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Drug Metabolism and Disposition: the... May 2024Physiologically-based pharmacokinetic (PBPK) modeling was used to predict the human pharmacokinetics and drug-drug interaction (DDI) of GDC-2394. PBPK models were...
Physiologically-based pharmacokinetic (PBPK) modeling was used to predict the human pharmacokinetics and drug-drug interaction (DDI) of GDC-2394. PBPK models were developed using in vitro and in vivo data to reflect the oral and IV PK profiles of mouse, rat, dog and monkey. The learnings from preclinical PBPK models were applied to a human PBPK model for prospective human PK predictions. The prospective human PK predictions were within 3-fold of the clinical data from the first in human (FIH) study, which was used to optimize and validate the PBPK model and subsequently used for DDI prediction. Based on the majority of PBPK modeling scenarios using the in vitro CYP3A induction data (mRNA and activity), GDC-2394 was predicted to have no-to-weak induction potential at 900 mg BID. Calibration of the induction mRNA and activity data allowed for the convergence of DDI predictions to a narrower range. The plasma concentrations of the 4β-hydroxycholesterol (4β-HC) were measured in the multiple ascending dose (MAD) study to assess the hepatic CYP3A induction risk. There was no change in plasma 4β-HC concentrations after 7 days of GDC-2394 at 900 mg BID. A dedicated DDI study found that GDC-2394 has no induction effect on midazolam in humans, which was reflected by the totality of predicted DDI scenarios. This work demonstrates the prospective utilization of PBPK for human PK and DDI prediction in early drug development of GDC-2394. PBPK modeling accompanied with CYP3A biomarkers can serve as a strategy to support clinical pharmacology development plans. This work presents the application of PBPK modeling for prospective human PK and DDI prediction in early drug development. The strategy taken in this report represents a framework to incorporate various approaches including calibration of in vitro induction data and consideration of CYP3A biomarkers to inform on the overall CYP3A related DDI risk of GDC-2394.
PubMed: 38811156
DOI: 10.1124/dmd.123.001633 -
Pain Physician May 2024Lumbar medial branch blocks (MBB) are some of the most commonly performed pain procedures in the United States. Diagnostic MBBs are performed to confirm if the generator... (Observational Study)
Observational Study
BACKGROUND
Lumbar medial branch blocks (MBB) are some of the most commonly performed pain procedures in the United States. Diagnostic MBBs are performed to confirm if the generator of low back pain is the facet joint. However, with diagnostic injections, false positive blocks may occur.
OBJECTIVES
Our prospective observational study aims to investigate the effects of midazolam sedation on patients' perceived intensity of pain relief following lumbar MBB.
STUDY DESIGN
This is a single-center multi-site prospective observational study registered on clinicaltrials.gov (NCT04453449).
SETTING
The study was approved by the Henry Ford Health System Institutional Review Board (IRB) in June 2020 (IRB# 14010) and registered on clinicaltrials.gov in July 2020 (NCT04453449). This manuscript adheres to the applicable EQUATOR STROBE guidelines for an observational cohort study.
METHODS
Patients that underwent MBB without sedation were compared to sedated patients. Patients were asked to complete the Numeric Rating Scale (NRS) at baseline, one day after their diagnostic blocks, as well as 4 weeks and 8 weeks after their lumbar radiofrequency ablation (RFA). The primary outcome is the difference between baseline NRS pain scores and the lowest reported score in the 8 hours following MBB. For patients who proceed to RFA, the frequency of false positive blocks was evaluated. A patient was considered to have a false positive block when they failed to achieve 50% pain relief from RFA after 2 successful sequential MBBs.
RESULTS
There was no significant difference in the NRS pain score change between the sedated and non-sedated groups for diagnostic block one (P = 0.167) and diagnostic block 2 (P = 0.6145). There was no significant difference of false positive rates between non-sedation and sedation patients at 4-weeks post-RFA (P = 0.7178) and at 8-weeks post-RFA (P = 1.000).
LIMITATIONS
Some of the limitations of this study include its nonrandomized design, patient self-reported pain scores, as well as the small variability in the injection technique of proceduralists and in the anatomical location of the injection site.
CONCLUSIONS
This study showed that midazolam did not change patients' perceived intensity of pain following MBB, as well as false positive rates after RFA. Larger studies are required to draw definitive conclusions.
Topics: Humans; Low Back Pain; Prospective Studies; Zygapophyseal Joint; Female; Male; Middle Aged; Nerve Block; Adult; Midazolam; Hypnotics and Sedatives; Lumbar Vertebrae; Pain Measurement; Lumbosacral Region; Aged
PubMed: 38805536
DOI: No ID Found -
Brazilian Journal of Anesthesiology... May 2024Midazolam is routinely used as preanesthetic medication in pediatric patients. Recently, dexmedetomidine has emerged as an alternative as a premedicant. We aimed to add... (Review)
Review
BACKGROUND
Midazolam is routinely used as preanesthetic medication in pediatric patients. Recently, dexmedetomidine has emerged as an alternative as a premedicant. We aimed to add more evidence about the efficacy and safety of two common routes of administration for pediatric premedication: oral midazolam versus intranasal dexmedetomidine.
METHODS
We systematically searched Randomized Controlled Trials (RCTs) involving patients ≤ 18 years old undergoing preanesthetic medication and comparing intranasal dexmedetomidine with oral midazolam. Risk Ratio (RR) and Mean Difference (MD) with 95% Confidence Intervals (95% CI) were computed using a random effects model. Trial-sequential analyses were performed to assess inconsistency.
RESULTS
Sixteen RCTs (1,239 patients) were included. Mean age was 5.5 years old, and most procedures were elective. There was no difference in satisfactory induction or mask acceptance (RR = 1.15, 95% CI 0.97-1.37; p = 0.11). There was a higher incidence of satisfactory separation from parents in the dexmedetomidine group (RR = 1.40; 95% CI 1.13-1.74; p = 0.002). Dexmedetomidine was also associated with a reduction in the incidence of emergence agitation (RR=0.35; 95% CI 0.14-0.88; p = 0.02). Heart rate and mean arterial pressure were marginally lower in the dexmedetomidine group but without clinical repercussions.
CONCLUSION
Compared with oral midazolam, intranasal dexmedetomidine demonstrated better separation from parents and lower incidence of emergence agitation in pediatric premedication, without a difference in satisfactory induction. Intranasal dexmedetomidine may be a safe and effective alternative to oral midazolam for premedication in pediatric patients.
PubMed: 38801889
DOI: 10.1016/j.bjane.2024.844520 -
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 -
Journal of Personalized Medicine Apr 2024Reducing a child's level of anxiety before magnetic resonance imaging (MRI) procedures allows for better behavioral outcomes. The aim of this retrospective study was to...
BACKGROUND
Reducing a child's level of anxiety before magnetic resonance imaging (MRI) procedures allows for better behavioral outcomes. The aim of this retrospective study was to evaluate anxiolytic efficacy of Midazolam/γ-cyclodextrin oral formulation.
METHODS
We retrospectively reviewed 100 medical charts of children who, between 1 February and 31 July 2022, underwent MRI under general anesthesia with or without premedication with midazolam/γ-cyclodextrin. Primary outcome was comparison of behavior to facemask positioning, while secondary endpoints were degree of drugs acceptance, anxiolytic effect evaluation, child's behavior on separation, and sevoflurane need.
RESULTS
Facemask positioning was accepted by 58% of the midazolam/γ-cyclodextrin group compared to 22% of children in the control group. The rate of acceptance was >90%. At the moment of separation from parent, none of the premedicated children needed to be restrained compared to 18% in the control group. A lower percentage of sevoflurane was needed for eye-closure at induction of anesthesia and for anesthesia maintenance. At emergence from anesthesia, 46% of children in the premedicated group compared to 66% of children in the control group showed transient agitation.
CONCLUSIONS
Midazolam/γ-cyclodextrin showed a good profile of acceptance, satisfactory anxiolytic properties, and reduced need for anesthetics when administered to children before MRI under general anesthesia.
PubMed: 38793054
DOI: 10.3390/jpm14050472 -
Veterinary Sciences May 2024Locoregional anaesthetic techniques are invaluable for providing multimodal analgesia for painful surgical procedures. This prospective, randomised study describes a...
Locoregional anaesthetic techniques are invaluable for providing multimodal analgesia for painful surgical procedures. This prospective, randomised study describes a nerve stimulator-guided brachial plexus blockade (BPB) in rabbits undergoing orthopaedic surgery in comparison to systemic lidocaine. Premedication was provided with intramuscular (IM) medetomidine, fentanyl, and midazolam. Anaesthesia was induced (propofol IV) and maintained with isoflurane. Nine rabbits received a lidocaine BPB (2%; 0.3 mL kg), and eight received a lidocaine constant rate infusion (CRI) (2 mg kg IV, followed by 100 µg kg min). Rescue analgesia was provided with fentanyl IV. Carprofen was administered at the end of the surgery. Postoperative pain was determined using the Rabbit Grimace Scale (RGS) and a composite pain scale. Buprenorphine was administered according to the pain score for two hours after extubation. Rabbits were filmed during the first two hours to measure distance travelled and behaviours. Food intake and faeces output were compared. Every rabbit in CRI required intraoperative rescue analgesia compared to none in BPB. However, rabbits in both groups had similar pain scores, and there was no difference in the administration of postoperative analgesia. There were no significant differences in food intake or faeces production over 18 h, and no significant differences in distance travelled or behaviours examined during the first two hours. BPB seems superior for intraoperative analgesia. Postoperatively, both groups were comparable.
PubMed: 38787185
DOI: 10.3390/vetsci11050213 -
Veterinary Sciences Apr 2024Dexmedetomidine is an a-agonist commonly used in veterinary practice. Occasionally, the administered dose of dexmedetomidine may result in insufficient sedation, and an...
Dexmedetomidine is an a-agonist commonly used in veterinary practice. Occasionally, the administered dose of dexmedetomidine may result in insufficient sedation, and an additional dose or drug may be required. The sedative effects of seven different drugs administered at subsequent time points after an initial, insufficient dose of dexmedetomidine were evaluated. Seven adult cats participated in this crossover, blind, randomised study. The groups consisted of two consecutive doses of dexmedetomidine (15 + 10 μg/kg) (DD) or a dose of dexmedetomidine (15 μg/kg) followed by either NS 0.9% (DC-control group), tramadol 2 mg/kg (DT), butorphanol 0.2 mg/kg (DBT), buprenorphine 20 μg/kg (DBP), ketamine 2 mg/kg (DK), or midazolam 0.1 mg/kg (DM). Sedation was evaluated using the Grint sedation scale. In all groups, atipamezole was administered at the end of the evaluation, and recovery was assessed using the Lozano and Sams recovery scales. The DC and DM groups exhibited minimal sedative effects. The maximum sedative effect was observed in the DD and DK groups, while sedation in the DD and DK groups was significantly higher compared to the DC group. Recovery in all groups was uneventful, except in the DM group, where it was prolonged and difficult, although no statistically significant difference was detected. Therefore, insufficient sedation with dexmedetomidine can be enhanced by a subsequent dose of dexmedetomidine, ketamine, or butorphanol, whereas the addition of midazolam reduces sedation and prolongs recovery.
PubMed: 38787158
DOI: 10.3390/vetsci11050186 -
Journal of Yeungnam Medical Science May 2024Myringotomy with tympanostomy tube insertion (MTI) is a superficial surgical procedure used to prevent hearing loss in children with serous otitis media. Intravenous...
BACKGROUND
Myringotomy with tympanostomy tube insertion (MTI) is a superficial surgical procedure used to prevent hearing loss in children with serous otitis media. Intravenous anesthesia, often ketamine, is preferred for this procedure because of its ability to induce sedation without compromising airway reflexes. However, ketamine alone may be insufficient and potentially lead to spontaneous movement during surgery. This study evaluated the effectiveness of midazolam and fentanyl as adjuvants to ketamine in reducing spontaneous movement during MTI and enhancing the quality of recovery.
METHODS
This study involved two groups of 30 patients each: one group received intravenous ketamine (1.5 mg/kg) with an equal volume of normal saline (K group), while the other received a combination of midazolam, fentanyl, and ketamine (0.05 mg/kg, 1 μg/kg, and 1.5 mg/kg, respectively; MFK group). We assessed side effects, intraoperative patient movement, surgeon satisfaction, and emergence agitation scores.
RESULTS
The MFK group exhibited significantly lower scores for patient movement (p<0.01) and emergence agitation (p<0.01) and markedly higher surgeon satisfaction scores (p<0.01) than the K group.
CONCLUSION
Administering a midazolam-fentanyl-ketamine combination effectively reduced spontaneous movement during surgery and emergence agitation during recovery without prolonging discharge times in children undergoing MTI.
PubMed: 38778719
DOI: 10.12701/jyms.2024.00276 -
Cureus Apr 2024Magnetic resonance imaging (MRI) is a critical diagnostic tool that often requires patient sedation to ensure optimal image quality and patient comfort, particularly in... (Review)
Review
Evaluating Sedation Strategies for Magnetic Resonance Imaging: A Comprehensive Review of Intravenous Fentanyl, Butorphanol, and Midazolam in Adult and Pediatric Populations.
Magnetic resonance imaging (MRI) is a critical diagnostic tool that often requires patient sedation to ensure optimal image quality and patient comfort, particularly in those with anxiety or an inability to remain still. This comprehensive review examines the efficacy, safety, and practical considerations of three commonly used intravenous sedatives, namely, fentanyl, butorphanol, and midazolam, in adult populations undergoing MRI procedures. This review highlights the pharmacological profiles, advantages, and limitations associated with each sedative agent through a detailed analysis of current literature, clinical guidelines, and practice-based evidence. Fentanyl is noted for its potent analgesic properties and rapid onset of action, making it suitable for painful procedures. Butorphanol, with its unique opioid agonist-antagonist activity, presents an alternative with a balance between analgesia and sedation, potentially offering a safer profile for certain patient populations. Midazolam, widely recognized for its anxiolytic and amnestic effects, remains a staple in managing procedure-related anxiety. The review further discusses patient selection criteria, dosing strategies, and the importance of individualized sedation planning to enhance patient experience and procedural outcomes. Future directions highlight the potential of emerging sedation agents and non-pharmacological approaches to improve patient comfort and compliance. The findings underscore the necessity for healthcare providers to adapt sedation practices to the specific needs of each patient, considering both the clinical context and the inherent characteristics of the sedative agents. This review aims to guide clinicians in selecting the most appropriate sedation strategy for adult patients undergoing MRI, optimizing patient care and diagnostic efficacy.
PubMed: 38770500
DOI: 10.7759/cureus.58593 -
Veterinary Research Forum : An... 2024The purpose of this study was to investigate the effects of three anesthetic agents, with premedication of medetomidine and midazolam, on electrocardiographic variables...
The purpose of this study was to investigate the effects of three anesthetic agents, with premedication of medetomidine and midazolam, on electrocardiographic variables in dogs. Ten adult mixed breed dogs were used in a crossover design study, where they received ketamine, propofol and isoflurane treatments with a one-week washout period between them. In all three groups, medetomidine was administered first followed by midazolam after 15 min. Then, after 20 min, group 1 received ketamine intravenously (IV), group 2 received propofol (IV), and group 3 received isoflurane (inhalation). In all dogs, electrocardiographs were taken before and after premedication's, as well as every 15 min during anesthesia. Medetomidine significantly decreased heart rate and P wave amplitude and increased PR interval, R wave amplitude, QT interval, and T wave amplitude. Midazolam increased the amplitude of the R and T waves. Ketamine increased the heart rate and PR interval. Propofol increased the heart rate for up to 15 min, decreased the PR interval for up to 30 min, and the QT interval for up to 45 min. Isoflurane increased the heart rate and decreased the amplitude of R and T waves. The results showed that the drugs used in this study did not have many side effects on electrocardiographic variables and could be used without serious concern. The most important side effects observed were a severe reduction in heart rate and 1 degree atrioventricular (AV) block and, to a lesser extent, 2 degree AV block caused by medetomidine and midazolam which were masked by the anesthetics.
PubMed: 38770200
DOI: 10.30466/vrf.2024.2008055.3954