Effects of canrenone in patients with metabolic syndrome

Background: Metabolic syndrome is becoming a common disease due to a rise in obesity rates among adults.

Objectives: The aim was to evaluate the effects of canrenone compared to placebo on metabolic and inflammatory parameters in patients affected by metabolic syndrome.

A total of 145 patients were treated with placebo or canrenone, 50 mg/day, for 3 months and then 50 mg b.i.d. till the end of the study.

Blood pressure, body weight, body mass index, fasting plasma glucose (FPG), fasting plasma insulin, HOMA-IR, lipid profile, plasma aldosterone, brain natriuretic peptide, high-sensitivity C-reactive protein (Hs-CRP), tumor necrosis factor-α (TNF-α) and M value were evaluated.

Results: A decrease of blood pressure was observed in canrenone group compared to baseline; moreover, systolic blood pressure value recorded after 6 months of canrenone therapy was lower than the one recorded with placebo. Canrenone gave a significant decrease of FPI and HOMA index, and an increase of M value both compared to baseline and to placebo. Canrenone also decreased triglycerides and FPG was not observed with placebo. Canrenone also decreased plasma aldosterone, Hs-CRP and TNF-α compared to baseline and to placebo.

Conclusion: Canrenone seems to be effective in reducing some factors involved in metabolic syndrome and in improving insulin-resistance and the inflammatory state observed in these patients.     

螺内酯代谢物血药浓度的测定及健康人体药动学

目的:建立反相高效液相色谱法测定螺内酯的代谢物——坎利酮的血药浓度,并研究其在健康人体的药动学。方法:以乙酸乙酯为萃取溶剂,采用 Hypersil C_(18)柱(4.6 mm×250 mm,5 μm),流动相:乙腈-0.02 mol·L~(-1)磷酸氢二铵溶液(45:55);流速为1.0 mL·min~(-1),检测波长为280 nm。结果:坎利酮在9.375～300μg·L~(-1)范围有良好色谱响应线性关系(r=0.9999),提取回收率均大于73.3%,日内与日间 RSD 均小于4.8%。人体药动学参数 C_(max)为(172.1±43.3)μg·L~(-1),T_(max)为(4.0±1.2)h,T_(1/2ke)为(16.8±4.3)h,AUC_(0-t)为(3246.1±800.4)μg·h·L~(-1),AUC_(0-∞)为(3649.1±960.4)μg·h·L~(-1)。结论:本方法是测定螺内酯活性代谢物——坎利酮血药浓度的可靠定量方法,适用于螺内酯的人体药动学研究。     

Multiple dose kinetics of spironolactone and canrenoate-potassium in cardiac and hepatic failure

Summary Plasma concentrations of canrenone and canrenoate were measured in 43 patients treated with spironolactone 50–400 mg/day, and in one patient treated with canrenoate-K 3×200 mg/day. The cumulation of canrenone and canrenoate was followed in 9 patients recovering from myocardial infarction, without congestive heart failure or cirrhosis, who received spironolactone 2×100 mg/day. The cumulation half-life was 1–4 days, which may partly explain the delayed clinical action of spironolactone. The plasma elimination half-life of canrenone and canrenoate in six of these patients lay between 13.5 and 24 h. After 10 doses it was unchanged in three patients and had decreased only slightly in three others. Steady state minimum plasma levels of canrenone and canrenoate were measured in 33 patients with congestive heart failure or cirrhosis who received spironolactone 50–400 mg/day for at least three weeks. There was up to 15 fold inter-individual variation in the plasma levels of canrenone amongst those receiving spironolactone 200 mg/day. No statistically significant correlation was found between steady state levels of canrenone and plasma creatinine or the results of bromsulphalein liver function tests. In one patient with severe congestive heart failure given canrenoate-K 3×200 mg/day, cumulation of canrenone and canrenoate occurred for seven days, followed by a gradual decline in their plasma levels until the eleventh day of therapy. A loading dose is recommended for initiation of spironolactone therapy.     

Effect of the aldosterone antagonist canrenone on plasma aldosterone concentration and plasma renin activity,and on the excretion of aldosterone and electrolytes by man

Summary Canrenone was administered in doses of 2×82 mg and 2×164 mg per day over a period of 10 days to diabetic patients without cardiovascular, liver or kidney involvement. Aldosterone excretion and plasma aldosterone increased only slightly during both regimes. There was a clear-cut increase in aldosterone excretion only after discontinuation of carenone. Excretion of sodium potassium and fluid was not significantly changed either during or after treatment. The lack of effect of canrenone on the kidney was in contrast to the significant decrease in serum sodium and increase in serum potassium, and the significant, dose-dependent rise in plasma renin activity following canrenone administration. The increased plasma renin activity persisted for some days after discontinuation of canrenone. It is suggested that canrenone primarily exerted its effect in the distal part of the large intestine where ionic movements are most affected by aldosterone. The disproportionately slight increase in plasma aldosterone concentration and aldosterone excretion, in spite of the greatly elevated plasma renin activity and serum potassium level, is considered to be due to a direct inhibitory effect of canrenone on aldosterone production in the adrenals.     

Clinically insignificant negative interferences of spironolactone, potassium canrenoate, and their common metabolite canrenone in new dimension vista Loci digoxin immunoassay

Spironolactone, a potassium-sparing diuretic metabolized to canrenone is often used with digoxin to treat various conditions including congestive heart failure. Potassium canrenoate is a similar drug, which is also metabolized to canrenone. Due to reported both positive and negative interference of spironolactone, potassium canrenoate, and their common metabolite canrenone with digoxin immunoassays, we investigated potential interference of these compounds with the new homogenous sequential chemiluminescent assay for digoxin based on the luminescent oxygen channeling technology (LOCI digoxin) for application on the Dimension and Vista platform. When aliquots of a drug-free serum pool were supplemented with various amounts of spironolactone, potassium canrenoate, or canrenone and apparent digoxin values were measured using Dimension Vista LOCI digoxin assay, we observed no detected value except when aliquots were supplemented with very high amounts of potassium canrenoate or canrenone. However, we observed that apparent digoxin concentrations were very low. When aliquots of a serum digoxin pool (prepared by pooling specimens from patients receiving digoxin), were further supplemented with various amounts of spironolactone, potassium canrenoate, or canrenone and serum digoxin concentrations were remeasured using the LOCIdigoxin assay, only statistically significant falsely lower digoxin values (negative interference) were observed in specimens containing very high amounts of canrenone or potassium canrenoate. However, such small bias may not have any clinical significance. We conclude that new Dimension Vista LOCI digoxin assay is virtually free from interferences of spironolactone, potassium canrenoate, and their common metabolite canrenone.     

螺内酯片健康人体药动学及生物等效性评价

目的:研究螺内酯在中国健康人体内的药动学和生物等效性。方法:采用随机双周期交叉设计, 18名健康志愿者单剂量口服200 mg螺内酯,HPLC法测定血浆中螺内酯的代谢物坎利酮的浓度。结果:参比制剂和受试制剂药-时曲线均符合一房室模型,受试制剂和参比制剂的代谢物坎利酮的药动学参数如下:t_(mux)分别为(4．2±s 1．2)和(4．7±1．6)h,C_(mux)分别为(160±47)和(150±43)μg·L~(-1),t_(1/2ke)分别为(18±5)和(19±4)h,AUC_(0～72)分别为(3168±688)和(3267±627)μg·h·L~(-1),AUC_(0～∞)分别为(3611±768)和(3759±642)μg·h·L~(1-)。与参比制剂相比,受试制剂的相对生物利用度为(106±26)％。结论:所建立的方法适用于螺内酯的人体药动学研究;经方差分析和双向单侧t检验证明,2种制剂具有生物等效性。     

Comparison of plasma levels of canrenone and metabolites after base hydrolysis in young and elderly subjects following single and multiple doses of spironolactone

Summary Plasma levels of canrenone and total metabolites after base hydrolysis were compared in young and elderly subjects following single and multiple doses of spironolactone. After the initial dose on Day 1, plasma levels of canrenone and total metabolites were higher in the young than in the elderly group, and significant differences were found between the two age groups in the AUC for both canrenone and total metabolites. However, these differences between the two age groups diminished after multiple dosing on Day 8, and the steady state predose plasma levels of canrenone and total metabolites were significantly higher in the elderly subjects. The accumulation ratios of canrenone and total metabolites were significantly higher in the elderly than in the young subjects. Both canrenone and canrenoic acid were extensively bound to plasma protein, but no differences were found between the two age groups in protein binding. Observed differences in plasma levels after single and multiple dosing between young and old subjects may be consequences of many factors such as 1.) a proportionate shift in metabolism with age; 2.) impaired oral absorption of the parent compound; and/or 3.) altered volume of distribution of the drug.     

Elimination of canrenone in congestive heart failure and chronic liver disease

Summary The elimination half-life (T1/2) of canrenone, the principal unconjugated metabolite of spironolactone, was 59 h (range 32–105 h) in 5 patients with chronic liver disease and 37 h (range 19–48 h) in 7 patients with congestive heart failure. In comparison the T1/2 in normal subjects was 13.5–24 h in previous reports and 20.5 h in the present study. However there was no evidence of greater cumulation of canrenone in the plasma of those patients with a prolonged T1/2.     

Comparative effect of canrenone or hydrochlorothiazide addition to valsartan/amlodipine combination on urinary albumin excretion in well-controlled type 2 diabetic hypertensive patients with microalbuminuria

Objective: To compare the effect of adding canrenone or hydrochlorothiazide (HCTZ) to valsartan/amlodipine combination on urinary albumin excretion (UAE) in microalbuminuric type 2 diabetic hypertensives.

Research design and methods: After a 2-week placebo period and after 4 weeks of valsartan 160 mg plus amlodipine 5 mg combination, 120 patients whose blood pressure (BP) was not controlled (> 130/80 mmHg) were randomized to canrenone 25 mg or HCTZ 12.5 mg in addition to the previous therapy for 24 weeks. After the first 6 weeks of triple therapy, canrenone or HCTZ doses were doubled in the patients whose BP was yet uncontrolled. At the end of each period (placebo, dual combination and triple combination therapy), clinic and ambulatory BP measurements were recorded and 24 h UAE was evaluated.

Results: Both triple combinations produced greater clinical and ambulatory BP reduction than dual therapy, with no difference between the two groups. UAE was reduced by both regimens, but the decrease associated with canrenone add-on therapy was more pronounced. At week 24, UAE decreased by 45.3% in the canrenone group and by 20.3% in the HCTZ group (p < 0.01).

Conclusions: These findings indicate that, despite similar BP-lowering effect, the addition of canrenone to valsartan/amlodipine combination was more effective in reducing UAE than HCTZ addition.