The effect-kinetics of the new benzodiazepine midazolam was evaluated in six subjects after single oral (7.5 and 15 mg) and intravenous (0.075 mg/kg) doses and infusion programs. The drug is bound to plasma proteins by 94%, and less than 0.5% is excreted unchanged in urine. Hepatic elimination is rapid: t1/2 beta is 2.4 +/- 0.8 hr (mean +/- S.D) and total body clearance is 283 +/- 43 ml/min (plasma) or 502 +/- 105 ml/min (blood). This substantial first-pass effect leads to bioavailability of only 44%, despite very rapid absorption (t1/2abs = 0.23 +/- 0.37 hr) after oral dosing. There is good intraindividual linear correlations (r between 0.68 and 0.97) between plasma levels and dynamic effects, as assessed by the d2 letter cancellation test and a sedation index formed from visual analogue scales.

Midazolam kinetics were evaluated in six healthy male subjects after single oral (15 mg)and intravenous (0.075 mg/kg) doses. The three-part randomized crossover study consisted of a morning dose in supine position (part A) and morning (part B) and evening (part C) doses under ambulant (sitting/walking) conditions. While no significant changes could be observed in the absorption and distribution process or the elimination half lives, total plasma clearance was higher during part A (616+/-157 ml/min, P=0.01) and C(463+/-82 ml/min, P=0.02), than in part B (317+/-110 ml/min, +/-SD). Since the intrinsic (oral) clearance was also higher during part A (1656+/-657 ml/min, P=0.003) and C(1310+/-579 ml/min, P=0.024) than during part B(710+/-241 ml/min), bioavailability did not change (range 37 to 44%). These data indicate that posture and circadian rhythm are important variables affecting blood flow-dependent hepatic elimination of midazolam.

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We report a case of fibroblastic rheumatism (FR). Only eight other cases of this recently described entity have been reported previously. FR is characterized by polyarthralgia and joint stiffness without joint destruction, associated with cutaneous nodules and sclerodactyly. Histology shows an increase in the number of fibroblasts and marked dermal fibrosis. Rheumatological and skin manifestations may improve with corticosteroid therapy. In our patient, immunohistochemical studies of involved and uninvolved skin showed an increase in fibronectin and tenascin deposition. In the dermis, the hyperplastic cells had phenotypic features of muscle, suggesting myofibroblastic differentiation. Ultrastructural study showed an increase in active fibroblastic cells with features of myofibroblasts. A hyperproliferative capacity was observed in fibroblasts cultured from involved skin. Biochemical studies of the production of collagen and non-collagen proteins were performed on these cultured cells, and showed a reduction in collagen and non-collagen protein synthesis by FR fibroblasts. Thus, FR appears to differ from other fibrotic skin diseases such as scleroderma, in that dermal fibrosis may be due predominantly to fibroblast proliferation with myofibroblastic differentiation without any increase in collagen synthesis.

The pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 has been studied in 6 healthy male volunteers following a single intravenous dose of 2.5 mg. The drug was only slightly bound to plasma proteins (40 +/- 8%, mean +/- SD). A negligible amount (less than 0.2% of the dose) of unchanged drug was recovered in urine. Hepatic elimination was rapid, as shown by a short t1/2 of 0.9 +/- 0.2 h, and high total plasma and blood clearances of 691 +/- 216 ml/min and 716 +/- 199 ml/min, respectively. The fast decline of plasma levels from about 60 to 2 ng/ml accounts for the short-lasting reversal of benzodiazepine-induced sedation by Ro 15-1788.

An automated column-switching technique coupled to isocratic high-performance liquid chromatography (HPLC) with fluorescence detection was developed for simultaneous determination of dextromethorphan and its three major metabolites, dextrorphan, hydroxymorphinan, and methoxymorphinan. After cleavage of conjugates by incubation with glucuronidasearylsulfatase at 37 degrees C for 15 h, plasma samples were injected directly into the HPLC system. Dextromethorphan and metabolites were retained on a cleanup column (10 x 4.6 mm internal diameter [ID]) filled with cyanopropyl (CN) material (Hypersil CPS, 10-microns article size) while interfering proteins and lipids were washed to waste. After column switching, the drugs were eluted from the cleanup column and separated on Spherisorb CN material (5-microns particle size, column size 250 x 4.6 mm ID). Fluorescence detection was carried out with an excitation wavelength of 220 nm and an emission wavelength of 305 nm. Sample cleanup and HPLC separation were completed within 20 min. Regression analyses found linearity (r > 0.99) between drug concentration and detector response over a wide range-5-220 ng/ml for dextromethorphan, 5-550 ng/ml for dextrorphan, 5-500 ng/ml for hydroxymorphinan, and 5-200 ng/ml for methoxymorphinan. The limit of quantification was approximately 5 ng/ml, and the recovery was > 90% for all compounds. At concentrations of 20-500 ng/ml, the intra- and interassay coefficients of variation ranged from 3.5 to 14.6% and from 7.0 to 14.0%, respectively. The method is suitable for in vivo phenotyping of CYP2D6 activity, which catalyzes the O-demethylation of dextromethorphan to dextrorphan, and is also applicable to pharmacokinetic studies in man.

The pharmacodynamic interaction between midazolam and the specific benzodiazepine antagonist Ro 15–1788 has been investigated in six healthy male volunteers. Hypnotic steady‐state concentrations of midazolam (55 ± 11 ng/mL; mean ± SD) have been achieved rapidly by an intravenous bolus of 0.07 mg/kg and maintained by an individual but constant infusion rate of 0.025 to 0.04 mg/kg/hr for eight hours. Following a two‐hour control period, the antagonist (2.5 mg) or the solvent were injected double‐blind in random order. Three hours later, the other medication was administered. Whereas plasma levels of midazolam remained constant throughout the complete eight‐hour trial (Clearance = 670 ± 96 mL/min) concentrations of Ro 15–1788 declined rapidly with an elimination half‐life between 0.7 and 1.8 hours and a total plasma clearance of 702 ± 235 mL/min. Concentrations of Ro 15–1788 approached the analytic limit of 2 ng/mL within three hours. The pharmacodynamic response to midazolam and the antagonist was assessed by a sedation index using visual analogue scales, reaction time (RT) measurements, and transformed Fourier analysis of the power spectrum of the recorded electroencephalogram (EEG). About 30 to 45 seconds following the injection of Ro 15–1788, hypnotic action of midazolam was completely reversed as visualized by return to alpha rhythm in the EEG, shortening of prolonged RT, and normalization of the elevated sedation index. The antagonistic action lasted for about two to three hours. The abrupt arousal from sleep was not associated with any unpleasant sensations, however, three subjects experienced a profound perspiration for about ten minutes following the injection of Ro 15–1788. In conclusion, a small intravenous bolus of 2.5 mg Ro 15–1788 reverses rapidly the hypnotic action of midazolam. The relative short duration of the antagonistic effect is due to the fast hepatic elimination of Ro 15–1788, which might be a suitable antidote of benzodiazepine‐induced oversedation in special clinical situations.

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