Spironolactone

Ochs, Hermann R.; Greenblatt, David J.; Bodem, G; Smith, Thomas W.

doi:10.1016/0002-8703(78)90052-2

Cited by 66 publications

(25 citation statements)

References 137 publications

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“…The best information on the therapeutic potency of SC8109 relative to spironolactone comes from a study comparing the drugs in patients with chronic liver disease where SC8109 had diuretic potency approximately 40% that of spironolactone in the original formulation (Gantt & Dyniewicz, 1959), or 10% that of the formulation used here (Shaldon et al, 1963). Furthermore, in oedematous states (Liddle, 1957(Liddle, , 1958Bolte et al, 1958;Kerr et al, 1958;Slater et al, 1959), primary hyperaldosteronism (Salassa et al, 1958) and essential hypertension (Bolte et al, 1958), the evidence suggests that oral doses of about 1 g of SC8109 were required to produce therapeutic effects comparable to those produced by approximately 100 mg spironolactone in its currently marketed form (Ochs et al, 1978).…”

Section: Discussionmentioning

confidence: 99%

“…However, another steroidal aldosterone antagonist, SC8109, was extensively studied in patients (Liddle, 1958;Slater, 1960;Gantt, 1961;Drill, 1962). SC8109 (17-hydroxy-3-oxo-19-nor-17a-pregn-4-ene-21 car-boxylic acid, y lactone) structurally resembles spironolactone ( Figure 1) which has found use in the treatment of oedematous states and essential hypertension (Ochs et al, 1978). Both compounds have been shown to be competitive aldosterone antagonists in animals (Kagawa, Cella & Van Arman, 1957;Liddle, 1957;Kagawa, Sturtevant 1959 ;Slater et al, 1959;Kagawa 1960) and in man (Liddle, 1957;1958;Ross & Bethune, 1959;Gantt, 1961).…”

Section: Introductionmentioning

confidence: 99%

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Quantitative comparison of aldosterone antagonists in normal human subjects: prediction of therapeutic potency.

McInnes¹,

Harrison²,

Shelton³

et al. 1981

Brit J Clinical Pharma

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1 The potency of single doses of the aldosterone antagonist SC8109 relative to spironolactone in reversing the urinary electrolyte effects of fludrocortisone was examined in a double-blind, balanced, crossover study in six healthy volunteers. 2 For the urinary ratio log10 10 Na/K, the relative potency of SC8109: spironolactone on a weight basis was 0.08:1 (95% confidence limits 0.04-0.13:1). 3 The potency of SC8109 relative to spironolactone for natriuresis and antikaliuresis was 0.10:1 and 0.05:1, respectively. 4 The results show excellent agreement with clinical experience where SC8109 was considered to have one tenth the potency of spironolactone. We suggest that the human bioassay employed in this study provides quantitative information which should be predictive of the therapeutic potency of aldosterone antagonists.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quantitative comparison of aldosterone antagonists in normal human subjects: prediction of therapeutic potency.

McInnes¹,

Harrison²,

Shelton³

et al. 1981

Brit J Clinical Pharma

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“…The steroid spironolactone (SL) is a therapeutic drug used as a diuretic in patients with edema or ascites (Ochs et al, 1978) and shows inductive properties on biotransformation enzymes in humans and experimental animals (Ochs et al, 1978;Catania et al, 2004). SL also induces choleresis in the rat as a result of a substantial increase in BSIF, whereas BSDF is impaired by this steroid as a result of decreased bile salt pool size .…”

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confidence: 99%

Beneficial Effect of Spironolactone Administration on Ethynylestradiol-Induced Cholestasis in the Rat: Involvement of Up-Regulation of Multidrug Resistance-Associated Protein 2

Ruiz

Villanueva²,

Luquita³

et al. 2007

Drug Metabolism and Disposition

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ABSTRACT:The effect of spironolactone (SL) administration on 17␣-ethynylestradiol (EE)-induced cholestasis was studied, with emphasis on expression and activity of Mrps. Adult male Wistar rats were divided into the following groups: EE (5 mg/kg daily for 5 days, s.c.), SL (200 mol/kg daily for 3 days, i.p.), EE؉SL (same doses, SL administered the last 3 days of EE treatment), and controls. SL prevented the decrease in bile salt-independent fraction of bile flow induced by EE, in association with normalization of biliary excretion of glutathione. Western blot studies indicate that EE decreased the expression of multidrug resistance-associated protein 2 (Mrp2) by 41% and increased that of Mrp3 by 200%, whereas SL only affected Mrp2 expression (؉60%) with respect to controls. The EE؉SL group showed increased levels of Mrp2 and Mrp3 to the same extent as that registered for the individual treatments.Real-time polymerase chain reaction studies indicated that upregulation of Mrp2 and Mrp3 by SL and EE, respectively, was at the transcriptional level. To estimate Mrp2 and Mrp3 activities, apical and basolateral excretion of acetaminophen glucuronide (APAPglu), a common substrate for both transporters, was measured in the recirculating isolated perfused liver model. Biliary/perfusate excretion ratio was decreased in EE (؊88%) and increased in SL (؉36%) with respect to controls. Coadministration of rats with SL partially prevented (؊53%) impairment induced by EE in this ratio. In conclusion, SL administration to EE-induced cholestatic rats counteracted the decrease in bile flow and biliary excretion of glutathione and APAP-glu, a model Mrp substrate, findings associated with up-regulation of Mrp2 expression.

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“…served in vitro, can be extrapolated to the in vivo situation, taking into account the short plasma half-life of spironolacAcknowledgment: We are grateful to Mr. R. Michiels for tone. 20,21 Metabolites of spironolactone with a longer plasma technical assistance and Mrs. R. Santy for secretarial assishalf-life might also cause vasodilatation. The vasodilatory tance.…”

Section: Methodsmentioning

confidence: 99%

Effects of Varying Doses of Spironolactone Without and With Nitrates on Portal Vein Pressure and Kidney Function in Partial Portal Vein Ligated Rats

et al. 1996

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volume in portal hypertension and hence by reducing the The optimal dose of spironolactone to reduce portal splanchnic flow. 5,6 However, a correlation between the decline vein pressure, alone or in combination with isosorbidein plasma volume and portal pressure could not be shown. 5-7 5-mononitrate (IsMn), has not been identified. We studAcute and chronic administration of nitrovasodilators lowers ied the effects of 8 days oral treatment with spironolac-HVPG 8,9 but a concomitant reduction of the glomerular filtratone, IsMn or both on portal pressure, plasma volume tion rate and activation of the renine-aldosterone system with and renal sodium handling in rats with partial portal reduced water and sodium excretion have been observed. 10,11 vein ligation. At daily doses of 0.33; 0.50; 1, and 1.50 mg/ This might explain the worsening or development of ascites kg, spironolactone reduced portal pressure (all P õ .05) observed in some patients. 12 The combination of nitrates with as compared with placebo. Only the highest dose signifispironolactone might offer the advantage that spironolactone cantly lowered plasma volume (10.1 { 0.7 vs. 13.0 { 0.3 could counteract the activation of the renine-aldosterone sysmL; P õ .03) and enhanced urinary fractional sodium tem and the development of ascites. Furthermore, if spironoexcretion (0.73 { 0.04 vs. 0.58 { 0.03%; P õ .03) and the lactone lowers portal pressure by a reduction in plasma vol-(Na / )/(K / ) ratio in urine (0.43 { 0.04 vs. 0.30 { 0.03; P õ ume, it might enhance the portal pressure lowering effect of .02). IsMn at doses of 0.25; 0.50, and 1 mg/kg decreased nitrates. Therefore, the aim of the present study, using a portal pressure (all P õ .05) without a change in plasma portal hypertensive rat model, was to investigate the effects volume but with a tendency (not significant) to lower of different doses of spironolactone, isosorbide-5-mononitrate fractional sodium excretion. IsMn impaired free water (IsMn), and their combination, on portal pressure, plasma clearance at doses of 0.5 and 1 mg/kg (P õ .05). Combinavolume, water, and sodium household. Male Wistar rats, with a body weight beeffect of spironolactone is opposed. Low doses of spiro-tween 209 and 240 g (mean 226 g) underwent partial portal vein nolactone are as effective as a higher dose to reduce ligation, as described previously. 13 Three weeks postoperatively, aniportal pressure. This reduced portal pressure was inde-mals were randomly assigned to one of the following treatments given by daily gavage: placebo, i.e., 2 mL saline (n Å 8); spironolacpendent of changes in plasma volume and diuretic effect, tone, 0.33 mg/kg body weight (n Å 6), 0.50 mg/kg (n Å 6), 1 mg/kg which suggests that spironolactone might have a direct (n Å 6), and 1.50 mg/kg (n Å 6); IsMn, 0.25 mg/kg (n Å 6), 0.50 mg/ vasoactive effect on the splanchnic circulation. To counkg (n Å 8), and 1 mg/kg (n Å 11); spironolactone, 1 mg/kg in combinateract sodium retention of nitrovasodilators, combination with IsMn, 0.5 mg/kg (n Å 8) and 1...

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Spironolactone

Cited by 66 publications

References 137 publications

Quantitative comparison of aldosterone antagonists in normal human subjects: prediction of therapeutic potency.

Quantitative comparison of aldosterone antagonists in normal human subjects: prediction of therapeutic potency.

Beneficial Effect of Spironolactone Administration on Ethynylestradiol-Induced Cholestasis in the Rat: Involvement of Up-Regulation of Multidrug Resistance-Associated Protein 2

Effects of Varying Doses of Spironolactone Without and With Nitrates on Portal Vein Pressure and Kidney Function in Partial Portal Vein Ligated Rats

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