ozolinone and etozolin

The effect on urinary electrolyte excretion, renin release and plasma norepinephrine of single oral doses of 400 mg etozolin (E) and of 40 mg furosemide (F) were studied in hypertensive patients with normal (n = 6) and impaired kidney function (n = 6). E caused a marked saluresis up to 24 hours, showing its long duration of action. F, however, displayed a brief, brisk peak diuresis, followed by a rebound from the 4th to the 24th hours. The brisk peak diuresis induced by F was associated with pronounced release of renin, almost twice that induced by E. In chronic renal failure the renin release in relation to the magnitude of the diuresis was increased, i.e. the sensitivity of these patients to changes in water homeostasis was increased. E and F stimulated the sympathetic system to roughly the same extent. Patients with essential hypertension had higher plasma levels of norepinephrine than hypertensive patients with chronic renal failure. In addition, hypertensive patients with normal renal function (n = 4) and varying degrees of renal impairment (n = 11) were also given 400 mg daily for 2 weeks. Effects on blood pressure and electrolyte homeostasis were monitored, as well as the plasma kinetics of metabolite I, ozolinone. At the end of the 2 week treatment E had significantly lowered systolic (-12 mm Hg) and diastolic (-9 mm Hg) blood pressure, and had produced a significant loss of body weight, without altering plasma electrolytes or blood chemistry. There was no accumulation of the effective metabolite ozolinone under conditions of severe impairment of kidney function.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Antihypertensive Agents; Diuretics; Female; Furosemide; Humans; Hypertension; Kidney Failure, Chronic; Kinetics; Male; Middle Aged; Norepinephrine; Renin; Thiazoles

The single dose kinetics of (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene)acetate (etozolin) and its active metabolite ozolinone were determined in 6 healthy volunteers, in 12 patients with acute hepatitis and in 15 patients with hepatic cirrhosis with ascites. In hepatitis, the elimination half-life of etozolin was 4 times longer resulting in a 2 fold rise in the AUC. At the same time, plasma levels of ozolinone were lower and consequently the AUC of his metabolite was reduced. In cirrhosis, the plasma level time curves of etozolin and ozolinone differed significantly from the controls and also from those of the patients with acute hepatitis. For etozolin Cmax was reduced to about 1/2, the elimination half-life being increased by a factor of 5. This resulted in a 3 fold higher AUC. As for ozolinone the reduction of plasma levels was more pronounced--Cmax fell to 1/6 of the control value--so that in spite of a longer elimination half-life, the AUC fell to 1/2. Ascites concentrations of etozolin and ozolinone were almost identical to the plasma concentration. The results suggest that acute hepatitis and hepatic cirrhosis lead to a reduced formation of ozolinone. As a result, etozolin accumulates and plasma levels of oxolinone drop. Moreover, both substances enter the ascites to a significant degree. It is concluded that these changes in the kinetics of this lipophilic diuretic do not allow a reliable dosage regimen in patients with hepatic cirrhosis and ascites.

Topics: Acute Disease; Adult; Aged; Ascites; Ascitic Fluid; Diuretics; Half-Life; Hepatitis, Viral, Human; Humans; Liver Cirrhosis; Male; Middle Aged; Thiazoles

The placental transfer of etozolin and its pharmacologically active metabolite ozolinone was studied in 48 patients during the first (44 patients) and second (4 patients) trimester. 24 patients received a single oral dose of etozolin 400 mg 2-20 h prior to interruption of pregnancy by curettage or prostaglandin infusion. 24 other patients received 3 oral doses of etozolin 400 mg (11 patients) or 800 mg (13 patients) on 3 consecutive days, and pregnancy was terminated 2-10 h after the last dose. The fetal tissue/maternal serum and placental tissue/maternal serum ratios of etozolin and ozolinone were found to lie between 0.3 and 0.6. The serum levels were lower in pregnant than in non-pregnant patients. The low placental and fetal concentrations of etozolin and ozolinone suggest that these drugs may prove useful when a diuretic is indicated in the treatment of oedema and hypertension during pregnancy.

Topics: Administration, Oral; Adolescent; Adult; Diuretics; Female; Fetus; Humans; Maternal-Fetal Exchange; Placenta; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Second; Thiazoles

Topics: Chromatography, High Pressure Liquid; Female; Fetus; Humans; Maternal-Fetal Exchange; Piperidines; Placenta; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Second; Reference Values; Thiazoles

A sensitive and specific method for the determination of the diuretic Ethyl (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetate (etozolin, Elkapin) and its pharmacologically active main metabolite, (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetic acid (ozolinone), at therapeutic concentrations in plasma is described. The method is based on high performance liquid chromatography and the use of two structurally similar internal standards. Etozolin and its metabolite are extracted from the plasma into dichloromethane at pH 9 and pH 5, respectively, and the resulting residues are analyzed on a silica gel column. The elution peaks are detected by UV absorption at 281 nm. The sensitivity for both compounds is 20 ng/ml plasma. The precision of the method is about +/- 5%. The applicability to pharmacokinetic studies of etozolin is shown.

Topics: Benzothiadiazines; Chromatography, High Pressure Liquid; Diuretics; Humans; Piperidines; Sodium Chloride Symporter Inhibitors; Thiazoles; Time Factors