Olprinone

Olprinone is a selective phosphodiesterase 3 (PDE3) inhibitor. Olprinone is used as cardiotonic agent with positive inotropic and vasodilating effects. Olprinone has been reported to improve microcirculation and attenuate inflammation. Olprinone is often used to increase cardiac output after cardiopulmonary bypass (CPB). Olprinone was infused at a rate of 0.2 μg/kg/min when weaning from CPB was started. Olprinone has also shown potent antioxidative and anti-inflammatory effects in the meconium-induced oxidative lung injury.

Phase I clinical trial of olprinone in liver surgery.[Pubmed:28028637]

Surg Today. 2017 Aug;47(8):918-927.

PURPOSE: Post-hepatectomy liver failure is one of the most serious complications liver surgeons must overcome. We previously examined Olprinone, a selective phosphodiesterase III inhibitor, and demonstrated its hepatoprotective effects in rats and pigs. We herein report the results of a phase I clinical trial of Olprinone in liver surgery (UMIN000004975). METHODS: Twenty-three patients who underwent hepatectomy between 2011 and 2015 were prospectively registered. In the first 6 cases, Olprinone (0.1 mug/kg/min) was administered for 24 h from the start of surgery. In the remaining 17 cases, Olprinone (0.05 mug/kg/min) was administered from the start of surgery until just before the transection of the liver parenchyma. The primary endpoint was safety, and the secondary endpoint was efficacy. For the evaluation of efficacy, the incidence of post-hepatectomy liver failure in 20 hepatocellular carcinoma patients was externally compared with 20 propensity score-matched patients. RESULTS: No intraoperative side effects were observed, and the morbidity rates in the analyzed cohorts were acceptable. The rate of post-hepatectomy liver failure frequency tended to be lower in the Olprinone group. CONCLUSIONS: The safety of Olprinone in liver surgery was confirmed. The efficacy of Olprinone will be re-evaluated in clinical trials.

A Double-Blind Placebo-Controlled Study of the Effects of Olprinone, a Specific Phosphodiesterase III Inhibitor, for Preventing Postoperative Atrial Fibrillation in Patients Undergoing Pulmonary Resection for Lung Cancer.[Pubmed:26204331]

Chest. 2015 Nov;148(5):1285-1292.

BACKGROUND: We previously reported that patients with elevated preoperative B-type natriuretic peptide (BNP) levels have an increased risk for postoperative atrial fibrillation following lung cancer surgery. The present study evaluated whether the specific phosphodiesterase III inhibitor Olprinone can reduce the incidence of postoperative atrial fibrillation in patients with elevated BNP levels undergoing pulmonary resection for lung cancer. METHODS: A prospective randomized study was conducted with 40 patients who had elevated preoperative BNP levels (>/= 30 pg/mL) and underwent scheduled lung cancer surgery. All patients were in sinus rhythm at surgery. Low-dose Olprinone or placebo was continuously infused for 24 h and started just before anesthesia induction. The primary end point was the incidence of postoperative atrial fibrillation. The secondary end points were perioperative hemodynamics and levels of BNP, WBC counts, and C-reactive protein. RESULTS: The incidence of postoperative atrial fibrillation was significantly lower in the Olprinone group than in the placebo group (10% vs 60%, P < .001). Patients in the Olprinone group showed significantly lower BNP, WBC counts, and C-reactive protein levels after surgery. CONCLUSIONS: Continuous infusion of Olprinone during lung cancer surgery was safe and reduced the incidence of postoperative atrial fibrillation following pulmonary resection in patients with elevated preoperative BNP levels. TRIAL REGISTRY: Japan Primary Registries Network; No.: JPRN-UMIN2404; URL: http://www.umin.ac.jp/ctr/.

Hepatoprotective effect by pretreatment with olprinone in a swine partial hepatectomy model.[Pubmed:24700629]

Liver Transpl. 2014 Jul;20(7):838-49.

Excessive portal flow to a small remnant liver or small-for-size graft is a primary factor of small-for-size syndrome. We demonstrated that Olprinone (OLP), a phosphodiesterase III inhibitor, had a hepatoprotective effect in a rat extended hepatectomy model and a small-for-size liver transplantation model through a modification of the portal venous pressure (PVP). To identify the appropriate dose and duration of treatment for clinical applications, we conducted experiments with a swine partial hepatectomy model. Twenty microminipigs were divided into 4 groups that received the following treatments: (A) saline (control group), (B) OLP at 0.3 mug/kg/minute (preoperative and postoperative administration), (C) OLP at 0.1 mug/kg/minute (preoperative administration), and (D) OLP at 0.3 mug/kg/minute (preoperative administration). The pigs underwent 70% partial hepatectomy. Hemodynamic changes, including changes in PVP, were examined. Liver biopsy was performed 1 and 3 hours after hepatectomy. Blood samples were collected until postoperative day 7 (POD7). In comparison with group A, PVP elevations, periportal edema, and sinusoidal hemorrhaging were attenuated after left Glisson's ligation in groups C and D. Pretreatment with OLP in groups C and D preserved the microstructure of sinusoids and improved the prothrombin activity 1 and 3 hours after hepatectomy. These animals showed better recovery of the remnant liver volume and the plasma disappearance rate of indocyanine green on POD7. In contrast, group B showed exacerbation of liver damage. Measurements of the serum OLP concentration showed that 10 ng/mL OLP was appropriate for a hepatoprotective effect. In conclusion, pretreatment with OLP shows hepatoprotective effects in a swine partial hepatectomy model. OLP may have the potential to ameliorate patients' outcomes after hepatectomy or liver transplantation.

Stabilization of Kv1.5 channel protein by the inotropic agent olprinone.[Pubmed:26368666]

Eur J Pharmacol. 2015 Oct 15;765:488-94.

Olprinone is an inotropic agent that inhibits phosphodiesterase (PDE) III and causes vasodilation. Olprinone has been shown to be less proarrhythmic and possibly affect expression of functional Kv1.5 channels that confer the ultra-rapid delayed-rectifier K+ channel current (IKur) responsible for action potential repolarization. To reveal involvement of Kv1.5 channels in the less arrhythmic effect of Olprinone, we examined effects of the agent on the stability of Kv1.5 channel proteins expressed in COS7 cells. Olprinone at 30-1000 nM increased the protein level of Kv1.5 channels in a concentration-dependent manner. Chase experiments showed that Olprinone delayed degradation of Kv1.5 channels. Olprinone increased the immunofluorescent signal of Kv1.5 channels in the endoplasmic reticulum (ER) and Golgi apparatus as well as on the cell surface. Kv1.5-mediated membrane currents, measured as 4-aminopyridine-sensitive currents, were increased by Olprinone without changes in their activation kinetics. A protein transporter inhibitor, colchicine, abolished the Olprinone-induced increase of Kv.1.5-mediated currents. The action of Olprinone was inhibited by 4-aminopyridine, and was not mimicked by the application of 8-Bromo-cAMP. Taken together, we conclude that Olprinone stabilizes Kv1.5 proteins at the ER through an action as a chemical chaperone, and thereby increases the density of Kv1.5 channels on the cell membrane. The enhancement of Kv1.5 currents could underlie less arrhythmogenicity of Olprinone.