盐酸伊伐布雷定单层渗透泵控释片的制备与体外释药行为

制备日服1次的盐酸伊伐布雷定（IVB）单层渗透泵控释片。建立了释放度测定方法,单因素考察助悬剂、促渗剂和老化条件等对释药曲线的影响。以片芯中聚氧乙烯（PEO）的用量、控释衣膜中聚乙二醇（PEG）的比例和包衣增重进行3因素3水平的正交设计。最终处方为IVB 16.25 mg,PEO N80 60 mg,羟丙甲基纤维E5 10 mg,乳糖111.75 mg,硬脂酸镁2 mg;包衣液中PEG 15%,醋酸纤维素85%,包衣增重7.5%。体外释药行为表明,药物释放不受环境pH影响,无剂量倾泻风险,释药动力为膜内外渗透压差。IVB渗透泵片能够降低给药次数,提高患者的顺应性,具有临床应用价值。     

Financial impact of ivabradine on reducing heart failure penalties under the Hospital Readmission Reduction Program

Objective: The introduction of the Hospital Readmission Reduction Program (HRRP) has led to renewed interest in developing strategies to reduce 30?day readmissions among patients with heart failure (HF). In this study, a model was developed to investigate whether the addition of ivabradine to a standard-of-care (SoC) treatment regimen for patients with HF would reduce HRRP penalties incurred by a hypothetical hospital with excess 30?day readmissions.

Research design: A model using a Monte Carlo simulation framework was developed. Model inputs included national hospital characteristics, hospital-specific characteristics, and the ivabradine treatment effect as quantified by a post hoc analysis of the Systolic Heart failure treatment with the I_f inhibitor ivabradine Trial (SHIFT).

Results: The model computed an 83% reduction in HF readmission penalty payments in a hypothetical hospital with a readmission rate of 22.95% (excess readmission ratio = 1.056 over the national average readmission rate of 21.73%), translating into net savings of $44,016. A sensitivity analysis indicated that the readmission penalty is affected by the specific characteristics of the hospital, including the readmission rate, size of the ivabradine-eligible population, and ivabradine utilization.

Conclusions: The results of this study indicate that the addition of ivabradine to an SoC treatment regimen for patients with HF may lead to a reduction in the penalties incurred by hospitals under the HRRP. This highlights the role ivabradine can play as part of a wider effort to optimize the care of patients with HF.     

Ivabradine reversed nondipping heart rate in rats with l‐NAME‐induced hypertension

We hypothesized that decreasing elevated night‐time heart rate (HR) in hypertension by administering a bradycardic agent (ivabradine) at bedtime could bring cardiovascular benefit. Since rats are nocturnal animals, they exhibit circadian rhythms phase‐shifted relative to humans. Sixty‐six Wistar rats were divided into non‐diseased controls and rats with l ‐NAME‐induced hypertension to compare the haemodynamic effects of daytime‐dosed and night‐time‐dosed ivabradine. l ‐NAME‐induced hypertension inverted the physiological 5.6% night‐to‐day HR dip to an undesirable HR rise by 11.1%. Ivabradine dosed at daytime (the rat's resting phase) reverted a night‐to‐day HR rise to HR dip by 14.2%. These results suggest a cardiovascular benefit of ivabradine dosed at the human's resting phase (night‐time) for hypertensive patients with nondipping HR.     

Ventricular arrhythmia suppression with ivabradine in a patient with catecholaminergic polymorphic ventricular tachycardia refractory to nadolol,flecainide, and sympathectomy

Conventional treatment strategies for catecholaminergic polymorphic ventricular tachycardia (CPVT) include avoidance of strenuous exercise and competitive sports, drugs such as ß-blockers and flecainide and, cervical sympathectomy. An implantable cardioverter-defibrillator (ICD) has been utilized if the response to these strategies is inadequate; however, ICD use in CPVT patients, in addition to usual complications, is associated with an increased risk of life-threatening electrical storm. Ivabradine is a selective inhibitor of hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 generated funny current (I_f), which has been shown to be efficacious in suppression of inappropriate sinus tachycardia, junctional tachycardia, atrial tachycardia, and ventricular ectopy in humans. We report an 18-year-old male with a severe CPVT phenotype refractory to flecainide, nadolol, and sympathectomy who exhibited suppression of ventricular arrhythmias after initiation of ivabradine. These findings are of importance as ivabradine could be an important add-on therapy in CPVT patients who are drug refractory or are unable to continue conventional therapies at the recommended doses.     

Differential effects of ivabradine and ryanodine on pacemaker activity in canine sinus node and purkinje fibers

Effects of Ivabradine and Ryanodine on Cardiac Pacemakers . Introduction: It is generally accepted that at least 2 major mechanisms contribute to sinus node (SN) pacemaking: a membrane voltage (mainly I_f) clock and a calcium (Ca) clock (localized submembrane sarcoplasmic reticulum Ca²⁺ release during late diastolic depolarization). The aim of this study was to compare the contributions of each mechanism to pacemaker activity in SN and Purkinje fibers (PFs) exhibiting normal or abnormal automaticity. Methods and Results: Conventional microelectrodes were used to record action potentials in isolated spontaneously beating canine SN and free running PF in control and in the presence of 0.1 μM isoproterenol. Ryanodine (0.1–3 μM) and ivabradine (3 μM) were used to inhibit sarcoplasmic reticulum Ca²⁺ release or I_f, respectively. To induce automaticity at low membrane potentials, PFs were superfused with BaCl₂. In SN, ivabradine reduced the rate whereas ryanodine had no effect. Isoproterenol significantly accelerated automatic rate, which was decreased by ivabradine and ryanodine. In normally polarized PFs, ryanodine had no effects on the automatic rate in the absence or presence of isoproterenol, whereas ivabradine inhibited both control and isoproterenol‐accelerated automaticity. In PF depolarized with BaCl₂, ivabradine decreased BaCl₂‐induced automatic rate while ryanodine had no effect. Conclusion: In canine SN, I_f contributes to both basal automaticity and β‐adrenergic‐induced rate acceleration while the ryanodine‐inhibited Ca clock appears more involved in β‐adrenergic regulation of pacemaker rate. In PF, normal automaticity depends mainly on I_f. Inhibition of basal potassium conductance results in high automatic rates at depolarized membrane potentials with SN‐like responses to inhibition of membrane and Ca clocks. (J Cardiovasc Electrophysiol, Vol. 23, pp. 650–655, June 2012)     

Randomized Trial of Ivabradine in Patients With Hyperadrenergic Postural Orthostatic Tachycardia Syndrome

BackgroundPostural orthostatic tachycardia syndrome (POTS) is a complex, multifaceted disorder that impairs functional status and quality of life. Current pharmacological treatments are limited.ObjectivesThis study investigated the effect of ivabradine (selective blocker of the I_funny channel in the sinoatrial node) on heart rate, quality of life (QOL), and plasma norepinephrine (NE) levels in patients with hyperadrenergic POTS defined by plasma NE >600 pg/ml and abnormal tilt table test.MethodsIn total, 22 patients with hyperadrenergic POTS as the predominant subtype completed a randomized, double-blinded, placebo-controlled, crossover trial with ivabradine. Patients were randomized to start either ivabradine or placebo for 1 month, and then were crossed over to the other treatment for 1 month. Heart rate, QOL, and plasma NE levels were measured at baseline and at the end of each treatment month.ResultsThe average age was 33.9 ± 11.7 years, 95.5% were women (n = 21), and 86.4% were White (n = 23). There was a significant reduction in heart rate between placebo and ivabradine (p < 0.001). Patients reported significant improvements in QOL with RAND 36-Item Health Survey 1.0 for physical functioning (p = 0.008) and social functioning (p = 0.021). There was a strong trend in reduction of NE levels upon standing with ivabradine (p = 0.056). Patients did not experience any significant side-effects, such as bradycardia or hypotension, with ivabradine.ConclusionIvabradine is safe and effective in significantly improving heart rate and QOL in patients with hyperadrenergic POTS as the predominant subtype.     

Antianginal Efficacy of Ivabradine/Metoprolol Combination in Patients With Stable Angina

Medical treatment is the main clinical strategy for controlling patients with chronic stable angina and improving their quality of life (QoL). Ivabradine treatment on top of metoprolol decreases angina symptoms and improves QoL in patients with stable angina and coronary artery disease (CAD). This is a post hoc analysis (636 CAD patients given ivabradine/metoprolol free combination) of a prospective, noninterventional study that included 2403 patients with CAD and stable angina. Data were recorded at baseline at 1 and 4 months after inclusion. Patient QoL was assessed using the EQ‐5D questionnaire. From baseline to study completion; ivabradine administration on top of metoprolol decreased heart rate (HR) from 80.8 ± 9.6 to 64.2 ± 6.2 bpm (P < 0.001). Mean number of angina attacks decreased from 2.0 ± 2.0/wk to 0.2 ± 0.6/wk (P < 0.001), whereas nitroglycerin consumption decreased from 1.4 ± 1.9 times/wk to 0.1 ± 0.4 times/wk (P < 0.001). The percentage of patients in Canadian Cardiovascular Society angina class III to IV decreased from 15.4% to 1.9% (P < 0.001). The improvement of symptoms and angina class led to a significant 14.7‐point increase in EQ‐5D questionnaire score (P < 0.001). Patients with increased HR showed greater improvement (P = 0.001). Adherence to treatment during the entire trial was high (98%). Ivabradine combined with metoprolol significantly decreased angina symptoms and use of nitroglycerin in patients with stable angina and CAD, leading to improved QoL. The benefits observed with this combination explain the high rate of adherence to treatment.     

伊伐布雷定联合比索洛尔对冠心病PCI术后患者心脏康复的影响

目的：研究伊伐布雷定联合比索洛尔对冠心病经皮冠状动脉介入（PCI）术后患者心脏康复的影响。方法：选取于某院行PCI术的冠心病患者84例,随机分为观察组（n=42）及对照组（n=42）,观察组在常规冠心病二级预防治疗的基础上给予比索洛尔1.25 mg联合伊伐布雷定治疗,对照组在常规冠心病二级预防治疗的基础上仅给予比索洛尔5~10 mg口服。分别于治疗前、治疗4周及治疗12周时监测两组患者的6 min步行实验的距离、6 min步行实验的心率及血氧饱和度、左室射血分数、左室收缩末期内径、左室舒张末期内径、左室间隔厚度及左心室壁厚度。结果：观察组与对照组比较,在治疗12周时,6 min步行试验的距离、LVEF及左室正常舒张功能的比例明显增加,LVEDD、LVESD及6 min步行实验时的心室率明显降低,差异均具有统计学意义（P<0.05）;与治疗前相比,在治疗4周及12周时,观察组的6 min步行试验的距离、LVEF及左室正常舒张功能的比例明显增加,LVEDD、LVESD及6 min步行实验时的心室率明显降低,差异均具有统计学意义（P<0.05）;研究期间,观察组不良反应发生率低于对照组,但无统计学差异（P>0.05）。结论：伊伐布雷定联合比索洛尔对冠心病PCI术后患者的心脏康复的长期效果优于单纯比索洛尔治疗,不增加不良反应,是一种安全有效的治疗方案。