精氨酸加压素 V2受体拮抗剂托伐普坦的合成进展

心力衰竭是一种常见的综合征,虽然它的发病机制和治疗研究迅速发展,但是发病率和死亡率都很高。精氨酸加压素是导致心力衰竭死亡率居高的原因之一。托伐普坦是2009年美国上市世界上首个口服精氨酸加压素V2受体拮抗剂。本文综述了托伐普坦的合成方法及部分中间体的合成,并评价其优缺点。     

莫扎伐普坦的合成工艺研究

目的 研究莫扎伐普坦的合成工艺.方法 以邻氨基苯甲酸甲酯为起始原料,经Ⅳ-磺酰化、烃化、环合、脱羧、M甲基化、还原胺化等反应制得关键中间体8;以对氨基苯甲酸甲酯为原料,经Ⅳ.酰化、酯水解和酰氯化制得另一中间体11;8与11于丙酮中反应制得目标化合物.结果与结论 目标化合物的结构经1H-NMR、MS等确证.总收率达14....     

伴有低钠血症的心力衰竭治疗新药——托伐普坦

心力衰竭时常伴随低钠血症。心力衰竭的一般治疗方法对低钠血症疗效不佳。托伐普坦是精氨酸加压素V_2受体的拮抗药。托伐普坦通过抑制肾脏集合管水的重吸收,使肾脏对水的排泄增加,起到纠正低钠血症、增加尿量、改善心力衰竭症状等作用。临床研究表明托伐普坦在伴有低钠血症的心力衰竭治疗中发挥重要作用。     

托伐普坦片治疗低钠血症的效果及安全性观察

目的观察托伐普坦片对抗利尿激素分泌不高(SIADH)及其它原因引起的非低容量性、非急性低钠血症患者的疗效及安全性。方法 38例因充血性心力衰竭、肝功能衰竭伴腹水形成、慢性肾功能不全或抗利尿激素分泌不当等疾病引起体液潴留和低钠血症的患者,予口服托伐普坦片治疗。结果口服托伐普坦片者都有血钠浓度和血渗透压的显著升高。结论托伐普坦片能够显示良好的提高血清钠浓度作用,对低钠血症患者有明显疗效。没有严重并发症和不良反应,临床应用中简便且安全。     

托伐普坦治疗肝硬化腹水伴低钠血症研究进展

肝硬化腹水伴低钠血症的治疗是目前临床治疗的一大难题。托伐普坦是一种血管加压素V2受体拮抗药,可以升高血浆中钠离子浓度,抑制肾脏对水的重吸收,促进水分从尿液排出。影响托伐普坦疗效的因素有尿钠浓度、血清钠浓度、肾小球滤过率、血尿素氮水平等。用药期间应注意观察患者血压、心率、血清钠水平、肝功能,及早发现不良反应并对症治疗。     

托伐普坦治疗顽固性心力衰竭合并低钠血症的效果观察

目的：探讨托伐普坦治疗顽固性心力衰竭合并低钠血症的效果。方法选取2014年8~12月河南省人民医院收治的60例心力衰竭患者作为研究对象,随机分为观察组和对照组,各30例。对照组采用常规治疗,观察组在对照组的基础上给予口服托伐普坦治疗。比较两组治疗前后的尿量、血钠、NT-proBNP及左心室射血分数（LVEF）、左室舒张末期内径（LVEDD）及E/A比值。结果观察组治疗后的尿量为（2635依856）ml/24 h,显著多于对照组的（1360依390）ml/24 h,差异有统计学意义（P<0.05）。观察组治疗后的体重下降（0.95依0.65）kg/d,显著多于对照组的（0.30依0.45）kg/d,差异有统计学意义（P<0.05）。观察组治疗后的血钠水平显著高于对照组治疗后,差异有统计学意义（P<0.05）。观察组治疗后的NT-proBNP水平显著低于对照组治疗后,差异有统计学意义（P<0.05）。观察组治疗后的LVEF、E/A比值显著高于对照组治疗后,差异有统计学意义（P<0.05）。观察组治疗后的LVEDD显著低于对照组治疗后,差异有统计学意义（P<0.05）。结论托伐普坦治疗顽固性心力衰竭合并低钠血症的效果显著,能有效增加血钠浓度和增加尿量,改善心功能。     

托伐普坦在心衰治疗中的临床研究进展

通过查阅托伐普坦的相关文献,系统回顾托伐普坦在心衰治疗中的临床研究进展。临床试验表明,托伐普坦对心衰的治疗具有良好的前景,同时不会损害肾功能,而且其重要的不良反应-饥渴感能被很好地耐受。基于大量临床试验数据,托伐普坦可以为心衰患者提供一种新的治疗选择。     

托伐普坦治疗恶性腹腔积液合并低钠血症的临床观察

目的： 观察托伐普坦治疗恶性腹腔积液合并低钠血症患者后的血钠及24 h尿量等指标变化。方法： 38例恶性腹腔积液合并低钠血症患者随机分为观察组和对照组,对照组给予常规利尿处理,观察组在常规治疗基础上联用托伐普坦片,治疗7 d后,比较两组患者治疗前后血钠、24 h尿量、腹围及体重等指标的变化,并观察治疗期间两组不良反应发生情况。结果： 治疗后观察组的血钠水平较治疗前显著升高（P<0.01）,治疗后两组24 h尿量均较治疗前增多（P<0.01）,且治疗后观察组24 h尿量明显高于对照组（P<0.01）。观察组4例患者出现口干不适,两组间差异无统计学意义,治疗期间两组患者均未出现严重不良反应。结论： 托伐普坦治疗恶性腹腔积液合并低钠血症患者的疗效确切,可以改善患者的生存质量,且安全可靠。     

充血性心力衰竭合并低钠血症应用托伐普坦治疗的疗效研究

目的探讨充血性心力衰竭合并低钠血症患者应用托伐普坦治疗的临床效果。方法100例充血性心力衰竭合并低钠血症患者,随机分为对照组和试验组,每组50例。对照组采用传统常规药物治疗,试验组在对照组基础上采用托伐普坦治疗。比较两组患者的临床疗效、血清钠离子浓度、尿量以及明尼苏达心力衰竭生活质量量表(MLHFQ)评分。结果治疗后,试验组患者血清钠离子浓度(145.11±11.24)mmol/L以及尿量(2634.29±104.21)ml高于对照组的(135.16±11.26)mmol/L、(2420.22±110.19)ml,MLHFQ评分(50.16±12.10)分低于对照组的(71.26±10.53)分,差异有统计学意义(P<0.05)。试验组患者治疗总有效率80.0%高于对照组的40.0%,差异有统计学意义(P<0.05)。结论充血性心力衰竭合并低钠血症患者采用托伐普坦治疗的临床效果显著,可有效改善患者临床症状,值得临床推广。     

Tolvaptan: a selective vasopressin type 2 receptor antagonist in congestive heart failure

The neurohormone arginine vasopressin plays a significant role in the regulation of volume homeostasis, which is mediated via vasopressin type 2 (V₂) receptors in the collecting tubules of the kidney. Diseases that are accompanied by abnormal volume homeostasis, including congestive heart failure and cirrhosis, are a frequent cause of hospital admissions and increasing healthcare costs. Recently, several nonpeptide V₂ receptor antagonists have emerged as promising agents in the management of these conditions with the advantage of having no electrolyte abnormalities, neurohormonal activation or worsening renal insufficiency. Tolvaptan, a highly selective nonpeptide V₂ receptor antagonist, has demonstrated an improvement in the volume status, osmotic balance and haemodynamic profile in preclinical and Phase II trials in patients with congestive heart failure and is currently undergoing testing in Phase III trials. This review discusses the evidence for the potential uses of tolvaptan, and its pharmacology and pharmacokinetics, particularly in congestive heart failure.     

Tolvaptan for the treatment of heart failure: a review of the literature

Introduction: It has been > 25 years since it was first discovered that arginine vasopressin levels are elevated in heart failure and this elevation is proportional to the severity of heart failure. Tolvaptan is an oral nonpeptide V₂-selective antagonist and has been shown to induce free water excretion without increasing urine sodium, an effect termed ‘aquaresis’.

Areas covered: This paper aims to review the physiology, chemistry, pharmacokinetics, clinical efficacy and safety of tolvaptan in HF. A PubMed literature search was performed using ‘tolvaptan’ and the MeSH term ‘heart failure’, yielding 89 references.

Expert opinion: Clinical trials conducted in ambulatory and hospitalized patients with HF have found treatment with tolvaptan causes rapid and sustained body weight reductions concurrent with increases in urine output, improves and/or normalizes serum sodium in hyponatremic patients, reduces signs and symptoms of congestion and increases thirst. However, tolvaptan has not been shown to decrease HF re-hospitalization or mortality. As an adjunct to standard therapy, tolvaptan is unique in that it is virtually the only novel agent tested in patients hospitalized for acute heart failure syndrome (AHFS) to reach its primary end point for short-term efficacy without causing deleterious side effects. There is theoretical concern that chronic V₂ receptor blockade may cause harmful long-term side effects via enhanced V_1a receptor activation, potentially offsetting any favorable effects on congestion and hyponatremia. The ‘vaptan’ class of drugs is an active and promising area for clinical investigation and future research is necessary to clarify the therapeutic role of selective and nonselective vasopressin inhibition in chronic HF and AHFS.     

Tolvaptan for Volume Management in Heart Failure

Volume management in acute decompensated and chronic heart failure (HF) remains a significant challenge. Although progress has been made in the development of mortality-reducing neurohormonal regimens in the reduced ejection fraction population, no clinical trial has yet demonstrated anything more than symptomatic relief or biomarker reduction with pharmacotherapeutic volume-based interventions made in the acutely decompensated individual or those with evolving outpatient congestion. As the number of patients with HF continues to grow, in addition to HF-related hospitalizations, identifying therapies that have the potential to aid in diuresis more safely and efficaciously is paramount to decreasing inpatient length of stay and preventing unnecessary admissions. More recently, a significant amount of research has been dedicated to the use of vasopressin antagonists, specifically tolvaptan, as adjunctive therapy to loop and thiazide diuretics. Although these agents do not seem to have a pervasive role in fluid management in the acute decompensated and chronic HF populations, they are effective tools to have available for specific clinical situations. This review summarizes the literature surrounding the use of tolvaptan for volume management in congestive HF, as well as offering practical guidance for use of this agent.     

V2 receptor antagonism with tolvaptan in heart failure

The prevalence and incidence of congestive heart failure continues to increase. The two hallmarks of this syndrome, sodium and water retention, are frequently a therapeutic challenge. Most conventional diuretics act primarily as saluretics by inhibiting renal tubular electrolyte reabsorption, which, due to osmotic pressure, promotes excretion of isotonic fluid. The peptide hormone arginine vasopressin vasoconstricts at the V_1A receptor and promotes water reabsorption via the V₂ receptor in the renal collecting duct by inserting aquaporin-2 water channels into the luminal membrane. Tolvaptan, the first orally available non-peptide V₂ receptor antagonist, acts as a potent aquaretic. In this paper, the authors review the pharmacology of tolvaptan and discuss the results of the initial clinical trials with this potent new drug.     

Recent advances in the treatment of hyponatremia

Hyponatremia is a common and potentially serious electrolyte disorder, most often caused by excessive arginine vasopressin (AVP) secretion. Conventional management of hyponatremia is based on graded steps starting from water restriction in mild cases to administration of saline in symptomatic cases, which may not be effective. A major new approach in the treatment of hyponatremia is the development of AVP receptor antagonists that directly inhibit the effect of increased AVP which results in the excretion of electrolyte free water. This review summarizes pathophysiology, conventional treatment and future directions in the treatment of hyponatremia.     

Tolvaptan: a vasopressin antagonist for the management of euvolemic and hypervolemic hyponatremia

Tolvaptan is a new vasopressin antagonist developed for the treatment of hypervolemic or euvolemic hyponatremia. It has greater affinity for the V₂ receptor than native vasopressin or any other vasopressin antagonist. Blockade of the V₂ receptor induces solute-free water excretion without affecting normal electrolyte excretion. The pharmacokinetics and pharmacodynamics of tolvaptan are suitable for once-daily dosing. Throughout all phases of clinical studies, it was shown to be safe for short- and long-term use. Tolvaptan effectively increases serum sodium levels in patients with heart failure, cirrhosis and syndrome of inappropriate secretion of antidiuretic hormone. In patients hospitalized owing to heart failure, tolvaptan decreased bodyweight, increased urine output and improved dyspnea compared with placebo. However, tolvaptan has not proven to be beneficial for the long-term management of heart failure. Currently, tolvaptan is the only oral agent in its class available in the USA and Europe.     

Tolvaptan: the evidence for its therapeutic value in acute heart failure syndrome

Introduction:

Acute heart failure syndrome (AHFS) is one of the leading causes of hospital admission in the US. Tolvaptan is a vasopressin V₂ receptor antagonist that blocks the effect of arginine vasopressin (AVP) in reabsorbing water from the collecting ducts of the nephrons in congestive heart failure.

Aims:

To review the evidence for utilizing tolvaptan in the treatment of AHFS.

Evidence review:

Several clinical trials have sought to assess the clinical effects of tolvaptan in heart failure. Compared with placebo, tolvaptan has been shown to reduce bodyweight and improve serum sodium in patients with AHFS without worsening renal function. Tolvaptan appeared to be well tolerated with a good safety profile. It caused a significant reduction in pulmonary capillary wedge pressure compared with placebo, but has yet to demonstrate reversal of cardiac remodeling. A large-scale mortality trial showed no differences in long-term mortality rates between tolvaptan and placebo, although early symptom relief was apparent with tolvaptan and lower diuretic use.

Place in therapy:

Tolvaptan has shown to be safe and effective in treating congestion in AHFS. Free water excretion in fluid-overloaded patients vulnerable to cardiorenal compromise with standard diuretic therapy makes V₂ vasopressin receptor blockade an attractive adjunct to standard medical therapy aimed at reducing congestion in AHFS.