1. The pharmacokinetics of rolipram were studied in rat, rabbit, rhesus monkey and cynomolgus monkey using 14C- or 3H-labelled rolipram and a radioimmunoassay for measurement of unchanged drug. 2. Rolipram was rapidly and completely absorbed after oral doses of up to 50 mg/kg. Bioavailability was 0.1% in rhesus monkey, 3.7% in cynomolgus monkey, 3.6% in rabbit, 35% in rat, and 75% in man. 3. Rolipram was able to pass the blood-brain barrier achieving concentrations in brain twice those in plasma. 4. Plasma levels of the unchanged drug declined with a similar half-life of 1-3 h in all species investigated. In the rat, there were indications for a different clearance of the two rolipram enantiomers. 5. Labelled rolipram was excreted rapidly and completely. The main route of elimination was via the urine.

Plasma levels of S-(+)-rolipram and R-(-)-rolipram in six healthy male volunteers were measured by radioimmunoassay after intravenous injection of 0.1 mg and oral administration of 1.0 mg of the pure enantiomers. Following i.v. treatment, plasma levels of both isomers declined in three phases, with half-lives of 0.2 h, 0.6-0.9 h and 6-8 h. Total clearance was 6 ml.min-1.kg-1. Oral administration of 1.0 mg gave a peak concentration of 16 ng.ml-1 after 0.5 h. Bioavailability of (+)-rolipram was 77% and of the (-) enantiomer it was 74%. There was no significant difference in Cmax, half-life, total clearance or bioavailability between the two enantiomers.

1. The metabolism of D,L-rolipram in man was studied by comparison of h.p.l.c. radiochromatograms of plasma and urine obtained at various times following oral and/or s.c. administration to man, rat, rabbit, and rhesus and cynomolgus monkey. 2. Seven metabolites isolated previously from man, rat, and rhesus monkey urine by preparative h.p.l.c. and identified by mass spectrometry and n.m.r. analysis were used for metabolite identification. 3. In plasma, 3-5 metabolites were found in addition to the unchanged drug. In urine, which was the main excretion route for rolipram metabolites, > 10 metabolites were detected but not the parent compound. 4. Between 40 and 70% of the compounds eliminated renally, were identified by reference to isolated metabolites. 5. Biotransformation proceeded by ether cleavage at the methoxy and pentyloxy groups, and by hydroxylation in positions 2 or 3 of the pentyloxy ring followed by sulphation. 6. In man, not in the other species studied, the 5-position of the pyrrolidone ring was also hydroxylated. This compound cross-reacted with the antibody raised against rolipram which was used formerly for the determination of rolipram in biological fluids.

The effect of i.v. ergonovine tartrate infusions (0.05-20 micrograms/kg/min, 12 minutes duration) on coronary arteries was studied in 14 conscious dogs instrumented to continuously measure vascular diameter by an ultrasonic dimension gauge using 10-MHz piezoelectric crystals. Ergonovine induced a biphasic coronary response: small, transient dilation during the first minutes of infusion, followed by slowly developing constriction reaching its maximum 5 to 15 minutes after the end of the infusion and persisting at this level for at least 10 minutes. The threshold dosage for significant constriction was 0.05 microgram/kg/min. A dosage of 5 micrograms/kg/min (cumulative 60 micrograms/kg, corresponding to 35 micrograms/kg ergonovine maleate) caused a decline in mean left circumflex artery diameter by 137 +/- 15 micrometers (= 4.6%) without significantly altering heart rate, plasma catecholamines or plasma renin activity. Coronary venous O2 saturation did not decline, indicating the absence of coronary resistance vessel constriction. The epicardial artery constriction was not attenuated by a vasopressin antagonist. Under adrenergic blockade (2 mg/kg phentolamine and 2 mg/kg nadolol) or under ganglionic blockade (5 mg/kg pentolinium tartrate), ergonovine (5 micrograms/kg /min) caused substantial elevation in mean arterial pressure, while the decline in coronary artery diameter was attenuated. When this increase in arterial pressure was prevented by appropriate bleeding, the ergonovine-induced coronary constriction was not diminished by adrenergic or ganglionic blockade. The serotonin antagonist methysergide (0.5 mg/kg) completely abolished the ergonovine-induced coronary artery vasomotion. It is concluded that ergonovine in dogs causes an epicardial coronary artery constriction comparable to the diffuse coronary artery narrowing in men not suffering from variant angina pectoris. These constrictions are not mediated by an adrenergic mechanism.

Two thousand and ninety beef cattle livers from north-west Argentina were inspected at a large slaughterhouse in Salta; 13% were found to have lesions of fascioliasis and these were classified according to their severity. Of the livers condemned 182 (67.2%) were lightly affected, 77 (28.4%) moderately affected and only 12 (4.4%) severely affected. In a field survey 85 animals, mainly between 6 and 18 months old, were slaughtered and 12 (14%) had lesions of fascioliasis. The influence of Fasciola hepatica on weight gain in beef cattle was assessed on 2 farms. Infected animals were divided into 2 groups and I group was treated monthly. Only on 1 farm were the animals exposed continuously to infection. No differences in weight gain were found over 7 and 14 months respectively when compared to untreated controls. It was concluded that fascioliasis is widespread but at a low level in beef cattle.