Effect of polyoxyl 35 castor oil and Polysorbate 80 on the intestinal absorption of digoxin in vitro.

Surfactants are classically used to improve the solubilization of lipophilic drugs such as digoxin. Polysorbate 80 and Cremophor EL (polyoxyl 35 castor oil) are such surfactants but they may also modulate the action of P-glycoprotein, an energy-dependent "counter-transport" system implicated in the phenomenon of multidrug resistance in cancer cells. P-glycoprotein is also present in the intestine on the apical membrane of mature enterocytes and can potentially reduce the absorption of a wide range of drugs. In this study, using the improved everted gut sac method, the effects of Polysorbate 80, Cremophor EL and cyclosporin on the absorption of digoxin were studied. An increase in the uptake of digoxin in the presence of these three products could be shown with our in vitro model. Cremophor EL and Polysorbate 80 had no toxic effects at the concentrations used. These results suggest that surfactants such as Cremophor EL and Polysorbate 80 should not only support solubilization but can also modulate the P-glycoprotein system to improve the bioavailability of poorly absorbed drugs.

The Eurevie Study: contrasting effect of piretanide and thiazides in mild to moderate hypertension.

UNLABELLED: This study compares the loop diuretic piretanide 6 mg in a slow-release formulation (PIR) with hydrochlorothiazide 25 mg (HCT) and the fixed combination altizide 15 mg-spironolactone 25 mg (ALT-SP) in hypertension. 1105 mild to moderate hypertensive patients entered a three-week placebo wash-out period; 899 were randomized in a 6-month, double-blind, parallel group treatment phase; 800 completed the study. Primary end-points; serum potassium concentration and quality of life at one month; secondary end-points: ionic, renal and metabolic variables; blood pressure (BP) measurements. HCT and ALT-SP were compared only to PIR using Dunnett's or chi 2 tests. RESULTS: No difference was found for the overall quality of life. No change of serum potassium concentration at one month was found in PIR while small decreases were detected with ALT-SP (-0.1 mM) and HCT (-0.26 mM). Serum creatinine concentration increased significantly in ALT-SP when compared to PIR. All the drugs were effective in reducing BP: HCT had a higher rate of responders than PIR with similar mean BP falls and ALT-SP induced greater falls in blood pressure. CONCLUSION: PIR proves to be a potent antihypertensive drug without significant effect on serum electrolytes, plasma glucose and lipids. HCT was slightly more potent but induced a fall in serum potassium concentration with a significant risk of hypokalaemia. The addition of SP to ALT led to a more potent diuretic with a higher level of serum potassium and plasma creatinine disturbances.

Hemodynamic and pharmacokinetic study of propranolol and atenolol in cirrhosis patients.

The pharmacokinetic properties of propranolol and atenolol were evaluated both in 9 patients with cirrhosis and in 12 healthy subjects. The hemodynamic effects of the drugs were evaluated separately in the cirrhotic patients. Propranolol and atenolol significantly decreased wedged hepatic venous pressure and cardiac output in cirrhotic patients. Propranolol Cmax, tmax and AUC were significantly increased and plasma half-life was significantly prolonged in cirrhotic patients. In contrast, the corresponding pharmacokinetic values of atenolol were not significantly different in cirrhotic patients and in healthy subjects.

Interactions between smectite, a mucus stabilizer, and acidic and basic drugs. In vitro and in vivo studies.

The interaction of phenylbutazone and diazepam with smectite were studied in in-vivo and in-vitro. The kinetics of both drugs were investigated in healthy subjects after oral administration as monotherapy or in association with smectite. Smectite did not substantially alter the kinetics of phenylbutazone, whereas the peak plasma concentration of diazepam was reduced to 91%, and the time of peak concentration was prolonged by 153% of the control values. The in-vitro investigations were conducted at pH 5.5 and 8 and showed that there was no interaction between phenylbutazone and smectite, but that it adsorbed diazepam. The findings suggest that smectite delays the absorption of basic drugs and does not alter the absorption kinetics of acidic drugs.

Clinical pharmacology and pharmacokinetics of prizidilol in hypertensive patients.

We evaluated the clinical pharmacology of prizidilol, a compound with vasodilator and beta-blocking properties, in 12 hypertensive patients with normal renal function. A single dose of 600 mg prizidilol was given orally and blood samples were withdrawn at intervals for high-performance liquid chromatography assay. Blood pressure and heart rate were recorded every hour in supine and standing positions. A nitroglycerin test was performed at the 2nd, 4th, and 6th h for evaluation of cardiac beta-adrenoceptor activity. Results were compared with those after placebo intake the day before. Prizidilol produced a significant decrease in supine systolic and diastolic blood pressures (-22 and -24%, respectively), with a maximum effect 5 h after intake. Blood pressure changes were not different in slow and fast acetylators, suggesting that the acetylated metabolites were active. Heart rate decreased slightly but significantly during the first 2 h, but was similar to control levels thereafter. However, the nitroglycerin test data suggested a prolonged blockade of beta-adrenoceptor activity. Pharmacokinetics showed large variations among patients; several peaks were observed on the curves, indicating irregular absorption. The apparent plasma elimination half-life was 4.4 +/- 0.4 h. Total body clearance was high despite a very low renal clearance, indicating that the drug was eliminated mainly by the metabolic or intestinal route. No significant correlations were found among plasma concentration, blood pressure, and heart rate. In conclusion, prizidilol is a potent antihypertensive drug having equilibrated vasodilator and beta-blocking effects. The pharmacokinetic data suggest a first-pass effect and elimination by extra-renal routes.

Potentiation by an alpha-adrenolytic agent, nicergoline, of the cardiac effects of propranolol.

Ten young healthy volunteers were given placebo, propranolol (20 or 40 mg), nicergoline, an alpha blocking agent (30 mg) or the association of nicergoline (15 mg) and propranolol (20 mg) in a randomized double blind study. The results show that nicergoline potentiates the cardiodepressant action of propranolol, whereby the effects of 20 mg become the same as those of 40 mg given alone on cardiac output and myocardial oxygen demand, though the plasma propranolol levels are not changed. We, therefore, propose that nicergoline blocks alpha 1 agonist effects of propranolol, which are usually masked by the greater beta 1 blocking effects but could have clinical and therapeutic relevance.

[Pharmacokinetics of theophylline and circadian rhythm]. / Pharmacocinétique de la théophylline et rythme nycthéméral.

In the purpose to evaluate the circadian changes of theophylline pharmacokinetic, 8 healthy subjects (age range 22-39 y, weight 54-91 kg) were given a single oral dose of 4,5 mg/kg theophylline solution. Administration was made randomly at 9 a.m. after 12 hours fasting and at 9 p.m. After evening administration the subjects remained awake during the night and a standardized meal was served 4 h and 9 h after theophylline intake. Plasma theophylline concentrations were measured by a high performance liquid chromatography. Absorption is significantly faster in the morning than in the evening but C max values were identical. Plasma elimination half-life is significantly different (8,01 +/- 1,95 h in the morning, 6,23 +/- 1,75 h in the evening). No significant modifications were observed of the area under the curve, the body clearance, the apparent volume of distribution. There were no differences in the total body clearance, the area under the concentration-time curve, the apparent volume of distribution.

Effects of phenylbutazone on extravascular diffusion, protein binding and urinary excretion of cefazolin in rabbits.

The effects of an anti-inflammatory drug, phenylbutazone, on the disposition of a commonly used cephalosporin, cefazolin, were studied in rabbits. The following investigations were made: mathematical analysis of blood levels obtained after i.v bolous injection of cefazolin, alone or combined with phenylbutazone (10 mg/kg), injection 4 hr before; protein binding by ultracentrifugation in vitro; and renal excretion and distribution in extravascular fluid obtained from s.c. tissue cages in vivo. Single i.m. injections of cefazolin (30 mg/kg) were administered either alone or in combination with phenylbutazone (10 or 100 mg/kg i.m.) or 2 or 4 hr before. The mathematical analysis disclosed a competition of phenylbutazone on protein binding of cefazolin. In vitro, phenylbutazone reduced the extent of protein binding of the antibiotic (74-80 to 47-59%). Cefazolin appeared at higher concentrations in extravascular fluid in the presence of phenylbutazone than when administered alone. Phenylbutazone appeared to be responsible for a dose-dependent effect on renal excretion of cefazolin i.e., a reduction of secretion at low doses (10 mg/kg) and a possible reduction of tubular reabsorption at high doses (100 mg/kg). A bidirectional transport of cefazolin in rabbit tubules was thus shown. The interaction of phenylbutazone on the on the disposition of cefazolin appeared also dependent on the time of injection of the former and on the mode of administration of the antibiotic.

[Comparison of the effects of betablockers and captopril on the development of genetic hypertension in the rat]. / Effets comparés des betabloquants et du captopril sur le développement de l'hypertension génétique chez le rat.

The preventative effects of betablockers and captopril on the development of genetic hypertension in genetically hypertensive rats, were studied after long-term daily dosage by forced feeding, from the 5th to the 20th week of age of the animals. Of the drugs studied, captopril, atenolol and propranolol limited the development significantly, but pindolol only had a modest effect and acebutolol was ineffective. No correlation was found between the degree of prevention of genetic hypertension and the intensity of betablockade. Atenolol and propranolol prevent genetic hypertension by I) reducing cardiac output, a reduction which is not neutralised by the simultaneous change in peripheral resistance, 2) decreasing plasma renin concentrations, and 3) limiting the development of myocardial hypertrophy. Captopril is very effective in preventing the development of genetic hypertension and acts: 1) by causing an early and lasting fall in peripheral resistance related to the suppression of Angiotensin II, and possibly by potentialising the vasodilatation of bradykinins and, 2) by limiting myocardial hypertrophy.

Pharmacokinetics of atenolol in patients with terminal renal failure and influence of haemodialysis.

1 The pharmacokinetics of atenolol, after 200 mg orally, were studied in 18 patients with terminal renal insufficiency (creatinine clearance less than 5 ml/min), of whom twelve were being treated by chronic dialysis. 2 The peak plasma level, 1.59 +/- 0.43 mg/l, was reached in 4.7 +/- 2.1 h. 3 Without dialysis treatment, the apparent plasma half-life of atenolol was greatly increased (73.4 +/- 28.8 /). During dialysis, it dropped to 7.5 +/- 3.7 h but returned to 51.2 +/- 17.3 h after dialysis. The plasma atenolol plot was a rising slope for a few hours after the end of dialysis. 4 Renal clearance of atenolol was very low (4.6 +/- 1.5 ml/min). 5 Plasma clearance during dialysis was 42.6 +/- 21.3 ml/min for a mean blood flow-rate of 236 +/- 25 ml/min through a cuprophane membrane dialyser. 6 These results suggest that dosage should be modified for these patients.