Cilostazol

Cilostazol is specific inhibition of cyclic nucleotide phosphodiesterase 3 (PDE3) with IC50 value of 200 nM.[1]
PDE3 is one of phosphodiesterase. PDE3 plays an important role in regulating vascular smooth muscle, heart muscle and platelet aggregation, so, it is clinically significant. The PDE3 family consists of two members including PDE3A and PDE3B. PDE3A is mainly related cardiovascular function and PDE3B is mainly related to lipolysis. The activity of PDE3 is regulated by phosphorylation pathways. PDE 3 is activited via phosphorylation at different phosphorylation sites by protein kinase A and protein kinase B. PDE3 enzymes also are involved in regulation of vascular and  cardiac smooth muscle contractility.
Cilostazol prevents platelet aggregation by specifically and selectively inhibiting PDE3 in platelets with IC50 value of 200 nM. Cilostazol also cause intracellular cAMP levels increasing by inhibiting adenosine uptake leading to increased adenosine levels in cells. Cilostazol also inhibits the expression of platelet surface P-selectin, platelet factor 4 (PF4), thromboxane B2 production release. Cilostazol also cause decrease in triglyceride levels and an increase in high-density lipoprotein. [1]
Cilostazol may has effective function in dementia. Cilostazol has beneficial effects on learning impairment induced by Aβ25-35 in mice. Cilostazol attenuated the impairment induced by Aβ25-35 at 100 mg/kg.[2]
References:
[1].    Rondina MT, Weyrich AS: Targeting phosphodiesterases in anti-platelet therapy. Handb Exp Pharmacol 2012(210):225-238.
[2].    Hiramatsu M, Takiguchi O, Nishiyama A, Mori H: Cilostazol prevents amyloid beta peptide(25-35)-induced memory impairment and oxidative stress in mice. Br J Pharmacol 2010, 161(8):1899-1912.

Efficacy of cilostazol-based dual antiplatelet treatment in patients undergoing carotid artery stenting.[Pubmed:28290236]

Neurol Res. 2017 Aug;39(8):695-701.

BACKGROUND: It is essential that patients undergoing carotid artery stenting (CAS) receive optimal antiplatelet inhibition. Although a reduction in platelet reactivity and improved clinical outcomes occur when using adjunctive Cilostazol with dual antiplatelet therapy, this can lead to an increased risk of hemorrhagic complications. Therefore, our current study examined patients undergoing CAS and evaluated the impact of Cilostazol-based dual antiplatelet treatment on the outcomes. METHODS: Between 2010 and 2015, 137 consecutive patients underwent CAS. From 2010 to 2011 (period 1), 28 patients underwent CAS in conjunction with aspirin and clopidogrel dual antiplatelet treatment (DAPT). From 2010 to 2013 (period 2), 44 patients underwent a preoperative assessment of their platelet function, with the clopidogrel-resistant patients receiving adjunctive Cilostazol in addition to the aspirin and clopidogrel. From 2013 to 2015 (period 3), 65 patients underwent CAS in conjunction with Cilostazol and clopidogrel treatment. In all patients, the incidence of new ipsilateral ischemic lesions observed by diffusion-weighted imaging on the day after CAS, and ischemic or hemorrhagic events occurring within 30 days were assessed. RESULTS: Clopidogrel resistance was identified in 43% of the patients in period 1, in 16% in period 2, and in 5% in period 3 (P < 0.001). The on-treatment platelet reactivity results indicated that the PRU value during Cilostazol-based DAPT was significantly lower than that observed for the standard DAPT (P < 0.05). New ipsilateral ischemic lesions decreased by 9% and 8% in periods 2 and 3, respectively, versus a 25% decrease in period 1 (P = 0.047). However, there were no significant differences noted for any of the hemorrhagic or thromboembolic events. CONCLUSIONS: Compared to the standard aspirin and clopidogrel dual antiplatelet therapy, Cilostazol-based dual antiplatelet treatment reduces the rate of clopidogrel resistance and suppresses new ischemic lesions without hemorrhagic complications.

Oral Administration of Cilostazol Increases Ocular Blood Flow in Patients with Diabetic Retinopathy.[Pubmed:28367040]

Korean J Ophthalmol. 2017 Apr;31(2):123-131.

PURPOSE: To investigate the effect of Cilostazol on ocular hemodynamics and to determine whether the administration of Cilostazol increases the ocular blood flow in patients with diabetic retinopathy. METHODS: This prospective observational study investigated the effect of orally administered Cilostazol on diabetic retinopathy. Before and after administration for 1 week, pulsatile ocular blood flow (POBF) and retrobulbar hemodynamics were measured using a POBF analyzer and transcranial Doppler imaging, respectively. Visual acuity, intraocular pressure, and blood pressure were also evaluated before and after treatment. RESULTS: Twenty-five eyes of 25 patients were included in this study. POBF increased significantly (16.8 +/- 4.6 microL/sec vs. 19.6 +/- 6.2 microL/sec, p < 0.001) after administration of Cilostazol, while no significant change was identified in visual acuity, intraocular pressure, and blood pressure. Mean flow velocity in the ophthalmic artery as measured with transcranial Doppler imaging also increased significantly after medication (23.5 +/- 5.6 cm/sec vs. 26.0 +/- 6.9 cm/sec, p = 0.001). The change in POBF directly correlated with the change in mean flow velocity (r = 0.419, p = 0.007). CONCLUSIONS: Cilostazol was effective in increasing ocular blood flow in patients with diabetic retinopathy, possibly by modulating retrobulbar circulation.

Comparison of three different types of cilostazol-loaded solid dispersion: Physicochemical characterization and pharmacokinetics in rats.[Pubmed:28324691]

Colloids Surf B Biointerfaces. 2017 Jun 1;154:89-95.

The aim of this research was to compare three different types of Cilostazol-loaded solid dispersion system including solvent-evaporated, solvent-wetted and surface-attached solid dispersion. The effect of polymers and surfactants on the aqueous solubility of Cilostazol was investigated, leading to the selection of polyvinylpyrrolidone (PVP) and sodium lauryl sulphate (SLS). Employing a spray-drying technique, numerous surface-attached, solvent-evaporated and solvent-wetted solid dispersions were prepared with various amounts PVP and SLS using water, 90% ethanol and acetone, respectively. Their physicochemical properties, solubility, dissolution and oral bioavailability in rats were assessed compared to the drug powder. Among each solid dispersion system tested, the surface-attached, solvent-evaporated and solvent-wetted solid dispersions composed of Cilostazol, PVP and SLS at weight ratios of 3.0 : 0.75 : 1.5, 3.0 : 3.0 : 1.5 and 3.0 : 3.0 : 1.5, respectively, provided the highest drug solubility and dissolution. The solvent-evaporated solid dispersion gave homogeneous and very small spherical particles, in which the drug was changed to an amorphous state. In the solvent-wetted solid dispersion, the amorphous drug was attached to the polymer surface. Conversely, in the surface-attached solid dispersion, the carriers were adhered onto the surface of the unchanged crystalline drug. The solubility, dissolution and oral bioavailability were significantly increased in the order of solvent-evaporated>solvent-wetted>surface-attached>drug powder. Thus, the type of solid dispersion considerably affected the physicochemical properties, aqueous solubility and oral bioavailability. Furthermore, the Cilostazol-loaded solvent-evaporated solid dispersion with the highest oral bioavailability would be actively recommended as a practical oral pharmaceutical product.

Effect of cilostazol in treating diabetes-associated microvascular complications.[Pubmed:28293857]

Endocrine. 2017 May;56(2):240-244.

PURPOSE: Cilostazol (Pletal), a phosphodiesterase-3 inhibitor, was approved in the United States in 1999 to reduce symptoms of intermittent claudication. Cyclic adenosine monophosphate levels increase from inhibition of phosphodiesterase resulting in anti-platelet, anti-inflammatory, and vasodilatory effects. Diabetes mellitus is a chronic disease that causes endothelial and platelet dysfunction leading to both microvascular and macrovascular complications. This mini-review highlights the emerging evidence suggesting benefits of using Cilostazol in treating microvascular complications associated with diabetes mellitus. METHODS: A review of literature was conducted using PubMed and Embase databases focusing on Cilostazol use in diabetes mellitus. RESULTS: Cilostazol demonstrated renoprotective effects in patients with diabetic nephropathy by reducing serum soluble adhesion molecule-1 and monocyte chemoattractant protein-1. Cilostazol's anti-inflammatory actions predictably attenuate glomerular damage from increased leukocyte adherence. Additionally, Cilostazol delayed renal dysfunction secondary to type 2 diabetes mellitus as albuminuria was reduced most likely resulting from inhibition of nuclear factor kappa-induced inflammatory and endothelial markers. Cilostazol's anti-inflammatory actions in addition to its vasodilatory actions relieved retinal hypoxia and decreased excessive production of retinal blood vessels suggesting benefit in diabetic retinopathy. Cilostazol did not improve neuropathy symptom scores signifying that it may not be as beneficial in patients with diabetic peripheral neuropathy without diabetic nephropathy or diabetic retinopathy. CONCLUSIONS: Cilostazol's pleiotropic effects may be beneficial in patients with type 2 diabetes mellitus and diabetic nephropathy. Additional, larger studies need to be conducted to assess the benefits and risks of using Cilostazol as an alternative agent in treating patients with diabetic microvascular complications.

The pharmacology of cilostazol.[Pubmed:12180353]

Diabetes Obes Metab. 2002 Mar;4 Suppl 2:S14-9.

Cilostazol (6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone; OPC-13013) is a 2-oxo-quinoline derivative with antithrombotic, vasodilator, antimitogenic and cardiotonic properties. The compound is a potent inhibitor of phosphodiesterase (PDE) 3A, the isoform of PDE 3 in the cardiovascular system (IC50: 0.2 microM). In addition, there is inhibition of adenosine uptake, eventually resulting in changes in cAMP levels, dependent on the type of adenosine receptors (A1 or A2). Cilostazol inhibits platelet aggregation and has considerable antithrombotic effects in vivo. The compound relaxes vascular smooth muscle and inhibits mitogenesis and migration of vascular smooth muscle cells. In the heart, Cilostazol causes positive inotropic and chronotropic effects. Most, if not all, of these actions are cAMP-mediated, including the modification of cAMP-controlled gene expression. Cilostazol decreases levels of serum triglycerides and causes some increase in HDL-cholesterol levels. The compound has a number of additional effects which might contribute to its overall clinical efficacy. Cilostazol undergoes intensive and finally complete hepatic metabolism via the cytochrome P450 systems. This might result in some drug interaction, i.e. with erythromycin and omeprazole. The half-life is approximately 10 h, resulting in about 2-fold accumulation of the drug during repeated administration.

General pharmacological properties of cilostazol, a new antithrombotic drug. Part I: Effects on the central nervous system.[Pubmed:4074429]

Arzneimittelforschung. 1985;35(7A):1157-62.

The pharmacological effects of the new platelet aggregation inhibitor Cilostazol (6-(4-(1-cyclohexyl-1 H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, OPC-13013) on the central nervous system were studied. Cilostazol had little effect on the general behavior of mice up to a dose of 1000 mg/kg p.o. and caused disappearance of pinna reflex, alertness and startle response and slight ptosis in only one of 6 rats at a dose of 1000 mg/kg p.o. Cilostazol had little effect on spontaneous movement and motor coordination in mice and did not potentiate hexobarbital-induced hypnosis, antagonize methamphetamine-induced hypermotor activity, cause muscle relaxation or have an anticonvulsant effect. Cilostazol did not affect normal body temperature but slightly antagonized reserpine-induced hypothermia at 300 mg/kg p.o. in mice. Cilostazol did not show an analgesic effect by Haffner's method, but it did slightly inhibit acetic acid-induced writhing at doses higher than 300 mg/kg p.o. in mice. The inhibitory effect was considered to be due to its peripheral effect. Cilostazol had little effect on discriminated avoidance response in rats, EEG arousal response in rabbits or spinal reflex in cats. However, it did slightly increase the slow wave until about 2 h after administration at 1000 mg/kg p.o., but the slow-wave sleep period did not tend to persist for a long period. These results suggest that Cilostazol had little effect on the central nervous system.

General pharmacological properties of cilostazol, a new antithrombotic drug. Part II: Effect on the peripheral organs.[Pubmed:3000392]

Arzneimittelforschung. 1985;35(7A):1163-72.

The pharmacological effects of the new antithrombotic drug, Cilostazol (6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-qui nolinone, OPC-13013) on the peripheral nervous system and miscellaneous organs were studied. Cilostazol produced a very slight increase in beating rate of the isolated atrium and a very slight increase in contraction of the papillary muscle of guinea pigs induced by Cilostazol compared with that of isoproterenol (isoprenaline). The beating rate increasing effect was not antagonized by propranolol and it augmented isoproterenol's effect. When administered intravenously in anesthetized dogs, Cilostazol increased blood flow in the coronary, internal carotid, vertebral and femoral arteries and transiently decreased blood flow in the renal and superior mesenteric arteries probably because of blood pressure fall. In anesthetized dogs, Cilostazol decreased blood pressure by reducing the resistance in the peripheral blood vessels. An increase in heart rate, cardiac contractile force, myocardial oxygen consumption and respiration rate were also observed. In conscious rats, the drug increased heart rate. Cilostazol produced a slight relaxation of the smooth muscle of all organs except for blood vessels and slightly inhibited spontaneous motility of the isolated uterus of pregnant rats, the isolated ileum of rabbits and the ileum of rats in situ. It was considered that Cilostazol had no specific effects against norepinephrine, serotonin, acetylcholine or histamine based on the results that the drug was only slightly antagonistic against the contraction of rabbit aorta induced by norepinephrine and serotonin, the contraction of isolated guinea-pig ileum induced by acetylcholine, histamine and barium chloride and the contraction of the isolated uterus of non-pregnant rats induced by oxytocin. The drug had little effect on the contraction of the nictitating membrane induced by stimulation of the preganglionic sympathetic nerve in the cat. These results suggest that Cilostazol had little effect on the autonomic nervous system. Cilostazol slightly inhibited edema induced by carrageenin, but showed no diuretic effect and had little effect on neuromuscular transmission or the secretion of gastric juice, bile and pancreatic juice, and therefore it was considered to have no appreciable effect on the peripheral nervous system or organs except for its vasodilating and cardiac effects.

Cilostazol (OPC 13013) is a potent and selective inhibitor of phosphodiesterase (PDE) 3A, the isoform of PDE 3 in the cardiovascular system, with an IC50 of 0.2 μM.

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