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Journal of Pharmacokinetics and... Dec 2020CYP3A plays an important role in drug metabolism and, thus, can be a considerable liability for drug-drug interactions. Population pharmacokinetics may be an efficient...
CYP3A plays an important role in drug metabolism and, thus, can be a considerable liability for drug-drug interactions. Population pharmacokinetics may be an efficient tool for detecting such drug-drug interactions. Multiple models have been developed for midazolam, the typical probe substrate for CYP3A activity, but no population pharmacokinetic models have been developed for use with inhibition or induction. The objective of the current analysis was to develop a composite parent-metabolite model for midazolam which could adequately describe CYP3A drug-drug interactions. As an exploratory objective, parameters were assessed for potential cut-points which may allow for determination of drug-drug interactions when a baseline profile is not available. The final interaction model adequately described midazolam and 1'-OH midazolam concentrations for constitutive, inhibited, and induced CYP3A activity. The model showed good internal and external validity, both with full profiles and limited sampling (2, 2.5, 3, and 4 h), and the model predicted parameters were congruent with values found in clinical studies. Assessment of potential cut-points for model predicted parameters to assess drug-drug interaction liability with a single profile suggested that midazolam clearance may reasonably be used to detect inhibition (4.82-16.4 L/h), induction (41.8-88.9 L/h), and no modulation (16.4-41.8 L/h), with sensitivities for potent inhibition and induction of 87.9% and 83.3%, respectively, and a specificity of 98.2% for no modulation. Thus, the current model and cut-points could provide efficient and accurate tools for drug-drug liability detection, both during drug development and in the clinic, following prospective validation in healthy volunteers and patient populations.
Topics: Adult; Area Under Curve; Biological Variation, Population; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Female; Healthy Volunteers; Humans; Male; Metabolic Clearance Rate; Midazolam; Middle Aged; Models, Biological; Sensitivity and Specificity; Young Adult
PubMed: 32772302
DOI: 10.1007/s10928-020-09704-1 -
Journal of Zoo and Wildlife Medicine :... Jul 2023Cardiovascular disease is a frequent cause of death in the critically endangered Vancouver Island marmots (). This warrants the use of anesthetic protocols with minimal...
Cardiovascular disease is a frequent cause of death in the critically endangered Vancouver Island marmots (). This warrants the use of anesthetic protocols with minimal cardiovascular adverse effects. In this study, 12 adult male woodchucks () were used as models for Vancouver Island marmots. The objective was to compare the physiological effects of two premedication protocols during induction and maintenance of anesthesia with sevoflurane. The two premedications were ketamine 10 mg/kg and midazolam 0.5 mg/kg (KM) or ketamine 10 mg/kg, midazolam 0.5 mg/kg, and butorphanol 1.0 mg/kg (KMB), administered intramuscularly prior to mask induction. Each marmot underwent three anesthetic events and protocols were assigned using a blinded randomized crossover design. Heart rate, respiratory rate, oxygen saturation, and body temperature were recorded throughout, and blood gases were assessed following induction. Resistance to induction was scored and time to induction was recorded. Although mask induction with sevoflurane was successful in all events (mean induction time of 2.1 min), KMB premedication resulted in a faster induction (mean induction time reduced by 1.2 ± 0.3 min) and lower resistance scores. Both protocols resulted in significant cardiovascular and respiratory depression; however, animals that received KMB were more hypercapnic than KM by 8.8 ± 2.8 mm Hg ( = 0.03) (mean venous partial pressure of carbon dioxide [PvCO2] for all: 79.9 mm Hg). In conclusion, if shorter induction times are desired, KMB premedication is preferred. However, cardiorespiratory variables including blood pressure should be monitored, and endotracheal intubation is recommended to allow for ETCO2 monitoring and provision of intermittent positive pressure ventilation.
Topics: Animals; Male; Anesthesia, General; Anesthetics; Butorphanol; Heart Rate; Ketamine; Marmota; Midazolam; Premedication; Sevoflurane
PubMed: 37428688
DOI: 10.1638/2021-0162 -
Bratislavske Lekarske Listy 2021Sedation is an essential part of clinical practice. Despite this fact, we still lack data describing the exact impact of sedation on heart function. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Sedation is an essential part of clinical practice. Despite this fact, we still lack data describing the exact impact of sedation on heart function.
PURPOSE
To compare the changes in heart function, induced after sedation with either midazolam or dexmedetomidine, using cardiac magnetic resonance imaging (MRI).
METHODS
A total number of 30 volunteers were randomized into two groups: 15 participants in the midazolam group (MID) and 15 participants in the dexmedetomidine group (DEX). Every participant underwent a one-session cardiac MRI before and after sedation onset. The following parameters were recorded: left and right ventricle stroke volume (Ao-vol and Pul-vol resp.) and maximum flow velocity through the mitral valve during early (E-diast) and late diastole (L-diast). A monitor recorded values of mean blood pressure (MAP), pulse (P) and blood oxygen saturation (SpO2) in 5-minute intervals.
RESULTS
Dexmedetomidine led to a statistically significant decrease in Ao-vol (p = 0.006) and Pul-vol (p = 0.003), while midazolam decreased E-diast (p = 0.019) Ao-vol (p = 0.001) and Pul-vol (p = 0.01). The late diastolic filling was not influenced by the sedation technique.
CONCLUSION
Both sedation regimens worsened the systolic function of both ventricles. Midazolam moreover attenuated early diastolic filling of the left ventricle (Tab. 3, Fig. 4, Ref. 19).
Topics: Arterial Pressure; Dexmedetomidine; Heart Rate; Humans; Hypnotics and Sedatives; Midazolam
PubMed: 34002611
DOI: 10.4149/10.4149/BLL_2021_064 -
American Journal of Veterinary Research Nov 2022To evaluate 2 doses of alfaxalone on cardiopulmonary parameters, temperature, sedation, endotracheal intubation, the incidence of muscle tremors, and radiographic...
OBJECTIVE
To evaluate 2 doses of alfaxalone on cardiopulmonary parameters, temperature, sedation, endotracheal intubation, the incidence of muscle tremors, and radiographic positioning in Quaker parrots previously administered intranasal midazolam and butorphanol.
ANIMALS
10 healthy adult Quaker parrots (male = 5; female = 5).
PROCEDURES
A randomized, masked, crossover study was conducted where birds received midazolam (2 mg/kg) and butorphanol (2 mg/kg) intranasally 15 minutes prior to a low- or high-dose of intramuscular alfaxalone: 2 mg/kg (LDA) or 5 mg/kg (HDA), respectively. Heart (HR) and respiratory rate (RR), cloacal temperature, sedation quality, and ability to position for radiographs were recorded over time. The incidence of muscle tremors and the ability to intubate were recorded. Data were compared to baseline values and between treatments where appropriate. Significance was set at P < .05.
RESULTS
There were no significant differences in HR, RR, cloacal temperature, and sedation scores between treatments at any time point. Duration of time from midazolam-butorphanol administration to complete recovery from treatment administration was significantly shorter for LDA when compared to HDA (90 [60 to 195] vs 127.5 [90 to 10] minutes, respectively). Compared to baseline, sedation scores were significantly higher from T = 15 to 60 for LDA and from T = 15 to 75 for HDA. The incidence of muscle tremors was greater in HDA (9/10) than in LDA (7/10). All birds were successfully intubated and positioned for radiographs.
CLINICAL RELEVANCE
The combination of intranasal midazolam-butorphanol and intramuscular alfaxalone at the doses examined was a safe and effective method for sedating Quaker parrots. LDA produced adequate sedation with a shorter time to recovery and with fewer muscle fasciculations when compared to HDA.
Topics: Animals; Female; Male; Anesthetics; Butorphanol; Cross-Over Studies; Hypnotics and Sedatives; Injections, Intramuscular; Midazolam; Parrots; Pregnanediones; Tremor
PubMed: 36327169
DOI: 10.2460/ajvr.22.08.0140 -
Oxidative Medicine and Cellular... 2022Neuroinflammation is a critical pathological process of neurodegenerative diseases, and alleviating the inflammatory response caused by abnormally activated microglia...
Neuroinflammation is a critical pathological process of neurodegenerative diseases, and alleviating the inflammatory response caused by abnormally activated microglia might be valuable for treatment. The 18 kDa translocator protein (TSPO), a biomarker of neuroinflammation, is significantly elevated in activated microglia. However, the role of TSPO in microglia activation has not been well demonstrated. In this study, we evaluated the role of TSPO and its ligands PK11195 and Midazolam in LPS-activated BV-2 microglia cells involving mitophagy process and the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation. In the microglia-neuron coculture system, the neurotoxicity induced by LPS-activated microglia and the neuroprotective effects of PK11195 and Midazolam were evaluated. Our results showed that after being stimulated by LPS, the expression of TSPO was increased, and the process of mitophagy was inhibited in BV-2 microglia cells. Inhibition of mitophagy was reversed by pretreatment with PK11195 and Midazolam. And the NLRP3 inflammasome was increased in LPS-activated BV-2 microglia cells in the microglia-neuron coculture system; pretreatment with PK11195 and Midazolam limited this undesirable situation. Lastly, PK11195 and Midazolam improved the cell viability and reduced apoptosis of neuronal cells in the microglia-neuron coculture system. Taken together, TSPO ligands PK11195 and Midazolam showed neuroprotective effects by reducing the inflammatory response of LPS-activated microglia, which may be related to the enhancement of mitophagy and the inhibition of NLRP3 inflammasome.
Topics: Animals; Cell Line; Inflammasomes; Isoquinolines; Ligands; Lipopolysaccharides; Mice; Microglia; Midazolam; NLR Family, Pyrin Domain-Containing 3 Protein; Neurons; Neuroprotective Agents
PubMed: 35401924
DOI: 10.1155/2022/5896699 -
The Journal of Emergency Medicine Dec 2021Although the efficacy and safety profiles of both intranasal fentanyl and midazolam are well studied in pediatric patients, few studies examine their use in younger...
BACKGROUND
Although the efficacy and safety profiles of both intranasal fentanyl and midazolam are well studied in pediatric patients, few studies examine their use in younger children.
OBJECTIVES
To examine and report our experiences in a pediatric emergency department (ED) with intranasal fentanyl and midazolam in children aged 3 years and younger.
METHODS
This retrospective study investigated intranasal fentanyl and midazolam administration, alone and in combination, in children 3 years and younger treated in a pediatric ED.
RESULTS
Of 6198 patients included, 1762 received intranasal fentanyl alone, 1115 received intranasal midazolam alone, and 3321 received combination therapy. The median (interquartile range [IQR]) patient age was 2.2 (1.5-3) years. Initial median (IQR) fentanyl dose was 2.7 (2-3) µg/kg, with 13.3% receiving a repeat dose. Initial median (IQR) midazolam dose was 0.3 (0.2-0.3) mg/kg, with 3.3% receiving a second dose. Children receiving both fentanyl and midazolam had median (IQR) initial doses of 2.8 (2.1-3) µg/kg and 0.3 (0.2-0.3) mg/kg, respectively. Of these, 3.2% received repeat doses of both medications. Laceration repairs (33.8%) and incision and drainage (22.2%) accounted for the majority of indications. Only 2.9% (n = 178) received additional opioids. No serious adverse events requiring a reversal agent or respiratory support were reported.
CONCLUSIONS
Intranasal fentanyl and midazolam, alone and in combination, can provide analgesia and anxiolysis to children aged 3 years and younger in the ED setting. Further prospective studies are needed to better evaluate their safety and efficacy in this younger population.
Topics: Administration, Intranasal; Child; Child, Preschool; Emergency Service, Hospital; Fentanyl; Humans; Midazolam; Retrospective Studies
PubMed: 34920841
DOI: 10.1016/j.jemermed.2021.09.006 -
Journal of Stroke and Cerebrovascular... Dec 2021The ideal anesthetic for mechanical thrombectomy (MT) is a subject of debate. Recent studies have supported the use of monitored anesthesia care (MAC), but few have... (Comparative Study)
Comparative Study
OBJECTIVES
The ideal anesthetic for mechanical thrombectomy (MT) is a subject of debate. Recent studies have supported the use of monitored anesthesia care (MAC), but few have attempted to compare MAC neuroanesthetics. Our study directly compares midazolam and dexmedetomidine (DEX) on blood pressure control during thrombectomy and functional outcomes at discharge.
MATERIALS AND METHODS
We performed a retrospective review of an MT database, which consisted of 612 patients admitted between 2010-2019 to our tertiary stroke center. 193 patients who received either midazolam or DEX for MAC induction were identified. Primary and secondary outcomes were >20% maximum decrease in mean arterial pressure during MT and functional independence respectively.
RESULTS
146 patients were administered midazolam, while 47 were administered DEX. Decrease in blood pressure (BP) during MT was associated with lower rates of functional independence at last follow-up (p=0.034). When compared to midazolam, DEX had significantly higher rates of intraprocedural decrease in MAP at the following cut-offs: >20% (p<0.001), >30% (p=0.001), and >40% (p=0.006). On multivariate analysis, DEX was an independent predictor of >20% MAP decrease (OR 7.042, p<0.001). At time of discharge, NIHSS scores and functional independence (mRS 0-2) were statistically similar between DEX and midazolam. Functional independence at last known follow-up was statistically similar between DEX and midazolam (p = 0.643).
CONCLUSIONS
Use of DEX during MT appears to be associated with increased blood pressure volatility when compared to midazolam. Further investigation is needed to determine the impact of MAC agents on functional independence.
Topics: Anesthetics; Blood Pressure; Dexmedetomidine; Humans; Midazolam; Retrospective Studies; Thrombectomy; Treatment Outcome
PubMed: 34656971
DOI: 10.1016/j.jstrokecerebrovasdis.2021.106117 -
Journal of Avian Medicine and Surgery Nov 2022Chickens () often undergo veterinary procedures requiring sedation; however, there is little published research evaluating the efficacy of sedation protocols in this...
Chickens () often undergo veterinary procedures requiring sedation; however, there is little published research evaluating the efficacy of sedation protocols in this species. The objective of this study was to assess the effects of intramuscular alfaxalone and midazolam compared with intramuscular butorphanol and midazolam in chickens. In a complete crossover study, 11 healthy adult hens were randomly administered midazolam 2.5 mg/kg IM combined with either alfaxalone 15 mg/kg IM (AM, n = 11) or butorphanol 3 mg/kg IM (BM, n = 11), with a 35-day washout period between groups. Time to first effects, recumbency, standing, and recovery were recorded. Physiologic parameters and sedation scores were recorded every 5 minutes by 2 blinded investigators. Fifteen minutes after injection, positioning for sham whole body radiographs was attempted. At 30 minutes, flumazenil 0.05 mg/kg IM was administered to all hens. Peak total sedation score was significantly higher for AM compared with BM ( < 0.001). Mean ± SD or median (range) time to initial effects, recumbency, standing, and recovery in AM and BM were 1.9 ± 0.6 and 2.6 ± 0.9 ( = 0.02), 3.5 (1.6-7.6) and 4.8 (2.2-13.0) ( = 0.10), 40.3 (28.0-77.8) and 33.2 (5.2-41.3) ( = 0.15), and 71.2 (45.7-202.3) and 39.9 (35.9-45.9) minutes ( = 0.05), respectively. Radiographic positioning was successful in 6 of 11 (54.5%) and 0 of 11 (0%) birds in the AM and BM groups at 15 minutes, respectively. Heart and respiratory rates remained within acceptable clinical limits for all birds. Intramuscular AM resulted in significantly faster onset of sedative effects, significantly longer duration of recumbency, significantly higher peak sedation, and improved success of radiographic positioning compared with intramuscular BM. Intramuscular AM produces clinically effective sedation in chickens without clinically significant cardiorespiratory effects.
Topics: Animals; Female; Butorphanol; Midazolam; Chickens; Cross-Over Studies; Rhode Island
PubMed: 36468806
DOI: 10.1647/20-00087 -
Neuropsychopharmacology : Official... Oct 2023NMDA receptor antagonists have a vital role in extinction, learning, and reconsolidation processes. During the reconsolidation window, memories are activated into a... (Randomized Controlled Trial)
Randomized Controlled Trial
NMDA receptor antagonists have a vital role in extinction, learning, and reconsolidation processes. During the reconsolidation window, memories are activated into a labile state and can be reconsolidated in an altered form. This concept might have significant clinical implications in treating PTSD. In this pilot study we tested the potential of a single infusion of ketamine, followed by brief exposure therapy, to enhance post-retrieval extinction of PTSD trauma memories. 27 individuals diagnosed with PTSD were randomly assigned to receive either ketamine (0.5 mg/kg 40 min; N = 14) or midazolam (0.045 mg/kg; N = 13) after retrieval of the traumatic memory. 24 h following infusion, participants received a four-day trauma-focused psychotherapy. Symptoms and brain activity were assessed before treatment, at the end of treatment, and at 30-day follow-up. Amygdala activation to trauma scripts (a major biomarker of fear response) served as the main study outcome. Although PTSD symptoms improved equally in both groups, post-treatment, ketamine recipients showed a lower amygdala (-0.33, sd = 0.13, 95%HDI [-0.56,-0.04]) and hippocampus (-0.3 (sd = 0.19), 95%HDI [-0.65, 0.04]; marginal effect) reactivation to trauma memories, compared to midazolam recipients. Post-retrieval ketamine administration was also associated with decreased connectivity between the amygdala and hippocampus (-0.28, sd = 0.11, 95%HDI [-0.46, -0.11]), with no change in amygdala-vmPFC connectivity. Moreover, reduction in fractional anisotropy in bi-lateral uncinate fasciculus was seen in the Ketamine recipients compared with the midazolam recipients (right: post-treatment: -0.01108, 95% HDI [-0.0184,-0.003]; follow-up: -0.0183, 95% HDI [-0.02719,-0.0107]; left: post-treatment: -0.019, 95% HDI [-0.028,-0.011]; follow-up: -0.017, 95% HDI [-0.026,-0.007]). Taken together it is possible that ketamine may enhance post-retrieval extinction of the original trauma memories in humans. These preliminary findings show promising direction toward the capacity to rewrite human traumatic memories and modulate the fear response for at least 30 days post-extinction. When combined with psychotherapy for PTSD, further investigation of ketamine dose, timing of administration, and frequency of administration, is warranted.
Topics: Humans; Extinction, Psychological; Ketamine; Midazolam; Pilot Projects; Psychotherapy; Stress Disorders, Post-Traumatic
PubMed: 37270621
DOI: 10.1038/s41386-023-01606-3 -
Physiology & Behavior May 2023Phenotypes of inbred mice are strain-dependent, indicating the important influence of genetic background in biomedical research. C57BL/6 is one of the most commonly used...
Phenotypes of inbred mice are strain-dependent, indicating the important influence of genetic background in biomedical research. C57BL/6 is one of the most commonly used inbred mouse strains, and its two closely related substrains, C57BL/6J and C57BL/6N, have been separated for only about 70 years. These two substrains have accumulated genetic variations and exhibit different phenotypes, but it remains unclear whether they respond to anesthetics differently. In this study, commercially acquired wildtype C57BL/6J or C57BL/6N mice from two different sources were analyzed and compared for their response to a spectrum of anesthetics (midazolam, propofol, esketamine or isoflurane anesthesia) and their performance in a series of behavioral tests associated with neurological functions including open field test (OFT), elevated plus maze (EPM), Y maze, prepulse inhibition (PPI), tail strain test (TST) and forced swimming test (FST). Loss of the righting reflex (LORR) is used to measure the anesthetic effects. Our results suggested that the anesthesia induction time induced by either of the four anesthetics were comparable for the C57BL/6J and C57BL/6N mice. However, C57BL/6J or C57BL/6N mice do exhibit different sensitivity to midazolam and propofol. The anesthesia duration of midazolam of C57BL/6J mice was about 60% shorter than that of the C57BL/6N mice, while the LORR duration induced by propofol in C57BL/6J mice was 51% longer than that of the C57BL/6N. In comparison, the two substrains were anesthetized by esketamine or isoflurane similarly. In the behavioral analysis, the C57BL/6J mice exhibited a lower level of anxiety- and depression-like behaviors in OFT, EPM, FST and TST than the C57BL/6N mice. Locomotor activity and sensorimotor gating of these two substrains remained comparable. Our results stress the point that when selecting inbred mice for allele mutation or behavioral testing, the influence of even subtle differences in genetic background should be fully considered.
Topics: Mice; Animals; Propofol; Midazolam; Mice, Inbred C57BL; Isoflurane; Mice, Inbred Strains; Anesthetics; Anesthesia
PubMed: 36889487
DOI: 10.1016/j.physbeh.2023.114146