Renal and humoral effects of ibopamine, a dopamine agonist, in patients with liver cirrhosis.

We investigated the renal and humoral effects of short-term administration of ibopamine, an orally active dopamine agonist, in patients with liver cirrhosis. The patients were divided into two groups on the basis of sodium excretion with a constant sodium intake of 40 mEq/d. We also compared the effects of ibopamine with those induced by intravenous infusion of dopamine hydrochloride (3 micrograms/kg per minute) in similar patients. Ibopamine caused significant increases in urine output, glomerular filtration rate, and sodium excretion throughout the 4 hours of the trial in patients with basal sodium excretion rate greater than 20 mmol/d. These renal effects were associated with a significant reduction in plasma aldosterone concentration. In contrast, only a transient increase in glomerular filtration rate and a diminution in plasma aldosterone concentration were observed after ibopamine in the patients with a basal sodium excretion rate less than 20 mmol/d. The infusion of dopamine had renal effects similar to those of ibopamine in both groups of patients. These results indicate that in cirrhotic patients with normal sodium excretion, ibopamine exerts a diuretic and natriuretic effect similar to that of dopamine infusion. However, these properties of dopaminergic agents are apparently lost in patients with avid sodium retention.

Plasma lipids during extracorporeal circulation.

Total lipids, lipid classes, and per cent composition of fatty acids were investigated in plasma and stored subcutaneous fats of 19 subjects undergoing extracorporeal circulation (ECC). The tests were made before and 3, 20, 40, and 60 minutes after ECC was started. Hemodilution caused a general fall in total lipids and lipid classes. Evaluation of the lipid classes as percentages of the total lipids assumed to be 100 per cent allow the lipid variation due to hemodilution to be disregarded. A linear correlation between an increase in free fatty acids (FFA) and a decrease in triglycerides can thus be observed. This has been attributed to action of the lipase lipoproteic (LLP) activity stimulated by heparin, which is usually employed in ECC hemodilution. The hypothesis that FFA's are mobilized from stored subcutaneous fats was discounted.

Bilary and urinary excretion of five cardiac glycosides and its correlation with their physical and chemical properties.

Biliary and urinary excretion of five tritium-labelled cardiac glycosides, i.e. Ouabain, K-strophanthoside, Digoxin, Digitoxin and Deslanatoside C, were investigated in anaesthetized guinea-pigs 5 h after i.v. or enteral administration. Urinary excretion is the main route of elimination in the case of Ouabain and Deslanatoside C. Conversely, biliary excretion is predominant in the case of Digoxin and Digitoxin. K-strophanthoside is excreted both via bile and urine. In conscious guinea-pigs treated i.v. with the same cardiac glycosides the highest levels were observed in urine, bile, kidneys and liver. The relative values of those levels were in agreement with the excretion pattern observed in anaesthetized animals. An inverse linear relation (P less than 0.05) was encountered between biliary excretion rate and polarity of glycoside molecula. This correlation has been previously observed by other authors in other species, but not in the rabbit. This suggests that the correlation may not be considered generally applicable at present.

Tissues concentration and excretion of deslanatoside C-3H in newborn and growing rabbits.

Deslanatoside C-3H was injected (i.p. 50 microgram/kg) into rabbits of 1, 4, 10, 20 days and more than 1 year old. The rabbits were sacrificed 2 and 6 h after dosing. Levels in all tissues were higher in newborn rabbits, decreased in the older animals and then in most tissues increased in adults to different degrees, showing the highest values in kidneys. Biliary excretion and above all urinary excretion increased with age. Levels in atria, ventricles, aorta and liver in rabbits 1 and 4 days old were consistently higher at the 6th h than those at the 2nd h, these tissues showing a particularly marked avidity with Deslanatoside C; in the older animals this behaviour was reversed. These data and those of other Authors working on other glycosides (incleding Digoxin) and other species (including newborn children) lead to the conclusion that digitalis glycosides in new born species are excreted at a lower rate and incorporated in the body tissues at a higher rate than in adults. They may also in part explain the large dosages employed in human infants in comparison with adults, as the higher distribtuion volume retains a large amount of the injected glycoside.

Plasma turnover and excretion of K-strophanthoside-3H in human volunteers after parenteral administration.

Pharmacokinetic parameters of K-strophanthoside-3H, a short-acting cardiac glycoside, were investigated in healthy subjects, patients suffering from heart disease, renal failure and in cholecystectomized patients with a biliary T-tube inserted surgically, after parenteral administration of 250 mug of the glycoside. The healthy subjects, patients suffering from heart disease and those with the biliary T-tube showed a dominant half-time for plasma turnover of the glycoside of 15-16 h after the i.v. route and 18-22 h after the i.m. route and cumulative urinary excretion of the drug over a 24 h period of 37-42% (i.v. route) and 32-33% (i.m. route). The volumes of distribution were lower in patients with heart disease and patients with biliary fistula than in the healthy subjects. In patients suffering from renal failure the dominant half-time of plasma turnover was higher (33 h), while cumulative urinary excretion of the glycoside (12%) and the volumes of distribution were lower than in the healthy subjects. A peak of plasma levels 30 min after i.m. administration of K-strophanthoside-3H leads to the conclusion that this glycoside is rapidly absorbed when injected intramuscularly.

Bioavailability of digoxin in a new soluble pharmaceutical formulation in capsules.

The in vitro dissolution and the bioavailability of two pharmaceutical formulations of digoxin were compared, one being a common commercial tablet form and the other a solution of the glycoside in soft gelatin capsules. Digoxin capsules dissolved more readily in vitro and showed higher bioavailability than digoxin tablets in both dogs and humans. In dogs, the capsules and tablets were compared with an elixir of digoxin, which possesses complete bioavailability. The better bioavailability of digoxin capsules as compared with tablets may be explained by the fact that this formulation contains the cardiac glycoside in a solution.

Distribution of camazepam in rats and mice.

Camazepam, 5 mg/kg iv, was injected in rats and mice to study its distribution in the blood and brain. Peak blood levels were about 0.9 microgram/ml in rats and 0.6 microgram/ml in mice. Peak brain levels were about 1.5 microgram/g in rats and 0.8 microgram/g in mice. The apparent blood half-life of camazepam was 9 min in mice and 20 min in rats.

Pharmacological and toxicological properties of creatinol O-phosphate. A review.

N-Methyl-N-(beta-hydroxyethyl)guanidine O-phosphate (creatinol O-phosphate, COP) has proved to possess anti-ischemic and anti-arrhythmic activities associated with improved ionic balance and heart performance. These activities, which have also been shown in clinical studies, are more evident in pharmacological and clinical conditions involving a hypoxic damage of the heart muscle. Pharmacokinetic studies have shown that absorption of COP administered i.m. is complete. COP is distributed in all organs, and in particular, in the kidney, liver and myocardium. After being dephosphorylated, this drug is eliminated with urine. Dephosphorylation of COP occurs in the kidney and liver. COP crosses the membrane of the myocardial cell, concentrating in the cytosoluble fraction. The results of the toxicological studies confirm that COP has no side effects, is excellently tolerated and has a favourable therapeutic index.

Protective action of creatinol O-phosphate against serum CPK activity enhanced by isoprenaline in the rat.

Isoprenaline (ISP) in the rat (500 mg/kg s.c.) was shown to be able to enhance the creatin phosphokinase activity (CPK) in serum from 135 U/l in the control animals to about 600 U/l in 5 h, i.e. at the peak. When the rats were pretreated with N-methyl-N-(beta-hydroxyethyl)guanidine O-phosphate (creatinol O-phosphate, COP), the CPK enhancement was reduced to an extent related to the doses of COP (250, 500 and 1000 mg/kg i.p.). COP protection was about 16% with the lower dose but increased to 50% with the highest dose according to linear regression (COP doses versus CPK levels, p less than 0.01). The protective action against serum CPK enhancement evoked by ISP is common to other classes of drugs, such as beta-blocking agents, calcium antagonists and corticosteroids. In the case of COP and calcium antagonists a common mechanism, which has the effect or reducing myocardial calcium overload due to ISP, may be assumed on the basis of other previous investigations on the ion balance across the heart cell membrane and on the uptake and subcellular distribution of COP in the isolated perfused rat heart.