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PubMed1996

Comparative absorption kinetics of intramuscular midazolam and diazepam.

PURPOSE: This study investigates the rate and extent of absorption following intramuscular injection of midazolam and diazepam. METHODS: Four healthy male volunteers were recruited in this randomized three-way cross-over study. On one occasion each subject received simultaneous im injections of 5 mg midazolam and 10 mg diazepam in separate deltoid muscles. On two other separate occasions each subject received an iv infusion of 7.5 mg midazolam and 30 mg diazepam over five minutes. Frequent arterial blood samples were collected for up to two hours and venous blood samples were collected for up to 24 hours for midazolam and ten days for diazepam. A gas chromatography assay was used to determine the plasma concentrations of midazolam and diazepam. The im absorption profiles were estimated using constrained least-squares deconvolution. RESULTS: There were substantial intersubject variabilities in the estimated pharmacokinetic parameters (volume and clearances) of intravenous midazolam and diazepam. The mean (+/-sd) time to peak plasma concentration (Cmax) was shorter for im midazolam (17.5 +/- 6.5 min) relative to diazepam (33.8 +/- 7.5 min). The mean (+sd) time to peak absorption rate was also shorter for midazolam (9 +/- 2 vs 13.8 +/- 7.5 min). The peak rate of absorption was identical (0.18 mg. min-1) and bioavailability was 1.0 for both drugs. CONCLUSIONS: We conclude that midazolam has more rapid absorption than diazepam following im administration.

Absorption↗
PubMed1999

Midazolam effects on implicit and explicit memory processes in healthy subjects.

RATIONALE: Studying midazolam-induced amnesia offers an interesting approach to the organization of normal memory processes, since memory performance can be studied in the same subject in "on" and "off" drug conditions. OBJECTIVE: The present study investigated the effect of midazolam on skill learning. The task and the experimental design we used also allowed us to assess the effect of midazolam on priming and explicit memory. METHODS: Eighteen patients who underwent minor ear surgery and who were anaesthetized with intravenous midazolam, and 18 matched control subjects participated in a mirror reading task on 2 separate days. Patients were tested under midazolam on day 1 and without any medication on day 2. The mirror reading task was made of French words, some of which repeated across trial blocks, others being new. RESULTS: Patients under midazolam read new mirror written words faster with practice, which attested for intact skill learning. Moreover, they read repeated words faster than new words with practice, which was interpreted as reflecting intact priming abilities. These spared implicit memory capacities were observed along with severe explicit memory impairments. Learning for both new and repeated mirror written words on day 2 was similar in patients and in controls, which was interpreted as suggesting that the implicit learning that occurred on day 1 under midazolam was normal. CONCLUSIONS: The quality of skill learning, both in terms of speed of and lasting effect, was normal under midazolam in the task we used. In the context of the present task, midazolam offers an interesting, reversible model of amnesia.

Adult↗
PubMed1996

Effects of heat exposure in a Finnish sauna on the pharmacokinetics and metabolism of midazolam.

OBJECTIVE: The effect of short-term heat exposure in a Finnish sauna on hepatic first-pass metabolism and the capacity to metabolize midazolam were studied in a crossover trial. Midazolam oral (15 mg) and intravenous (0.05 mg.kg-1) was given to 6 healthy young male volunteers, in random order, during a control session and a sauna bathing session (temperature 85-100 degrees C, relative humidity 25-30%). Blood samples for the determination of plasma midazolam and alpha-hydroxy midazolam concentrations were taken for 6 h after drug administration. RESULTS: After oral administration, the bioavailability and clearance of midazolam were not affected by sauna bathing, nor was there a significant difference in alpha-hydroxy midazolam plasma concentration or the alpha-hydroxy midazolam/midazolam AUC-ratio between the sessions. Midazolam Cmax was increased and its t1/2 beta was prolonged during the sauna session, but the clinical relevance of the findings appears to be modest. The pharmacokinetics of intravenous midazolam were not affected by sauna bathing. CONCLUSIONS: Short-term heat exposure may not affect the first-pass metabolism or hepatic capacity to metabolize midazolam.

Adult↗
PubMed1998

The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin.

OBJECTIVE: To determine the effects of treatment with itraconazole and rifampicin (rifampin) on the pharmacokinetics and pharmacodynamics of oral midazolam during and 4 days after the end of the treatment. METHODS: Nine healthy volunteers received itraconazole (200 mg daily) for 4 days and, 2 weeks later, rifampicin (600 mg daily) for 5 days. In addition, they ingested 15 mg midazolam before the first treatment, 7.5 mg on the last day of itraconazole administration, and 4 days later, and 15 mg 1 day and 4 days after the last dose of rifampicin. The disposition of midazolam and its alpha-hydroxy metabolite was determined and its pharmacodynamic effects were measured. RESULTS: During itraconazole treatment, or 4 days after, alpha-hydroxymetabolite the dose-corrected area under the plasma midazolam concentration time curve (AUC0-infinity) was 8- or 2.6-fold larger than that before itraconazole (i.e. 1707 or 695 versus 277 ng x h x ml(-1)), respectively. One day after rifampicin treatment, the AUC0-infinity of midazolam was 2.3% (i.e. 4.4 ng x h x ml(-1)) of the before-treatment value and only 0.26% of its value during itraconazole treatment; 4 days after rifampicin, the AUC0-infinity was still only 13% (i.e. 27.1 ng x h x ml(-1)) of the before-treatment value. The peak concentration and elimination half-life of midazolam were also increased by itraconazole and decreased by rifampicin. The ratio of plasma alpha-hydroxymidazolam to midazolam was greatly decreased by itraconazole and increased by rifampicin. In addition, the effects of midazolam were greater during itraconazole and smaller 1 day after rifampicin than without treatment. CONCLUSION: Switching from inhibition to induction of cytochrome P450 3A (CYP3A) enzymes causes a very great (400-fold) change in the AUC of oral midazolam. During oral administration of CYP3A substrates that undergo extensive first-pass metabolism, similar changes in pharmacokinetics are expected to occur when potent inhibitors or inducers of CYP3A are added to the treatment. After cessation of treatment with itraconazole or rifampicin, the risk of significant interaction continues up to at least 4 days, probably even longer.

Administration, Oral↗
PubMed1995

Interaction between grapefruit juice and midazolam in humans.

OBJECTIVE: To investigate the effects of grapefruit juice on the pharmacokinetics and dynamics of midazolam. METHODS: Eight healthy male subjects participated in this open crossover study. Intravenous (5 mg) or oral (15 mg) midazolam was administered after pretreatment with water or grapefruit juice. We measured the pharmacokinetics and pharmacodynamics (reaction time, Digit Symbol Substitution Test [DSST], general impression judged by the investigators, and drug effect judged by the subjects) of midazolam and the pharmacokinetics of alpha-hydroxymidazolam. RESULTS: In comparison to water, pretreatment with grapefruit juice did not change the pharmacokinetics or pharmacodynamics of intravenous midazolam. After oral administration, pretreatment with grapefruit juice led to a 56% increase in peak plasma concentration (Cmax), a 79% increase in time to reach Cmax (tmax), and a 52% increase in the area under the plasma concentration-time curve (AUC) of midazolam, which was associated with an increase in the bioavailability from 24% +/- 3% (water) to 35% +/- 3% (Grapefruit juice; mean +/- SEM, p < 0.01) After oral administration of midazolam, pretreatment with grapefruit juice was associated with a 105% increase in tmax and with a 30% increase in the AUC of alpha-hydroxymidazolam. For oral midazolam, pretreatment with grapefruit juice led to significant increases in tmax for all dynamic parameters and in the AUC values for the reaction time and DSST, whereas the maximal dynamic effects remained unchanged. CONCLUSIONS: Pretreatment with grapefruit juice is associated with increased bioavailability and changes in the pharmacodynamics of midazolam that may be clinically important, particularly in patients with other causes for increased midazolam bioavailability such as advanced age, cirrhosis of the liver, and administration of other inhibitors of cytochrome P450.

Administration, Oral↗
PubMedDate not supplied

Midazolam in combination with propofol for sedation during local anesthesia.

STUDY OBJECTIVE: To compare the sedative, anxiolytic, and amnestic effects, as well as the recovery characteristics, when midazolam (vs. a placebo) is administered to patients receiving a propofol infusion for sedation during local anesthesia. DESIGN: Randomized, double-blind, placebo-controlled study to evaluate the perioperative effects of intravenous (IV) midazolam. SETTING: Outpatient surgery center of a university-affiliated medical center. PATIENTS: One hundred thirty-nine consenting, ASA physical status I, II, and III outpatients undergoing elective surgical procedures under local anesthesia. INTERVENTIONS: Patients were randomly assigned to receive either midazolam 2 mg IV or saline 2 ml IV prior to injection of local anesthesia. Intraoperative sedation was maintained using a variable-rate propofol infusion. MEASUREMENTS AND MAIN RESULTS: Preoperative assessment of sedation, anxiety, and amnesia was performed before and after IV midazolam. Intraoperative evaluations included level of sedation, as well as cardiovascular and respiratory measurements, at 1- to 5-minute intervals during the operation. Postoperatively, recovery of psychomotor function and patients' subjective feelings were assessed using the visual analog scale and questionnaires. Amnesia was assessed using picture recall during the perioperative period. In the operating room, midazolam 2 mg IV, compared with the placebo, produced a significantly greater increase in patients' level of sedation (7 +/- 13 mm to 49 +/- 21 mm for midazolam vs. 8 +/- 11 mm to 19 +/- 21 mm for the placebo; p less than 0.01) and a greater decrease in anxiety level (62 +/- 25 mm to 21 +/- 21 mm for midazolam vs. 54 +/- 27 mm to 53 +/- 22 mm for the placebo; p less than 0.01). Although the propofol dosage requirements to maintain comparable levels of sedation were similar in both groups, midazolam decreased patients' recall of intraoperative events (e.g., propofol-induced pain on injection and discomfort with local anesthetic injection) without significantly altering cardiorespiratory parameters or prolonging times to ambulation and discharge from the outpatient facility. CONCLUSIONS: Premedication with midazolam 2 mg IV produced increased sedation, amnesia, and anxiolysis when administered immediately prior to the propofol infusion as part of a sedation technique for outpatient surgery. This combination did not prolong the recovery room stay when compared with propofol alone.

Adult↗
PubMedDate not supplied

Which induction drug for cesarean section? A comparison of thiopental sodium, propofol, and midazolam.

STUDY OBJECTIVE: To determine maternal and neonatal effects of three different induction drugs (thiopental sodium, propofol, and midazolam) for cesarean section. DESIGN: Randomized, double-blind study. SETTING: Inpatient obstetric department at a general hospital. PATIENTS: 90 healthy patients undergoing elective cesarean section with general anesthesia. INTERVENTIONS: 3 groups of 30 patients each receiving thiopental 5 mg/kg, propofol 2.4 mg/kg, or midazolam 0.3 mg/kg for induction of anesthesia. MEASUREMENTS AND MAIN RESULTS: Time to induce anesthesia, hemodynamic changes, depth of anesthesia, recovery after anesthesia, placental transfer, and neonatal outcome (Apgar and neurobehavioral examinations) were studied. In the thiopental and midazolam groups, systolic blood pressure and heart rate rose following endotracheal intubation and skin incision (p < 0.001 and p < 0.0025, respectively), while in the propofol group, there was significant hypotension after induction (p < 0.005). Electroencephalographic patterns showed a light depth of anesthesia with propofol and midazolam between anesthesia induction and delivery, confirmed by the presence of clinical signs of light anesthesia in 50% of propofol patients and 43% of midazolam patients. Time to induce anesthesia was longer with midazolam (p < 0.0001). Neonates in the midazolam and propofol groups had lower Apgar and neurobehavioral scores than those in the thiopental group. Umbilical artery to umbilical vein ratios were above 1 in the propofol and midazolam groups. CONCLUSION: Thiopental still remains the first-choice induction drug for cesarean section. The slow induction time with midazolam may put the mother at risk for pulmonary inhalation. A plane of anesthesia that may risk awareness and potential neonatal depression is the main drawback of the two newer induction drugs.

Adult↗
PubMed2004

Differential effects of midazolam on inhibitory postsynaptic currents in CA1 pyramidal cells and dentate gyrus granule cells of rat hippocampal slices.

To examine regional differences of synaptic transmission, the effects of midazolam were observed on inhibitory postsynaptic currents (IPSCs) in CA1 pyramidal cells (CA1-PCs) and dentate gyrus granule cells (DG-GCs) in rat hippocampal slices. Midazolam is one of the most popular benzodiazepines. The monosynaptic IPSCs in the CA1-PCs and DG-GCs were evoked by electrical stimulation of GABAergic interneurons and recorded by whole cell patch-clamp techniques. The effects of specific concentrations of midazolam (0.3, 1, 10 and 75 microM) on the IPSCs in CA1-PCs and DG-GCs were examined at particular membrane potentials (20 mV steps, from -120 to +40 mV). In all midazolam concentrations tested, the conductance of the IPSCs was significantly larger than that in control and was increased by increasing the concentration of midazolam in CA1-PCs (normalized conductance, 0.3 microM, 121%; 1 microM, 125%; 10 microM, 147%; 75 microM, 147%). However, midazolam did not significantly change the conductance of the IPSCs in DG-GCs (normalized conductance, 0.3 microM, 92%; 1 microM, 92%; 10 microM, 91%; 75 microM, 115%). The normalized conductance was significantly different between the CA1-PCs and DG-GCs in 1 and 10 microM midazolam. The results strongly suggest that the differential effects of midazolam on IPSCs in CA1-PCs and DG-GCs could be, at least in part, due to the different sensitivity to midazolam of the GABA(A) receptor subtypes.

Animals↗
PubMed2006

Comparison of midazolam and simvastatin as cytochrome P450 3A probes.

OBJECTIVE: Our objective was to compare simvastatin with the validated probe midazolam in the assessment of cytochrome P450 (CYP) 3A activity. METHODS: This study used an open-label, fixed-sequential, 3-way crossover study design. Nineteen subjects received oral doses of 0.075 mg/kg midazolam and 40 mg simvastatin during 3 phases (baseline, after inhibition with 400 mg ketoconazole for 10 days, and after induction with 600 mg rifampin [INN, rifampicin] for 9 days). Serial plasma concentrations of midazolam and simvastatin were obtained. Oral clearances of midazolam and simvastatin were compared. RESULTS: Oral midazolam clearance decreased after pretreatment with ketoconazole (from a geometric mean of 25 mL x min(-1) x kg(-1) [range, 12-57 mL x min(-1) x kg(-1)] to 2.7 mL x min(-1) x kg(-1) [range, 1.2-8.5 mL x min(-1) x kg(-1)], P < .001) and increased after pretreatment with rifampin (to a geometric mean of 203 mL x min(-1) x kg(-1) [range, 125-371 mL x min(-1) x kg(-1)], P < .001). Oral simvastatin clearance decreased after ketoconazole (from a geometric mean of 312 mL x min(-1) x kg(-1) [range, 151-1478 mL x min(-1) x kg(-1)] to 25 mL x min(-1) x kg(-1) [range, 8.0-147 mL x min(-1) x kg(-1)], P < .001) and increased after rifampin (to a geometric mean of 3536 mL x min(-1) x kg(-1) [range, 413-10,329 mL x min(-1) x kg(-1)], P < .001). The change in simvastatin clearance was highly variable from baseline to inhibition (6- to 33-fold decrease) and from baseline to induction (2- to 39-fold increase) compared with midazolam (7- to 18-fold decrease during inhibition and 4- to 12-fold increase during induction). Midazolam and simvastatin oral clearances were correlated for all study phases (r = 0.5 and P = .03 for baseline and r = 0.53 and P = .02 for inhibition) but were weakest for induction (r = -0.031, P = .22). The area under the concentration-time curve inhibitory ratio for midazolam was 9.4 versus 12.4 for simvastatin (r = 0.3, P = .03). CONCLUSIONS: Compared with midazolam, simvastatin is a nonvalidated, suboptimal probe for studying CYP3A drug interactions because of its lack of CYP3A specificity.

Administration, Oral↗
PubMed2004

Preoperative intravenous midazolam: benefits beyond anxiolysis.

STUDY OBJECTIVE: To evaluate the effect of midazolam on the global perioperative experience, including patient satisfaction, postoperative nausea and vomiting, postoperative pain, and perioperative anxiety and amnesia. DESIGN: Prospective, randomized, placebo-controlled study. SETTING: Ambulatory surgical center affiliated with a tertiary-care hospital. PATIENTS: 88 ASA physical status I, II, and III patients scheduled for outpatient surgery. INTERVENTIONS: Patients were randomized into two groups to receive either 0.04 mg/kg of midazolam or placebo intravenously (IV) 20 minutes preoperatively. MEASUREMENTS: Perioperative measurements included blood pressure, heart rate, and oxygen saturation and the patient's level of anxiety; type of anesthetic administered; the anesthesiologist's guess at the treatment arm; perioperative dosages of fentanyl, morphine, and ondansetron; recovery room length of stay; frequency of nausea and vomiting, and level of postoperative pain in the 24 hours after surgery; the patient's overall satisfaction with the anesthetic, and whether the patient would recommend the premedication to a friend. MAIN RESULTS: Patient demographics, type of surgery/anesthesia, vital signs, case duration, recovery duration, and postoperative pain were all similar between the midazolam and placebo groups. As expected, IV midazolam was an effective anxiolytic. There was no evidence of retrograde amnesia. Fewer patients in the midazolam group suffered from postoperative nausea than did those in the placebo group (25%vs. 50%;p = 0.03), despite receiving similar perioperative antiemetic and opioid administration. Similarly, fewer patients in the midazolam group experienced postoperative vomiting than placebo group patients (8%vs. 21%), although this difference did not reach statistical significance. Only 42% of patients in the placebo group would recommend their premedication to a friend, compared with 85% of patients in the midazolam group (p < 0.001). CONCLUSIONS: In addition to the known anxiolytic effects of midazolam, midazolam premedication is an effective way to reduce the frequency of postoperative nausea, and perhaps vomiting, and increase patient satisfaction.

Adolescent↗
PubMed1997

Effect of chronic treatment with morphine, midazolam and both together on dynorphin(1-13) levels in the rat.

We have recently reported that midazolam, a benzodiazepine receptor agonist that is also a short acting anesthetic and analgesic drug, can produce analgesia and decrease morphine tolerance and dependence in the rat by interacting with the opioidergic system. This study was designed to investigate the chronic effect of midazolam and/or morphine on the levels of dynorphin(1-13) in the pituitary gland, different brain regions, spinal cord and peripheral tissues of the rat. Four sets of animals were used: (I) saline-saline; (II) midazolam (0.03, 0.3 or 3.0 mg/kg, body wt., i.p.)-saline; (III) saline-morphine (10.0 mg/kg, body wt., s.c.); and (IV) midazolam-morphine (0.03, 0.3 or 3.0 mg/kg midazolam + 10.0 mg/kg morphine) groups. The first saline or midazolam injection was given i.p. and after 30 min, the second injection of saline or morphine was given s.c. daily for 11 days. Animals were sacrificed on the 11th day, 60 min after the last injection and dynorphin(1-13) was measured in indicated tissues by radioimmunoassay method. The midazolam treated animals showed a significant decrease in dynorphin(1-13) levels in the cortex, cerebellum, cervical region of spinal cord, heart and adrenals, and a significant increase in the hypothalamus, striatum and lumbar region of the spinal cord. The morphine treated animals showed a significant decrease in dynorphin(1-13) levels in the pituitary gland, hypothalamus, hippocampus, striatum, cerebellum, pons, medulla, kidneys, adrenals and spleen, and a significant increase only in the lumbar region of the spinal cord. When both drugs were injected together there was no effect on pituitary gland, kidneys and spleen. These drugs antagonize each other's effect on dynorphin(1-13) in the hypothalamus, striatum, cerebellum, pons, medulla and heart. However, the midazolam-morphine combination significantly increases dynorphin(1-13) levels in the hippocampus, cortex, midbrain, cervical and lumbar regions of the spinal cord, and adrenals. These results suggest the involvement of dynorphin(1-13) in the inhibition of morphine-induced tolerance and dependence by midazolam in the rat. These results may also help us in understanding the intrinsic mechanisms involved in narcotic tolerance and dependence.

Adrenal Glands↗
PubMed1997

Met-enkephalin alteration in the rat during chronic injection of morphine and/or midazolam.

We have recently reported that the short-acting anesthetic and analgesic drug midazolam can produce analgesia and decrease morphine tolerance and dependence in the rat by interacting with the opioid system. This study was designed to investigate the effect of midazolam, morphine, and both together on met-enkephalin levels in the rat. Male Sprague-Dawley rats were divided into four groups: (1) saline-saline; (2) saline-morphine; (3) midazolam-saline, and (4) midazolam-morphine groups. First, a saline or midazolam injection was given intraperitoneally and after 30 min a second injection of saline or morphine was given subcutaneously once daily for 11 days. Animals were sacrificed on the 11th day 60 min after the last injection to measure met-enkephalin by radioimmunoassay. Morphine tolerant animals showed a significant increase in met-enkephalin levels in the cortex (137%) and midbrain (89%), and a significant decrease in met-enkephalin levels in the pituitary (74%), cerebellum (34%) and medulla (72%). Midazolam treated animals showed a significant decrease in met-enkephalin levels in the pituitary (63%), cortex (39%), medulla (58%), kidneys (36%), heart (36%) and adrenals (43%), and a significant increase in met-enkephalin levels in the striatum (54%) and pons (51%). When morphine and midazolam were injected together, midazolam antagonized the increase in met-enkephalin levels in cortex and midbrain region and the decrease in met-enkephalin level in the medulla region observed in morphine tolerant animals. These results indicate that morphine tolerance and dependence is associated with changes in the concentration of met-enkephalin in the brain. Midazolam may inhibit morphine tolerance and dependence by reversing some of the changes induced in met-enkephalin levels in brain by morphine in morphine tolerant and dependent animals.

Animals↗
PubMed1996

Rifampin drastically reduces plasma concentrations and effects of oral midazolam.

BACKGROUND: Midazolam is a short-acting benzodiazepine that is metabolized by CYP3A enzymes. Rifampin is a potent enzyme inducer that may seriously interact with some substrates of CYP3A4. METHODS: The possible interaction between rifampin and midazolam was investigated in a double-blind, randomized crossover study of two phases. Rifampin (600 mg once daily) or placebo was administered to 10 healthy subjects for 5 days. On the sixth day, the subjects were given 15 mg oral midazolam. Plasma samples were collected for determination of midazolam, and pharmacodynamic effects were measured for 10 hours. RESULTS: Rifampin pretreatment decreased the area under the plasma midazolam concentration-time curve by 96% (i.e., from 10.2 +/- 0.8 to 0.42 +/- 0.05 micrograms.min/ml [mean +/- SEM; p < 0.001]) and the maximum concentration by 94% (i.e., from 55 +/- 4 to 3.5 +/- 0.7 ng/ml [p < 0.001]). The elimination half-life of midazolam was decreased from 3.1 +/- 0.2 to 1.3 +/- 0.2 hours by rifampin (p < 0.001). During the rifampin phase, the pharmacodynamic effects of midazolam were markedly smaller than the effects during the placebo phase in all the tests (e.g., the Digit Symbol Substitution Test; p < 0.001). CONCLUSIONS: The observed substantial decrease in plasma concentrations and effects of midazolam most likely results from induction of CYP3A4 by rifampin in both the gut wall and the liver. Orally administered midazolam is ineffective during rifampin treatment.

Administration, Oral↗
PubMed1998

Quantification of 3-month intraindividual variability and the influence of sex and menstrual cycle phase on CYP3A activity as measured by phenotyping with intravenous midazolam.

OBJECTIVE: Intraindividual variability and the effects of sex and menstrual cycle phase on CYP3A activity were evaluated by phenotyping with use of midazolam as the probe drug. METHODS: Midazolam (0.025 mg/kg) was administered intravenously to 10 white male volunteers every 14 days for 3 months and to 10 white premenopausal female volunteers during the midfollicular and midluteal phases of the menstrual cycle for 3 complete cycles. Serum was collected for a 6-hour period, and enzyme activity was represented by midazolam plasma clearance. RESULTS: No difference in clearance was observed during the menstrual cycle phases. Mean +/- SD midazolam clearance was 0.00816 +/- 0.00252 L/min/kg during the midfollicular phase and 0.00818 +/- 0.00224 during the midluteal phase (P = .96). When the menstrual cycle phases were combined, mean midazolam clearance in women was 0.00817 +/- 0.00235 L/min/kg. Mean male midazolam clearance was 0.00766 +/ 0.00167 L/min/kg. There was no difference in midazolam clearance between men and women (P = .68). Coefficients of variation (CV%) for the 6 phenotyping visits were calculated and the median midazolam clearance CV% (25th to 75th percentile) was 9.75% (8.40% to 11.5%). CONCLUSIONS: Because no significant differences in midazolam clearance were noted between menstrual cycle phases or between sexes, pharmacokinetic and clinical investigations of CYP3A activity in adults may not require stratification on the basis of menstrual cycle phase or sex.

Adult↗
PubMed1999

High-dose discrimination training with midazolam: context determines generalization profile.

In previous work, greater differentiation among ligands for the benzodiazepine site was found in rats trained to discriminate among vehicle, 0.32, and 3.2 mg/kg midazolam than in animals trained to discriminate a single midazolam dose from vehicle (i.e., virtually all test drugs occasioned low-dose midazolam-appropriate responding, but most did not occasion high-dose midazolam-appropriate responding even at high test doses). A possibility was that merely training with 3.2 mg/kg-midazolam (not previously studied) would result in greater selectivity than training with lower midazolam doses. In the present study, rats were trained to discriminate 3.2 mg/kg i.p. midazolam from no drug under a two-lever, food-maintained, procedure; and drugs from the previous three-lever studies were tested. Triazolam, bretazenil, clonazepam, lorazepam, midazolam, zolpidem, chlordiazepoxide, pentobarbital, and flurazepam all dose-dependently occasioned >80% responding on the midazolam-appropriate lever in roughly that order of potency. Only triazolam had occasioned midazolam 3.2 mg/kg-appropriate responding in the previous work. The greater differentiation among these drugs in the dose-vs.-dose procedure likely was due to a training dose context rather than to the high training dose per se.

Animals↗
PubMed2002

[Use of midazolam in postoperative sedation of patients with multiple organ failure treated with hemodiafiltration. Clinical study and pharmacokinetics].

OBJECTIVES: Evaluate the risk of accumulation of midazolam and conjugated 1-hydroxy-midazolam in high-risk ICU patients treated by continuous veno-venous haemofiltration. STUDY DESIGN: A prospective pharmocokinetic and clinical evaluation in 11 patients, with hepatic and renal failure. METHODS: Midazolam and metabolites were dosed in plasma and ultratiltration liquid by chromatography. Sedation was assessed by a simplified Ramsay score (EDS) with 4 levels. RESULTS: The mean duration of continuous infusion was 11 +/- 6 days. Peak plasma levels were over 150 ng ml-1 during the first 3 days, but normalized after that, only by drug adjustment based on scoring and clinical observation. There was no progressive accumulation of OH-midazolam, in spite of high levels (> 1000 ng ml-1). The Sieving coefficient (S) was 0.11 +/- 0.10 and 0.44 +/- 0.15 for midazolam and conjugated OH-midazolam respectively. A significant clearance (9.6 +/- 1.9 ml min-1) was observed for the conjugated products. T 1/2 beta was 11 h and was correlated with the mean time of recovery. A significant correlation was found between sedation score and both midazolam (r = 0.47) and OH-midazolam (r = 0.32). CONCLUSION: OH-midazolam risk of accumulation and significant clearance by haemodiafiltration should be taken into account in the drug adjustment in patients treated by continuous veno-venous haemofiltration.

Adjuvants, Anesthesia↗
PubMed2001

A small dose of midazolam decreases the time to achieve hypnosis without delaying emergence during short-term propofol anesthesia.

STUDY OBJECTIVE: To evaluate the effect of a small dose of midazolam (10 microg kg(-1)) on induction and emergence during short-term propofol anesthesia and to investigate the effects of subsequent administration of flumazenil. DESIGN: Double-blinded, prospective, randomized study. SETTING: Operating room of a medical college hospital. PATIENTS: 30 male ASA physical status I and II patients (ages 51 to 75) scheduled for minor surgery under spinal anesthesia. INTERVENTIONS: Patients were randomly allocated to one of three groups: the placebo-propofol-placebo (PP) group, the midazolam-propofol-placebo (MP) group, or the midazolam-propofol-flumazenil (MF) group. After administering placebo or midazolam (10 microg kg(-1)), propofol 250 microg kg(-1) min(-1) was infused. Immediately after confirming that the patient was hypnotized, we terminated the propofol infusion and administered placebo or flumazenil (5 microg kg(-1)). MEASUREMENTS: The dose and the times required to achieve hypnosis (the first endpoint) and to emerge from anesthesia (the second endpoint). The plasma concentration at each endpoint was determined. MAIN RESULTS: Midazolam significantly decreased the dose and time needed to achieve hypnosis [PP vs. MP, 66 +/- 14 vs. 48 +/- 15 mg, 260 +/- 55 vs. 179 +/- 44 sec, respectively (mean +/- SD)]. Thus, the plasma concentration of propofol at hypnosis was significantly lower (PP vs. MP, 3.31 +/- 0.78 vs. 2.41 +/- 0.57 microg mL(-1)). The time to emerge from anesthesia was not prolonged by midazolam, and was further shortened by administration of flumazenil (PP, MP vs. MF, 237 +/- 77, 207 +/- 71 s vs. 126 +/- 56 sec, respectively). Flumazenil also reversed the reduction in propofol concentration induced by midazolam at emergence (PP, MP, and MF, 0.54 +/- 0.17, 0.37 +/- 0.15, and 0.59 +/- 0.22 microg mL(-1), respectively). CONCLUSIONS: Coadministration of 10 microg kg(-1)midazolam decreases the dose and time required to achieve hypnosis with propofol induction without delaying emergence from anesthesia. Additional administration of flumazenil further shortens the time to emerge from midazolam-propofol anesthesia.

Adjuvants, Anesthesia↗
PubMed1993

A potentially hazardous interaction between erythromycin and midazolam.

Interaction between erythromycin and midazolam was investigated in two double-blind, randomized, crossover studies. In the first study, 12 healthy volunteers were given 500 mg erythromycin three times a day or placebo for 1 week. On the sixth day, the subjects ingested 15 mg midazolam. In the second study, midazolam (0.05 mg/kg) was given intravenously to six of the same subjects, after similar pretreatments. Plasma samples were collected, and psychomotor performance was measured. Erythromycin increased the area under the midazolam concentration-time curve after oral intake more than four times (p < 0.001) and reduced clearance of intravenously administered midazolam by 54% (p < 0.05). In psychomotor tests (e.g., saccadic eye movements), the interaction between erythromycin and orally administered midazolam was statistically significant (p < 0.05) from 15 minutes to 6 hours. Metabolism of both erythromycin and midazolam by the same cytochrome P450IIIA isozyme may explain the observed pharmacokinetic interaction. Prescription of midazolam for patients receiving erythromycin should be avoided or the dose of midazolam should be reduced by 50% to 75%.

Administration, Oral↗