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PubMed2002

Oral midazolam premedication in preadolescents and adolescents.

UNLABELLED: We sought to determine the influence of preoperative oral midazolam on 1) sedation score, 2) measures of anesthetic emergence, 3) recovery times, and 4) bispectral index (BIS) measurements during sevoflurane/N(2)O anesthesia in adolescent patients. Fifty ASA I and II patients 10-18 yr of age were enrolled in a prospective double-blinded study. Patients were randomized to receive either 20 mg of midazolam (M group) or midazolam vehicle (P group) as premedication. Before the induction, sedation scores and BIS values were determined in all patients. After inhaled induction and intubation, expired sevoflurane was stabilized at 3% in 60% N(2)O and the corresponding BIS (BIS I) recorded. Upon completion of surgery, sevoflurane was stabilized at 0.5% and the BIS (BIS E) again recorded. Plasma midazolam levels were measured at the time of BIS I and BIS E. There were no significant differences between groups in awakening time, sevoflurane/N(2)O awakening concentrations, time to postanesthesia care unit discharge, or BIS I and BIS E measurements. Sedation scores and preinduction BIS values were significantly lower in Group M than in Group P, although only 40% of midazolam-treated patients exhibited detectable sedation, with marked interindividual variability in achieved plasma midazolam levels. Detectable preoperative sedation was predictive of delayed emergence. IMPLICATIONS: We demonstrated a measurable sedative effect of oral midazolam in adolescents which correlated with simultaneous bispectral index (BIS) measurement. Considering the overall group, midazolam premedication did not affect intraoperative BIS, emergence times, or recovery times compared with placebo controls. Detectable preoperative sedation, and not merely midazolam administration, was predictive of prolonged emergence.

Administration, Oral↗
PubMed2002

The influence of parecoxib, a parenteral cyclooxygenase-2 specific inhibitor, on the pharmacokinetics and clinical effects of midazolam.

UNLABELLED: Parecoxib, a parenteral cyclooxygenase-2 inhibitor, is undergoing clinical development as an analgesic/antiinflammatory drug for perioperative use. Parecoxib, an inactive prodrug, is hydrolyzed in vivo to valdecoxib, a substrate for hepatic cytochrome P450 (CYP) 3A4. Thus, potential exists for interactions with other CYP3A4 substrates. In this investigation, we determined the influence of parecoxib on the pharmacokinetics and clinical effects of midazolam, a CYP3A4 substrate, in volunteers. This was a randomized, balanced crossover, placebo-controlled, double-blinded clinical investigation. Twelve healthy subjects aged 23-41 yr were studied after providing IRB-approved informed consent. Midazolam 0.07 mg/kg IV infusion was administered 1 h after placebo (control) or parecoxib 40 mg IV. Venous midazolam concentrations were determined by using liquid chromatography-mass spectrometry/mass spectrometry assay. Pharmacokinetic variables were determined by noncompartmental analysis. Pharmacodynamic measurements included clinical end-points, cognitive function (memory; digit symbol substitution tests), subjective self-assessment of recovery (visual analog scales), and bispectral index. Midazolam plasma concentrations were similar between placebo and parecoxib-treated subjects. No differences were found in midazolam pharmacokinetics (maximal observed plasma concentration, clearance, elimination half-life, volume of distribution) or pharmacodynamics (clinical end-points, digit symbol substitution tests, memory, visual analog scales, bispectral index). Single-bolus parecoxib does not alter the pharmacokinetics or pharmacodynamics of midazolam infusion. Parecoxib did not affect CYP3A4 activity as assessed using midazolam clearance as the in vivo probe. IMPLICATIONS: Parecoxib, a parenteral cyclooxygenase-2 inhibitor intended for perioperative use as an analgesic/antiinflammatory drug, is a substrate for hepatic cytochrome P450 3A4. The potential for a drug interaction with midazolam, an in vivo CYP3A4 probe, was tested in healthy volunteers. Single-bolus parecoxib does not alter the pharmacokinetics or pharmacodynamics of midazolam.

Adult↗
PubMed1993

Transmucosal administration of midazolam for premedication of pediatric patients. Comparison of the nasal and sublingual routes.

BACKGROUND: Nasal transmucosal midazolam is effective for premedication of pediatric patients; however, 61-74% of these patients cry at nasal drug administration. Sublingual benzodiazepines, including midazolam, are effective in adults. The current blinded randomized study compared acceptance of and behavioral responses to transmucosal midazolam administered via the intranasal and sublingual routes. METHODS: Ninety-three patients aged 0.5-10 yr were stratified by age: 30 infants and toddlers, 0.5-2 yr; 39 preschoolers, 2.1-5 yr; and 24 school age, 5.1-10 yr. They were randomized to receive 0.2 mg/kg of midazolam in the nose or under the tongue without or with additional flavoring. For the group receiving sublingual flavored midazolam, the syringe tip was dipped in candy flavor and sugar. Duration of crying and compliance with instructions for sublingual drug administration were recorded. Hemoglobin oxygen saturation by pulse oximetry and sedation score were recorded by three observers before drug administration, at 2.5-min intervals for 10 min, at separation from parents, and during induction with halothane in O2. RESULTS: Children accepted midazolam administered via the sublingual route better than that given intranasally. In children not crying before drug administration, the frequency and duration of crying was greater following intranasal compared with sublingual administration (71% vs. 18% (P < 0.0001) and 48 +/- 56 vs. 25 +/- 49 s (P = 0.004), respectively). Lack of total compliance with instructions for sublingual administration did not alter drug effect, and there were no differences between the three study groups in maximum sedation, response to separation from parents, and behavior at induction of anesthesia; 80% displayed adequate or excellent behavior. Finally, the addition of candy flavor did not improve acceptance of or compliance with sublingual midazolam administration. CONCLUSIONS: Sublingual administration of midazolam is as effective as, and better accepted than, intranasal midazolam as a preanesthetic sedative in children.

Administration, Intranasal↗
PubMed1993

Hypnotic and anesthetic interactions between ketamine and midazolam in female patients.

BACKGROUND: Midazolam, if used with ketamine for induction and maintenance of anesthesia, may attenuate hyperdynamic circulatory effects and prevent undesirable emergenic reactions. The nature of the interaction between midazolam and ketamine used for anesthesia induction was studied in female patients. METHODS: Quantal dose-response curves were determined in 170 female patients for the drugs, individually and in combination. Two endpoints were assessed, loss of response to verbal command (hypnosis) and loss of response to a 5-s transcutaneous tetanus (anesthesia). At the hypnotic endpoint, interactions were analyzed by fitting the data to a mathematical model in which the response was analyzed in terms of the doses of the two drugs, and an additional term was included to describe nonadditive interactions. At the anesthetic endpoint, the decrease in ED50 of ketamine in the presence of midazolam was assessed because dose-related effects could not be demonstrated for midazolam alone. RESULTS: At the hypnotic endpoint, the ED50s were: 0.15 mg/kg midazolam (95% CIs 0.11-0.38 mg/kg), 0.37 mg/kg ketamine (95% CIs 0.08-0.44 mg/kg), and the combination of 0.086 mg/kg midazolam and 0.27 mg/kg ketamine (95% CIs 0.07/0.22-0.10/0.31 mg/kg), respectively. The hypnotic effects were found to be additive, and there was no evidence of an interaction. At the anesthetic endpoint, the ED50 of ketamine alone was 0.57 mg/kg (95% CIs 0.47-0.69) and the ED50 for ketamine in the presence of midazolam was also 0.57 mg/kg (95% CIs 0.48-0.79); 0.18 mg/kg midazolam was given at this point. Midazolam had no influence on the anesthetic dose of ketamine. CONCLUSIONS: When using the combination, doses employed should be adjusted according to the depth of central nervous system depression that is required.

Adolescent↗
PubMed1996

Semilinear canonical correlation applied to the measurement of the electroencephalographic effects of midazolam and flumazenil reversal.

BACKGROUND: The electroencephalographic (EEG) effect of benzodiazepines, and midazolam in particular, has been described using simple measures such as total power in the beta band, waves.s(-1) in the beta band and total power from aperiodic analysis. All these parameters failed to consistently describe the EEG effect of midazolam in a study in which large doses of midazolam were infused, and the effect subsequently reversed with flumazenil. Using a technique called semilinear correlation it is possible to extract a parameter from the EEG that is statistically optimally correlated with the apparent concentration of the benzodiazepine in the effect site. This method has been used to develop new univariate measures of the effects of opioids on the EEG but has not previously been applied to the EEG effects of benzodiazepines. METHODS: Data from ten subjects who received an infusion of midazolam were analyzed. The data were divided into "learning" and "test" sets. The learning set consisted of ten studies in which the volunteers received an infusion of 2.5 mg.min(-1) midazolam. Semilinear canonical correlation was used to extract an univariate descriptor of the EEG effect by weighting the different frequency bands of the EEG power spectrum. The test set comprised the same subjects on subsequent visits, in which the subjects received a continuous infusion of midazolam to maintain 20% or 80% of the peak drug effect for 3h. Twenty minutes after start of the midazolam infusion, the patient received an infusion of flumazenil to acutely reverse the benzodiazepine drug effect. The weights obtained from the learning set were tested prospectively in the test set, based on the coefficient of multiple determination, R(2), obtained by fitting the EEG effect to a sigmoid Emax model. RESULTS: The canonical univariate parameter of benzodiazepine drug effect on the EEG, when applied to the test set receiving the midazolam infusion with flumazenil reversal, yielded a median R(2) of 0.78. The median R(2) of six commonly used empirical EEG measures of drug effect ranged from 0.18 to 0.55. CONCLUSIONS: The canonical univariate parameter for benzodiazepine drug effect on the EEG correlates more accurately and consistently with the predicted EEG effects of midazolam and its reversal than previously reported EEG measures of benzodiazepine effect.

Adult↗
PubMed1998

Population pharmacokinetics of midazolam administered by target controlled infusion for sedation following coronary artery bypass grafting.

BACKGROUND: Midazolam is commonly used for short-term postoperative sedation of patients undergoing cardiac surgery. The purpose of this multicenter study was to characterize the pharmacokinetics and intersubject variability of midazolam in patients undergoing coronary artery bypass grafting. METHODS: With institutional review board approval, 90 consenting patients undergoing coronary artery bypass grafting were enrolled at three study centers. All subjects received sufentanil and midazolam via target-controlled infusions. After operation, midazolam was titrated to maintain deep sedation for at least 2 h. It was then titrated downward to decrease sedation for a minimum of 4 h more and was discontinued before tracheal extubation. Arterial blood samples were taken throughout the study and were assayed for midazolam and 1-hydroxymidazolam. Midazolam population pharmacokinetic parameters were estimated using NONMEM. Cross-validation was used to estimate the performance of the model. RESULTS: The pharmacokinetics of midazolam were best described by a simple three-compartment mammillary model. Typical pharmacokinetic parameters were V1 = 32.2 l, V2 = 53 l, V3 = 245 l, Cl1 = 0.43 l/min, Cl2 = 0.56 l/min, and Cl3 = 0.39 l/min. The calculated elimination half-life was 15 h. The median absolute prediction error was 25%, with a bias of 1.4%. The performance in the cross-validation was similar. Midazolam metabolites were clinically insignificant in all patients. CONCLUSIONS: The intersubject variability and predictability of the three-compartment pharmacokinetic model are similar to those of other intravenous anesthetic drugs. This multicenter study did not confirm previous studies of exceptionally large variability of midazolam pharmacokinetics when used for sedation in intensive care settings.

Adult↗
PubMed1998

Isobolographic analysis of the interactions between midazolam and propofol at GABA(A) receptors in embryonic mouse neurons.

BACKGROUND: Clinical studies suggest that midazolam and propofol interact synergistically to induce hypnosis, but these drugs do not interact synergistically to prevent movement in response to noxious stimuli. The mechanisms underlying these interactions are not certain but may occur at the level of the gamma-aminobutyric acid A (GABA(A)) receptor. METHODS: The authors evaluated the interactions between propofol and midazolam in modulating GABA(A) receptor activity in embryonic hippocampal neurons. The effects of midazolam and propofol on peak current evoked by submaximal concentrations of GABA were studied using the patch clamp method. Isobolographic analysis was undertaken by constructing concentration-response curves for midazolam and propofol alone and then evaluating the potency of combinations of midazolam and propofol. In other experiments, the concentration of GABA was increased and flurazepam was substituted for midazolam. RESULTS: Isobolographic analysis confirmed that midazolam and propofol interact synergistically to enhance currents evoked by low concentrations of GABA (1 microM). However, when the concentration of GABA was increased to 3 microM, the interaction was additive. The interaction between flurazepam and propofol was also additive for enhancement of currents evoked by 3 microM GABA. CONCLUSIONS: The interaction between midazolam and propofol was critically dependent on the concentration of GABA: Synergism was evident at low concentrations of GABA, but an additive interaction was apparent when the concentration of GABA was increased. Changes in GABA(A) receptor function may underlie the synergistic interaction between propofol and midazolam for clinical effects such as hypnosis. The clinical implication of the results is that the benefits of synergism observed at one concentration ratio of these drugs may not be apparent at another.

Anesthetics, Intravenous↗
PubMed2006

Midazolam inhibits proinflammatory mediators in the lipopolysaccharide-activated macrophage.

BACKGROUND: Midazolam, a benzodiazepine, has a hypnotic effect and is widely used as a sedative. The role of midazolam in activation of macrophages during sepsis is not known. The aim of this study was to evaluate the antiinflammatory actions of midazolam in cultured macrophages. METHODS: Using a macrophage cell line, RAW264.7 cells, the effect of midazolam on proinflammatory mediators and activation of mitogen-activated protein kinase was measured by Western blot. Nuclear factor-kappaB (NF-kappaB) activation and translocation of p65 subunit of NF-kappaB was measured using luciferase assay and immunocytochemistry. Superoxide production was measured by lucigenin chemiluminescence. RESULTS: Midazolam significantly inhibited lipopolysaccharide-induced up-regulation of both cyclooxygenase 2 and inducible nitric oxide synthase in a dose-dependent manner (approximately 3-30 microm). IkappaB-alpha degradation and NF-kappaB transcriptional activity induced by lipopolysaccharide were also suppressed by the midazolam. Nuclear translocation of the p65 subunit of NF-kappaB was inhibited by midazolam. Furthermore, midazolam suppressed phosphorylation of p38 mitogen-activated protein kinase and also inhibited lipopolysaccharide-induced superoxide production in macrophages. CONCLUSIONS: These results suggest that midazolam has an antiinflammatory action by inhibiting inducible nitric oxide synthase and cyclooxygenase-2 expression, possibly through suppression of NF-kappaB and p38 mitogen-activated protein kinase activation.

Animals↗
PubMed2002

A dose-ranging study of midazolam for postoperative sedation of patients: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the dose range, efficacy, and safety of midazolam for induction of sedation of mechanically ventilated postoperative patients in the intensive care unit. DESIGN: A randomized, double-blind, placebo-controlled study. SETTING: Thirteen intensive care units in Japan. PATIENTS: We included 98 patients undergoing general surgery who were ASA physical status I-III. The following inclusion criteria were applied to the patients after surgery: under mechanical ventilation, sedation level 2 or 3 on the Ramsay Sedation Scale, and any pain level but 4 on the Pybus and Torda Pain Scale. MEASUREMENTS AND RESULTS: Of the 98 patients initially enrolled in the study, 95 patients received one of the study medications: placebo (n = 24), 0.015 mg/kg midazolam (n = 21), 0.03 mg/kg midazolam (n = 26), or 0.06 mg/kg midazolam (n = 24). Level of sedation was assessed by using the Ramsay Sedation Scale before and 10 mins after medication. The proportions of patients with sedation level 4 or deeper after medication were 4.3%, 14.3%, 52.0%, and 90.9% in the placebo and the midazolam 0.015 mg/kg, 0.03 mg/kg, and 0.06 mg/kg groups, respectively. Safety was assessed by routine monitoring of body functions and monitoring for adverse events. Although midazolam dose-dependently reduced mean systolic arterial pressure, the changes in this variable were small; only one or two patients in each treatment group had decreases in systolic arterial pressure of >20%. No clear dose dependency was found for changes in other body functions measured in the intensive care unit. CONCLUSION: The proportion of patients who achieved a satisfactory level of sedation increased with an increasing dose of midazolam. Intravenous bolus injection of midazolam also dose-dependently reduced mean systolic arterial pressure. This study indicated that, balancing sedative efficacy and safety, from 0.03 to 0.06 mg/kg of midazolam provides relatively safe sedation in postoperative patients.

Adult↗
PubMed1983

Preclinical pharmacology of midazolam.

Midazolam, a new imidazobenzodiazepine, forms salts that are stable in water solution, and has an overall pharmacological potency similar to that of diazepam but a much shorter duration of action. It produces all the characteristic effects of the benzodiazepine class. Its metabolites account for only a negligible part, if any, of its pharmacological effects observed in the mouse. The time course of its anticonvulsant activity, studied with different experimental protocols and by different routes of administration, revealed an almost immediate onset of action. Midazolam was slightly more potent, and its duration of action was shorter than diazepam, in enhancing presynaptic inhibition in the spinal cord of cats and in depressing spontaneous activity of cerebellar Purkinje cells in the rat. Midazolam decreased spontaneous multiunit activity (MUA) in different nuclei of the brain in 'encéphale isolé' rats. This depression was reversed by Ro 15-1788, a recently discovered selective benzodiazepine antagonist. Midazolam and diazepam decreased the cyclic GMP level in the cerebellum of rats with about the same potency; the effect of midazolam was of much shorter duration than that of diazepam. Midazolam had one-third the potency of diazepam in displacing 3H-flunitrazepam in mouse brain in vivo, and also in this case the effect of midazolam was of brief duration, as compared with diazepam. Midazolam in therapeutic doses was virtually ineffective in the cardiovascular system of conscious dogs after p.o. or i.v. administration. No direct effects of the drug on autonomic functions were found. The animal data suggest the usefulness of midazolam as an oral sleep-inducer, as an agent for i.v. induction of anaesthesia and as an i.v. or i.m. anticonvulsant in status epilepticus or tetanus, because of its rapid onset of action and its excellent local tolerance as water-soluble injection form.

Animals↗
PubMed2006

Lack of a pharmacokinetic interaction between steady-state roflumilast and single-dose midazolam in healthy subjects.

AIMS: The aim of this study was to investigate the effects of roflumilast, an investigational PDE4 inhibitor for the treatment of COPD and asthma, on the pharmacokinetics of the CYP3A probe drug midazolam and its major metabolites. METHODS: In an open, randomized (for midazolam treatment sequence) study, 18 healthy male subjects received single doses of midazolam (2 mg oral and 1 mg i.v., 1 day apart) alone, repeated doses of roflumilast (500 microg once daily for 14 days) alone, and repeated doses of roflumilast together with single doses of midazolam (2 mg oral and 1 mg i.v., 1 day apart). RESULTS: A comparison of clearance and peak and systemic exposure to midazolam following administration of roflumilast indicated no effect of roflumilast dosed to steady state on the pharmacokinetics of midazolam. Point estimates (90% CI) were 0.97 (0.84, 1.13) for the AUC of i.v. midazolam and 0.98 (0.82, 1.17) for that of oral midazolam with and without roflumilast. CONCLUSIONS: Therapeutic steady state concentrations of roflumilast and its N-oxide do not alter the disposition of the CYP3A substrate midazolam in healthy subjects. This finding suggests that roflumilast is unlikely to alter the clearance of drugs that are metabolized by CYP3A4.

Adult↗
PubMed1988

Prolonged elimination of midazolam after i.m. administration.

The elimination pharmacokinetics of midazolam after i.m. administration was compared with combined i.m. and i.v. administration in a randomized study of 55 gynaecological patients in outpatient general anaesthesia. Group 1 (n = 40) received midazolam 0.1 mg/kg i.m. as premedication 45 min before induction of general anaesthesia with midazolam 0.3 mg/kg i.v. Group 2 (n = 15) received midazolam 0.1 mg/kg i.m. as premedication 45 min before induction of general anaesthesia with thiopentone 4 mg/kg. Serum midazolam concentration measurements were performed regularly post-induction for 7 h in each patient. The elimination half-life of midazolam after i.m. administration (Group 2) was 6.6 +/- 1.2 h (mean +/- s.e. mean), which was significantly longer (P less than 0.05) than the 3.9 +/- 0.3 h observed after the combined i.m. and i.v. administration of midazolam (Group 1), and significantly longer than 2.9 h obtained from a calculated i.v. administration curve. We postulate a slow i.m. depot release of midazolam, representing the rate-limiting step in the elimination of midazolam after i.m. administration.

Adult↗
PubMed1988

Pharmacokinetics of midazolam and alfentanil in outpatient general anesthesia. A study with concomitant thiopentone, flumazenil or placebo administration.

The pharmacokinetics of alfentanil, midazolam and thiopentone used for induction of short general anaesthesia were studied in 55 gynaecological outpatients. All the patients received midazolam as premedication. The patients received intravenous anaesthesia with alfentanil and either thiopentone or midazolam, supplemented with either nitrous oxide or air in oxygen ventilation, reversed by the end of anaesthesia with either placebo or flumazenil. Blood sampling for serum concentration measurements of midazolam, alfentanil and thiopentone was performed regularly for 7 h. The following mean pharmacokinetic parameters (mean +/- s.e. mean) were calculated for midazolam and alfentanil, respectively: elimination half-life 3.9 +/- 0.3 h and 1.2 +/- 0.05 h, apparent volume of distribution 107 +/- 61 and 31 +/- 1.5 l, total body clearance 20 +/- 0.7 l/h and 18 +/- 0.8 l/h. No influence of flumazenil on the kinetics of midazolam and no influence of thiopentone, midazolam, flumazenil or nitrous oxide on the kinetics of alfentanil was found. The serum levels of thiopentone were below the detection limit of the assay after 60 min, which made an evaluation of pharmacokinetic parameters impossible. Significant positive correlations were found in the individual patient between midazolam and alfentanil for all pharmacokinetic variables evaluated. For midazolam, an increase in the elimination half-life and the apparent volume of distribution was positively correlated to an increase of body-weight. For alfentanil, a decrease in the total body clearance and an increase in the elimination half-life were positively correlated to an increase of age. A prolonged elimination half-life of alfentanil was positively correlated to use of alcohol. High serum levels of thiopentone were positively correlated to increasing age of the patients.

Adult↗
PubMed1994

Response of pial vessel diameter and regional cerebral blood flow to CO2 during midazolam administration in cats.

Midazolam has been demonstrated to preserve the response of cerebral blood flow to CO2. However, the responsiveness of cerebral vessels or microcirculation during midazolam administration related to alteration of cerebral blood flow has not been explored. The purpose of this study was to examine the effects of midazolam on cerebral microcirculation. Nine cats were paralyzed and mechanically ventilated under nitrous oxide/oxygen anaesthesia. Using the closed cranial window technique and laser Doppler flowmetry, diameter of pial vessels and regional cerebral blood flow (rCBF) were examined on the surface of the cerebral cortex which was perfused by the middle cerebral artery. Before midazolam administration, haemodynamic variables, blood gases, rCBF, and diameter of pial vessels were determined as a control under normocapnia, hypocapnia, and hypercapnia conditions. After midazolam administration, given initially at 0.8 mg.kg-1.min-1 for 10 min and subsequently at 0.04 mg.kg-1.min-1 (total dose 10 mg.kg-1), the same variables were again analyzed. With regard to CO2 responsiveness, an 8.85% increase in rCBF was demonstrated for a Paco2 elevation of 1 kPa before midazolam administration, compared with a 7.47% increase after midazolam administration. With regard to the correlation between CO2 response and vessel diameter, arterioles less than 50 microns in diameter were more sensitive than those more than 50 microns in diameter, although there were no significant differences before or after midazolam administration. We conclude that CO2 responsiveness is preserved in terms of rCBF and vessel diameter after high doses of midazolam (10 mg.kg-1) in cats.

Animals↗
PubMed2004

Jet injector compared with oral midazolam for preoperative sedation in children.

BACKGROUND: This study compared onset of sedation and satisfaction with two needleless jet injectors with the oral route for the administration of midazolam. METHODS: Forty-five children ages 1-6 years were randomly assigned to receive either 0.5 mg kg(-1) oral midazolam, 0.2 mg kg(-1) subcutaneous midazolam by J-Tip injector or 0.2 mg kg(-1) intramuscular midazolam by Bioject injector. After midazolam administration the children were monitored for oxygen saturation, heart rate and level of sedation (0, alert; 1, calm; 2, drowsy; 3, dozing; 4, asleep) every 2 min for 20 min by a physician blinded to the route of administration. Patient satisfaction, resistance to treatment, success of delivery, problems with separation, and acceptance of mask at the time of induction were evaluated after midazolam treatment. RESULTS: The Bioject showed a faster onset of sedation than either the J-Tip injector or the oral midazolam (P < 0.05). The children were significantly less satisfied with the Bioject and J-Tip administration vs oral midazolam (P < 0.05). There were no differences in resistance, success of delivery, problems with separation, mask acceptance, arterial oxygen saturation or heart rate. CONCLUSION: Despite children being less satisfied with Bioject injection of midazolam, the procedure is safe, effective and provides a more rapid onset of preoperative sedation in children than either the J-Tip injection or oral route.

Administration, Oral↗
PubMed2006

Duration of pleconaril effect on cytochrome P450 3A activity in healthy adults using the oral biomarker midazolam.

The objective of this study was to evaluate the duration of oral pleconaril (a picornavirus inhibitor) effect on intestinal and hepatic cytochrome P450 (P450) 3A activity as assessed by oral midazolam. Healthy adults received oral midazolam (0.075 mg/kg) on days 1 (baseline), 7, 9, 13, 20, 27, and 34. Oral pleconaril (400 mg) three times daily for 15 doses was administered on days 2 through 7. Blood samples were collected during each day of midazolam dosing to determine plasma midazolam concentrations. On days 5, 6, and 7, blood samples were collected to determine plasma pleconaril concentrations. Midazolam pharmacokinetics were determined by noncompartmental analyses, with bioequivalence assessed by least-squares geometric mean ratios (LS-GMR) and 90% confidence intervals (90% CI). Eighteen subjects completed the study. Midazolam C(max) (LS-GMR; 90% CI) decreased 24% on day 7 (0.76; 0.66-0.87). Midazolam oral clearance increased 53% on day 7 (1.53; 1.38-1.69). Midazolam oral clearance remained different on days 9 (1.38; 1.25-1.52) and 13 (1.19; 1.07-1.31) versus day 1. Midazolam volume of distribution (1.82; 1.57-2.11) and elimination half-life (1.19; 1.03-1.38) were also different on day 7 in comparison with day 1. Oral pleconaril increased intestinal and hepatic CYP3A activity. The duration of increased CYP3A activity by pleconaril was at least 6 days (but no longer than 13 days) after pleconaril discontinuation.

Adult↗
PubMed2003

Prediction of the in vivo interaction between midazolam and macrolides based on in vitro studies using human liver microsomes.

Clinical studies have revealed that plasma concentrations of midazolam after oral administration are greatly increased by coadministration of erythromycin and clarithromycin, whereas azithromycin has little effect on midazolam concentrations. Several macrolide antibiotics are known to be mechanism-based inhibitors of CYP3A, a cytochrome P450 isoform responsible for midazolam hydroxylation. The aim of the present study was to quantitatively predict in vivo drug interactions in humans involving macrolide antibiotics with different inhibitory potencies based on in vitro studies. alpha- and 4-Hydroxylation of midazolam by human liver microsomes were evaluated as CYP3A-mediated metabolic reactions, and the effect of preincubation with macrolides was examined. The hydroxylation of midazolam was inhibited in a time- and concentration-dependent manner following preincubation with macrolides in the presence of NADPH, whereas almost no inhibition was observed without preincubation. The kinetic parameters for enzyme inactivation (K'app and kinact) involved in midazolam alpha-hydroxylation were 12.6 microM and 0.0240 min-1, respectively, for erythromycin, 41.4 microM and 0.0423 min-1, respectively, for clarithromycin, and 623 microM and 0.0158 min-1, respectively, for azithromycin. Similar results were obtained for the 4-hydroxylation pathway. These parameters and the reported pharmacokinetic parameters of midazolam and macrolides were then used to simulate in vivo interactions based on a physiological flow model. The area under the concentration-time curve (AUC) of midazolam after oral administration was predicted to increase 2.9- or 3.0-fold following pretreatment with erythromycin (500 mg t.i.d. for 5 or 6 days, respectively) and 2.1- or 2.5-fold by clarithromycin (250 mg b.i.d. for 5 days or 500 mg b.i.d. for 7 days, respectively), whereas azithromycin (500 mg o.d. for 3 days) was predicted to have little effect on midazolam AUC. These results agreed well with the reported in vivo observations.

Anti-Bacterial Agents↗
PubMed2000

Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study.

OBJECTIVE: To compare the safety and efficacy of midazolam given intranasally with diazepam given intravenously in the treatment of children with prolonged febrile seizures. DESIGN: Prospective randomised study. SETTING: Paediatric emergency department in a general hospital. SUBJECTS: 47 children aged six months to five years with prolonged febrile seizure (at least 10 minutes) during a 12 month period. INTERVENTIONS: Intranasal midazolam (0.2 mg/kg) and intravenous diazepam (0.3 mg/kg). MAIN OUTCOME MEASURES: Time from arrival at hospital to starting treatment and cessation of seizures. RESULTS: Intranasal midazolam and intravenous diazepam were equally effective. Overall, 23 of 26 seizures were controlled with midazolam and 24 out of 26 with diazepam. The mean time from arrival at hospital to starting treatment was significantly shorter in the midazolam group (3.5 (SD 1.8) minutes, 95% confidence interval 3.3 to 3.7) than the diazepam group (5.5 (2.0), 5.3 to 5.7). The mean time to control of seizures was significantly sooner (6.1 (3.6), 6.3 to 6.7) in the midazolam group than the diazepam group (8.0 (0.5), 7. 9 to 8.3). No significant side effects were observed in either group. CONCLUSION: Seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam, although midazolam was as safe and effective as diazepam. The overall time to cessation of seizures after arrival at hospital was faster with intranasal midazolam than with intravenous diazepam. The intranasal route can possibly be used not only in medical centres but in general practice and, with appropriate instructions, by families of children with recurrent febrile seizures at home.

Administration, Intranasal↗