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PubMed1994

Intrathecal midazolam reduces isoflurane MAC and increases the apnoeic threshold in rats.

The purpose of this study was to examine the anaesthetic requirement of intrathecal midazolam in a dose-response fashion in isoflurane-anaesthetized, tracheostomized rats, and to evaluate the apnoeic threshold after each intrathecal midazolam dose. Intrathecal midazolam, 5, 10, 20, and 30 micrograms, was administered to 25 anaesthetized tracheotomized rats. Isoflurane MAC was determined by the tail-clamp method. The effect of intrathecal midazolam on the apnoeic threshold was evaluated, and light and electron microscopy studies were performed on cervical, thoracic and lumbar sections of the spinal cord to investigate possible midazolam-induced neurotoxic effects. Intrathecal midazolam 5, 10, 20 and 30 micrograms decreased isoflurane MAC by 16%, 31%, 42%, and 53% respectively (P < 0.05). The apnoeic threshold was increased by midazolam 5 micrograms (from a PaCO2 of 4.25 +/- 0.55 to 5.28 +/- 0.76 kPa, P < 0.05) when compared with baseline values, but not further by additional doses. Light and electron microscopy studies on sections taken from the spinal cord of four animals did not show any morphological changes suggestive of midazolam-induced neurotoxicity when compared with similar preparations obtained from controls. These data suggest that intrathecal midazolam possesses dose-dependent antinociceptive properties which, associated with the ceiling effect of the apnoeic threshold obtained at the lowest midazolam dose and the lack of neurotoxic effects, may potentiate inhalational anaesthesia without producing marked respiratory depression.

Anesthesia, Spinal↗
PubMed1995

Sedative and ventilatory effects of midazolam infusion: effect of flumazenil reversal.

The purpose of this study was to evaluate the effects of flumazenil (1 mg i.v.) on the ventilatory response of premedicated patients receiving a continuous infusion of midazolam for sedation. After assessing baseline ventilatory function using a modified Read rebreathing method for determining hypercapnic ventilatory drive, 16 healthy outpatients were administered fentanyl, 50 micrograms i.v., and midazolam 2 mg i.v., followed by a variable-rate midazolam infusion, 0.3-0.5 mg.min-1. Upon termination of the midazolam infusion, serum midazolam concentrations were measured and ventilatory function was reassessed. Then, 10 ml either saline or flumazenil (1 mg) were administered according to a randomized, double-blind protocol. Ventilatory function was subsequently measured at 5 min, 30 min and 60 min intervals after study drug. Compared with the baseline value, midazolam infusion reduced tidal volume and increased respiratory rate and alveolar dead space. However, midazolam did not decrease the slope of the CO2-response curve. Flumazenil reduced the degree of midazolam-induced sedation and the decrease in tidal volume (P < 0.05), but not the change in resting respiratory rate. In some patients, the ventilatory response to hypercarbia actually decreased after flumazenil administration compared with the immediate prereversal (sedated) values. It is concluded that midazolam infusion, 0.43 mg.min-1, did not impair CO2-responsiveness. Flumazenil's effect on central ventilatory drive was more variable than its reversal of midazolam-induced sedation.

Adult↗
PubMed1997

Midazolam reverses histamine-induced bronchoconstriction in dogs.

PURPOSE: Midazolam has been used clinically as a sedative and as an anaesthetic induction agent. However, the bronchodilating effects of midazolam have not been comprehensively evaluated. We sought to determine relaxant effects of midazolam on the airway. METHODS: After our Animal Care Committee approved the study, eight mongrel dogs were anaesthetized with 30 mg.kg-1 pentobarbitone iv, and were paralysed with 200 micrograms.kg-1.hr-1 pancuronium. The trachea was intubated with an endotracheal tube (ID 7 mm) that had a second lumen for insertion of a superfine fibreoptic bronchoscope (OD 2.2 mm) to measure the bronchial cross-sectional area (BCA) continuously. The tip of the bronchoscope was placed at the level of the second or third bronchial bifurcation of the right bronchus. A videoprinter printed the BCA which was then measured with a NIH image program. Bronchoconstriction was produced with histamine (H) 10 micrograms.kg-1 followed by 500 micrograms.kg-1.hr-1. Thirty minutes later, 0 [saline], 0.01, 0.1 and 1.0 mg.kg-1 midazolam and 25 micrograms.kg-1 flumazenil were given. The BCA was assessed before (basal area) and 30 min after the start of H infusion, and was also measured five minutes after each midazolam and flumazenil iv. At the same time, arterial blood was sampled for plasma catecholamine measurement. RESULTS: Histamine infusion decreased BCA to 49.7 +/- 17.3% of basal BCA. More than 0.1 mg.kg-1 midazolam increased BCA up to 71.7 +/- 15.3% of the basal (1.0 mg.kg-1) (P < 0.01). Plasma adrenaline concentration was decreased from 6.9 +/- 3.8 to 3.7 +/- 1.9 ng.ml-1 by 1.0 mg.kg-1 midazolam (P < 0.05). Flumazenil did not antagonize the relaxant effect of midazolam but reversed the inhibitory effect of midazolam on histamine-induced adrenaline release. CONCLUSION: Midazolam has a spasmolytic effect on constricted airways but this bronchodilatation was not reversed by flumazenil.

Anesthetics, Intravenous↗
PubMed2006

High-dose midazolam therapy for refractory status epilepticus in children.

OBJECTIVE: To assess the efficacy of high-dose midazolam in the treatment of refractory status epilepticus in children. SETTING: Paediatric intensive care unit (PICU). DESIGN: Audit of clinical experience. SUBJECTS: Seventeen consecutive patients treated for episodes of refractory status epilepticus. INTERVENTIONS: Algorithm-driven administration of intravenous midazolam to control RSE. Regular, mandatory, patient evaluation to avoid delay in the appropriate escalation of therapy. Our target was the abolition of clinical seizures within 30 min of initiating treatment and early confirmation of cessation of all seizure activity using EEG. The algorithm had failed if clinical seizures persisted beyond 30 min despite the administration of midazolam at 24 microg/kg/min or if administration of a further acute anti-epileptic drug was required to achieve seizure control. MEASUREMENTS: The midazolam infusion rate, cumulative midazolam dose and duration of midazolam therapy at time of clinical seizure control were recorded. Haemodynamic parameters were recorded continuously. Episodes of algorithm failure, breakthrough seizures and seizure relapses were identified. Patient outcome was measured in terms of survival to PICU discharge. RESULTS: In 13 patients (76%) midazolam achieved clinical seizure control within 30 min of treatment initiation. Midazolam was eventually successful in treating 15 seizure episodes (88%). Breakthrough seizures occurred in 8 patients (47%). Relapse after discontinuation of therapy occurred in 1 patient (6%). No significant adverse effects attributable to the use of midazolam occurred. There were 3 deaths (18%) related to underlying CNS pathology. CONCLUSIONS: Midazolam can offer control of refractory status epilepticus without significant morbidity.

Adolescent↗
PubMed2003

A clinical study investigating the pharmacokinetic interaction between NN703 (tabimorelin), a potential inhibitor of CYP3A4 activity, and midazolam, a CYP3A4 substrate.

OBJECTIVE: NN703 (tabimorelin) is an orally active growth hormone (GH) secretagogue intended for use as an alternative to daily injections of GH. In vitro studies in human liver microsomes have indicated that NN703 is a mechanism-based inhibitor of CYP3A4. The aim of the present study was to investigate in man the effects of NN703 on the pharmacokinetics of midazolam, a substrate of CYP3A4. METHODS: Seventeen adult male subjects were enrolled in the study, and each received an oral dose of midazolam (7.5 mg) on four occasions: at baseline (day 1), after one dose of NN703 (day 3), after 7 days once daily NN703 treatment (day 9) and after a 7-day washout period (day 16). The pharmacokinetics of midazolam and its main metabolite, alpha-hydroxymidazolam, were investigated. RESULTS: Following a single dose of NN703 (day 3), the AUC of both midazolam and alpha-hydroxymidazolam increased by 64% and 34%, respectively (P=0.0001 for both). After repeated NN703 dosing (day 9), NN703 levels reached steady state, and midazolam AUC further increased to 93% relative to baseline (P=0.0001), whereas alpha-hydroxymidazolam AUC decreased slightly and was 11% higher than baseline (n.s.). Following the washout period (day 16), midazolam AUC decreased to values lower than those on day 3 and day 9, but still significantly (45%) higher than baseline levels (P=0.0001). The C(max) values of midazolam and alpha-hydroxymidazolam demonstrated a pattern similar to the AUC, but the effect following repeated NN703 dosing was more pronounced. The t(1/2) of midazolam increased from day 1 to day 3 (P=0.0483) but was essentially unchanged at steady state on day 9. CONCLUSION: This study shows that administration of NN703 and midazolam, a CYP3A4 substrate, leads to a significant increase in exposure of midazolam. This is consistent with NN703 inhibition of CYP3A4 activity.

Adjuvants, Anesthesia↗
PubMed2000

Effects of metronidazole on midazolam metabolism in vitro and in vivo.

OBJECTIVE: Case reports have described elevated concentrations of CYP3A4 substrates (e.g. cyclosporin) during metronidazole treatment. Therefore, we wanted to study whether metronidazole affects CYP3A4 activity, using midazolam as a model substrate in vitro and in vivo. METHODS: In the in vitro part of the study, the effects of various concentrations of metronidazole (0-500 microM) on the formation of 1'-hydroxymidazolam from midazolam were studied using human liver microsomal preparations (n = 4). In the in vivo part, the effects of metronidazole on the pharmacokinetics and pharmacodynamics of oral midazolam were evaluated in a randomised, placebo-controlled cross-over study in ten healthy subjects. The subjects took either 400 mg metronidazole or matched placebo orally twice daily for 3 days. On day 3, 15 mg midazolam was administered orally. Plasma concentrations of midazolam and 1'-hydroxymidazolam were determined up to 24 h. The effects of midazolam were measured up to 10 h. RESULTS: Metronidazole (10-500 microM) showed no inhibitory effect on 1'-hydroxymidazolam formation by human liver microsomes. In healthy volunteers, metronidazole had no statistically significant effects on the pharmacokinetics of midazolam and 1'-hydroxymidazolam, and also the ratio of 1'-hydroxymidazolam to midazolam in plasma remained unchanged by metronidazole. The four employed psychomotor tests did not show significant differences between the metronidazole and placebo phases. CONCLUSION: Metronidazole had no effects on the 1'-hydroxylation of midazolam in vitro or on the pharmacokinetics and pharmacodynamics of midazolam in vivo. These findings indicate that metronidazole is not an inhibitor of CYP3A4.

Administration, Oral↗
PubMed1997

Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam.

OBJECTIVE: Midazolam is a short-acting benzodiazepine hypnotic extensively metabolized by CYP3A4 enzyme. Orally ingested azole antimycotics, including fluconazole, interfere with the metabolism of oral midazolam during its absorption and elimination phases. We compared the effect of oral and intravenous fluconazole on the pharmacokinetics and pharmacodynamics of orally ingested midazolam. METHODS: A double-dummy, randomized, cross-over study in three phases was performed in 9 healthy volunteers. The subjects were given orally fluconazole 400 mg and intravenously saline within 60 min; orally placebo and intravenously fluconazole 400 mg; and orally placebo and intravenously saline. An oral dose of 7.5 mg midazolam was ingested 60 min after oral intake of fluconazole/placebo, i.e. at the end of the corresponding infusion. Plasma concentrations of midazolam, alpha-hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h. RESULTS: Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC0-3, AUC0-17) 2- to 3-fold, the elimination half-life of midazolam 2.5-fold and its peak concentration (Cmax) 2- to 2.5-fold compared with placebo. The AUC0-3 and the Cmax of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects of midazolam but no differences were detected between the fluconazole phases. CONCLUSION: We conclude that the metabolism of orally administered midazolam was more strongly inhibited by oral than by intravenous administration of fluconazole.

Administration, Oral↗
PubMed1993

Dynorphin A(1-17) mediates midazolam antagonism of morphine antinociception in mice.

Studies have shown that midazolam acts in the brain to antagonize the antinociception produced by morphine. The purpose of this study was to determine if spinal dynorphin A(1-17) (Dyn) was involved in the antagonistic effects of midazolam. A number of drugs when administered intracerebroventricularly (ICV) to mice release Dyn in the spinal cord to antagonize morphine-induced antinociception. In the present study using the mouse tail-flick test, midazolam administered ICV produced a dose related reduction of the antinociception induced by morphine given intrathecally (IT). The antagonistic action of midazolam against morphine-induced antinociception involved the release of Dyn in the spinal cord, as evidenced by the following results. 1) Administration of naloxone, nor-binaltorphimine and dynorphin antiserum, IT, eliminated the antagonistic effect of midazolam, given ICV, against morphine. Treatment with these opioid antagonists and dynorphin antiserum is known to inhibit the action of spinally released Dyn. 2) Production of desensitization to the effect of spinal Dyn by pretreating with morphine, 10 mg/kg subcutaneously 3 h before the tail-flick test, abolished the antagonistic action of midazolam given ICV. A 3-h pretreatment with midazolam, ICV, also produced desensitization to the antianalgesic action of Dyn given IT. 3) Elimination of the Dyn component of action of midazolam by administration of naloxone, nor-binaltorphimine and dynorphin antiserum, IT, uncovered slight antinociceptive activity of midazolam, given ICV. Coadministration of flumazenil (a benzodiazepine antagonist), bicuculline (a GABA antagonist) and picrotoxin (a chloride ion channel blocker) inhibited the midazolam effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1994

The anxiolytic effects of intravenous sedation using midazolam alone or in multiple drug techniques.

This study examines four drug combinations (midazolam, midazolam-midazolam, fentanyl-midazolam, and fentanyl-midazolam-methohexital) in a placebo-controlled double-blind clinical trial of intravenous sedation. It tests the hypothesis that there is no difference between the anxiolytic effect of the four combinations when compared with a saline placebo. Subjects were 207 mildly anxious young adults having their third molars removed. Cognitive measures of anxiety increased from preoperative levels in the placebo and both midazolam groups (P < .05). The anxiety response remained the same in the fentanyl-midazolam and fentanyl-midazolam-methohexital groups (P > .05). The level of successful anxiolysis ranged from 24% in the placebo group to 74% in the barbiturate group. Using the log likelihood method, comparisons suggest that the drug groups (from midazolam alone to the methohexital combination) have increasingly positive anxiolytic effects even when controlling for the effects of dental fear and intraoperative pain. The fentanyl-midazolam group is 8.1 and the methohexital group is 9.0 times more likely to have had a favorable outcome than the placebo group. Additional analyses of behavioral measures of anxiety yielded parallel results. Global evaluations after surgery were related to the success of anxiolysis for subjects in the active drug conditions (P < .05).

Adult↗
PubMedDate not supplied

Patient-controlled drug administration during local anesthesia: a comparison of midazolam, propofol, and alfentanil.

STUDY OBJECTIVE: To evaluate the perioperative effects of alfentanil, midazolam, and propofol when administered using a patient-controlled analgesia (PCA) device during local anesthesia. DESIGN: Randomized, single-blind comparative study. SETTING: Outpatient surgery center at a university teaching hospital. PATIENTS: Ninety outpatients undergoing minor elective surgical procedures with local anesthetic infiltration were assigned to one of three treatment groups. INTERVENTIONS: After premedication with midazolam 1 mg intravenously (IV) and fentanyl 50 micrograms IV, patients were allowed to self-administer 2 ml bolus doses of either alfentanil 250 micrograms/ml, midazolam 0.4 mg/ml, or propofol 10 mg/ml at minimal intervals of 3 minutes to supplement a basal infusion rate of 5 ml/hr. MEASUREMENTS AND MAIN RESULTS: The total intraoperative dosages of alfentanil, midazolam, and propofol were 2.7 +/- 1.1 mg, 4.7 +/- 2.7 mg, and 114 +/- 42 mg, respectively, for procedures lasting 48 +/- 28 minutes to 51 +/- 19 minutes (means +/- SD). Propofol produced more pain on injection (39% vs. 4% and 6% in the alfentanil and midazolam groups, respectively). Episodes of arterial oxygen saturation less than 90% were more frequent with alfentanil (28%) than with midazolam (3%) or propofol (13%). Using the visual analog scale, patients reported comparable levels of discomfort, anxiety, and sedation during the operation in all three treatment groups. Postoperative picture recall was significantly decreased with midazolam versus alfentanil and propofol. Finally, postoperative nausea was reported more frequently in the alfentanil group (29%) than in the midazolam (10%) or propofol (18%) groups, contributing to a significant prolongation of the discharge time in the alfentanil-treated patients. CONCLUSIONS: When self-administered as adjuvants during local anesthesia using a PCA delivery system, alfentanil, midazolam, and propofol were equally acceptable to patients. However, propofol and midazolam were associated with fewer perioperative complications than was alfentanil.

Adult↗
PubMed2005

Randomized clinical trial comparing intravenous midazolam and droperidol for sedation of the acutely agitated patient in the emergency department.

STUDY OBJECTIVE: We compare intravenous midazolam and droperidol for the onset of sedation of acutely agitated patients in the emergency department (ED). METHODS: This was a double-blind, randomized, clinical trial set in the ED of a university teaching hospital. Subjects were adults, acutely agitated because of mental illness, intoxication, or both, who received midazolam or droperidol, 5 mg intravenously, every 5 minutes until sedated. We analyzed time to sedation using survival analysis, median times to sedation, and proportions sedated at 5 and 10 minutes. RESULTS: Seventy-four patients received midazolam; 79 patients, droperidol. Survival analysis showed no difference in time to sedation (hazard ratio 0.86; 95% confidence interval [CI] 0.61 to 1.23), P=.42. Median time to sedation was 6.5 minutes for midazolam (median dose 5 mg) and 8 minutes for droperidol (median dose 10 mg), P=.075 (effect size 1.5 minutes; 95% CI 0 to 4 minutes). At 5 minutes, 33 of 74 (44.6%) patients from the midazolam group were adequately sedated compared with 13 of 79 (16.5%) patients from the droperidol group, a difference of 28.1% (95% CI 12.9% to 43.4%; P<.001). By 10 minutes, 41 of 74 (55.4%) from the midazolam group were sedated compared to 42 of 79 (53.2%) from droperidol, a difference of 2.2% (95% CI -14.9% to 19.3%; P=.91). Eleven adverse events occurred in the midazolam group and 10 in the droperidol group. Three patients required active airway management (3 patients with assisted ventilation and 1 patient intubated); all received midazolam. CONCLUSION: There is no difference in onset of adequate sedation of agitated patients using midazolam or droperidol. Patients sedated with midazolam may have an increased need for active airway management.

Adolescent↗
PubMed2004

Mechanisms of antiplatelet and antithrombotic activity of midazolam in in vitro and in vivo studies.

Midazolam is widely used as a sedative and anesthetic induction agent. The aim of this study was to systematically examine the inhibitory mechanisms of midazolam in platelet aggregation. In this study, midazolam concentration-dependently (15 and 30 microM) inhibited platelet aggregation in washed human platelets stimulated by thrombin (0.05 U/ml). Midazolam (15 and 30 microM) also inhibited phosphoinositide breakdown and intracellular Ca(+2) mobilization in platelets stimulated by thrombin (0.05 U/ml). In addition, midazolam (15 and 30 microM) increased the formation of cyclic AMP but not cyclic GMP or nitric oxide. The thrombin-evoked increase in pHi was markedly inhibited in the presence of midazolam (15 and 30 microM). Rapid phosphorylation of a platelet protein of molecular weight (Mr.) 47,000 (P47), a marker of protein kinase C activation, was triggered by thrombin (0.05 U/ml). This phosphorylation was markedly inhibited by midazolam (15 and 30 microM). Midazolam (30 microM) did not significantly reduce the electron spin resonance signal intensity of hydroxyl radicals in activated platelets. In the vivo study, intravenous injection of midazolam (10 microg/g) significantly prolonged the latent period of inducing platelet plug formation in mesenteric venules. These results indicate that midazolam can significantly prevent thrombus formation in vivo. Its antiplatelet activity may be involved in the inhibition of the activation of phospholipase C and the Na(+)/H(+) exchanger and increased cyclic AMP formation. These lead to lower intracellular Ca(+2) mobilization and phosphorylation of P47.

Blood Platelets↗
PubMed2005

Anticonvulsant treatment of sarin-induced seizures with nasal midazolam: an electrographic, behavioral, and histological study in freely moving rats.

Centrally mediated seizures and convulsions are common consequences of exposure to organophosphates (OPs). These seizures rapidly progress to status epilepticus (SE) and contribute to profound brain injury. Effective management of these seizures is critical for minimization of brain damage. Nasal application of midazolam (1.5 mg/kg) after 5 min of sarin-induced electrographic seizure activity (EGSA) ameliorated EGSA and convulsive behavior (238 +/- 90 s). Identical treatment after 30 min was not sufficient to ameliorate ECoG paradoxical activity and convulsive behavior. Nasal midazolam (1.5 mg/kg), together with scopolamine (1 mg/kg, im) after 5 min of EGSA, exerted a powerful and rapid anticonvulsant effect (53 +/- 10 s). Delaying the same treatment to 30 min of EGSA leads to attenuation of paroxysmal ECoG activity in all cases but total cessation of paroxysmal activity was not observed in most animals tested. Cognitive tests utilizing the Morris Water Maze demonstrated that nasal midazolam alone or together with scopolamine (im), administered after 5 min of convulsions, abolished the effect of sarin on learning. Both these treatments, when given after 30 min of convulsions, only decreased the sarin-induced learning impairments. Whereas rats which were not subject to the anticonvulsant agents did not show any memory for the platform location, both treatments (at 5 min as well as at 30 min) completely abolished the memory deficits. Both treatments equally blocked the impairment of reversal learning when given at 5 min. However, when administered after 30 min, midazolam alone reversed the impairments in reversal learning, while midazolam with scopolamine did not. Rats exposed to sarin and treated with the therapeutic regimen with the exclusion of midazolam exhibited severe brain lesions that encountered the hippocampus, pyriform cortex, and thalamus. Nasal midazolam at 5 min prevented brain damage, while delaying the midazolam treatment to 30 min of EGSA resulted in brain damage. The addition of scopolamine to midazolam did not alter the above observation. In summary, nasal midazolam treatment briefly after initiation of OP-induced seizure leads to cessation of EGSA and prevented brain lesions and behavioral deficiencies in the rat model.

Administration, Intranasal↗
PubMed2005

Cerebral and plasma kinetics of a high dose of midazolam and correlations with its respiratory effects in rats.

Benzodiazepine poisoning causes coma and respiratory depression. Our objective was to determine whether, and to what extent, arterial blood gas disturbances correlated with blood or cerebral kinetics of midazolam. A 160 mgkg(-1) single dose of midazolam was infused intravenously over 20 min in catheterized male Sprague-Dawley rats. Midazolam kinetics was simultaneously determined in plasma and brain using striatal microdialysis. Midazolam concentrations were measured using a high-performance liquid chromatographic assay with ultraviolet detection. Midazolam (160 mgkg(-1)) reproducibly induced deep coma with respiratory acidosis. Plasma midazolam kinetics was well described by a bi-exponential model, with an elimination half-life of 6.4+/-1.8 h. The striatal dialysate concentration peaked at 50.0+/-8.9 min after the end of infusion, with a significant delay to peak concentration compared to plasma. Respiratory depression, assessed by the elevation in PaCO2, was more closely correlated with midazolam striatal dialysate rather than plasma kinetics. These results suggest a central mechanism for midazolam respiratory effects at toxic doses in rats. In conclusion, our study showed a delayed onset in peak PaCO2 and pH effects after the slow infusion of a toxic dose of midazolam in rats. The effects on arterial blood gases were better correlated with midazolam striatal concentrations than with plasma concentrations. This study may contribute to better understanding of benzodiazepine-induced respiratory depression in poisonings.

Acidosis↗
PubMed1998

Midazolam premedication improves tolerance of transesophageal echocardiography.

Patient premedication for transesophageal echocardiography (TEE) is still under debate, especially the use of sedatives. We performed a double-blind, placebo-controlled study to clarify the efficacy of low-dose intravenous midazolam as premedication for TEE. Placebo or midazolam (< or =50 kg, 2.0 mg intravenously; 50 to 80 kg, 2.5 mg; and > or =80 kg, 3.0 mg intravenously) was given in addition to topical anesthesia to 200 consecutive in- and outpatients. Blood pressure, heart rate, and oxygen saturation were monitored. Patients were interviewed immediately, and 2 to 10 days after TEE. Sixteen patients received an additional dose of midazolam, and in 12 follow-up was incomplete. Patients taking midazolam reported less gag reflex at probe introduction and during TEE, as did the examiners (p < 0.05 to 0.0001). Probe manipulations were found to produce less discomfort after midazolam administration (p < 0.005). Midazolam patients experienced less dyspnea (p < 0.01) despite a minimal decrease in oxygen saturation of 2% (p < 0.0001). The following day patients taking midazolam reported less sore throats, and painful swallowing was less frequent (p < 0.01 to 0.001). Systolic blood pressure decreased slightly in the midazolam group (132 +/- 24 to 121 +/- 20 mm Hg, p < 0.0001). The rate of minor complications showed no difference. Thus, TEE probe introduction and manipulation was tolerated better after low-dose midazolam premedication, and patients experienced less pharyngeal discomfort the day after. Midazolam was well tolerated and the complication rate did not increase. Thus low-dose, short-acting benzodiazepine premedication improves patient comfort during and after TEE and generous use can be recommended.

Anesthetics, Intravenous↗
PubMed2003

Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe.

BACKGROUND: Aprepitant is a neurokinin(1) receptor antagonist that enhances prevention of chemotherapy-induced nausea and vomiting when added to conventional therapy with a corticosteroid and a 5-hydroxytryptamine(3) (5-HT(3)) antagonist. Because aprepitant may be used with a variety of chemotherapeutic agents and ancillary support drugs, which may be substrates of cytochrome P450 (CYP) 3A4, assessment of the potential of this drug to inhibit CYP3A4 activity in vivo is important. The effect of aprepitant on in vivo CYP3A4 activity in humans with oral midazolam used as a sensitive probe of CYP3A4 activity was evaluated in this study. METHODS: In this open-label, randomized, single-period study, 16 healthy male subjects were enrolled. Subjects received one of two oral aprepitant regimens for 5 days (8 subjects per regimen): (1) 125 mg aprepitant on day 1 and then 80 mg/d on days 2 to 5 or (2) 40 mg aprepitant on day 1 and then 25 mg/d on days 2 to 5. All subjects also received a single oral dose of midazolam, 2 mg, at prestudy (3 to 7 days before aprepitant treatment) and on days 1 and 5 (1 hour after aprepitant administration). RESULTS: Coadministration of midazolam and 125/80 mg aprepitant increased the midazolam area under the plasma concentration-time curve by 2.3-fold on day 1 (P <.01) and by 3.3-fold on day 5 (P <.01), as compared with midazolam alone (prestudy). The 125/80-mg regimen of aprepitant also increased the midazolam maximum observed concentration by 1.5-fold on day 1 (P <.05) and by 1.9-fold on day 5 (P <.01). The midazolam half-life values increased from 1.7 hours (prestudy) to 3.3 hours on both day 1 and day 5. Coadministration of 40/25 mg aprepitant and midazolam did not result in significant changes in the midazolam area under the plasma concentration-time curve, maximum observed concentration, and half-life at either day 1 or day 5. CONCLUSIONS: The 5-day 125/80-mg regimen of aprepitant produced moderate inhibition of CYP3A4 activity in humans, as measured with the use of midazolam as a probe drug.

Adult↗
PubMed1996

First-pass metabolism of midazolam by the human intestine.

The in vivo intestinal metabolism of the CYP3A probe midazolam to its principal metabolite, 1'-hydroxymidazolam, was investigated during surgery in 10 liver transplant recipients. After removal of the diseased liver, five subjects received 2 mg midazolam intraduodenally, and the other five received 1 mg midazolam intravenously. Simultaneous arterial and hepatic portal venous blood samples were collected during the anhepatic phase; collection of arterial samples continued after reperfusion of the donor liver. Midazolam, 1'-hydroxymidazolam, and 1'-hydroxymidazolam glucuronide were measured in plasma. A mass balance approach that considered the net change in midazolam (intravenously) or midazolam and 1'-hydroxymidazolam (intraduodenally) concentrations across the splanchnic vascular bed during the anhepatic phase was used to quantitate the intestinal extraction of midazolam after each route of administration. For the intraduodenal group, the mean fraction of the absorbed midazolam dose that was metabolized on transit through the intestinal mucosa was 0.43 +/- 0.18. For the intravenous group, the mean fraction of midazolam extracted from arterial blood and metabolized during each passage through the splanchnic vascular bed was 0.08 +/- 0.11. Although there was significant intersubject variability, the mean intravenous and intraduodenal extraction fractions were statistically different (p = 0.009). Collectively, these results show that the small intestine contributes significantly to the first-pass oxidative metabolism of midazolam catalyzed by mucosal CYP3A4 and suggest that significant first-pass metabolism may be a general phenomenon for all high-turnover CYP3A4 substrates.

Adolescent↗
PubMed1999

Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: effect of ketoconazole.

BACKGROUND: The cytochrome P450 3A (CYP3A) isoforms are responsible for the metabolism of a majority of therapeutic compounds, and they are abundant in the intestine and liver. CYP3A activity is highly variable, causing difficulty in the therapeutic use of CYP3A substrates. A practical in vivo probe method that characterizes both intestinal and hepatic CYP3A activity would be useful. OBJECTIVES: To determine the intestinal and hepatic contribution to the bioavailability of midazolam with use of the CYP3A inhibitor ketoconazole. METHODS: The pharmacokinetics of midazolam was assessed in nine (six men and three women) healthy individuals after single doses of 2 mg intravenous and 6 mg oral midazolam (phase I). These pharmacokinetic values were compared with those obtained after single doses of 2 mg intravenous and 6 mg oral midazolam and three doses of 200 mg oral ketoconazole (phase II). RESULTS: After ketoconazole therapy, area under the concentration versus time curve of midazolam increased 5-fold after intravenous midazolam administration (P < or = .001) and 16-fold after oral midazolam administration (P < or = .001). Intrinsic clearance decreased by 84% (P = .003). Total bioavailability increased from 25% to 80% (P < .001). The intestinal component of midazolam bioavailability increased to a greater extent than the hepatic component (2.3-fold [P = .003] and 1.5-fold [P < or = .001], respectively). In the control phase, female subjects had greater midazolam clearance values than the male subjects. CONCLUSIONS: Ketoconazole caused marked inhibition of CYP3A activity that was greater in the intestine than the liver. Administration of single doses of oral and intravenous midazolam with and without oral ketoconazole exemplifies a practical method for differentiating intestinal and hepatic CYP3A activity.

Administration, Oral↗