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PubMed1969

Treatment of hypertension with hydrochlorothiazide and spironolactone.

A comparison was made of the antihypertensive effect of a daily dose of 150 mg. of hydrochlorothiazide (HCT) with one of 150 mg. of spironolactone (SL) in 48 patients with essential hypertension.The blood pressure values after six weeks of therapy with HCT were not significantly different from those after SL. Treatment of 25 of these patients with the two agents combined did not reduce the blood pressure further. Blood urea nitrogen concentrations increased with both HCT and SL treatment.With combined treatment there was a further increase in blood urea nitrogen concentration and a decrease in serum sodium concentrations without weight loss beyond that achieved with either HCT or SL alone.

Blood Pressure↗
PubMed1978

Stability of pediatric liquid dosage forms of ethacrynic acid, indomethacin, methyldopate hydrochloride, prednisone and spironolactone.

The stability of liquid dosage forms of ethacrynic acid (1 mg/ml), indomethacin (2 mg/ml), methyldopate hydrochloride (25 mg/ml), prednisone (0.5 mg/ml) and spironolactone (2 mg/ml), which often are compounded extemporaneously, was studied. One or two liquid dosage forms of each of the five drugs was prepared with the pure drug or the powder from a commercial dosage form using aqueous sorbitol or simple syrup alone or with a 10% (v/v) solution of alcohol in water. The dosage forms were stored at 24 C in amber-colored bottles for 21-224 days and assayed by various methods. All solutions studied were stable for at least 84 days. A solution was considered stable if it retained 90% of its drug concentration. Except for the prednisone solution, all solutions were stable for at least 164 days; however, the solution of methyldopate hydrochloride prepared from the pure drug became discolored after 98 days. The liquid dosage forms studied have limited stability but can be used by the pharmacist when extemporaneous oral solutions of these drugs are needed.

Child↗
PubMed1978

A study on cerium-induced liver injury in rats after pretreatment with spironolactone, phenobarbital, pregnenolone-16 alpha-carbonitrile and nafenopin.

A number of drugs known to induce liver microsomal enzymes were studied with respect to their effect on the elevated liver triglyceride (TG) concentration and serum glutamic oxaloacetic acid transaminase (GOT) and glutamic pyruvic acid transaminase (GPT) activities induced by an i.v. injection of cerium in rats. Pretreatment with pregnenolone - 16 alpha - carbonitrile (PCN) and 2-methyl-2-[p-(1,2,3,4-tetrahydronaphth-1-yl)phenoxy]-propionic acid (nafenopin) decreased the liver TG concentration significantly. Spironolactone and phenobarbital pretreatment also decreased the TG level in comparison to controls, but the difference was not statistically significant. Both GOT- and GPT-activities in serum increased on the first day after cerium injection and reached a maximum after 3 days. All the drugs significantly reduced the elevated levels. After 7 days the activity was almost normal in all the surviving animals.

Alanine Transaminase↗
PubMed1979

[Relative bioavailability of a new spironolactone preparation (author's transl)].

The investigations have been performed to determine the relative bioavailability of canrenon from Acelat 100 capsules in comparison with canrenon from a spironolactone standard preparation available on the German market. This was carried out by comparing the areas under the serum fluctuation curves after oral application of both preparations as well as by urine excretion extrapolated infinitely. The preparations were administered together with a standard breakfast. Subsequently up to 48 h blood was withdrawn from the Vena cubiti. According to a known method serum samples were analysed spectrophotometrically. The data obtained were fitted to an open two-compartment model with the RIP-procedure. The core of the program is a Gauss-Newton iteration (minimising the last squares). These are the results: By intraindividual comparison of the areas under the serum fluctuation curves of canrenon a relative bioavailability of 116.27% (s = 16.84) of canrenon from Acelat 100 could be calculated versus canrenon from the standard. Urine excretion, extrapolated infinitely, showed a 4% higher excretion of canrenon after application of Acelat 100 compared to standard. Both results are not significantly different in the range of biological scattering. The further pharmacokinetic parameters calculated were within the range of the literature available.

Adult↗
PubMed1978

Pancreatic cancer treated with carmustine, fluorouracil, and spironolactone: a randomized study.

A prospective randomized trial between two drug regimens in 38 patients with advanced pancreatic carcinoma was performed. The two-drug regimen consisted of carmustine and fluorouracil. The survival rate and response to these two drugs was compared to a three-drug regimen consisting of these same two drugs plus spironolactone. Objective partial responses were rare in both groups, being 3/18 in the two-drug group and 2/20 in the three-drug group. Life table analysis in previously untreated patients from time of treatment shows longer survival for the three-drug group, but this difference was not statistically significant.

Adult↗
PubMed1983

[Clinical study of the efficacy of oral potassium canrenoate and spironolactone in essential arterial hypertension].

A group of 13 male and 8 female out-patients (mean age: 40.57 years), with primary arterial hypertension, was submitted to two periods of treatment in a cross-over study with spironolactone and potassium canrenoate. Each preparation was given at the dose of 200 mg/day per os for 21 days, with a 10-day interval between treatments. Both preparations proved active on the systolic and diastolic pressure values controlled 7 days. However, potassium canrenoate showed a greater and more rapid effect, particularly on diastolic arterial pressure, as also demonstrated by the statistical analyses. PRA and aldosteronemia increased with both treatments, but this increase resulted significantly lower with potassium canrenoate. The minor stimulating action on the renin-angiotensin-aldosterone mechanism by potassium canrenoate may be the reason for its greater anti-hypertensive effect. Both treatments were perfectly tolerated locally and systemically.

Administration, Oral↗
PubMed1984

Testosterone, 17 Ks, 17 beta E2 FSH-LH variations and hirsutism modifications during spironolactone therapy.

The research here reported concerns 9 hirsute women, four of them with PCO and five with idiopathic hirsutism, who underwent treatment with spironolactone. 4 non hirsute hypertensive cases served as control. For one year hair growth, testosterone, 17 Ks, estradiol and gonadotropins behaviours were studied in all of the patients. Results clearly show that the peripherical response (the hair) to the therapy is only just sufficient, and corresponds to a good reduction of the androgenic hormones in blood. However, there is also an LH gonadotropin secretion reduction which is statistically scarcely significant. If the therapeutic response of hair were good, fetal risk could be prevented with safe and contemporaneous contraception. However, since the response is scarcely sufficient, we do not think this therapy is more advisable than other ones.

17-Ketosteroids↗
PubMed1980

[Debatable questions of strophanthin and spironolactone treatment in certain forms of acute myocardial infarct].

The results of clinical and instrumental examination of 67 patients and experimental findings provide evidence of myocardial resistance to cardiac glycosides in acute myocardial infarction complicated by the initial stage of cardiac insufficiency. It is suggested that symptoms of secondary hyperaldosteronism may develop in acute myocardial infarction and that medication with cardiac glycosides in combination with spironolactones is expedient.

Adult↗
PubMed1995

Effect of phenobarbital, spironolactone and pregnenolone-16 alpha-carbonitrile on rat hepatic beta-glucuronidase.

beta-Glucuronidase cleaves beta-glucuronides of drugs, steroids, as well as macromolecular compounds containing glucuronic acid bound with a beta-glycoside bond. Therefore, the study of induction of this enzyme by known microsomal enzyme inducers is of obvious interest. The effect of phenobarbital, spironolactone and pregnenolone-16 alpha-carbonitrle on the rat liver beta-glucuronidase was studied. These compounds augmented the activity of this enzyme, in the above increasing order. These results are discussed in view of the influence on pharmacokinetics of many drugs. Furthermore, they may lead to new therapeutic approaches for certain diseases.

Animals↗
PubMedDate not supplied

Hepatic metabolism of spironolactone. Production of 3-hydroxy-thiomethyl metabolites.

Spironolactone (SP) is used clinically as a renal aldosterone antagonist and as an antiandrogen. It is known that the drug is extensively metabolized and that metabolites mediate its therapeutic actions, but hepatic metabolism of SP has not been comprehensively investigated. Hepatic disposition may also be important in the toxicity of SP, because the parent compound prevents the hepatocarcinogenic effects of its metabolite, canrenone (CAN). Using a combination of in vivo and in vitro approaches, we studied the metabolism of SP by guinea pig livers. The major compounds detected in livers in vivo following SP treatment were the known metabolites, 7 alpha-thiomethyl-spirolactone (TM) and CAN, and a previously uncharacterized compound whose mass spectral and UV absorption characteristics suggested that it was an A-ring-reduced derivative of TM. In vitro incubation of liver homogenates with SP also resulted in the formation of the unknown metabolite. A combination of MS and NMR spectroscopy was used to identify unequivocally the unknown metabolites as 3 alpha-hydroxy-TM. Another metabolite produced in vitro was identified as 3 beta-hydroxy-TM. It is possible that these two new metabolites of SP contribute to the pharmacological actions of the drug. In addition, production of 3 alpha-hydroxy-TM suggests a mechanism to account for the prevention of CAN-induced carcinogenicity by SP. TM may block the conversion of CAN to mutagenic 3-hydroxy-CAN metabolites by serving as a competitive substrate for hepatic 3-keto reductases.

Animals↗
PubMedDate not supplied

Identification of spironolactone metabolites in plasma and target organs of guinea pigs.

Spironolactone (SL) is a renal aldosterone antagonist that is used clinically in the treatment of hypertension and congestive heart failure. Among the side effects of the drug are degradation of cytochrome P-450 and inhibition of steroidogenesis in the testes. It has long been recognized that the effects of SL are mediated by metabolites of the drug, but questions remain about the identities of the active metabolites. Because tissue metabolites of SL had not previously been investigated, experiments were done to determine the identities of metabolites in target organs after SL administration to guinea pigs. Metabolites were identified by HPLC and MS. The major plasma metabolite was 7 alpha-thiomethyl-SL (TM) with smaller amounts of canrenone (CAN) and 7 alpha-thio-SL (TH) also present. In kidneys, TM also was the principal metabolite, but CAN was the only other compound consistently found. By contrast, in testes, substantial amounts of SL and TH were present in addition to TM and CAN. It is possible that local metabolism of SL contributes to the differences in metabolite profiles between plasma and target organs. Data also suggest that TM is principally responsible for the renal antimineralocorticoid effects of SL and support the purported role of TH in the degradation of testicular cytochrome P-450.

Animals↗
PubMed1993

Involvement of cytochrome P-450IIIA in metabolism of potassium canrenoate to an epoxide: mechanism of inhibition of the epoxide formation by spironolactone and its sulfur-containing metabolite.

In vitro metabolism studies of potassium canrenoate (PC) were conducted to examine whether spironolactone (SP) and/or its sulfur-containing metabolites inhibit the PC metabolic pathways to mutagenic metabolites and to elucidate the mechanism for any observed inhibitory effect. The mechanistic study was conducted using liver microsomes prepared from male and female rats with and without pretreatment of a cytochrome (Cyt) P-450IIIA inducer [pregnenolone-16 alpha-carbonitrile (PCN) or dexamethasone (DEX)] and with and without a Cyt P-450IIIA inhibitor, triacetyloleandomycin (TAO). The present study demonstrates that SP and its sulfur-containing metabolite 7 alpha-thio-spirolactone substantially inhibited the formation of promutagen 6 beta, 7 beta-epoxycanrenone (6 beta, 7 beta-epoxy-CAN) from PC. The sulfur-containing metabolite of SP that inhibit promutagen formation were not formed from PC, although a glutathione conjugate of PC was formed. The formation rate of 6 beta, 7 beta-epoxy-CAN was greater in liver microsomes prepared from rats pretreated with a Cyt P-450IIIA inducer (PCN or DEX) than in liver microsomes prepared from the untreated rats. The formation rate of the epoxide metabolite was lower after in vitro addition of TAO. Pretreatment of animals with TAO 4 hr before sacrifice produced similar results. Erythromycin, which is N-demethylated by Cyt P-450IIIA, also reduced the formation rate of 6 beta, 7 beta-epoxy-CAN. Inhibition of PC metabolism to 6 beta, 7 beta-epoxy-CAN by TAO and erythromycin, and its induction by DEX and PCN, suggest involvement of Cyt P-450IIIA, which is in turn inhibited by SP and 7 alpha-thio-spirolactone.

Animals↗
PubMed1977

[Relations between hypotensive effect and modifications of volemia and plasma renin activity in patients with essential hypertension treated using spironolactone].

The hypotensive effect of spironolactone and its relation to the changer in volaemia and renin activity induced by the drug were studied in 12 hospitalised patients with essential hypertension. After 4 weeks, arterial pressure was significantly decreased in direct relation to reductions in plasma volume in 9 subjects in both the erect and the recumbent position. These reductions were probably responsible for an increase in renin activity noted (sometimes at significant levels) in all subjects. It would appear that such increase does not impede the hypotensive effect of the drug. The hypotensive response was, in fact, less marked in only 3 patients, whose basal renin levels were themselves high.

Adult↗
PubMed1997

[Type 4 renal tubular acidosis caused by spironolactone. A case report].

The authors describe a case of type 4 renal tubular acidosis, observed in a subject with liver cirrhosis, the pathogenetic cause of which was probably the assumption of spironolactone. It is thought that, even if such an eventuality is not very frequent, it must be considered in clinical practice, in view of the negative consequences that the reduction in urinary ammonium excretion and hyponatriemia, together with this particular form of acidosis, may have on the neurological state of the patients.

Acidosis, Renal Tubular↗
PubMed1997

[Conn's syndrome. Study of systemic cardiovascular hemodynamics after medical treatment with spironolactone and after surgical treatment].

OBJECTIVES: Assess hemodynamic effect of Conn's syndrome in order to better prepare patients for surgical resection of their adenoma. PATIENTS AND METHODS: Hemodynamic investigations were conducted before any treatment in 13 patients with Conn's syndrome. Results were compared with those in 13 control subjects with permanent primary hypertension. In the 13 patients with Conn's syndrome, the same hemodynamic parameters were studied in 13 after drug therapy using spironolactone and in 8 after surgery. RESULTS: Hypertension was associated with a significant increase in stroke volume and a non-significant increase in cardiac index. Blood pressure normalized after sprironolactone and after surgery in parallel with a significant decrease in blood volume. DISCUSSION: These hemodynamic disorders in Conn's disease patients suggest that the increase in stroke volume is a consequence of increased venous return and more likely, in myocardium contractility or a combination of both. CONCLUSION: These hemodynamic characteristics of Conn's disease should be useful in guiding monitoring schemes for these patients in the perioperative period.

Adolescent↗
PubMed1976

Opposite effects of spironolactone and amiloride on potassium excretion in a patient with ascites due to liver cirrhosis.

Potassium excretion was enhanced by spironolactone and it was inhibited by amiloride in a patient with ascites. One drug's effect was counteracted by the other when they were used in combination. Individual variation in the sites of action of antikaluretic drugs might be a possible explanation for the unpredictable changes in potassium excretion induced by these agents.

Amiloride↗
PubMed1998

Effects of spironolactone-altizide on left ventricular hypertrophy.

OBJECTIVE: To investigate the effects of the association spironolactone (25 mg)/altizide (15 mg) as monotherapy on left ventricular hypertrophy (LVH) in patients with mild to moderate hypertension. Additionally, to study the correlation between left ventricular mass (LVM) index and electrocardiographic (ECG) criteria for LVH. METHODS AND RESULTS: This was an open, prospective study of 6 months. Patients with mild to moderate essential hypertension were treated with spironolactone/altizide for two months and were included in the study if their blood pressure (BP) at the end of this first treatment period was normalised according to protocol criteria (systolic BP < 160 mm Hg and diastolic BP < 95 mm Hg). Patients then entered a second 4-month treatment period. LVM was determined by echocardiography performed at the beginning of treatment and after 6 months. LVH was defined as LVM > or = 100 g/m2 in women and LVM > or = 131 g/m2 in men. Echocardiograms were interpreted blindly by two echocardiography reading laboratories. Seventy-one patients with a normalised BP after two months of treatment, were enrolled in the study. Changes in LVM index were studied in 31/71 patients with LVH (25 women and 6 men, mean LVM index +/- (SD) 119.9 +/- 16.4 g/m2 in women and 147.8 +/- 10.9 g/m2 in men). Spironolactone/altizide significantly reduced LVM index by 10%, from 125.3 +/- 22.5 to 114.2 +/- 25.1 g/m2 (p < 0.005). Posterior and septal wall thickness decreased by 4% (p = 0.06) and 5% (p = 0.026), respectively. End-diastolic dimension was reduced by 3%, from 50.3 +/- 3.3 to 48.9 +/- 3.4 mm (p = 0.006). The posterior wall thickness to end-diastolic dimension ratio remained unchanged. Complete regression of LVH according to mass criteria occurred in 11 patients out of 31 (34.5%). The observed changes in ECG voltage criteria were in accordance with a decrease of LVM index. CONCLUSION: In this open study, the potassium-sparing diuretic spironolactone/altizide decreases LVM index in hypertensive patients, who were selected for follow-up because they had echocardiographic LVH and because their BP had normalised during an initial 2-month treatment period.

Benzothiadiazines↗