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.     

Conversion of spironolactone to canrenone and disposition kinetics of spironolactone and canrenoate-potassium in rats

Summary The metabolic conversion of spironolactone (I) to canrenone (II) was investigated using a chemical model reaction by treatment of spironolactone in aqueous medium at pH 13. The dethioacetylation proceeds in two steps, i.e., a fast hydrolysis to the 7-thiol function present in congeners VI and VI₀ (K ₁=0.42 min^–1), and a rate limiting step by elimination of H₂S yielding the 4,6-dien-3-one function present in canrenone (II) and canrenoate (III) (K ₂=0.13 h^–1). The metabolic conversion of I to II was evaluated by intravenously injecting equimolar amounts of I, the 7-thiol VI, II and III. Following injection of I, the only fluorigenic metabolites detectable were II, III, and an intermediate polar metabolite, which was identified by tlc and mass spectrometry as the 7-thiol-17-hydroxycarboxylic acid VI₀. The plasma t _1/2 of I was 4 and 5 min, respectively, in two rats. The t _1/2 of VI₀ amounted to 8 and 12 min, respectively, and roughly corresponded to the formation rate canrenone (II). Injection of the 7-thiol VI resulted in plasma concentrations of VI₀, II and III similar to those obtained from injection of I. It can be concluded that hydrolysis of the 7-thioacetyl I to the 7-thiol VI is a very rapid metabolic step, that the -lactone ring is in a rapid enzymatic equilibrium with the corresponding -hydroxylic acids, and that elimination of H₂S from VI yielding II is the overall rate limiting step in the metabolic conversion of I to II. The elimination of intravenous doses of ³H-I and ³H-III occurred predominantly by biliary excretion of polar conjugated metabolites (80 and 95%, respectively, of the dose over 12 h) followed by extensive enterohepatic cycling. Urinary excretion remained below 3% of the dose over 12 h in bile fistula rats.     

Disposition kinetics of spironolactone in hepatic failure after single doses and prolonged treatment

Summary Six male patients with histologically characterised, decompensated liver disease who had not previously received spironolactone, were given orally Aldactone^® 7 mg/kg with³H-spironolactone 100 µCi. The kinetics of the drug were studied in plasma and urine for 6 days. Then, Aldactone^® 7 mg/kg was given daily for 12 consecutive days, and the pharmacokinetics of a single dose of³H-spironolactone were re-examined. The kinetics of total radioactivity, as well as of fluorigenic metabolites in plasma, after the first single dose of spironolactone did not differ in patients and normal test subjects; similar percentages of the dose given were excreted within 6 days in urine from patients (47.47±4.88%) and from controls (53.68±2.04%). The kinetics of CH₂Cl₂/H₂O distribution coefficients of labelled material in plasma and urine, as well as TLC analysis of the CH₂Cl₂ soluble fraction, revealed no significant differences from controls. After treatment for 12 days with spironolactone, 4 out of 6 patients showed marked acceleration in the rate of elimination of radioactivity from plasma and a corresponding increase in excretion of labelled compounds in urine. Analysis of the excretion products in urine revealed proportionally increased excretion and no evidence of selective induction of a single degradation step. In contrast, delayed elimination was observed in the 2 other patients after 12 days' treatment. However, this was due to dehydration and oliguria caused by over-treatment with the diuretic.     

螺内酯治疗慢性心力衰竭的临床观察

目的观察常规药物加用螺内酯治疗慢性心力衰竭(CHF)的临床疗效。方法40例心功能Ⅲ~Ⅳ级的CHF患者随机分为治疗组和对照组,各20例。对照组采用常规药物治疗,治疗组则在此基础上加用螺内酯。治疗18周后,观察两组的心功能改善情况以及左室舒张末期内径、左室射血分数的变化。结果治疗组的总有效率为95.0%,对照组为65.0%,两组比较,有显著性差异(P<0.05)。治疗后,治疗组的左室舒张末期内径、左室射血分数较对照组有明显变化(P<0.05)。结论常规药物加用螺内酯治疗CHF的疗效显著,螺内酯在CHF的治疗中有重要意义。     

螺内酯治疗慢性心力衰竭的疗效观察

目的：观察血管紧张素转化酶抑制剂和醛固酮受体拮抗剂治疗慢性心力衰竭的有效性和安全性。方法：将84例慢性心力衰竭患者随机分为常规治疗组（对照组）和螺内酯治疗组（治疗组）,1个疗程6个月,比较两组治疗前后的血压、血生化、心功能分级和超声心动图各指标的变化。结果：两组治疗后的心功能均较前改善,但治疗组较对照组改善更明显,其血浆醛固酮浓度、左室舒张末期容积、左室收缩末期容积和左室射血分数均优于对照组。结论：在常规慢性心力衰竭治疗药物的基础上加用螺内酯可改善左心功能,延缓疾病的进展。     

Association of beta-blocker dose with serum procollagen concentrations and cardiac response to spironolactone in patients with heart failure

Study Objective . To determine whether β-blocker dose influences cardiac collagen turnover and the effects of spironolactone on cardiac collagen turnover in patients with heart failure. Design . Prospective clinical study. Setting . Two heart failure centers. Patients . Eighty-eight spironolactone-naïve patients with heart failure who were taking β-blockers. Intervention . In a subset of 29 patients, spironolactone was started at 12.5 mg/day with the dosage titrated to 25 mg/day if tolerated. Measurements and Main Results . Venous blood samples were collected from each patient. Serum procollagen type I and type III aminoterminal peptides (PINP and PIIINP) were determined by radioimmunoassay and compared between the 25 patients receiving low doses (< 50% of recommended target dose) and the 63 patients receiving high doses (≥ 50% of recommended target dose) of β-blockers. Patients receiving low-dose β-blockers had higher mean ± SD PIIINP concentrations (6.6 ± 3.5 vs 4.9 ± 2.6 μg/L, p=0.03) and tended to have higher PINP concentrations (74.0 ± 44.1 vs 57.1 ± 28.6 μg/L, p=0.10) compared with those receiving high doses. A repeat blood sample was collected from the 29 patients who received spironolactone after 6 months of therapy. Changes in procollagen peptides also were compared in this subset between low-dose (9 patients) and high-dose (20 patients) β-blocker groups. Low β-blocker doses were associated with greater reductions in concentrations of PINP (median [intraquartile range] −14.3 μg/L [-9.8 to −19.3 μg/L] vs −2.5 μg/L [5.9 to −9.8 μg/L], p=0.02) and PIIINP (-1.4 μg/L [-0.9 to −2.4 μg/L] vs 0.1 μg/L [0.9 to −1.3 μg/L], p=0.045) with spironolactone therapy than high β-blocker doses. In addition, 100% of the patients in this subset taking low-dose β-blockers versus only 35% taking higher doses had reductions in both markers of cardiac fibrosis. Conclusion . Spironolactone may benefit patients with heart failure who cannot tolerate upward titration of β-blocker dosages, at least in terms of its effects on cardiac remodeling.     

卡维地洛联合螺内酯对慢性心力衰竭患者心功能的影响

目的 探讨卡维地洛联合螺内酯对慢性心力衰竭(Chronic heart failure,CHF)患者心功能的影响。方法 选择200例诊断为CHF的患者作为研究对象,采用随机数字表法平均分为观察组与对照组,在常规治疗的基础上分别给予卡维地洛联合螺内酯治疗与单独卡维地洛治疗。随访观察6月,比较两组患者心脏功能、血浆脑钠肽(Brain Natriuretic Peptide,BNP)及谷胱甘肽过氧化物酶(Glutathioneperoxidase,GSH-PX)的差异。结果 观察组总有效率93.0%明显高于对照组84.0%,差异有统计学意义(P<0.05)。治疗后两组LVEF、LVEDD及BNP均较治疗前降低,而LVESD及GSH-PX较治疗前升高,差异有统计学意义(P<0.05);观察组较对照组改善更明显,差异有统计学意义(P<0.05)。结论 卡维地洛联合螺内酯治疗CHF可以更好改善患者心功能,抑制心肌重塑,降低心衰指标。     

Aldosterone receptor blockers spironolactone and canrenone: two multivalent drugs

Canrenone is a derivative of spironolactone with lower antiandrogen activity. The drug is used only in few countries and can block all the side effects of aldosterone (ALDO). The drug is effective even in the presence of normal concentrations of ALDO. Mineralcorticoid receptor antagonists block the inflammatory activity of ALDO at the level of target tissues as heart, vessels and mononuclear leukocytes. Canrenone reduces the progression of insulin resistance and of microalbuminuria in type 2 diabetes and other related diseases. Both canrenone and hydrochlorothiazide can enhance the effect of treatment with ACE inhibitors and angiotensin II receptor blockers on microalbuminuria, but ALDO receptor blockers are more active. This different action is due to the fact that only canrenone blocks mineralocorticoid receptors. Serum potassium and renal function should be monitored before and during the treatment. ALDO receptor blockers are recommended in addition to polytherapy for resistant hypertension, but there are no studies on the effect of the drug as first-choice therapy.     

螺内酯治疗慢性心力衰竭疗效观察

目的探讨螺内酯治疗慢性心力衰竭的疗效。方法46例心力衰竭患者随机分为对照组和观察组各23例,对照组常规运用利尿剂、血管扩张剂和洋地黄制剂,观察组在对照组基础上加用螺内酯,2组均治疗1个月后,对治疗效果进行评价。结果2组治疗后心功能Ⅰ、Ⅱ级患者比率均增加,Ⅲ、Ⅳ级比率均降低,差异均有统计学意义（P〈0．05或P〈0．01）,观察组心功能改善情况优于对照组,差异均有统计学意义（P〈0．05）。结论螺内酯治疗慢性心力衰竭疗效确切,值得临床推广应用。     

螺内酯治疗50例慢性心力衰竭患者疗效观察

目的观察螺内酯治疗老年人（〉60岁）慢性心力衰竭患者心功能改善的疗效。方法将50例慢性心力衰竭患者随机分为两组,常规治疗加螺内酯（治疗组）和不加螺内酯组（对照组）。随访6个月,比较治疗前后患者6min步行距离,血钾、心脏超声（左室射血分数、左室舒张末期内径）、肾功能。结果6个月后治疗组6mill步行距离明显高于对照组（213．4-21）mVS（165±15）m,OP〈0．05）;血清K无明显增高（4．9±O．14）mmol／LVS（4．3±0．16）mmol／L,（P〉0．05）。左室舒张末期内径（LVEDD）明显降低（4s±6）mmvs（52±10）mm,（P〈0．05）;治疗组病死率及再住院率较对照组明显下降（P〈0．05）。结论螺内酯能明显改善心力衰竭患者心功能,血清钾无明显增高,安全有效,副作用少。     

螺内酯联合非洛地平对慢性心力衰竭患者B型钠尿肽前体及心功能的影响

目的探讨小剂量螺内酯联合非洛地平对慢性心力衰竭（CHF）B型钠尿肽前体（NT—proBNP）以及心功能的影响。方法将98例CHF患者按照数字表法随机分为观察组和对照组,各49例。两组患者均予标准三联抗心衰治疗,观察组联用螺内酯（20—40mg／d）和非洛地平（5mg／d）。两组治疗前和治疗后6周分别进行心功能（NYHA）分级评估、6min步行距离测定以及NT－proBNP含量测定并比较。结果观察组总有效率为93．88％,明显高于对照组的40．82％（Z=－2．051,P〈0．05）;治疗6周后两组6min步行距离均显著改善（t=3．196、5．048,均P〈0．05）,且观察组优于对照组（t=4．595,P〈0．05）;治疗6周后两组NT—proBNP含量均显著降低（t=－4．402、－13．191,均P〈0．05）,且观察组改善更显著（t=－8．431,P〈0．05）。结论应用小剂量螺内酯联合非洛地平治疗CHF疗效肯定。     

厄贝沙坦联合螺内酯在慢性心力衰竭中的应用效果

目的 研究厄贝沙坦联合螺内酯在慢性心力衰竭中的应用效果及对病人心功能的影响.方法 选择慢性心力衰竭病人60例,按随机数字表法均分为观察组、对照组.对照组采用常规治疗,观察组加用厄贝沙坦联合螺内酯治疗.观察两组临床疗效,心功能指标,血压、心率,血清B型脑钠肽(BNP)及高敏C-反应蛋白(hs-CRP)水平.结果 治疗后,观察组(86.67%)总有效率与对照组(63.33%)比较,差异有统计学意义(P<0.05);两组病人心功能指标较治疗前改善,但观察组改善更明显,左室舒张末期内径(LVDd)[(52.33±4.92) mm vs (59.46±5.57) mm]、左室收缩末期内径(LVSd)[(40.24±4.13) mm vs (46.95±4.87) mm]、左室射血分数(LVEF)[(48.62%±7.13%) vs (42.41%±6.65%)],差异有统计学意义(P<0.05);两组病人血压、心率较治疗前下降,但观察组下降更明显[舒张压(75.36±3.54) mmHg vs (85.47±4.09) mmHg,收缩压(130.65±8.74) mmHg vs (139.22±9.35) mmHg,心率(76.72±10.56)次/分钟 vs (82.59±11.34)次/分钟],差异有统计学意义(P<0.05);两组BNP、hs-CRP水平较治疗前下降,但观察组下降更明显[BNP(1.71±0.34) μg·L-1 vs (2.48±0.57) μg·L-1,hs-CRP(6.26±1.03) μg·L-1 vs (8.79±1.12) μg·L-1],差异有统计学意义(P<0.05).结论 厄贝沙坦与螺内酯联合治疗慢性心力衰竭应用疗效确切,能有效改善病人心功能,延缓病情的发展.     

螺内酯对慢性肺原性心脏病心肺功能作用观察

目的通过随机的螺内酯评价研究试验,讨论螺内酯对慢性肺原性心脏病患者右心功能和肺功能的影响,并探究其可能的机制。方法选择符合肺原性心脏病诊断标准的患者150例,将150例患者随机分为2组;螺内酯组80例,对照组70例。治疗前及治疗后6个月分别检测以下指标：患者右室流出道内径、右心室内径、右肺动脉内径、用力肺活量（FVC）、第一秒用力呼气容积（FEV1）、最大呼气流量（PEF）及3个月及6个月的血钾变化。结果螺内酯治疗后,右室流出道内径、右心室内径、右肺动脉内径与治疗前有显著差异（P〈0.05）,治疗后两组FEV1及PEF的改善有显著差异性（P〈0.05）。结论小剂量螺内酯治疗慢性肺原性心脏病,可改善患者心肺功能,显著降低死亡率,对血钾浓度无影响。     

螺内酯对充血性心力衰竭患者心室重塑及心功能影响的研究

目的 观察洛汀新加用两种不同剂量螺内酯对慢性心力衰竭患者心室重塑、TNF-α、血管紧张素Ⅱ（AngⅡ）、醛固酮（Ald）及射血分数（EF）等的影响。方法 心功能Ⅲ-Ⅳ级心力衰竭患者90例，随机分为洛汀新10mg（A组）、洛汀新10mg加螺内酯20mg（B组）、洛汀新10mg加螺内酯40mg（C组）三组，治疗12周，测定治疗前后TNF-α、Ald、AngⅡ、左房直径（LA）、左室舒张末直径（LVEDD）、左室舒张末容积（LVEDV）及EF值的变化。结果 （1）三组TNF-α、Ald、AngⅡ、LA、LVEDD、LVEDV均较治疗前降低（P〈0．01）。（2）心室重塑及EF得到一定改善，EF较治疗前升高（P〈0．01）。（3）C组疗效优于A、B两组。结论 重度心衰患者在常规应用洛汀新的基础上加用螺内酯可通过进一步降低TNF-α、Ald、AngⅡ水平而明显改善心室重塑及EF值，且在小范围内有一定剂量依赖性。     

洛汀新联合螺内酯对心力衰竭患者神经体液及心功能影响的研究

目的:观察洛汀新加用两种不同剂量螺内酯对慢性心力衰竭患者神经体液及心功能的影响。方法:心功能Ⅲ-Ⅳ级心力衰竭患者90例,随机分为洛汀新10mg(A)组、洛汀新10mg加螺内酯20mg(B)组、洛汀新10mg加螺内酯40mg(C)组,治疗12周,测定治疗前后TNF-α、IL-1、IL-6、NE及EF值的变化。结果:三组TNF-α、IL-1、IL-6、NE均较同组治疗前降低(P<0.01);三组EF均较同组治疗前明显改善(P<0.01);C组疗效优于A、B两组。结论:重度心力衰竭患者在常规应用洛汀新的基础上加用螺内酯可进一步降低TNF-α、IL-1、IL-6及NE的水平,且明显改善心功能。     

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.     

螺内酯对充血性心力衰竭患者心率变异性和QT离散度的影响

目的观察螺内酯对充血性心力衰竭（CHF）患者心率变异性（HRV）和QT间期离散度（QTd）的影响。方法CHF患者44例随机分为对照组（20例）和螺内酯组（24例），均接受标准治疗，包括：硝酸酯类、利尿剂（不包括螺内酯）、血管紧张素转换酶抑制剂、地高辛，螺内酯组在标准治疗基础上口服螺内酯（40mg／d），共8周。治疗前后测定HRV指标及QTd。结臬螺内酯治疗8周后24h连续正常RR间期标准差（SDNN）、24h连续5min正常RR间期标准差的均值（SDNN—i）、24h连续5min正常RR间期均值的标准差（SDANN）、相邻正常RR间期差值均方根（rMSDD）、HF和LH／HF较对照组有显著提高（P〈0．05），而LF／HF、HR和QTd较对照组有显著性降低（P〈0．05）。结论螺内酯能够增加心力衰竭患者的HRV，降低QT离散度。     

醛固酮拮抗剂治疗充血性心力衰竭研究

了解醛固酮与充血性心力衰竭发生和发展的相关性,研究醛固酮拮抗剂在治疗充血性心力衰竭中疗效     

不同剂量螺内酯治疗充血性心力衰竭合并高钾血症的临床分析

目的 比较不同剂量螺内酯治疗心力衰竭合并高钾血症的效果.方法 将80例心力衰竭合并高钾血症患者根据随机数字表法分为治疗组与对照组各40例,在常规治疗基础上,对照组给予大剂量螺内酯治疗,治疗组给予小剂量螺内酯治疗.结果 经治疗后治疗组与对照组的总有效率分别为92.5％和90.0％ （P＞0.05）,两组患者LVEF、LVMI值比较差异无统计学意义（P＞0.05）;两组患者治疗前血钾水平差异无统计学意义（P＞0.05）,治疗后均明显下降（P＜0.05）,且组间差异有统计学意义（P＜0.05）.结论 螺内酯能有效改善心力衰竭合并高钾血症患者的心功能,而小剂量的应用又能有效降低高血钾危险,具有良好的有效性与安全性.