Evaluation of the anticonvulsant activity of the phosphodiesterase III inhibitor cilostazol in the animal model of epilepsy

The present study is objected to evaluate the anticonvulsant activity of the phosphodiesterase III inhibitor cilostazol in the animal model of epilepsy. Conventional anti-epileptic rodent models like Maximal Electric Shock (MES)- induced convulsions and Pentylenetetrazol (PTZ) induced convulsions were used. The animals were randomly divided into six groups, with six rats in every group. Here anti-epileptic activity of cilostazol with two different doses (10 mg/kg i.p and 20 mg/kg i.p) was compared with standard drug and standard drug + Cilostazol two different doses (10 mg/kg i.p and 20 mg/kg i.p). Cilostazol (20 mg/kg i.p) exhibited an anticonvulsant effect in MES-induced and PTZ induced convulsion models over the Control group and cilostazol (10 mg/kg i.p). Standard drugs were shown superiority in seizure suppression activity than cilostazol (20 mg/kg i.p). The time duration of onset of clonic convulsion and period of clonic convulsions in PTZ induced convulsion were increased and decreased respectively when compared to Standard drug + cilostazol both doses and standard drug alone. Phenytoin abolished convulsions induced by MES- convulsion model. So the present study established that cilostazol has low anticonvulsant efficacy in comparison with conventional drugs (Phenytoin and Sodium Valproate). The potentiating effect of cilostazol with standard drugs was also demonstrated.

The Protective Effect of Cilostazol in Genotoxicity Induced by Methotrexate in Human Cultured Lymphocytes

Background: Methotrexate is an antagonist of folic acid that has been shown to be genotoxic to healthy body cells via induction of oxidative stress. Cilostazol is a phosphodiesterase III inhibitor and a potent antioxidant drug. Objectives: To evaluate the potential protective effect of cilostazol on methotrexate genotoxicity. Results: Methotrexate significantly increased the frequency of CAs and SCEs (p < 0.0001) as compared to control cultures. This chromosomal damage induced by methotrexate was considerably decreased by pretreatment of the cells with cilostazol (P < 0.01). Moreover, the results showed that methotrexate resulted in a notable reduction (P < 0.01) in cells kinetic parameters, the mitotic index (MI) and the proliferative index (PI). Similarly, cilostazol significantly reduced the mitotic index, which could be related to the anti-proliferative effect (P < 0.01). Conclusion: Methotrexate is genotoxic, and cilostazol could prevent the methotrexate-induced chromosomal damage with no modulation of methotrexate-induced cytotoxicity.

Is Milrinone Effective for Infants with Mild-to-Moderate Congenital Diaphragmatic Hernia?

Objective Pulmonary hypertension with left ventricular dysfunction commonly occurs in congenital diaphragmatic hernia (CDH). Milrinone, a phosphodiesterase-III inhibitor with lusitropic and vasodilator effects, is used in up to 30% of CDH infants across the United States. No randomized trials have tested the efficacy or safety of milrinone in CDH neonates. Study Design We performed a paired retrospective analysis of CDH infants to assess the efficacy of milrinone treatment (N = 24 pairs). Efficacy was assessed by change in oxygenation index (OI) and calculated pulmonary artery pressure (PAP). We evaluated safety on the basis of risks factors such as nonoperative bleeding, dysrhythmia, hypokalemia, and thrombocytopenia. Results The median age of milrinone initiation was 18 hours (interquartile range [IQR]: 9–38) and the median duration was 127 hours (IQR: 95–194). PAP did not change from the baseline of 49 ± 11 mm Hg (milrinone) and 53 ± 11 mm Hg (no milrinone; p = 0.327). Baseline OI was 9.6 ± 6.5. There was a similar decrease in OI (median [IQR]; milrinone: 58% [16–74]; vs. no milrinone: 65% [50–71]; p = 0.221 between groups; p < 0.005 within groups). Baseline left ventricle measurements were similar. Both groups showed significant improvement over time. No adverse events were noted. Conclusion In OI-matched untreated neonates with mild-to-moderate CDH, milrinone use was associated with neither improved OI, PAP, or left ventricular measurements, nor adverse events. Study limitations warrant prospective randomized controlled trials.

Positive inotropes

Inotropic agents are substances used to improve cardiac output and end-organ perfusion in severe forms of acute heart failure. However, inappropriate use of inotropic agents may be associated with severe adverse effects and death. Despite clear indications to restrict their use to acute heart failure patients presenting with signs of end-organ hypoperfusion, the current use of inotropes is very frequent and often unnecessary. This chapter reviews mechanisms of action of current and future inotropes (including catecholamines, phosphodiesterase-III inhibitors, calcium sensitizers, cardiac myosin activators, and istaroxime) and discusses their clinical use in acute heart failure.

Positive inotropes

Inotropic agents are substances used to improve cardiac output and end-organ perfusion in severe forms of acute heart failure. However, inappropriate use of inotropic agents may be associated with severe adverse effects and death. Despite clear indications to restrict their use to acute heart failure patients presenting with signs of end-organ hypoperfusion, the current use of inotropes is very frequent and often unnecessary. This chapter reviews mechanisms of action of current and future inotropes (including catecholamines, phosphodiesterase-III inhibitors, calcium sensitizers, cardiac myosin activators, and istaroxime) and discusses their clinical use in acute heart failure.

Abstract 17908: Milrinone Lacks Acute Inotropic And Lusitropic Effects Under Constant Afterload Conditions

Introduction: Phosphodiesterase III inhibitors are known to improve cardiac output in patients with heart failure. Whether this is due to a reduction in afterload, a positive inotropic effect, or an interaction of these factors is uncertain. We compared the inotropic and lusitropic effects of milrinone to those of commonly used catecholamines in a working Langendorff model under constant loading conditions. Methods: Sprague Dawley rats (n=35, 350-400 grams) were anesthetized and heparinized for cardiac explantation. The aorta and left atrium were immediately cannulated by a single experimenter. Left atrial pressure (10 mmHg) and aortic pressure (90 mmHg) were fixed. A conductance catheter (Millar) was inserted into the left ventricle. Following baseline measurements, infusions of milrinone, dopamine, dobutamine, epinephrine, or norephinephrine, alone and in commonly-used combinations, were initiated into the left atrium for 10 minute periods. Changes in cardiac output, contractility (dP/dTmax), diastolic performance (-dP/dT and Tau) relative to baseline were compared between groups by linear regression analysis. Results: Cardiac output increased in linear fashion for each of the catecholamines: Dobutamine>>Dopamine>Norepinephrine>Epinephrine (P<0.001 for each). Dobutamine, Norepinephrine, and Dopamine (P<0.05) significantly increased diastolic function, including negative dP/dT (C) and Tau (D), none of which were changed by Milrinone infusion. Conclusions: When afterload is fixed using a Starling resistor, milrinone at commonly used doses does not acutely change systolic or diastolic performance or cardiac output. It is possible that clinical improvements are due to milrinone’s vasodilatory properties.