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This study aimed to characterize the pharmacokinetics and pharmacodynamics of midazolam after intranasal administration to healthy volunteers. Eight participants were given 0.25 mg/kg intranasally and 2 mg intravenously in a randomized, crossover fashion. Blood samples for determination of plasma concentrations of midazolam and measures of cognitive function (using the digit symbol substitution test) were obtained at baseline and 5, 10, 20, 30, 45, 60, 90, 120, 180, 240, and 360 minutes after administration of study medications. Plasma samples were analyzed by gas chromatography (% coefficient of variation < 10%). Pharmacokinetic data were fitted using iterative two-stage analysis to a two-compartment model. Pharmacodynamic data were fitted by a baseline subtraction Hill-type model. The mean (SD) for total clearance, distributional clearance, volume of distribution in the central compartment, volume of distribution in the peripheral compartment, absorption rate constant, bioavailability, and half-life were 0.57 (0.26) L/hr/kg, 0.31 (0.29) L/hr/kg, 0.27 (0.14) L/kg, 0.67 (0.11) L/kg, 2.46 (1.72) hr-1, 50% (13%), and 3.1 (0.84) hours, respectively. The mean (SD) for the concentration at which the effect is half maximal (EC50) and the maximal effect or the maximal change in effect measure from baseline (Emax) were 63.1 (21.2) ng/mL and 52.8 (21.1) correct substitutions, respectively. After intranasal administration, midazolam concentrations rapidly achieve values considered sufficient to induce conscious sedation and produce predictable changes in digit symbol substitution score.

Systemic corticosteroids are almost universally used in the treatment of severe acute asthma but the optimum length of treatment with corticosteroids following recovery from an acute attack of asthma is not established. Thirty-five patients admitted with acute asthma and treated with oral prednisolone 40 mg daily in addition to bronchodilator therapy until full recovery, with stable peak expiratory flow recordings (PEF) within 15% of their previous best PEF or predicted PEF were studied. They were all discharged home on regular inhaled corticosteroids and regular or as required use of bronchodilators and randomized to receive either prednisolone 40 mg daily or placebo for the first 14 days. Median PEF values increased from 31% predicted on admission to hospital to 71% predicted on discharge from hospital in the active treatment group (19 patients) and from 32-73% in the placebo group (16 patients). There was no difference between the two groups in the median values of the forced expiratory volume in one second, forced vital capacity, total lung capacity or diurnal variation in PEF either at the time of discharge from hospital or at 14 and 28 days after discharge from hospital. This study suggests that there is no need to reduce prednisolone gradually following recovery from an exacerbation of asthma, provided systemic corticosteroid treatment is continued until a satisfactory and stable PEF is achieved.

Background -Corticosteroid trials are an important part of the assessment of patients with chronic airways obstruction, but false negative results will occur if the treatment is not taken. To determine compliance low dose phenobarbitone has been used as a marker. Methods -Thirty six patients referred to a chest clinic for assessment oftheir airways obstruction were studied. They were instructed to take eight capsules (each containing 5 mg prednisolone and 0-5 mg phenobarbitone) per day for two weeks. The response was assessed by home peak flow monitoring and clinic spirometric tests. Plasma phenobarbitone levels were measured after the trial to enable calculation of the dose to plasma concentration ratio (level to dose ratio, LDR) and the result was compared with the reference range for fully compliant individuals. Results -Five patients defaulted from follow up, 23 had LDR values within the expected range, and eight had low LDR values consistent with poor compliance. The nine patients with steroid responsive disease (>20% improvement in peak flow or spirometric parameters) all had LDR values in the expected range. Conclusion -Excluding those who defaulted whose compliance must be questionable, eight (26%) patients did not fully comply with the steroid trial. Not all patients who fail to respond to a two week home steroid trial have a steroid "unresponsive" disease.

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