Milrinone在离体肺保护中应用的实验研究

目的 :本研究是探讨Milrinone(米力农 )对离体肺保护的作用。材料与方法 :以离体兔肺模型为肺保护实验对象 ,以肺动脉灌洗再次肺动脉灌注为实验方法 ,以新西兰兔 2 4只为实验动物 ,随机分为两组 ,每组 12只。一组用LPD液行肺动脉灌洗和保存 ,另一组用米力农加LPD液组成实验组 ,用同样的方法灌洗和保存。保存 18h后 ,观察病理形态、含水量以及测量NO(一氧化氮 )、SOD(超氧化物歧化酶 )及MDA(丙二醛 )的含量。结果 :肉眼见组织新鲜红润 ,部分组织充血、水肿及淤血 ;光镜下两组的肺泡、支气管及毛细血管结构完整 ,高倍视野下对照组较实验组肺泡上皮及毛细血管上皮细胞肿胀、肥大 ,少部分组织可见肺泡内有红细胞渗出、间隔增宽等。实验组的含水量低于对照组 (P <0 0 5 )。实验组肺组织中的NO及SOD含量高于对照组 (P <0 .0 5 ) ,MDA含量低于对照组 (P <0 0 5 )。结论 :米力农能清除氧自由基 ,有较强的抗氧化性 ,能较明显的减轻肺的再灌注损伤。在LPD液中加入米力农 ,能够对离体肺起到更好的保护效果。离体兔肺再灌注模型是一种较理想的实验动物模型。

Effect of Milrinone Induced Insulin Resistance on Glucose and Lipid Metabolism in Rats

Aim To investigate the effects of milrinone (a selective phosphodiesteraseIII inhibitor PDE_3 ) on insulin secretion, blood glucose, plasma free fatty acids (FFA) anddose-response relationship, and assess possible effects of milrinone on glucose metabolism andinsulin sensitivity in conscious rats. Methods The catheterized nonstressed rats were administeredvarious doses of milrinone (1, 5, 25μmoL·kg^(-1)) and were compared with controls. Ahyperinsulinaemic-eugly-caemic clamp was established in counscious rats, andmilrinone(25μmoL·kg^(-1)) and 25% dimethyl sulfoxide (DMSO, as a control) were given at 120 minduring hyperinsulinaemic-euglycaemic clamping. Glucose turnover was determind with by gaschromatograph mass spectrometer (GC-MS). Results After dosing, plasma FFA levels in 3 milrinonegroups significantly increased, compared with the controls and before dosing. The percentages ofelevation of FFA by the different milrinone doses were very similar, 50%, and 52% , 55% for 1, 5,and 25 μmoL·kg^(-1), repectively, at 2 min after dosing. Plasma insulin levels were significantlyelevated in the 5 and 25 μmoL·kg^(-1) groups, and the effect of milrione on glucose concentrationwas detectable only in 25μmoL·kg^(-1) group. During hyperinsulinaemic clamping, there weresignificant increase, in plasma FFA (from 173 +- 15 to 634 +- 87μmoL·kg^(-1)) and hepatic glucoseproduction (HGP), and a significant decrease in glucose infusion rates (GIR) to about 21% and aslight increase in plasma insulin after milrinone treatment. Conclusion Milrinone impaires theability of insulin to suppress lipolysis and HGP, and insulin-mediated glucose utilization inperipheral tissue. Therefore, milrinone administration may induce an acute insulin resistance invivo.

Comparison of inhaled milrinone, nitric oxide and prostacyclin in acute respiratory distress syndrome

AIM To evaluate the safety and efficacy of inhaled milrinone in acute respiratory distress syndrome(ARDS).METHODS Open-label prospective cross-over pilot study where fifteen adult patients with hypoxemic failure meeting standard ARDS criteria and monitored with a pulmonary artery catheter were recruited in an academic 24-bed medico-surgical intensive care unit. Random sequential administration of i NO(20 ppm) or nebulized epoprostenol(10 μg/mL) was done in all patients. Thereafter, inhaled milrinone(1 mg/mL) alone followed by inhaled milrinone in association with inhaled nitric oxide(iN O) was administered. A jet nebulization device synchronized with the mechanical ventilation was use to administrate the epoprostenol and the milrinone. Hemodynamic measurements and partial pressure of arterial oxygen(PaO_2) were recorded before and after each inhaled therapyadministration.RESULTS The majority of ARDS were of pulmonary cause(n = 13) and pneumonia(n = 7) was the leading underlying initial disease. Other pulmonary causes of ARDS were: Post cardiopulmonary bypass(n = 2), smoke inhalation injury(n = 1), thoracic trauma and pulmonary contusions(n = 2) and aspiration(n = 1). Two patients had an extra pulmonary cause of ARDS: A polytrauma patient and an intra-abdominal abscess Inhaled nitric oxide, epoprostenol, inhaled milrinone and the combination of inhaled milrinone and i NO had no impact on systemic hemodynamics. No significant adverse events related to study medications were observed. The median increase of PaO 2 from baseline was 8.8 mmH g [interquartile range(IQR) = 16.3], 6.0 mm Hg(IQR = 18.4), 6 mm Hg(IQR = 15.8) and 9.2 mm Hg(IQR = 20.2) respectively with i NO, epoprostenol, inhaled milrinone, and i NO added to milrinone. Only i NO and the combination of inhaled milrinone and i NO had a statistically significant effect on PaO 2. CONCLUSION When comparing the effects of inhaled NO, milrinone and epoprostenol, only NO significantly improved oxygenation. Inhaled milrinone appeared safe but failed to improve oxygenation in ARDS.

Effects of milrinone on inflammatory response-related gene expressions in cultured rat cardiomyocytes

Congestive heart failure(CHF)is defined as a cardiac dysfunction leading to low cardiac output and inadequate tissue perfusion.Intravenous positive inotropes are used to increase myocardial contractility in hospitalized patients with advanced heart failure.Milrinone is a phosphodiesterase Ⅲ inhibitor and used most commonly for inotropic effect.The well-known PROMISE study investigated the effects of milrinone on mortality in patients with severe CHF,and concluded that long-term therapy with milrinone increased morbidity and mortality armong patients with advanced CHF.Previous studies have suggested that phosphodiesterase inhibitors can have potential effects on inflammatory pathways.Hence,we hypothesized that milrinone may alter inflammatory gene expressions in cardiomyocytes,thus leading to adverse clinical outcomes.We used rat cardiomyocyte cell line H9 C2 and studied the impact of exposing cardiomyocytes to milrinone(10 μmol/L)for 24 hours on inflammatory gene expressions.RNA extracted from cultured cardiomyocytes was used for whole rat genome gene expression assay(41 000 genes).The following changes in inflammatory response-related gene expressions were discovered.Genes with increased expressions included:THBS2(+ 9.98),MMP2(+3.47),DDIT3(+2.39),and ADORA3(+3.5).Genes with decreased expressions were:SPP1(-5.28)and CD14(-2.05).We found that the above mentioned gene expression changes seem to indicate that milrinone may hinder the inflammatory process which may potentially lead to adverse clinical outcomes.However,further in vivo and clinical investigations will be needed to illustrate the clinical relevance of these gene expression changes induced by milrinone.

治疗心衰的新药Amrinone和Milrinone

近年来,已经出现了许多新的正性变力性药物。氨联吡啶酮(Amrinone,AM)已被用作静脉用药,它是双吡啶的衍生物。二联吡啶酮(Milrinone,MI)的应用也具有临床研究的基础,它是氨联吡啶酮的衍生物。最近,美国正准备批准在临床上使用 MI 的静脉和口服的两种制剂。

Effect of milrinone on the cardiac function and N-terminal pro-brain natriuretic peptide levels in patients with senile refractory heart failure

Objective:To study the effect of milrinone on the cardiac function and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in patients with senile refractory heart failure. Methods:90 patients with senile refractory heart failure who were treated in our hospital between August 2013 and August 2016 were collected and divided into control group (n=45) and observation group (n=45) according to the random number table. The control group received regular clinical treatment, and the observation group received regular + milrinone treatment. The cardiac function and serum NT-proBN contents were compared between two groups of patients before and after treatment.Results: Before treatment, the differences in ultrasound and serum cardiac function indexes and serum NT-proBN levels were not statistically significant between two groups of patients. After treatment, ultrasound serum cardiac function parameter LVEDD level in observation group was lower than that in control group while CI and SV levels were higher than those in control group;serum cardiac function indexes Cys-C, GDF-15, sST2 and H-FABP contents were lower than those in control group;serum NT-proBNP content was lower than that in control group.Conclusion: Milrinone therapy can optimize the cardiac function and reduce the serum NT-proBN levels in patients with senile refractory heart failure.

Effect of the adjuvant milrinone therapy on cardiac function, myocardial remodeling and RAAS system activity in patients with chronic heart failure

Objective:To explore the effect of the adjuvant milrinone therapy on cardiac function, myocardial remodeling and RAAS system activity in patients with chronic heart failure. Methods: A total of 110 patients with chronic heart failure who were treated in the hospital between January 2015 and January 2017 were divided into control group (n=55) and observation group (n=55) by random number table method. Control group received conventional therapy for chronic heart failure, and the observation group received milrinone on the basis of conventional therapy. The differences in ultrasound cardiac function and myocardial remodeling index levels as well as serum RAAS index contents were compared between the two groups before and after treatment.Results: Before treatment, the differences in ultrasound cardiac function and myocardial remodeling index levels as well as serum RAAS index contents were not statistically significant between the two groups. After treatment, CO and SV levels of both groups of patients were significantly higher than those before treatment while LADd, LVEDd, LVPWT, IVST and LVMI levels as well as serum PRA, AngⅡ and ALD contents were significantly lower than those before treatment, and CO and SV levels of observation group were significantly higher than those of control group while LADd, LVEDd, LVPWT, IVST and LVMI levels as well as serum PRA, AngⅡ and ALD contents were significantly lower than those of control group.Conclusion: Adjuvant milrinone therapy can effectively enhance the cardiac function, inhibit the myocardial remodeling and decrease the RAAS system activity in patients with chronic heart failure.

治疗充血性心衰的新药Milrinone

充血性心衰患名病程的晚期可能难于用毛地黄,利尿剂和血管舒张剂治疗奏效。在找寻口服有效的变力药物的研究中发展了Amrinone(A),A系联吡啶化合物,具有正件变力(肌力)和血管舒张作用。虽然A的静注制剂已在美国上市。

甲氰吡酮(Milrinone)

本品是美国Sterling制药公司的Winth-rop药厂继氨吡酮(Amrinone)之后研究开发的第二个新强心药。它能抑制心脏的磷酸二酯酶,产生正性肌力使心肌收缩力加强,并能扩张外周血管,临床适用于治疗充血性心力衰竭。在动物试验中发现狗口服给药30min起效,持续6h以上,作用比氨吡酮强10～30倍;它的注射剂已于1987年12月获美国FDA批准;口服制剂尚待审批中。国内重庆医药工业研究所与中国药科大学正在研制。 [化学名称] (1)(3,4’bipyridine)-5-carbonitrile,1,6-dihydro-2-methyl-6-oxo。 (2)1,6-Dihydro-2-methyl-6oxo-(3,4’-bipyridine)

PDE3与亮甲酚蓝在绵羊卵母细胞体外培养中的应用研究

[目的]探讨磷酸二酯酶3(PDE3)特异性抑制剂Milrinone与亮甲酚蓝染色液(BCB)相结合在绵羊卵母细胞体外培养中的应用。[方法]比较了BCB对绵羊卵母细胞的筛选与传统的形态分级之间的差异,以及对胚胎后期发育的影响;研究了Milrinone对绵羊卵母细胞的最佳抑制时间,并用于BCB-卵母细胞体外培养。[结果]A、B级卵母细胞中BCB+卵母细胞的比例为64.42%,极显著高于C级卵母细胞的17.00%;BCB+卵母细胞的成熟率(86.16%)、卵裂率(85.29%)、囊胚率(34.40%)分别极显著高于BCB-卵母细胞(50.94%、36.19%和6.73%);6 h是Milrinone对绵羊卵母细胞的最佳抑制时间,该试验组体外培养效率显著高于其他组;Milrinone对BCB-卵母细胞抑制培养6 h,极显著提高了体外胚胎发育率。[结论]为提高绵羊卵母细胞体外培养效率提供了依据。

Application of PDE3 and Brilliant Cresyl Blue in In-vitro Culture of Sheep Oocyte

[Objective] The aim of this study was to increase the viability of sheep oocytes in vitro by using phosphodiesterase type 3（PDE 3） inhibitor milrinone combined with brilliant cresyl blue（BCB） staining.[Method] The differences between BCB tested and morphologically selected oocytes,as well as the effect of them on embryo development were compared;and then suitable inhibitive time of milrinone to sheep oocytes in vitro was studied and used in BCB-oocytes for in vitro embryo production（IVEP）.[Result] The BCB＋ oocytes percentage in A-and B-level sheep oocytes was 64.42%,which was extremely significantly higher than that in C-level（17.0%）.The maturing rate,cleavage rate and blastocyst rate of BCB＋ oocytes（86.16%,85.29% and 34.40%） of was significantly higher than those of BCB-oocytes（50.94%,36.19% and 6.73%）.The best time for PDE 3 inhibitor delaying the sheep oocyte mature in vitro was 6 h.In addition,the rate of embryo development in vitro could be significantly increased by inhibiting the BCB-oocytes for 6 h with Milrinone.[Conclusion] The study will provide reference for improving the efficiency of sheep oocytes culture in vitro.

Novel role of phosphodiesterase inhibitors in the management of end-stage heart failure

In advanced heart failure(HF), chronic inotropic therapy with intravenous milrinone, a phosphodiesterase Ⅲ inhibitor, is used as a bridge to advanced management that includes transplantation, ventricular assist device implantation, or palliation. This is especially true when repeated attempts to wean off inotropic support result in symptomatic hypotension, worsened symptoms, and/or progressive organ dysfunction. Unfortunately, patients in this clinical predicament are considered hemodynamically labile and may escape the benefits of guidelinedirected HF therapy. In this scenario, chronic milrinone infusion may be beneficial as a bridge to introduction of evidence based HF therapy. However, this strategy is not well studied, and in general, chronic inotropic infusion is discouraged due to potential cardiotoxicity that accelerates disease progression and proarrhythmic effects that increase sudden death. Alternatively, chronic inotropic support with milrinone infusion is a unique opportunity in advanced HF. This review discusses evidence that long-term intravenous milrinone support may allow introduction of beta blocker(BB) therapy. When used together, milrinone does not attenuate the clinical benefits of BB therapy while BB mitigates cardiotoxic effects of milrinone. In addition, BB therapy decreases the risk of adverse arrhythmias associated with milrinone. We propose that advanced HF patients who are intolerant to BB therapy may benefit from a trial of intravenous milrinone as a bridge to BB initiation. The discussed clinical scenarios demonstrate that concomitant treatment with milrinone infusion and BB therapy does not adversely impact standard HF therapy and may improve left ventricular function and morbidity associated with advanced HF.