Hypnotics should never be used in patients with sleep apnea.

Although benzodiazepine medication is generally considered to be inappropriate for patients with obstructive sleep apnea, further investigation is required to evaluate this. Non-benzodiazepine hypnotics may improve sleep quality without causing respiratory depression. In central sleep apnea, hypnotics not only improve sleep but also decrease apnea frequency probably by reducing arousals and elevating arterial PCO2. Consequently, I submit that the statement 'hypnotics should not be used in patients with sleep apnea' should be changed to 'hypnotics may sometimes be used in patients with sleep apnea'.

The pharmacokinetics of pirtenidine in the rat and dog.

1. Pharmacokinetic studies on the topical antimicrobial agent, pirtenidine, have been conducted in male Sprague-Dawley rats and beagle dogs, using a validated h.p.l.c. method with u.v. detection to measure the drug in plasma. 2. Following a single i.v. bolus dose to the rat (equivalent to 1.35 mg base/kg) or dog (equivalent to 0.23 mg base/kg), the drug was extensively distributed with an apparent volume of distribution of 8.61/kg in rat and 3.31/kg in dog. Clearance was high (rat 2.71/h/kg; dog 1.51/kg) which resulted in a short terminal half-life in both species (2.2 and 1.5 h respectively). 3. Following a single oral dose to rats (equivalent to 4.5 mg base/kg) plasma pirtenidine concentrations were generally below the minimum quantifiable level of the analytical method (1 ng/ml). A maximum possible bioavailability of 0.3% was estimated. 4. After administering the same oral dose to dogs plasma concentrations rose slowly (t 1/2 abs = 1.2 h) to a peak (49.7 ng/ml) at 5.0 h post-dose. The terminal elimination half-life was 2.1 h. The absolute bioavailability was 10%.

The comparative pharmacokinetics and gastric toxicity of bezafibrate and ciprofibrate in the rat.

1. The comparative gastric toxicology and pharmacokinetics of two phenoxyisobutyrate derivatives have been evaluated in the Fischer rat. 2. After oral administration of single daily doses for 7 days, the plasma elimination half-life for bezafibrate was rapid (t1/2 of 4-5 h) in comparison to ciprofibrate (t1/2 of 76 h). 3. The area under the plasma drug concentration versus time curve (AUC) 0-24 (micrograms.h/ml +/- SD) for bezafibrate (dose 125 mg/kg per day) was 1553 +/- 334, which was less than half the value of 3748 +/- 358 achieved by ciprofibrate (10 mg/kg per day) after 7 days. 4. Oral administration of ciprofibrate at 10 mg/kg every 48 h produced similar sustained plasma concentrations to those achieved by bezafibrate 125 mg/kg dosed every 12 h. The AUC 0-48 values (micrograms.h/ml +/- SD) achieved were 5124 +/- 450 for bezafibrate compared to 4207 +/- 240 for ciprofibrate. 5. In chronic oral multidose studies with ciprofibrate and bezafibrate, similar gastric toxicity (neuroendocrine cell hyperplasia) occurred in the rat when dose regimens were adjusted to compensate for the pharmacokinetic differences between these two drugs.

The relationship between the pharmacokinetics of amrinone in the marmoset and platelet effects.

The pharmacokinetic characteristics of amrinone have been studied in six female marmosets following oral administration of 1, 12.5, 25, 50 and 75 mg.kg-1 and an intravenous dose of 1mg.kg-1. The mean plasma AUC0 infinity was determined at each dose level; the values obtained were 2.5, 18.7, 33.9, 103 and 312 micrograms.h.ml-1 for the oral doses of 1, 12.5, 25, 50 and 75 mg.kg-1 respectively and 1.9 micrograms.h.ml-1 for the intravenous dose of 1mg.kg-1. Mean maximum observed plasma concentrations were 0.6, 7.1, 11.7, 23.7 and 40.0 micrograms.ml-1 respectively following oral doses. Over the range 1 to 50 mg.kg-1 the AUC0 infinity was linear; at 75 mg.kg-1 the AUC0 infinity was disproportionately greater. Elimination appeared to be first order over the dose range 1 to 50 mg.kg-1 and the t1/2 in the marmoset was approximately 1 to 3 hours over this dose range. The plasma levels achieved are discussed in relation to the observed effects on the platelet population in this species following chronic administration at high dose levels.

The bioavailability and metabolism of trilostane in normal subjects, a comparative study using high pressure liquid chromatographic and quantitative cytochemical assays.

High pressure liquid chromatographic (HPLC) analysis of plasma taken over 8 h from ten normal male subjects medicated with 120 mg of trilostane revealed that the drug is rapidly metabolised into at least one metabolite, 17-keto trilostane. Both compounds were detected in the blood stream at concentrations greater than 2 X 10(-7) M within an hour and were cleared from the blood by 6-8 h. Approximately 3 times the concentration of metabolite was detected compared to the parent compound in most samples analysed. There were large subject to subject variations in the handling of drug. Standard curves of pure 17-keto trilostane and trilostane were parallel as assessed by cytochemical bioassay. This assay is based upon the inhibition of 3 beta-hydroxysteroid dehydrogenase activity in unfixed tissue sections of the dioestrous rat ovary. The relative potency of the metabolite compared to trilostane was 1.71 (95% confidence 1.5-2.0) over the dose range 0.15-1.5 microM. Thus, the metabolite may be the major active agent when trilostane is administered for clinical purposes. In a further 4 volunteers, who also received 120 mg trilostane and were sampled over an 8 h period, plasma was analysed independently by HPLC and cytochemical assays. In the majority of cases the bioactivity recorded (relative to a trilostane standard curve) was substantially higher than the molar sum of circulating trilostane and 17-keto-trilostane (as assessed by HPLC). However, if the relative potency of 17-keto-trilostane is taken into consideration, correlation between the two assays was excellent (r = 0.947, n = 18, P less than 0.001). This also suggests that no further active metabolites were present in the plasma samples. The drug profiles seen in the second study were essentially the same as described for the first 10 volunteers. The combination of a bioassay, which detects trilostane-like bioactivity, and HPLC, which reveals the type of metabolism, should aid our understanding of the clinical value of this potentially important drug.

Effect of digoxin on right ventricular function in severe chronic airflow obstruction. A controlled clinical trial.

The effect of digoxin on the right and left ventricular ejection fractions in 15 patients with pulmonary heart disease caused by severe chronic airflow obstruction was studied in a double-blind, randomized, placebo-controlled trial. All patients were ambulatory and had clinical features of right but not left ventricular dysfunction. Equilibrium radionuclide angiography showed reduced right ventricular ejection fraction in all patients and reduced left ventricular ejection fraction in four. After 8 weeks of digoxin treatment, the abnormal left ventricular ejection fractions were normal; right ventricular ejection fractions increased only in those patients who had had abnormal left ventricular ejection fractions. We conclude that in patients with pulmonary heart disease, the right ventricular ejection fraction is abnormal and improves with digoxin treatment only when the left ventricular ejection fraction also is initially abnormal.

Oral and intravenous propranolol during exercise.

The intrinsic sinoatrial (SA) rate at rest and during exercise was measured in 5 normal male subjects after prolonged oral and acute intravenous administration of propranolol and atropine. At rest, the intrinsic SA rate was similar after both oral and intravenous propranolol. At the higher levels of power output on a cycle ergometer, cardiac rate was slower after oral than after intravenous propranolol. When the intravenous study was repeated with the use of an additional dose of propranolol, cardiac rate was lower at comparable levels of power output, but not as low as that after oral propanolol. Differences in responses were interpreted as reflecting varying degrees of beta blockade, the most complete being that after prolonged oral propranolol administration of 320 mg daily. The intravenous dose of propranolol usually used to obtain the "pharmacologically isolated heart" at rest is too small to induce full beta blockade in exercise.