Olprinone, a Selective Phosphodiesterase III Inhibitor, Has Protective Effects in a Septic Rat Model after Partial Hepatectomy and Primary Rat Hepatocyte.

Olprinone (OLP) is a selective inhibitor of phosphodiesterase III and is used clinically in patients with heart failure and those undergoing cardiac surgery; however, little is known about the effects of OLP on hepatoprotection. The purpose of this study aimed to determine whether OLP has protective effects in in vivo and in vitro rat models of endotoxin-induced liver injury after hepatectomy and to clarify the mechanisms of action of OLP. In the in vivo model, rats underwent 70% partial hepatectomy and lipopolysaccharide treatment (PH/LPS). OLP administration increased survival by 85.7% and decreased tumor necrosis factor-α, C-X-C motif chemokine ligand 1, and inducible nitric oxide synthase (iNOS) mRNA expression in the livers of rats treated with PH/LPS. OLP also suppressed nuclear translocation and/or DNA binding ability of nuclear factor kappa B (NF-κB). Pathological liver damage induced by PH/LPS was alleviated and neutrophil infiltration was reduced by OLP. Primary cultured rat hepatocytes treated with the pro-inflammatory cytokine interleukin-1ß (IL-1ß) were used as a model of in vitro liver injury. Co-treatment with OLP inhibited dose-dependently IL-1ß-stimulated iNOS induction and NF-κB activation. Our results demonstrate that OLP may partially inhibit the induction of several inflammatory mediators through the suppression of NF-κB and thus prevent liver injury induced by endotoxin after liver resection.

Phosphodiesterase 3 inhibitors do not influence lactate kinetics and clinical outcomes in patients with septic shock: A multicentre cohort study.

PURPOSE: We investigated the association between the administration of phosphodiesterase 3 inhibitors (PDE3i) and lactate kinetics, resolution of organ failure, ICU and hospital length of stay (LOS) and hospital mortality in a retrospective cohort of patients with septic shock and persistently elevated lactate concentrations. MATERIAL AND METHODS: Patients with septic shock and two arterial lactate concentrations ≥4 mmol/L with at least 4 h between measurements were eligible. Clinical data of the first four days of admission were collected in an online database. For each patient, the area between the actual lactate concentrations and 2.2 mmol/L (AUClact2.2), was calculated for three days. RESULTS: Data on 229 patients from 10 hospitals were collected, of whom 123 received PDE3i (54%). First, a linear multivariate model was developed to predict AUClact2.2 (R2 = 0.57). Adding PDE3i as a cofactor did not affect R2. Second, 60 patients receiving PDE3i at any time between days 0 and 2 were compared to 60 propensity matched no-PDE3i patients. Third, 30 patients who received PDE3i from ICU admission to day 3 were compared to 30 propensity-matched no-PDE3i patients. These analyses showed no differences in AUClact2.2, SOFA scores, ICU or hospital LOS or hospital mortality between treatment groups. CONCLUSIONS: No association was found between the administration of PDE3i and lactate kinetics, resolution of organ failure, ICU or hospital LOS or hospital mortality.

Cilostazol improves the prognosis after hepatectomy in rats with sinusoidal obstruction syndrome.

BACKGROUND AND AIM: Safe radical hepatectomy is important for patients with colorectal liver metastases complicated by sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy. This study aimed to investigate the impact of preoperative administration of cilostazol (CZ), an oral selective phosphodiesterase III inhibitor, on hepatectomy in rat SOS model. MATERIAL AND METHODS: Rats were divided into NL (normal liver), SOS (monocrotaline [MCT]-treated), and SOS + CZ (MCT + CZ-treated) groups. MCT or CZ was administered orally, and a 30% partial hepatectomy was performed 48 h after MCT administration. Postoperative survival rates were evaluated (n = 9, for each). Other rats were sacrificed on postoperative days (POD) 1 and 3 and evaluated histologically, immunohistochemically, biochemically, and using transmission electron microscopy (TEM), focusing particularly on SOS findings, liver damage, and liver sinusoidal endothelial cell (LSEC) injury. RESULTS: The cumulative 10-day postoperative survival rate was significantly higher in the SOS + CZ group than in the SOS group (88.9% vs 33.3%, P = 0.001). Total SOS scores were significantly lower in the SOS + CZ group than in the SOS group on both POD 1 and 3. Serum biochemistry and immunohistochemistry showed that CZ reduced liver damage after hepatectomy. TEM revealed that LSECs were significantly preserved morphologically in the SOS + CZ group than in the SOS group on POD 1 (86.1 ± 8.2% vs 63.8 ± 9.3%, P = 0.003). CONCLUSION: Preoperative CZ administration reduced liver injury by protecting LSECs and improved the prognosis after hepatectomy in rats with SOS.

Cilostazol Stimulates Angiogenesis and Accelerates Fracture Healing in Aged Male and Female Mice by Increasing the Expression of PI3K and RUNX2.

Fracture healing in the aged is associated with a reduced healing capacity, which often results in delayed healing or non-union formation. Many factors may contribute to this deterioration of bone regeneration, including a reduced 'angiogenic trauma response'. The phosphodiesterase-3 (PDE-3) inhibitor cilostazol has been shown to exert pro-angiogenic and pro-osteogenic effects in preclinical studies. Therefore, we herein analyzed in a stable closed femoral fracture model whether this compound also promotes fracture healing in aged mice. Forty-two aged CD-1 mice (age: 16-18 months) were daily treated with 30 mg/kg body weight cilostazol (n = 21) or vehicle (control, n = 21) by oral gavage. At 2 and 5 weeks after fracture, the femora were analyzed by X-ray, biomechanics, micro-computed tomography (µCT), histology, immunohistochemistry, and Western blotting. These analyses revealed a significantly increased bending stiffness at 2 weeks (2.2 ± 0.4 vs. 4.3 ± 0.7 N/mm) and an enhanced bone formation at 5 weeks (4.4 ± 0.7 vs. 9.1 ± 0.7 mm3) in cilostazol-treated mice when compared to controls. This was associated with a higher number of newly formed CD31-positive microvessels (3.3 ± 0.9 vs. 5.5 ± 0.7 microvessels/HPF) as well as an elevated expression of phosphoinositide-3-kinase (PI3K) (3.6 ± 0.8 vs. 17.4 ± 5.5-pixel intensity × 104) and runt-related transcription factor (RUNX)2 (6.4 ± 1.2 vs. 18.2 ± 2.7-pixel intensity × 104) within the callus tissue. These findings indicate that cilostazol accelerates fracture healing in aged mice by stimulating angiogenesis and the expression of PI3K and RUNX2. Hence, cilostazol may represent a promising compound to promote bone regeneration in geriatric patients.

Cilostazol May Improve Outcomes Even in Patients with Aneurysmal Subarachnoid Hemorrhage Aged 75 Years and Older: Multicenter Cohort Study and Propensity Score-Matched Analyses.

BACKGROUND: The opportunities to treat elderly patients with aneurysmal subarachnoid hemorrhage (aSAH) are increasing globally, but the outcome remains poor. This study seeks to investigate treatment-related factors that can modify functional outcomes in patients with aSAH aged ≥75 years. METHODS: A total of 202 patients with aSAH aged ≥75 years prospectively enrolled in 9 primary stroke centers from 2013 to 2021 were retrospectively analyzed. Clinical variables including treatments for hydrocephalus, angiographic vasospasm, and delayed cerebral ischemia were compared between patients with good (modified Rankin Scale [mRS] score 0-2) and poor (mRS score 3-6) outcomes at 90 days from onset, followed by multivariate analyses to find independent outcome determinants. A modifiable treatment-related variable was evaluated after propensity score matching with adjustments for age, sex, pre-onset mRS score, aSAH severity, and treatment modality. RESULTS: More than half of patients showed World Federation of Neurological Societies grades IV-V on admission. Univariate analyses showed that advanced age, worse pre-onset mRS score, more severe neurologic status on admission, higher modified Fisher grade on admission computed tomography scans, and acute and chronic hydrocephalus were associated with poor outcomes. In contrast, administration of a phosphodiesterase type III inhibitor, cilostazol, was associated with good outcomes in both univariate (P = 0.036) and multivariate analyses (adjusted odds ratio, 0.305; 95% confidence interval, 0.097-0.955; P = 0.042). Propensity score matching analyses showed that patients treated with cilostazol had better outcomes (P = 0.016) with fewer incidences of delayed cerebral infarction (P = 0.008). CONCLUSIONS: Even in patients with aSAH aged ≥75 years, cilostazol administration may lead to better outcomes by suppressing the development of delayed cerebral infarction.

Cilostazol attenuates cardiac oxidative stress and inflammation in hypercholesterolemic rats.

Atherosclerosis is a multifactorial chronic disease associated with pro-inflammatory and pro-oxidative cardiovascular states. Cilostazol, a selective phosphodiesterase 3 inhibitor (PDE3), is clinically used in the treatment of intermittent claudication and secondary prevention of cerebral infarction. The aim of this study was to evaluate the cardioprotective effects of cilostazol and the molecular mechanisms involved in hypercholesterolemic rats. Male Wistar rats were divided into four groups: control group (C) and control + cilostazol group (C+CILO), that were fed a standard chow diet, and hypercholesterolemic diet group (HCD) and HCD + cilostazol (HCD+CILO) that were fed a hypercholesterolemic diet. Cilostazol treatment started after 30 days for C+CILO and HCD+CILO groups. Animals were administered cilostazol once a day for 15 days. Subsequently, serum and left ventricles were extracted for evaluation of lipid profile, inflammatory, and oxidative biomarkers. The HCD group displayed increased serum lipid levels, inflammatory cytokines production, and cardiac NF-kB protein expression and decreased cardiac Nrf2-mediated antioxidant activity. Conversely, the cilostazol treatment improved all these cardiac deleterious effects, inhibiting NF-kB activation and subsequently decreasing inflammatory mediators, reestablishing the antioxidant properties through Nrf2-mediated pathway, including increased SOD, GPx, and catalase expression. Taken together, our results indicated that cilostazol protects hypercholesterolemia-induced cardiac damage by molecular mechanisms targeting the crosstalk between Nrf2 induction and NF-kB inhibition in the heart.

Post-stroke treatment with K-134, a phosphodiesterase 3 inhibitor, improves stroke outcomes in the stroke-prone spontaneously hypertensive rat model-A comparative evaluation of antiplatelet drugs.

Post-stroke antiplatelet therapy has been proved to reduce the risk of recurrent stroke; however, it may also increase the incidence of intracranial hemorrhage that could offset any benefits. Therefore, the balance between the benefits and risks of antiplatelet drugs is a critical issue to consider. In the present study, we have compared the effects of post-stroke administration of antiplatelet agents on functional outcomes in the stroke-prone spontaneously hypertensive rat (SHRSP), an established animal model that mimics human lacunar stroke and cerebral small vessel disease. We confirmed that a potent phosphodiesterase 3 (PDE3) inhibitor, K-134, significantly improved post-stroke survival rate and survival time, attenuated stroke-induced neurological deficits, and decreased the incidence of cerebral lesion caused by intracerebral hemorrhage and softening. Similarly, cilostazol showed beneficial effects, though to a lower extent with respect to the survival outcome and neurological symptoms. On the other hand, a P2Y12 inhibitor, clopidogrel significantly improved survival outcomes at the higher dose but caused massive bleeding in the brain at both low and high doses. In contrast, no hemorrhagic lesion was observed in K-134-treated SHRSPs despite its antiplatelet activity. Our findings indicate that K-134 may have a superior post-stroke therapeutic outcome in comparison to other antiplatelet drugs.

Update on Cilostazol: A Critical Review of Its Antithrombotic and Cardiovascular Actions and Its Clinical Applications.

Cilostazol, a phosphodiesterase III inhibitor, has vasodilating and antiplatelet properties with a low rate of bleeding complications. It has been used over the past 25 years for improving intermittent claudication in patients with peripheral artery disease (PAD). Cilostazol also has demonstrated efficacy in patients undergoing percutaneous revascularization procedures for both PAD and coronary artery disease. In addition to its antithrombotic and vasodilating actions, cilostazol also inhibits vascular smooth muscle cell proliferation via phosphodiesterase III inhibition, thus mitigating restenosis. Accumulated evidence has shown that cilostazol, due to its "pleiotropic" effects, is a useful, albeit underutilized, agent for both coronary artery disease and PAD. It is also potentially useful after ischemic stroke and is an alternative in those who are allergic or intolerant to classical antithrombotic agents (eg, aspirin or clopidogrel). These issues are herein reviewed together with the pharmacology and pharmacodynamics of cilostazol. Large studies and meta-analyses are presented and evaluated. Current guidelines are also discussed, and the spectrum of cilostazol's actions and therapeutic applications are illustrated.

Model difference in the effect of cilostazol on the development of experimental pulmonary hypertension in rats.

BACKGROUND: Preventing pulmonary vascular remodeling is a key strategy for pulmonary hypertension (PH). Causes of PH include pulmonary vasoconstriction and inflammation. This study aimed to determine whether cilostazol (CLZ), a phosphodiesterase-3 inhibitor, prevents monocrotaline (MCT)- and chronic hypoxia (CH)-induced PH development in rats. METHODS: Fifty-one male Sprague-Dawley rats were fed rat chow with (0.3% CLZ) or without CLZ for 21 days after a single injection of MCT (60 mg/kg) or saline. Forty-eight rats were fed rat chow with and without CLZ for 14 days under ambient or hypobaric (air at 380 mmHg) CH exposure. The mean pulmonary artery pressure (mPAP), the right ventricle weight-to-left ventricle + septum weight ratio (RV/LV + S), percentages of muscularized peripheral pulmonary arteries (%Muscularization) and medial wall thickness of small muscular arteries (%MWT) were assessed. Levels of the endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (peNOS), AKT, pAKT and IκB proteins in lung tissue were measured using Western blotting. Monocyte chemotactic protein (MCP)-1 mRNA in lung tissue was also assessed. RESULTS: mPAP [35.1 ± 1.7 mmHg (MCT) (n = 9) vs. 16.6 ± 0.7 (control) (n = 9) (P < 0.05); 29.1 ± 1.5 mmHg (CH) (n = 10) vs. 17.5 ± 0.5 (control) (n = 10) (P < 0.05)], RV/LV + S [0.40 ± 0.01 (MCT) (n = 18) vs. 0.24 ± 0.01 (control) (n = 10) (P < 0.05); 0.41 ± 0.03 (CH) (n = 13) vs. 0.27 ± 0.06 (control) (n = 10) (P < 0.05)], and %Muscularization and %MWT were increased by MCT injection and CH exposure. CLZ significantly attenuated these changes in the MCT model [mPAP 25.1 ± 1.1 mmHg (n = 11) (P < 0.05), RV/LV + S 0.30 ± 0.01 (n = 14) (P < 0.05)]. In contrast, these CLZ effects were not observed in the CH model. Lung eNOS protein expression was unchanged in the MCT model and increased in the CH model. Lung protein expression of AKT, phosphorylated AKT, and IκB was downregulated by MCT, which was attenuated by CLZ; the CH model did not change these proteins. Lung MCP-1 mRNA levels were increased in MCT rats but not CH rats. CONCLUSIONS: We found model differences in the effect of CLZ on PH development. CLZ might exert a preventive effect on PH development in an inflammatory PH model but not in a vascular structural change model of PH preceded by vasoconstriction. Thus, the preventive effect of CLZ on PH development might depend on the PH etiology.

Cilostazol for Secondary Stroke Prevention: History, Evidence, Limitations, and Possibilities.

Cilostazol is a PDE3 (phosphodiesterase III) inhibitor with a long track record of safety that is Food and Drug Administration and European Medicines Agency approved for the treatment of claudication in patients with peripheral arterial disease. In addition, cilostazol has been approved for secondary stroke prevention in several Asian countries based on trials that have demonstrated a reduction in stroke recurrence among patients with noncardioembolic stroke. The onset of benefit appears after 60 to 90 days of treatment, which is consistent with cilostazol's pleiotropic effects on platelet aggregation, vascular remodeling, blood flow, and plasma lipids. Cilostazol appears safe and does not increase the risk of major bleeding when given alone or in combination with aspirin or clopidogrel. Adverse effects such as headache, gastrointestinal symptoms, and palpitations, however, contributed to a 6% increase in drug discontinuation among patients randomized to cilostazol in a large secondary stroke prevention trial (CSPS.com [Cilostazol Stroke Prevention Study for Antiplatelet Combination]). Due to limitations of prior trials, such as open-label design, premature trial termination, large loss to follow-up, lack of functional or cognitive outcome data, and exclusive enrollment in Asia, the existing trials have not led to a change in clinical practice or guidelines in Western countries. These limitations could be addressed by a double-blind placebo-controlled randomized trial conducted in a broader population. If positive, it would increase the evidence in support of long-term treatment with cilostazol for secondary prevention in the millions of patients worldwide who have experienced a noncardioembolic ischemic stroke.

Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock.

BACKGROUND: Cardiogenic shock is associated with substantial morbidity and mortality. Although inotropic support is a mainstay of medical therapy for cardiogenic shock, little evidence exists to guide the selection of inotropic agents in clinical practice. METHODS: We randomly assigned patients with cardiogenic shock to receive milrinone or dobutamine in a double-blind fashion. The primary outcome was a composite of in-hospital death from any cause, resuscitated cardiac arrest, receipt of a cardiac transplant or mechanical circulatory support, nonfatal myocardial infarction, transient ischemic attack or stroke diagnosed by a neurologist, or initiation of renal replacement therapy. Secondary outcomes included the individual components of the primary composite outcome. RESULTS: A total of 192 participants (96 in each group) were enrolled. The treatment groups did not differ significantly with respect to the primary outcome; a primary outcome event occurred in 47 participants (49%) in the milrinone group and in 52 participants (54%) in the dobutamine group (relative risk, 0.90; 95% confidence interval [CI], 0.69 to 1.19; P = 0.47). There were also no significant differences between the groups with respect to secondary outcomes, including in-hospital death (37% and 43% of the participants, respectively; relative risk, 0.85; 95% CI, 0.60 to 1.21), resuscitated cardiac arrest (7% and 9%; hazard ratio, 0.78; 95% CI, 0.29 to 2.07), receipt of mechanical circulatory support (12% and 15%; hazard ratio, 0.78; 95% CI, 0.36 to 1.71), or initiation of renal replacement therapy (22% and 17%; hazard ratio, 1.39; 95% CI, 0.73 to 2.67). CONCLUSIONS: In patients with cardiogenic shock, no significant difference between milrinone and dobutamine was found with respect to the primary composite outcome or important secondary outcomes. (Funded by the Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario; ClinicalTrials.gov number, NCT03207165.).

PDE3-inhibitor enoximone prevented mechanical ventilation in patients with SARS-CoV-2 pneumonia.

BACKGROUND: Standard care in severe SARS-CoV-2 pneumonia complicated by severe dyspnea and respiratory failure, consists of symptom reduction, ultimately supported by mechanical ventilation. Patients with severe SARS-CoV-2, a prominent feature of COVID-19, show several similar symptoms to Critical Asthma Syndrome (CAS) patients, such as pulmonary edema, mucus plugging of distal airways, decreased tissue oxygenation, (emergent) exhaustion due to severe dyspnea and respiratory failure. Prior application of elective phosphodiesterase (PDE)3-inhibitors milrinone and enoximone in patients with CAS yielded rapid symptomatic relief and reverted the need for mechanical ventilation, due to their bronchodilator and anti-inflammatory properties. Based on these observations, we hypothesized that enoximone may be beneficial in the treatment of patients with severe SARS-CoV-2 pneumonia and prominent CAS-features. METHODS: In this case report enoximone was administered to four consecutive patients (1 M; 3 F; 46-70 y) with emergent respiratory failure due to SARS-CoV-2 pneumonia. Clinical outcome was compared with three controls who received standard care only. RESULTS: After an intravenous bolus of enoximone 20 mg followed by 10 mg/h via perfusor, a rapid symptomatic relief was observed: two out of four patients recovered within a few hours, the other two (with comorbid COPD GOLD II/III) responded within 24-36 h. Compared to the controls, in the enoximone-treated patients respiratory failure and further COVID-19-related deterioration was reverted and mechanical ventilation was prevented, leading to reduced hospital/ICU time. DISCUSSION: Our preliminary observations suggest that early intervention with the selective PDE3-inhibitor enoximone may help to revert respiratory failure as well as avert mechanical ventilation, and reduces ICU/hospital time in patients with severe SARS-CoV-2 pneumonia. Our findings warrant further research on the therapeutic potential of PDE3-inhibition, alone or in combination with other anti-COVID-19 strategies.

Role of Cilostazol in Prevention of Vasospasm After Aneurysmal Subarachnoid Hemorrhage-A Systematic Review, Meta-Analysis, and Trial Sequential Analysis.

OBJECTIVE: Cerebral vasospasm is a common complication after aneurysmal subarachnoid hemorrhage (aSAH). Many drugs have been tried to mitigate cerebral vasospasm and delayed cerebral ischemia. Cilostazol, a selective inhibitor of phosphodiesterase 3, is a promising agent in preventing cerebral vasospasm and delayed cerebral ischemia after aSAH. The objective of this article was to ascertain the effect of cilostazol on cerebral vasospasm after aSAH by performing meta-analysis and trial sequential analysis. METHODS: A systematic search of the literature was performed, and all the eligible randomized controlled trials were included in the meta-analysis and trial sequential analysis. RESULTS: A total of 454 articles were identified using the search criteria. Six articles were selected for systematic review and the 4 randomized controlled trials were included in the meta-analysis. The pooled odds ratio for symptomatic vasospasm, new-onset infarct, and angiographic vasospasm was 0.35 (95% confidence interval [CI], 0.21-0.59; P < 0.0001), 0.38 (95% CI, 0.21-0.66; P = 0.0007) and 0.49 (95% CI, 0.31-0.80; P = 0.004), respectively. The pooled risk ratio for unfavorable outcome was 0.52 (95% CI, 0.37-0.74; P = 0.0003). CONCLUSIONS: Cilostazol decreases the prevalence of symptomatic vasospasm, new-onset infarct, and angiographic vasospasm when administered after aSAH. Trial sequential analysis increased the precision of our results because the defined thresholds of effect were met by the available studies. However, further studies involving patients from other geographic areas are required to confirm the generalization of the results.

Could cilostazol be beneficial in COVID-19 treatment? Thinking about phosphodiesterase-3 as a therapeutic target.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) that has emerged and rapidly spread across the world. The COVID-19 severity is associated to viral pneumonia with additional extrapulmonary complications. Hyperinflammation, dysfunctional immune response and hypercoagulability state are associated to poor prognosis. Therefore, the repositioning of multi-target drugs to control the hyperinflammation represents an important challenge for the scientific community. Cilostazol, a selective phosphodiesterase type-3 inhibitor (PDE-3), is an antiplatelet and vasodilator drug, that presents a range of pleiotropic effects, such as antiapoptotic, anti-inflammatory, antioxidant, and cardioprotective activities. Cilostazol also can inhibit the adenosine uptake, which enhances intracellular cAMP levels. In the lungs, elevated cAMP promotes anti-fibrotic, vasodilator, antiproliferative effects, as well as mitigating inflammatory events. Interestingly, a recent study evaluated antiplatelet FDA-approved drugs through molecular docking-based virtual screening on viral target proteins. This study revealed that cilostazol is a promising drug against COVID-19 by inhibiting both main protease (Mpro) and Spike glycoprotein, reinforcing its use as a promising therapeutic approach for COVID-19. Considering the complexity associated to COVID-19 pathophysiology and observing its main mechanisms, this article raises the hypothesis that cilostazol may act on important targets in development of the disease. This review highlights the importance of drug repurposing to address such an urgent clinical demand safely, effectively and at low cost, reinforcing the main pharmacological actions, to support the hypothesis that a multi-target drug such as cilostazol could play an important role in the treatment of COVID-19.

Literature review and meta-analysis of the efficacy of cilostazol on limb salvage rates after infrainguinal endovascular and open revascularization.

BACKGROUND: Current clinical guidelines recommend the use of cilostazol in the treatment of patients with infrainguinal peripheral artery disease (PAD) who experience intermittent claudication. However, the role of cilostazol therapy in patients with advanced PAD and critical limb ischemia (CLI) remains unclear. To conduct a meta-analysis of randomized controlled trials and cohort studies that evaluated the effect of cilostazol vs standard antiplatelet therapy on limb-related and arterial patency-related outcomes. We also reviewed literature pertinent to the effect of cilostazol on wound healing in patients with advanced PAD. METHODS: We performed a MEDLINE, EMBASE, COCHRANE (CENTRAL), SCOPUS, and US Clinical Trials database search for all trials and studies since 1999 that compared cilostazol with standard antiplatelet therapy in the setting of infrainguinal PAD revascularization procedures (endovascular or open). Aggregate data was collected from four randomized control trials and six retrospective cohort studies. The end point incidence ratios and treatment effects were generated from each study and reported as hazard ratios (HR) using a random-effect model. We also reviewed 10 studies that evaluated the effect of cilostazol on wound healing in patients with advanced PAD. RESULTS: From more than 25,000 total patients, 3136 patients met our inclusion criteria. All patients had at least lifestyle-impacting intermittent claudication, and more than 50% met the definition of CLI (Rutherford class ≥4). Patient age range was 53 to 83 years, and the majority were male (66%). The mean follow-up time averaged 2 years across all studies. Meta-analysis revealed that cilostazol treatment favored amputation-free survival (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.69-0.91), limb salvage rate (HR, 0.42; 95% CI, 0.27-0.66), decreased repeat revascularization (risk ratio [RR], 0.44; 95% CI, 0.37-0.52), and decreased restenosis (RR, 0.68; 95% CI, 0.61-0.76). Cilostazol treatment also increased freedom from target lesion revascularization (RR, 1.35; 95% CI, 1.21-1.53) with no difference in all-cause mortality. Effective wound healing was found to be an inconsistent outcome measure in patients receiving cilostazol therapy. CONCLUSIONS: We observed that cilostazol therapy has a beneficial impact on all limb-related and arterial patency-related outcomes, but no effect on all-cause mortality in patients with advanced PAD and CLI undergoing revascularization procedures. Additional studies are needed to evaluate the effect of cilostazol therapy on wound healing in patients with advanced PAD.

Pretreatment with a Phosphodiesterase-3 Inhibitor, Milrinone, Reduces Hepatic Ischemia-Reperfusion Injury, Minimizing Pericentral Zone-Based Liver and Small Intestinal Injury in Rats.

BACKGROUND Severe pericentral zone (zone 3)-based liver injury (LI) may become intractable, with allograft dysfunction after liver transplantation. The phosphodiesterase-3 inhibitor, milrinone, has been reported to attenuate hepatic ischemia-reperfusion injury (IRI). This study clarified how hepatic IRI involved zone 3-based LI, in which zone milrinone was effective, and whether milrinone could improve small intestinal injury (SII) with hepatic IRI. MATERIAL AND METHODS Rats were divided into sham, ischemia-reperfusion (IR), or IR+milrinone groups (n=13 per group). Milrinone was administered intraportally via intrasplenic injection, and whole hepatic ischemia was induced for 30 min. Five hours after reperfusion, serum chemistry and histopathological findings were compared. Expression of CD34 for the detection of altered sinusoidal endothelium as sinusoidal capillarization and cleaved caspase-3 as an apoptosis marker were analyzed via immunohistochemistry. Survival rates were examined after 45 min of whole hepatic ischemia. RESULTS Serum aspartate aminotransferase and direct bilirubin levels were significantly decreased in the IR+milrinone group compared with those of the IR group. The degree of LI, sinusoidal capillarization and apoptosis at zone 3 in the IR group was significantly increased compared with those at the periportal zone (zone 1). These findings at zone 3 in the IR group were improved in the IR+milrinone group. SII with villus congestion and apoptosis in the IR group was significantly attenuated in the IR+milrinone group. The 7-day survival rate was significantly elevated in the IR+milrinone group as compared with that of the IR group. CONCLUSIONS A hepatic IRI model caused zone 3-based LI and SII, which were attenuated by intraportal administration of milrinone.

Possible mechanisms mediating the protective effect of cilostazol in L-arginine induced acute pancreatitis in rats: role of cGMP, cAMP, and HO-1.

Acute pancreatitis (AP) is an inflammatory disorder with a high mortality rate. Cilostazol is a selective phosphodiesterase-3 inhibitor drug that is commonly used as an antiplatelet, antithrombotic, and vasodilator drug. It exhibits antioxidant, anti-inflammatory, and anti-apoptotic activities, but its effect on AP has not been fully elucidated yet. The present study aimed to investigate the effects of cilostazol on L-arginine-induced AP and the possible protective mechanisms. A rat model of AP was established by a single i.p. injection of 3-g/kg L-arginine on day 13 of the experiment. The treated groups received a single daily oral dose of either 100 or 300 mg/kg/day for 14 consecutive days. Rats with AP showed histopathological changes of pancreatic tissue injury together with increased serum amylase enzyme activity and decreased serum insulin, pancreatic adiponectin, and cGMP levels. Moreover, AP rats showed increased pancreatic inflammatory biomarker (TNF-α, VCAM-1, and MPO) levels with decreased anti-inflammatory IL-10 levels. In addition, oxidative stress biomarkers (MDA and NO) were increased in AP with decreased antioxidant SOD activity and GSH level. Moreover, HO-1 immunostaining was increased in the AP group. Cilostazol pretreatment reversed the histopathological change; decreased the amylase activity and the levels of TNF-α, VCAM-1, and MPO; and increased the levels of insulin, adiponectin, cGMP, cAMP, and IL-10. Moreover, cilostazol decreased MDA and NO but increased SOD and GSH. Lastly, cilostazol increased the HO-1 immunostaining more than in the AP group. These data suggest that cilostazol protects against L-arginine-induced AP, which may be related to an increase in cGMP, cAMP, and upregulation of HO-1 with subsequent anti-inflammatory and antioxidant properties.

Low-Dose Phosphodiesterase III Inhibitor Reduces the Vascular Amyloid Burden in Amyloid-ß Protein Precursor Transgenic Mice.

A previous study reported that relatively high-dose cilostazol (0.3%) promoted the drainage of cerebrovascular amyloid-ß (Aß) protein in Aß Precursor Protein (APP) transgenic mice overexpressing vasculotropic Aß. We investigated whether lower-dose cilostazol can decrease micro-hemorrhages and Aß deposition in the brain using APP transgenic mice. At baseline, 14-month-old female Tg2576 mice were randomly assigned to a control group (vehicle), aspirin group (0.01% aspirin), or cilostazol group (0.01% cilostazol). The severity of cerebral micro-hemorrhages (i.e., number), area of senile plaque, and severity of vascular amyloid burden (quantified with cerebral amyloid angiopathy (CAA) score (=number of Aß-positive vessels × severity of amyloid burden of Aß-positive vessels) were evaluated in the brain of mice aged 15 and 21-23 months. At 15 months, no differences were shown in each pathological change among the three groups. At 21-23 months, there were no differences in the severity of cerebral micro-hemorrhages or area of senile plaque among the three groups. However, the CAA score was significantly lower in the cilostazol compared to the control group (p = 0.046, Mann-Whitney U test), although no difference was seen between the control and aspirin group. Our study showed that lower-dose cilostazol could reduce the vascular amyloid burden without increasing cerebral micro-hemorrhages in APP transgenic mice.

Comparing the effects of milrinone and olprinone in patients with congestive heart failure.

Phosphodiesterase-3 (PDE3) inhibitors are widely used among patients with congestive heart failure (CHF). However, no studies have compared the cardiovascular outcomes between different PDE3 inhibitors in CHF management. In this report, we retrospectively compared the clinical benefits of two PDE3 inhibitors, milrinone and olprinone, to determine which better controls the progression of CHF. A total of 288 hospitalized patients who received PDE3 inhibitors [(milrinone; n = 77 and olprinone; n = 211, respectively)] for CHF were retrospectively enrolled. The primary endpoint was defined as having a major adverse cardiovascular and cerebrovascular event (MACCE) or cardiac death by day 60. Kaplan-Meier curves and multivariate Cox proportional models were used to compare the outcomes for patients treated with milrinone and olprinone. We found no significant differences in the baseline characteristics between the two groups. In patients treated with milrinone, a greater incidence of a MACCE or cardiac death was observed (log rank; P = 0.005 and P = 0.01, respectively). Milrinone-treated patients with ischemic heart disease and chronic kidney disease (CKD) at stage ≥ 4 presented with greater incidence of MACCE (log rank; P < 0.001 and P = 0.006, respectively). Similarly, these patients were significantly more likely to succumb to cardiac death (log rank; P < 0.001 and P = 0.02). Multivariate Cox proportional hazard models demonstrated that milrinone treatment was an independent predictor of MACCE [hazard ratio (HR) 3.17; 95% CI 1.64-6.10] and cardiac death (HR 2.64; 95% CI 1.42-4.91). Oral administration of a ß-blocker at discharge occurred more often in the olprinone-treated patients than in the milrinone-treated patients (63% vs. 29%, P = 0.004). We compared the outcomes of milrinone and olprinone treatment in patients with CHF. Those treated with milrinone were more likely to succumb to a MACCE or cardiac death within 60 days of treatment, which was especially true for patients with ischemic heart disease or CKD.