Quantitative prediction of metabolic inhibition of midazolam by itraconazole and ketoconazole in rats: implication of concentrative uptake of inhibitors into liver. (1/994)

To evaluate the extent of drug-drug interaction concerning metabolic inhibition in the liver quantitatively, we tried to predict the plasma concentration increasing ratio of midazolam (MDZ) by itraconazole (ITZ) or ketoconazole (KTZ) in rats. MDZ was administered at a dose of 10 mg/kg through the portal vein at 60 min after bolus administration of 20 mg/kg ITZ or during 0.33 mg/h/body of KTZ infusion. The ratio values in the area under the plasma concentration curve of MDZ in the presence of ITZ and KTZ was 2.14 and 1.67, respectively. The liver-unbound concentration to plasma-unbound concentration ratios of ITZ and KTZ were 11 approximately 14 and 1.3, respectively, suggesting a concentrative uptake of both drugs into the liver. ITZ and KTZ competitively inhibited the oxidative metabolism of MDZ in rat liver microsomes, and Ki values of ITZ and KTZ were 0.23 microM and 0.16 microM, respectively. We predicted the ratio values of MDZ in the presence of ITZ and KTZ, using Ki values and unbound concentrations of both drugs in the plasma or liver. The predicted ratio values in the presence of ITZ or KTZ calculated by using unbound concentration in the plasma were 1.03 approximately 1.05 and 1.39, whereas those calculated using unbound concentration in the liver were 1.73 approximately 1.97 and 1.51, respectively, which were very close to the observed ratio values. These findings indicated the necessity to consider the concentrative uptake of inhibitors into the liver for the quantitative prediction of the drug-drug interactions concerning metabolic inhibition in the liver.  (+info)

Postoperative behavioral outcomes in children: effects of sedative premedication. (2/994)

BACKGROUND: Although multiple studies document the effect of sedative premedication on preoperative anxiety in children, there is a paucity of data regarding its effect on postoperative behavioral outcomes. METHODS: After screening for recent stressful life events, children undergoing anesthesia and surgery were assigned randomly to receive either 0.5 mg/kg midazolam in 15 mg/kg acetaminophen orally (n = 43) or 15 mg/kg acetaminophen orally (n = 43). Using validated measures of anxiety, children were evaluated before and after administration of the intervention and during induction of anesthesia. On postoperative days 1, 2, 3, 7, and 14, the behavioral recovery of the children was assessed using the Post Hospitalization Behavior Questionnaire. RESULTS: The intervention group demonstrated significantly lower anxiety levels compared with the placebo group on separation to the operating room and during induction of anesthesia (F[1,77] = 3.95, P = 0.041). Using a multivariate logistic regression model, the authors found that the presence or absence of postoperative behavioral changes was dependent on the group assignment (R = 0.18, P = 0.0001) and days after operation (R = -0.20, P = 0.0001). Post hoc analysis demonstrated that during postoperative days 1-7, a significantly smaller number of children in the midazolam group manifested negative behavioral changes. At week 2 postoperatively, however, there were no significant differences between the midazolam and placebo groups. CONCLUSIONS: Children who are premedicated with midazolam before surgery have fewer negative behavioral changes during the first postoperative week.  (+info)

Effect of butorphanol tartrate on shock-related discomfort during internal atrial defibrillation. (3/994)

BACKGROUND: In patients with atrial fibrillation, intracardiac atrial defibrillation causes discomfort. An easily applicable, short-acting analgesic and anxiolytic drug would increase acceptability of this new treatment mode. METHODS AND RESULTS: In a double-blind, placebo-controlled manner, the effect of intranasal butorphanol, an opioid, was evaluated in 47 patients with the use of a step-up internal atrial defibrillation protocol (stage I). On request, additional butorphanol was administered and the step-up protocol continued (stage II). Thereafter, if necessary, patients were intravenously sedated (stage III). After each shock, the McGill Pain Questionnaire was used to obtain a sensory (S), affective (A), evaluative (E), and total (T) pain rating index (PRI) and a visual analogue scale analyzing pain (VAS-P) and fear (VAS-F). For every patient, the slope of each pain or fear parameter against the shock number was calculated and individual slopes were averaged for the placebo and butorphanol group. All patients were cardioverted at a mean threshold of 4.4+/-3.3 J. Comparing both patient groups for stage II, the mean slopes for PRI-T (P=0.0099), PRI-S (P=0.019), and PRI-E (P=0.015) became significantly lower in the butorphanol group than in the placebo group. Comparing patients who received the same shock intensity ending stage I and going to stage II, in those patients randomized to placebo the mean VAS-P (P=0.023), PRI-T (P=0. 029), PRI-S (P=0.030), and PRI-E (P=0.023) became significantly lower after butorphanol administration. CONCLUSIONS: During a step-up internal atrial defibrillation protocol, intranasal butorphanol decreased or stabilized the value of several pain variables and did not affect fear. Of the 3 qualitative components of pain, only the affective component was not influenced by butorphanol. The PRI evaluated pain more accurately than the VAS.  (+info)

Intranasal midazolam for premedication of children undergoing day-case anaesthesia: comparison of two delivery systems with assessment of intra-observer variability. (4/994)

Midazolam is often used for paediatric premedication. We have compared two methods of administering midazolam intranasally in 44 surgical day-case children allocated randomly to receive midazolam 0.2 mg kg-1 as drops or midazolam 0.1 mg kg-1 from an intranasal spray device. Behaviour was recorded on a four-point scale by the parent, nurse and anaesthetist. Coefficients were obtained representing the change in behaviour score. There was no significant difference in method of administration (coefficient 0.13, P = 0.39). Children were significantly more distressed at the time of premedication and at the time of venous cannulation (coefficients 1.31 and 0.70) than at baseline. There was no significant difference in the assessments between observers. Midazolam by either method was equally effective but acceptability of the premedication was poor in both groups. Intranasal midazolam cannot be recommended as a method for routine premedication of young children.  (+info)

Sedation depends on the level of sensory block induced by spinal anaesthesia. (5/994)

We have investigated the relationship between the extent of spinal block and occurrence of sedation. In a first series of 43 patients, the distribution of sedation score (measured on the Ramsey scale) was related to the extent of spinal block (pinprick). In a second series of 33 patients, the relationship between sedation score and spinal block persisted after injection of midazolam 1 mg. This study confirmed that high spinal block was associated with increased sedation.  (+info)

Characterization of the pharmacodynamic interaction between parent drug and active metabolite in vivo: midazolam and alpha-OH-midazolam. (6/994)

The pharmacodynamic interaction between midazolam and its active metabolite alpha-OH-midazolam was investigated to evaluate whether estimates of relevant pharmacodynamic parameters are possible after administration of a mixture of the two. Rats were administered 10 mg/kg of midazolam, 15 mg/kg of alpha-OH-midazolam, or a combination of 3.6 mg/kg of midazolam and 35 mg/kg of alpha-OH-midazolam. Increase in the 11.5- to 30-Hz frequency band of the electroencephalogram was used as the pharmacodynamic endpoint. The pharmacodynamics of midazolam and alpha-OH-midazolam after combined administration were first analyzed according to an empirical and a competitive interaction model to evaluate each model's capability in retrieving the pharmacodynamic estimates of both compounds. Both models failed to accurately estimate the true pharmacodynamic estimates of midazolam and alpha-OH-midazolam. The pharmacodynamic interaction was subsequently analyzed according to a new mechanism-based model. This approach is based on classical receptor theory and allows estimation of the in vivo estimated receptor affinity and intrinsic in vivo drug efficacy. The relationship between stimulus and effect is characterized by a monotonically increasing function f, which is assumed to be identical for midazolam and alpha-OH-midazolam. The pharmacodynamic interaction is characterized by the classical equation for the competition between two substrates for a common receptor site. This mechanism-based interaction model was able to estimate the pharmacodynamic parameters of both midazolam and alpha-OH-midazolam with high accuracy. It is concluded that pharmacodynamic parameters of single drugs can be estimated after a combined administration when a mechanistically valid interaction model is applied.  (+info)

First-pass midazolam metabolism catalyzed by 1alpha,25-dihydroxy vitamin D3-modified Caco-2 cell monolayers. (7/994)

Cytochrome P-450 (CYP) 3A4 accounts for approximately 50% of all P-450s found in the small intestine (Paine et al., 1997) and contributes to the extensive and variable first-pass extraction of drugs such as cyclosporine and saquinavir. We recently demonstrated that CYP3A4 expression in a differentiated Caco-2 subclone is increased when cell monolayers are treated with 1alpha,25-dihydroxy-vitamin-D3 (Schmiedlin-Ren et al., 1997). This improved metabolic capacity permits the in vitro modeling of first-pass intestinal metabolic kinetics. Midazolam (MDZ) 1'-hydroxylation was used as a specific probe for CYP3A-mediated metabolism in modified Caco-2 monolayers. Caco-2 cells were grown to confluence on laminin-coated culture inserts, and then for two additional weeks in the presence of 1alpha,25-dihydroxy vitamin-D3. Cell monolayers were subsequently exposed to MDZ for varying lengths of time and concentrations. The amount of MDZ in the monolayer increased rapidly after apical drug administration, reaching a pseudo steady state within 6 min. The cellular uptake rate was considerably slower after a basolateral dose. By either route of administration, the rate of 1'-hydroxymidazolam formation was stable and linear for 2 h. Under basolateral sink conditions and low apical MDZ dosing concentration (1-8 microM), the first-pass extraction ratio was found to be approximately 15%. Higher dosing concentrations led to saturation of the hydroxylation reaction and reduction in the extraction ratio. The modified Caco-2 cell monolayer is an excellent model for studying drug absorption and first-pass intestinal metabolic kinetic processes. In this system, the selective CYP3A probe MDZ was rapidly absorbed, yet extensively metabolized, as is observed in vivo.  (+info)

Midazolam metabolism by modified Caco-2 monolayers: effects of extracellular protein binding. (8/994)

It has been suggested that the binding of a drug to plasma proteins will influence the intestinal extraction efficiency when drug is delivered to the mucosal epithelium via either the gut lumen or vasculature. We evaluated this hypothesis using cytochrome P-450 (CYP)3A4-expressing Caco-2 monolayers as a model for the intestinal epithelial barrier and midazolam as a CYP3A-specific enzyme probe. The rate of 1'-hydroxylation was measured following apical or basolateral midazolam administration to monolayers incubated in the presence or absence of 4 g/dl of human serum albumin (HSA) in the basolateral compartment medium. The midazolam-free fraction in culture medium containing HSA was 3.3%. Inclusion of HSA in the basolateral medium decreased peak intracellular midazolam accumulation after an apical midazolam dose (3 microM) by 35% and reduced the 1'-hydroxymidazolam formation rate by approximately 20%. Because of the accelerated diffusion of midazolam through the cell monolayer and into the basolateral compartment, there was a 61% reduction in the first-pass metabolic extraction ratio: 13.3 +/- 0. 12% for control versus 5.2 +/- 1% with HSA. Compared with control, addition of HSA resulted in a 91% decrease in the peak intracellular midazolam level and a 86% decrease in the rate of 1'-hydroxylation after the administration of midazolam into basolateral medium. These findings suggest that, in vivo, binding of a drug to plasma proteins will impact both first-pass and systemic intestinal midazolam extraction efficiency. Furthermore, the effect will be more pronounced for a drug that is delivered to mucosal enterocytes by way of arterial blood, compared with oral drug delivery.  (+info)