Antilipidemic drugs. Part 4: The metabolic fate of the hypolipidemic agent isopropyl-[4'-(p-chlorobenzoyl)-2-phenoxy-2-methyl]-protionate (LF 178) in rats, dog and man

The excretion and plasma concentrations of radioactivity and chromatographic patterns of radioactive components in plasma and excreta have been compared in rats, dogs and man after oral doses of the hypolipidemic agent isopropyl-[4'-(p-chlorobenzoyl)-2-phenoxy-2-methyl]-propionate (LF 178; procetofene; Lipanthyl?). 2. In rats, 48.1% of a single dose of 25 mg/kg was excreted in the urine, and 48.6% in the faeces. In dogs, 23.1% of a single dose at the same level was excreted in the urine, and 71.8% in the faeces, but 88.1% of a dose of 300 mg to man was excreted in the urine, and only 5.1% in the faeces. Peak levels of radioactivity in the plasma of all three species studied were similar (20--30 mug/ml) after doses at these levels and concentrations declined thereafter with half-lives of 7--24 h in rats and dogs, and 7 h in man. The half-life of radioactivity concentrations in rat plasma was not altered by repeated daily doses for 7 days. 3. Whole-body autoradiography of rats showed that radioactivity was largely associated with the liver, kidneys and gut, which are the organs of biotransformation and excretion, although relatively high levels were present in lungs and blood, and small amounts of radioactivity had a widespread distribution into some peripheral tissues during 2--7 h after dosing. 4. The available chromatographic evidence indicated that the most important biotransformation pathway appeared to be ester hydrolysis to LF 178 acid and formation of water soluble conjugates of this acid. This pathway appeared similar to that of the related drug clofibrate (ethyl p-chlorophenoxyisobutyrate).     

Ultrasonic blood flow measurements: transcutaneous compared with implanted cuff

Experiments were undertaken in our laboratory to establish relationships between flow parameters calculated from implanted ultrasonic cuff signals and those obtained with a transcutaneous probe. Analog signals were received from crystals surgically implanted on the right carotid, right femoral, and abdominal aorta of a mature male beagle dog. Near these locations, transcutaneous measurements were made using a prescribed technique. From these ultrasonic signals, the following time dependent flow parameters were calculated: spatial velocities, velocity profiles, diameters, flows, and velocity frequency distributions. Using these measurements, a comparison between the implanted cuff and transcutaneous probe was made. In addition to high reproductibility, results confirm a strong correlation between the two techniques; consequently, the validity of the less traumatic transcutaneous method is substantiated.     

Treatment of pregnancy toxaemia in ewes by induction of parturition

Treatment of pregnancy toxaemia in ewes by induction of parturition is reported. The efficacy of 3 formulations of dexamethasone, at different dosages, is recorded and discussed.     

Propranolol therapy in patients undergoing myocardial revascularization

The records of 185 consecutive patients having myocardial revascularization were reviewed with regard to preoperative administration of propranolol and intraoperative or postoperative complications. Tachycardia and hypertension before cardiopulmonary bypass were slightly more common in patients never taking propranolol or those who had discontinued it for more than 48 hours before operation. There was no statistically significant difference in the incidence of postbypass hypotension among patients who took propranolol within 24 hours of operation, those who discontinued it more than 24 hours before operation, and those who never took the drug. Operative mortality was not significantly different among patients who received propranolol within 48 hours of operation (3%), those who never took it and those who discontinued it more than 48 hours before operation (4%). Early in the series, five patients had an acute myocardial infarction within 48 hours after routine preoperative withdrawal of propranolol. Because complete withdrawal of propranolol in patients with unstable angina pectoris may lead to acute myocardial infarction, we recommend gradual withdrawal of the drug during 48 hours before operation. If this is not possible because anginal pain recurs or intensifies, then reduced doses may be given safely up to 10 hours before revascularization, provided that the patient is a satisfactory candidate for bypass and that adequate myocardial revascularization can be accomplished.     

Acute reductions in serum testosterone levels by narcotics in the male rat: stereospecificity, blockade by naloxone and tolerance

The effects of a single injection of morphine (20 mg/kg) on serum testosterone levels were examined in the male rat. Within 2 hours after the morphine injection, testosterone levels were significantly lower than control levels. The decline in testosterone levels reached a maximum 4 hours after the administration of morphine, at which time testosterone levels were reduced by more than 85% with respect to controls. The ability of a large number of narcotics to depress serum testosterone levels, 4 hours after their administration, was also examined. All narcotics depressed testosterone levels significantly and their potency relative to morphine was comparable to that observed in several other preparations, such as the guinea-pig ileum and mouse vas deferens. The testosterone-depleting effects of the narcotics appear to represent specific narcotic effects since the (-)-isomers of the narcotics were considerably more potent than the (+)-isomers, naloxone competitively inhibited the effects of morphine on testosterone levels and tolerance developed to the testosterone-depleting effects of these drugs. Acute treatment with morphine also lowered serum luteinizing hormone levels, and this reduction preceded the fall in testosterone levels by 1 to 2 hours.     

Gas exchange during exercise in healthy people II. Venous admixture

1. Venous admixture/cardiac output ratio (Qva/Qt) has been measured in twenty-four healthy volunteer subjects of both sexes aged 20-71 years, at rest and during the steady state of treadmill exercise at two rates of work, and breathing air and breathing oxygen. 2. With oxygen breathing, Qva/Qt was considerably less during exercise than during the time subjects were taking either normal or deep breaths of oxygen at rest, and did not significantly increase with the intensity of exercise. It is postulated that the increase in ventilation during exercise opens most or all of those alveoli which, during oxygen breathing at rest, close because of critically low ventilation/perfusion (V/Q) ratios. 3. With air breathing, Qva/Qt fell from rest to exercise (especially in older subjects), presumably due to improved ventilation of alveoli at the lung bases. With an increase in work rate Qva/Qt increased in all age groups. This increase was not due to increase in the shunt fraction (Qs/Qt), nor to limitation of diffusing capacity; it arose from an increase in V/Q variance. 4. Equations have been derived for the prediction of normal Qva/Qt during exercise, with or without correction for the effects of increasing pulmonary capillary temperature. These effects do not materially influence the accuracy of prediction, but may be relevant to some of the interpretations. In particular, they provide a further indication that Qs/Qt probably cannot be measured by breathing oxygen at rest, even in deep breathing.