.22 to 0.78). Midazolam caused a higher risk of delirium, a longer time up to extubation, and ICU length of stay, but a lower incidence of bradycardia. No significant evidence indicated midazolam was associated with a higher risk of hypotension or increased duration of mechanical ventilation. Clinicians should balance midazolam’s potential risks with its benefits. While other sedatives may be catering to patients at a higher delirium risk, midazolam remains indispensable for hemodynamically compromised patients, such as those with bradycardia. Precise sedation management is crucial for patient safety and outcomes.

To systematically review the literature comparing the efficacy and safety of dexmedetomidine and midazolam when used for procedural sedation. We searched MEDLINE, EMBASE and COCHRANE for clinical trials comparing dexmedetomidine and midazolam for procedural sedation up to June 20, 2016. Inclusion criteria: clinical trial, human subjects, adult subjects (≥18 years), article written in English, German, French or Dutch, use of study medication for conscious sedation and at least one group receiving dexmedetomidine and one group receiving midazolam. Exclusion criteria: patients in intensive care, pediatric subjects and per protocol use of additional sedative medication other than rescue medication. Outcome measures for efficacy comparison were patient and clinician satisfaction scores and pain scores; outcome measures for safety comparison were hypotension, hypoxia, and circulatory and respiratory complications. We identified 89 papers, of which 12 satisfied the inclusion and exclusion criteria; 883 patients were included in these studies. Dexmedetomidine was associated with higher patient and operator satisfaction than midazolam. Patients receiving dexmedetomidine experienced less pain and had lower analgesic requirements. Respiratory and hemodynamic safety were similar. Dexmedetomidine is a promising alternative to midazolam for use in procedural sedation. Dexmedetomidine provides more comfort during the procedure for the patient and clinician. If carefully titrated, the safety profiles are similar.

Midazolam is a rapidly effective benzodiazepine drug that is widely used as a sedative worldwide. Due to its poor solubility in a neutral aqueous solution, the clinical use of midazolam is significantly limited. As one of the most promising formulations for poorly water-soluble drugs, nanocrystals have drawn worldwide attention. We prepared a stable nanosuspension system that causes little muscle irritation. The particle size of the midazolam nanocrystals (MDZ/NCs) was 286.6 ± 2.19 nm, and the crystalline state of midazolam did not change in the size reduction process. The dissolution velocity of midazolam was accelerated by the nanocrystals. The pharmacokinetics study showed that the AUC0–t of the MDZ/NCs was 2.72-fold (p < 0.05) higher than that of the midazolam solution (MDZ/S), demonstrating that the bioavailability of the MDZ/NC injection was greater than that of MDZ/S. When midazolam was given immediately after the onset of convulsions, the ED50 for MDZ/NCs was significantly more potent than that for MDZ/S and DZP/S. The MDZ/NCs significantly reduced the malondialdehyde content in the hippocampus of the seizures model rats and significantly increased the glutathione and superoxide dismutase levels. These results suggest that nanocrystals significantly influenced the dissolution behavior, pharmacokinetic properties, anticonvulsant effects, and neuroprotective effects of midazolam and ultimately enhanced their efficacy in vitro and in vivo.

Genetic polymorphism can result in abnormal pharmacodynamics that subsequently leads to the individual variance in sedative effects and adverse reactions. The aim of this study was to elucidate the association between midazolam-related genetic polymorphism and sedative effects, including adverse reactions, under conscious sedation during upper gastrointestinal endoscopy. We prospectively enrolled 100 eligible patients undergoing upper gastrointestinal endoscopy. The efficacy of the sedation, adverse reactions, plasma concentration of midazolam and 1-hydroxymidazolam were investigated as well as the genetic polymorphism of MDR1 and CYP3A5 . The correlation between genetic polymorphism and sedative effects was assessed. Regarding MDR1 gene, the plasma concentration of midazolam was greater in patients with CGC haplotype ( P  = 0.012), while it was lower in patients with CAC haplotype ( P  = 0.005) than in those with other haplotypes. However, genetic polymorphism of neither MDR1 nor CYP3A5 correlated with the plasma concentration of 1-hydroxymidazolam. CGT haplotype of MDR1 was significantly correlated with sedation grade after midazolam administration ( P  = 0.042). In contrast, genetic polymorphism of CYP3A5 was not correlated with sedation grade. There was no association between genetic polymorphism of MDR1 or CYP3A5 and selected adverse reactions related to midazolam. Genetic polymorphism of MDR1 influences the concentration of midazolam and the sedation grade. However, it is not associated with adverse reactions such as paradoxical response and retrograde amnesia.

Background Liposomes are closed vesicles made of the same phospholipid bilayer as biological membranes and are capable of containing drugs, and so they have been investigated as useful drug carriers for drug delivery. We previously developed liposome-encapsulated midazolam (LE-midazolam) for oral administration, but midazolam is metabolized in the liver, and for clinical use the encapsulation of the liposomes needed to be improved to increase the bioavailability of midazolam. The surfaces of pharmaceutical liposomes are generally coated with polyethylene glycol (PEGylation) because it prevents their capture by phagocytes and helps them to avoid the reticuloendothelial system. Therefore, we considered that PEGylation could reduce the metabolism of orally administered encapsulated midazolam in the liver. Methods Midazolam solution, LE-midazolam solution, and PEGylated liposome-encapsulated midazolam (PEG-LE-midazolam) solution were prepared, and the characteristics of the liposomes in these solutions were evaluated. Furthermore, these solutions were orally administered to rabbits, and the resultant plasma midazolam concentrations were measured. The effects of the PEGylation of LE-midazolam on the plasma concentration and bioavailability of orally administered midazolam were also evaluated. Results The PEG-LE-midazolam solution contained a higher percentage of larger liposomes than the LE-midazolam solution. The area under the concentration-time curve (AUC) of the LE-midazolam solution was significantly higher than that of the midazolam solution, but there was no difference between the AUC values of the PEG-LE-midazolam and midazolam solutions. Conclusions These findings suggest that liposome encapsulation may reduce the first-pass effect following oral administration, but PEGylation is not expected to improve the bioavailability of orally administered midazolam.

In this trial, subjects in status epilepticus were given either intramuscular midazolam or intravenous lorazepam by paramedics before arrival in the ER. Seizures were controlled in more subjects with midazolam, and midazolam was at least as safe and effective as lorazepam. Early termination of prolonged epileptic seizures in response to intravenous administration of benzodiazepines by paramedics in the prehospital setting is associated with better patient outcomes. The randomized, controlled Prehospital Treatment of Status Epilepticus (PHTSE) trial (ClinicalTrials.gov number, NCT00004297) compared diazepam, lorazepam, and placebo given intravenously by paramedics to treat subjects with prolonged convulsive seizures. 1 The trial showed that both these benzodiazepines were an effective prehospital treatment for seizures, as compared with placebo. The proportion of subjects whose seizures were terminated at the time of arrival in the emergency department was 59.1% in the group receiving intravenous lorazepam, 42.6% in the . . .

Human cytochrome P450 3A4 (CYP3A4) is a major hepatic and intestinal enzyme that oxidizes more than 60% of administered therapeutics. Knowledge of how CYP3A4 adjusts and reshapes the active site to regioselectively oxidize chemically diverse compounds is critical for better understanding structure–function relations in this important enzyme, improving the outcomes for drug metabolism predictions, and developing pharmaceuticals that have a decreased ability to undergo metabolism and cause detrimental drug–drug interactions. However, there is very limited structural information on CYP3A4–substrate interactions available to date. Despite the vast variety of drugs undergoing metabolism, only the sedative midazolam (MDZ) serves as a marker substrate for the in vivo activity assessment because it is preferentially and regioselectively oxidized by CYP3A4. We solved the 2.7 Å crystal structure of the CYP3A4–MDZ complex, where the drug is well defined and oriented suitably for hydroxylation of the C1 atom, the major site of metabolism. This binding mode requires H-bonding to Ser119 and a dramatic conformational switch in the F–G fragment, which transmits to the adjacent D, E, H, and I helices, resulting in a collapse of the active site cavity and MDZ immobilization. In addition to providing insights on the substrate-triggered active site reshaping (an induced fit), the crystal structure explains the accumulated experimental results, identifies possible effector binding sites, and suggests why MDZ is predominantly metabolized by the CYP3A enzyme subfamily.

IntroductionEvidence on the safety of doses for conscious sedation in ERCP is currently lacking. The recent BSG guidelines suggest minimal to moderate sedation in level 1–2 ERCP. More complex ERCPs or combined endoscopic ultrasound (EUS) and ERCP procedures require deep sedation or general anaesthetic. The previous JAG guidance suggests no more than 2mg Midazolam and 50µg Fentanyl for patients aged 70 or above and no more than 5mg Midazolam and 100µg Fentanyl for patients under age 70. This recommendation has been extrapolated from diagnostic endoscopy. For the more complex cases, the availability of deep sedation is often unavailable for endoscopy in most centres. We aim to examine our practice of adopting a dual sedationist-endoscopist model for conscious sedation. We aim to establish safety profile of using sedation beyond the previous recommendations and its impact on endoscopic performance.MethodRetrospective review of all ERCP from September 2022 to September 2023. Doses of Midazolam and Fentanyl were reviewed in accordance to patients’ age group. Cases that required repeat endoscopy were reviewed for the cause and cases requiring reversal agents for sedation were identified. Further analysis was done on patients who had combined EUS-ERCP. The standards for meeting sedation recommendations was adapted from Joint Advisory Group (JAG) Guide to Meeting the Quality and Safety Standards. Sedation was administered in small increments (1mg for Midazolam and 25µg for Fentanyl) and titrated to response while monitoring oxygen saturations and heart rate during the procedure by either the trainee or trainer while the other performs the endoscopy.Results497 cases of ERCP done with conscious sedation between September 2022 to 2023. All were done with Fentanyl and Midazolam. Doses for cases which exceeded recommendations for Midazolam were 45.1% (n=224) and Fentanyl were 68.8% (n=342). The median dose of Midazolam was 3.3mg and Fentanyl was 100µg for all ages. There were 168 cases for combined EUS-ERCP, 162 cases were done under conscious sedation. The median dose of Midazolam was 4mg and Fentanyl was 125µg. 2 combined procedures (1.2%) could not be completed due to intolerance. 4 cases (0.8%) of ERCP required repeat under deep sedation and was incomplete due to inadequate tolerance. One patient (0.2%) needed reversal agents for respiratory depression. The highest dose recorded was Fentanyl 400µg and 10mg Midazolam with no adverse events.ConclusionThe use of conscious sedation is safe when given in small increments with close monitoring. The doses should be tailored to each individual and their response. The dual sedationist-endoscopist model is effective as there is low rate of failure (0.8%) from intolerance as sedation is given proactively as opposed to reactively. Furthermore, combined EUS-ERCP procedure can also be done effectively under conscious sedation in our experience.