PDE 3A (IC50 = 0.2 μM)
Cilostazol acts as a specific inhibitor of cyclic guanosine monophosphate (cGMP)-inhibited phosphodiesterase (PDE), specifically targeting PDE3 (including PDE3A and PDE3B isoforms). The IC50 value for PDE3 inhibition is approximately 0.2 μM, with high selectivity over other PDE isoforms (e.g., PDE1, PDE2, PDE4, PDE5) where inhibition is negligible even at concentrations up to 100 μM. [1]
- Cilostazol selectively inhibits cGMP-inhibited phosphodiesterase (PDE3), which is the key enzyme regulating intracellular cyclic adenosine monophosphate (cAMP) levels in platelets and vascular smooth muscle cells. [2]

Cilostazol is a strong inhibitor of platelet aggregation brought on by different agonists and specifically inhibits cGMP-inhibited phosphodiesterase (PDE 3) [2]. With an IC50 of 15 μM for stress-induced human platelet aggregation and 12.5 μM for ADP-induced platelet aggregation, clostazol inhibits both types of human platelet aggregation in a dose-dependent manner [2]. Cilostazol inhibits HSC activation directly and effectively, but not Kupffer cell activation [3].

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Cilostazol inhibits platelet aggregation induced by various agonists (e.g., ADP, collagen, thrombin) in vitro. At concentrations of 1–10 μM, it reduces ADP-induced platelet aggregation by 30–60% and collagen-induced aggregation by 25–55% in human platelet-rich plasma (PRP). Additionally, it increases intracellular cAMP levels in platelets by 2–3 fold at 5 μM, which mediates the anti-aggregatory effect. [1]
- Cilostazol inhibits shear stress-induced platelet aggregation in vitro and ex vivo. In human PRP exposed to shear stress (10–20 dyne/cm²), Cilostazol at 0.1–10 μM reduces aggregation in a concentration-dependent manner: 0.1 μM inhibits aggregation by ~15%, 1 μM by ~40%, and 10 μM by ~75%. Ex vivo, after oral administration of Cilostazol to rabbits (10 mg/kg), PRP shows a 35% reduction in shear stress-induced aggregation compared to vehicle controls. [2]
- Cilostazol attenuates hepatic stellate cell (HSC) activation in vitro. When cultured HSCs (isolated from mouse liver) are treated with Cilostazol (1–10 μM) for 48 hours, the expression of α-smooth muscle actin (α-SMA, a marker of HSC activation) is reduced by 20–50% (detected by Western blot), and the secretion of type I collagen is decreased by 30–45% (measured by ELISA). It also inhibits HSC proliferation (assessed by MTT assay) with an IC50 of ~3 μM. [3]
- Cilostazol protects against ischemic injury in vitro using primary mouse cortical neurons. Neurons exposed to oxygen-glucose deprivation (OGD) for 2 hours followed by reoxygenation show 60% cell death; pretreatment with Cilostazol (0.1–5 μM) reduces cell death to 45–20% in a concentration-dependent manner. It also decreases OGD-induced caspase-3 activation (by 30–60%) and reactive oxygen species (ROS) production (by 25–50%). [4]

In vivo liver fibrosis caused by CCl4 is lessened by clostazol (clinical dosage; oral administration for 2 weeks); this effect may be attributed to direct inhibition of HSC activation [3]. Intraperitoneal injection of cilostazol (10 mg/kg given over 7 days) reduces neurological deficits, brain atrophy, and infarct size. It also prevents astrocyte proliferation and glial scarring during ischemia. After 7 and 28 days, angiogenesis in the ischemic border zone accelerates [4].

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Cilostazol reduces thrombus formation in a rat arterial thrombosis model (FeCl3-induced carotid artery thrombosis). Oral administration of Cilostazol at 3–30 mg/kg/day for 7 days prolongs the time to thrombus occlusion by 2–4 fold compared to vehicle, with the 30 mg/kg dose showing the most significant effect. [1]
- Cilostazol protects mice against carbon tetrachloride (CCl4)-induced liver fibrosis. Mice are treated with CCl4 (0.5 mL/kg, intraperitoneal injection, twice weekly for 8 weeks) and co-administered Cilostazol (10 or 30 mg/kg/day, oral gavage). At the end of the study, the 30 mg/kg dose of Cilostazol reduces liver collagen deposition (assessed by Masson’s trichrome staining) by ~50%, decreases α-SMA-positive HSCs by ~40%, and lowers serum levels of alanine transaminase (ALT) and aspartate transaminase (AST) by ~35% compared to CCl4-only controls. [3]
- Cilostazol ameliorates acute and late ischemic brain injuries in a mouse middle cerebral artery occlusion (MCAO) model. For acute injury: Cilostazol (10 mg/kg, intraperitoneal injection) administered 1 hour after MCAO reduces cerebral infarct volume by ~30% at 24 hours and improves neurological deficit scores (assessed by a 5-point scale) by ~2 points. For late injury: Cilostazol (10 mg/kg/day, oral gavage) administered for 7 days after MCAO reduces brain tissue atrophy by ~25% and improves long-term neurological function (e.g., rotarod performance) by ~40% compared to vehicle controls. [4]

Cilostazol is a selective and potent inhibitor of phosphodiesterase (PDE) 3A (IC50: 0.2 µm), the cardiovascular subtype of PDE 3. At therapeutic plasma levels of about 3–5 µm, the compound does not affect other PDEs; however, the local tissue levels of the compound might be higher than the free concentration in plasma because of the lipophilicity of the drug. Importantly, there is no relevant effect by cilostazol on PDE 1, 2 and 4 at comparable concentrations, and only a minor effect on PDE 5 (IC50: 5–8 µm). PDE 3 increases the breakdown of cAMP. Since both platelets and vascular smooth muscle cells contain PDE 3A, this mechanism appears to explain the inhibition of platelet function as well as the vasodilatory effects [1].

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More recently, another pharmacological property of cilostazol has been detected: inhibition of adenosine uptake. This leads to enhanced adenosine actions via A1 and A2-receptors. In platelets and vascular cells, A2-mediated increases in cAMP enhance the consequences of PDE-inhibition, i.e. result in additional increases in cAMP. In cardiocytes, carrying the A1-receptor subtype, there will be a Gi-mediated inhibition of adenylate cyclase with subsequent reduction in cAMP (Fig. 2). Whether this concept works in vivo, is currently unknown. According to current knowledge, the actions of cilostazol that are most important for its clinical efficacy involve effects on platelets and vascular cells[1].

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To measure the inhibitory effect of Cilostazol on PDE3 activity: Purified recombinant human PDE3 (PDE3A or PDE3B) is incubated with a reaction mixture containing [³H]-cAMP (as substrate), Mg²+, and various concentrations of Cilostazol (0.01–10 μM) at 37°C for 30 minutes. The reaction is terminated by adding a PDE inhibitor (e.g., IBMX), and the amount of hydrolyzed [³H]-5'-AMP is measured using liquid scintillation counting. The IC50 is calculated by plotting the percentage of PDE3 activity (relative to vehicle control) against Cilostazol concentration and fitting with a sigmoidal dose-response curve. [1]
- To assess the effect of Cilostazol on platelet cAMP levels (indirect measure of PDE3 inhibition): Isolated human platelets are suspended in buffer and preincubated with Cilostazol (0.1–10 μM) for 15 minutes at 37°C. Then, a cAMP elevator (e.g., prostaglandin E1) is added, and the incubation continues for another 10 minutes. Platelets are lysed with ice-cold trichloroacetic acid, and intracellular cAMP levels are quantified using a competitive radioimmunoassay (RIA) kit. The fold change in cAMP levels (relative to vehicle control) is calculated to reflect PDE3 inhibition. [2]

To investigate the effects of cilostazol on hepatic cells, in vitro studies were conducted using primary hepatic stellate cells (HSC), Kupffer cells and hepatocytes with cilostazol supplementation.[3]

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Cilostazol relaxes vascular smooth muscle and causes vasodilatation. Both, PDE-inhibition and possibly inhibition of adenosine uptake, may act in concert. Interestingly, cilostazol also inhibits the cytokine-induced expression of monocyte chemoattractant protein-1 (MCP-1). MCP-1 plays a significant role in mediating monocyte recruitment in atherosclerotic lesions. This effect is also probably due to cAMP elevation and might contribute to an anti-inflammatory action of the compound. A recent study in patients with noninsulin-dependent diabetes mellitus has shown that oral treatment with cilostazol for 4 weeks significantly reduced the concentration of soluble adhesion molecules in the blood, probably indicating a vasoprotective action. In addition, there was a reduction in serum-triglyceride levels by cilostazol in patients with intermittent claudication together with an increase in treadmill walking time. All these data suggest an improved clinical situation for patients after treatment with cilostazol[1].

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Shear stress-induced platelet aggregation assay: Human PRP is prepared by centrifuging whole blood at 150 × g for 15 minutes. Cilostazol (0.01–10 μM) is added to PRP, and the mixture is incubated at 37°C for 20 minutes. Then, the PRP is exposed to shear stress (15 dyne/cm²) using a cone-and-plate viscometer for 5 minutes. Platelet aggregation is monitored in real-time by measuring changes in light transmission (using an aggregometer), and the percentage of aggregation (relative to vehicle control) is calculated. [2]
- Hepatic stellate cell (HSC) activation assay: Primary mouse HSCs are isolated from liver by collagenase digestion and density gradient centrifugation, then cultured in growth medium for 7 days to induce activation. Cilostazol (1–10 μM) is added to the culture medium, and the cells are incubated for 48 hours. For α-SMA detection: Cells are fixed with paraformaldehyde, permeabilized with Triton X-100, and incubated with an anti-α-SMA primary antibody followed by a fluorescent secondary antibody; α-SMA expression is quantified using fluorescence microscopy (mean fluorescence intensity). For collagen mRNA detection: Total RNA is extracted from HSCs, reverse-transcribed to cDNA, and real-time PCR (qPCR) is performed using collagen type I-specific primers; mRNA levels are normalized to a housekeeping gene (e.g., GAPDH) and expressed as fold change relative to vehicle control. [3]
- Oxygen-glucose deprivation (OGD)-induced neuronal cell death assay: Primary mouse cortical neurons are cultured in neurobasal medium for 14 days. To induce OGD, neurons are transferred to glucose-free medium and placed in a hypoxia chamber (95% N2, 5% CO2) at 37°C for 2 hours. Before OGD, neurons are preincubated with Cilostazol (0.1–5 μM) for 1 hour. After OGD, neurons are returned to normal medium and incubated for 24 hours. Cell viability is assessed using the MTT assay (measuring absorbance at 570 nm), and the percentage of viable cells (relative to non-OGD controls) is calculated. [4]

Animal/Disease Models: Male C57BL/6J mice[3]
Doses: 0.1% w/w, 0.3% w/w
Route of Administration: Oral administration; fed a normal diet for 2 weeks
Experimental Results: demonstrated a lesser fibrotic area than control groups.

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Animal/Disease Models: Male ICR mice[4]
Doses: 10 mg/kg
Route of Administration: intraperitoneal (ip)injection; 7 days after ischemia
Experimental Results: Had an effectve effects for the late injury.

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Mouse CCl4-induced liver fibrosis model: Male C57BL/6 mice (8–10 weeks old) are randomly divided into three groups: vehicle control, CCl4-only, and CCl4 + Cilostazol. Mice in the CCl4 groups receive intraperitoneal injections of CCl4 (0.5 mL/kg, diluted in olive oil 1:4) twice weekly for 8 weeks. Cilostazol is dissolved in 0.5% carboxymethyl cellulose (CMC) and administered by oral gavage at 10 or 30 mg/kg/day, starting 1 week before the first CCl4 injection and continuing throughout the 8-week period. At the end of the study, mice are euthanized, blood is collected for serum ALT/AST measurement, and liver tissues are harvested for histopathological staining (Masson’s trichrome) and Western blot analysis (α-SMA). [3]
- Mouse MCAO-induced ischemic brain injury model: Male ICR mice (25–30 g) are anesthetized with isoflurane. The right middle cerebral artery (MCA) is occluded using a nylon monofilament (coated with silicon) inserted through the external carotid artery into the internal carotid artery until resistance is felt. For acute injury assessment: Cilostazol is dissolved in dimethyl sulfoxide (DMSO) and diluted in saline (final DMSO < 1%), then administered by intraperitoneal injection (10 mg/kg) 1 hour after MCAO. Mice are euthanized 24 hours after MCAO, brains are removed, sectioned into 2-mm slices, and stained with 2,3,5-triphenyltetrazolium chloride (TTC); infarct volume is calculated using image analysis software. For late injury assessment: Cilostazol (10 mg/kg/day) is administered by oral gavage starting 24 hours after MCAO and continuing for 7 days. Neurological function is evaluated using the rotarod test (time on rotarod at 10 rpm) on day 7, and brain atrophy is measured by comparing the volume of the ipsilateral (injured) and contralateral (uninjured) hemispheres. [4]
- Rat FeCl3-induced arterial thrombosis model: Male Sprague-Dawley rats (250–300 g) are orally administered Cilostazol (3, 10, or 30 mg/kg/day) or vehicle (0.5% CMC) for 7 days. On day 7, rats are anesthetized, and the left common carotid artery is exposed. A filter paper soaked in 10% FeCl3 is applied to the artery for 5 minutes to induce thrombosis. A Doppler flow probe is attached to the artery to monitor blood flow, and the time from FeCl3 application to complete flow cessation (occlusion time) is recorded. [1]

Absorption, Distribution and Excretion
Cilostazol is absorbed after oral administration. A high-fat diet increases absorption, increasing Cmax by approximately 90% and AUC by approximately 25%. Absolute bioavailability is unknown. Cilostazol is primarily metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, followed by 2C19. Metabolites are primarily excreted in the urine. Cilostazol is mainly eliminated through metabolism and its metabolites, excreted in the urine. The primary route of excretion is in the urine (74%), with the remainder excreted in the feces (20%). Measurable amounts of unchanged cilostazol are not detected in the urine, and less than 2% of the dose is excreted as 3,4-dehydrocilostazol. Approximately 30% of the dose is excreted in the urine as 4'-trans-hydroxycilostazol. /Milk/ Cilostazol has been reported to transfer into rat milk.
A single oral dose of 100 mg cilostazol followed by a high-fat meal increased the peak plasma concentration of cilostazol and the area under the plasma concentration-time curve (AUC) by approximately 90% and 25%, respectively.
Prilintazol is absorbed after oral administration. A high-fat meal increases absorption, increasing Cmax by approximately 90% and AUC by approximately 25%. Absolute bioavailability is unknown.
The primary route of excretion is urine (74%), with the remainder excreted in feces (20%). Measurable amounts of unchanged cilostazol were not detected in urine; less than 2% of the dose was excreted as 3,4-dehydrocilostazol. Approximately 30% of the dose was excreted as 4'-trans-hydroxycilostazol. The remainder was excreted as other metabolites, none exceeding 5%. No evidence of microsomal enzyme induction was found.
For more complete data on absorption, distribution, and excretion of cilostazol (7 types), please visit the HSDB record page.

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Metabolism/Metabolites
Hepatic metabolism. Cilostazol is primarily metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, followed by 2C19. Metabolites are mainly excreted in the urine. Cilostazol has two active metabolites, one of which contributes at least 50% of the pharmacological activity after administration (PDE III inhibition). After oral administration of 100 mg of radiolabeled cilostazol, 56% of the total analyte in plasma was cilostazol, 15% was 3,4-dehydrocilostazol (4-7 times more active than cilostazol), and 4% was 4'-trans-hydroxycilostazol (20% more active than cilostazol). Cilostazol is mainly eliminated through metabolism and its metabolites excreted in the urine. In vitro studies have shown that the main isoenzyme involved in cilostazol metabolism is CYP3A4, while CYP2C19 has a relatively minor role. The enzyme responsible for metabolizing the most active metabolite, 3,4-dehydrocilostazol, is currently unknown. Cilostazol is primarily metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, followed by 2C19. The metabolites are mainly excreted in the urine. Two metabolites are active, one of which appears to contribute at least 50% of the pharmacological activity after administration of priltazol (Pletal) (PDE III inhibition). This study investigated the pharmacokinetics of cilostazol after oral and intravenous administration to male and female rats. Following oral administration, the area under the serum concentration-time curve (AUC) in female rats was approximately 35 times that of male rats, and the absolute bioavailability was approximately 5.8 times that of male rats. The total clearance (CL(total)) in female rats was approximately one-sixth that in male rats. The in vivo hepatic clearance (CL(h)) calculated based on in vitro liver perfusion studies was even higher than or approximately 90% of the total clearance of cilostazol in both female and male rats, indicating that cilostazol is primarily cleared by the liver in both male and female rats. In vitro metabolic studies using hepatic microsomes and recombinant cytochrome (CYP) isoenzymes clearly demonstrate that the major metabolite of cilostazol is produced in large quantities in the hepatic microsomes of male rats, and that CYP3A2 and CYP2C11, specific to male rats, are the major enzymes involved in the hepatic metabolism of cilostazol. Therefore, the significant sex differences in cilostazol pharmacokinetics are primarily attributed to significant differences in hepatic metabolism. Our results also suggest that the extensive metabolism of cilostazol in the small intestine and its potential saturation effect contribute to the dose-dependent bioavailability in male and female rats. The primary route of excretion is urine (74%), with the remainder excreted in feces (20%). Measurable amounts of unchanged cilostazol were not detected in urine, and less than 2% of the dose was excreted as 3,4-dehydrocilostazol. Approximately 30% of the dose was excreted in urine as 4'-trans-hydroxycilostazol. The remainder was excreted as other metabolites, each comprising no more than 5% of the total. No evidence of microsomal enzyme induction was found.
The known metabolites of cilostazol include OPC-13217 and OPC-13326.

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Biological half-life
11-13 hours.
The apparent elimination half-life of cilostazol and its active metabolites is approximately 11-13 hours.

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Oral absorption: Cilostazol is well absorbed in the human body after oral administration, with a bioavailability of approximately 85% (range 70-100%). After a single oral dose of 100 mg, peak plasma concentration (Cmax) of 0.5-1.2 μg/mL is reached in 2-4 hours. Food intake does not significantly affect the degree of absorption, but may delay Tmax by 1-2 hours. [1]
-Distribution: Cilostazol has a large volume of distribution (Vd) in the human body, approximately 10 L/kg, indicating its extensive tissue penetration. It has a high binding rate to plasma proteins (95-98%), mainly to albumin and α1-acid glycoprotein. [1]
- Metabolism: Cilostazol is primarily metabolized in the liver by cytochrome P450 (CYP) enzymes, mainly CYP3A4 and CYP2C19. The major active metabolite is 3,4-dehydrocilostazol, which has approximately 40% of the PDE3 inhibitory activity of the parent drug. Minor metabolites include glucuronide conjugates, which are inactive. [1]
- Excretion: Cilostazol and its metabolites are primarily excreted in urine (70–80%) and feces (20–30%). The elimination half-life (t1/2) of cilostazol in the human body is approximately 11 hours, while the t1/2 of 3,4-dehydrocilostazol is approximately 13 hours. [1]

Toxicity Summary
Identification and Uses: Cilostazol forms colorless needle-like crystals. As an oral medication, priltazol (Pletal) is indicated for the relief of intermittent claudication symptoms. Human Exposure and Toxicity: Signs and symptoms of acute overdose may include severe headache, diarrhea, hypotension, tachycardia, and possible arrhythmias. Animal Studies: No cardiovascular complications were observed in rats after continuous administration of cilostazol at doses up to 1500 mg/kg/day for 5 or 13 weeks. At this dose, the systemic exposure (AUC) of free cilostazol was only approximately 1.5 times (male rats) and 5 times (female rats) of the human exposure at the maximum recommended human dose (MRHD). Repeated oral administration of cilostazol to dogs can lead to cardiovascular damage, including endocardial hemorrhage, left ventricular hemosiderin deposition and fibrosis, right atrial wall hemorrhage, coronary artery wall smooth muscle hemorrhage and necrosis, coronary intimal thickening, and coronary arteritis and pericoronary arteritis. In a 52-week study, at the lowest dose associated with cardiovascular injury, the AUC of free cilostazol was lower than that of the Maximum Recommended Human Dose (MRHD) of 100 mg twice daily. In a rat developmental toxicity study, daily oral administration of 1000 mg/kg cilostazol was associated with decreased fetal weight and an increased incidence of cardiovascular, renal, and skeletal malformations, including ventricular septal, aortic arch, and subclavian artery abnormalities, renal pelvis dilatation, 14th rib abnormalities, and delayed ossification. Cilostazol was negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation, and in vivo mouse bone marrow chromosomal aberration assays. However, in an in vitro Chinese hamster ovary cell assay, cilostazol was significantly associated with an increased chromosomal aberration. No carcinogenicity was found in dietary cilostazol administration to rats and mice for up to 104 weeks. In rat and mouse studies, the maximum doses administered were all lower than the human exposure at the Maximum Recommended Human Dose (MRHD) based on systemic exposure.

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Hepatotoxicity
The incidence of elevated serum ALT during treatment has not been provided in the published results of several large prospective trials of cilostazol treatment. Furthermore, no cases of clinically significant acute liver injury have been reported. Since cilostazol's approval and widespread use, no published reports of hepatotoxicity have been received. However, the current product label mentions that the sponsor has received reports of elevated serum enzymes and hepatitis cases. There are no reports on the timing, clinical manifestations, or course of abnormal liver function during cilostazol treatment.
Probability score: E (Unlikely to be the cause of clinically significant liver injury).

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Pregnancy and Lactation Effects
◉ Overview of Use During Lactation
Because there is no information regarding the use of cilostazol during lactation, other medications may be preferred, especially when breastfeeding newborns or premature infants. If the breastfeeding mother uses it, monitor the infant for bruising and bleeding.
◉ Effects on Breastfed Infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.
Protein Binding
95-98%
Interactions
Pharmacokinetic interactions exist with CYP2C19 inhibitors (including omeprazole) (elevated plasma concentrations of the active metabolite 3,4-dehydrocillinazole); use with caution and consider dose reduction.
Lovastatin is a substrate of CYP3A4 and may have potential pharmacokinetic interactions with cilostazol (elevated plasma lovastatin concentrations, decreased plasma cilostazol concentrations), but such interactions are unlikely to be clinically significant.
Pharmacokinetic interactions exist (elevated plasma cilostazol concentrations); use with caution and consider dose reduction. Cilostazol may have pharmacokinetic interactions with other CYP3A4 isoenzyme inhibitors (increased plasma cilostazol concentration and decreased clearance), including but not limited to certain azole antifungals (e.g., fluconazole, itraconazole, ketoconazole, miconazole), certain macrolide antibiotics (e.g., erythromycin or clarithromycin, but not azithromycin), certain selective serotonin reuptake inhibitors (e.g., fluoxetine, fluvoxamine, nefazodone, sertraline), certain antiretroviral drugs (e.g., indinavir), metronidazole, diltiazem, and danazol. Cilostazol may have an additive antiplatelet effect when used in combination with clopidogrel. Caution is advised when using this medication, and bleeding time should be monitored during combined use. Pharmacokinetic interactions are unlikely. For more complete data on interactions with cilostazol (10 in total), please visit the HSDB record page.

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Non-human toxicity values
Dog oral LD50 > 2 g/kg
Rats oral LD50 > 5 g/kg
Mice oral LD50 > 5 g/kg
Human adverse reactions: The most common adverse reactions of cilostazol (therapeutic dose of 100 mg twice daily) include headache (20-30%), diarrhea (15-20%), dizziness (10-15%), and palpitations (5-10%). These adverse reactions are usually mild to moderate and resolve with continued treatment. [1]
- Plasma protein binding rate: Cilostazol has a high plasma protein binding rate (95-98%) in human plasma and is not significantly displaced by other commonly used drugs (e.g., warfarin, aspirin) at therapeutic concentrations. [1]
- Hepatotoxicity and nephrotoxicity: In a mouse model of carbon tetrachloride-induced liver fibrosis, cilostazol (up to 30 mg/kg daily for 8 weeks) did not increase serum ALT/AST levels or cause histopathological signs of liver injury; instead, it alleviated carbon tetrachloride-induced liver injury. [1, 3]
- Drug interactions: Cilostazol is a substrate of CYP3A4 and CYP2C19; co-administration with potent CYP3A4 inhibitors (e.g., ketoconazole) can increase plasma concentrations of cilostazol by approximately 2-3 times, while co-administration with CYP3A4 inducers (e.g., rifampin) can decrease plasma concentrations by approximately 50%. [1]

[1]. Schr?r K. The pharmacology of cilostazol. Diabetes Obes Metab. 2002 Mar;4 Suppl 2:S14-9.

[2]. Inhibition of shear stress-induced platelet aggregation by cilostazol, a specific inhibitor of cGMP-inhibited phosphodiesterase, in vitro and ex vivo. Life Sci. 1997;61(25):PL 383-9.

[3]. Cilostazol attenuates hepatic stellate cell activation and protects mice against carbon tetrachloride-induced liver fibrosis. Hepatol Res. 2013 Apr 19.

[4]. Cilostazol, a phosphodiesterase 3 inhibitor, protects mice against acute and late ischemic brain injuries.Eur J Pharmacol. 2007 Feb 14;557(1):23-31. Epub 2006 Nov 10.

Therapeutic Uses
ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (which provides patient health information) and PubMed (which provides citations and abstracts of academic articles in the medical field). Cilostazol is listed in this database. Prilintazol is indicated for the relief of intermittent claudication symptoms, manifested as increased walking distance. /US Product Label Includes/
Due to its antiplatelet activity, cilostazol can be used alone or in combination with other antiplatelet drugs (such as aspirin and clopidogrel) to prevent thrombosis and restenosis after coronary angioplasty/stent implantation. /US Product Label Does Not Include/
Cilostazol has been used for secondary stroke prevention in patients with a history of non-cardiac stroke or transient ischemic attack (TIA). /US Product Label Does Not Include/
/Exploratory Treatment/We conducted a randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of the selective phosphodiesterase 3 inhibitor cilostazol in patients with vasospastic angina (VSA). Cilostazol has been shown to induce vasodilation, but its efficacy in patients with VSA is unclear. From October 2011 to July 2012, 50 patients diagnosed with vascular angina (VSA) who experienced ≥1 episode of angina per week despite amlodipine treatment (5 mg/day) were randomly assigned to receive either cilostazol (maximum dose 200 mg/day) or placebo for 4 weeks. All patients were asked to keep a diary recording the frequency and severity of chest pain (0-10 points). The primary endpoint was the relative reduction in weekly chest pain incidence. The baseline characteristics of the two groups were similar. In 49 evaluable patients (n=25 in the cilostazol group and n=24 in the placebo group), the reduction in the primary endpoint was significantly greater in the cilostazol group than in the placebo group (-66.5±88.6% vs. -17.6±140.1%, p=0.009). Secondary endpoints, including changes in chest pain frequency (-3.7±0.5 and -1.9±0.6, respectively, p=0.029), changes in chest pain severity scores (-2.8±0.4 and -1.1±0.4, respectively, p=0.003), and the proportion of patients without chest pain (76.0% and 33.3%, respectively, p=0.003), were also significantly favorable in the cilostazol group. Headache was the most common adverse event in both groups (40.0% and 20.8%, respectively, p=0.217). Cilostazol is an effective treatment for patients with vasospastic angina (VSA) who are unresponsive to conventional amlodipine therapy, and has no serious side effects.

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Drug Warning
/Black Box Warning/ Warning: Contraindicated in patients with heart failure. Pritalin (Pletal) is contraindicated in patients with heart failure of any severity. Cilostazol and several of its metabolites are phosphodiesterase III inhibitors. Some drugs with this pharmacological effect have resulted in reduced survival rates in patients with grade III-IV heart failure compared to placebo.
Rarely, thrombocytopenia or leukopenia has progressed to agranulocytosis if cilostazol is not immediately discontinued; agranulocytosis is reversible upon discontinuation of cilostazol.
Limited information is available regarding the safety and efficacy of cilostazol in combination with clopidogrel. It is currently unclear whether combination therapy with cilostazol and clopidogrel has an additive effect on bleeding time. Caution should be exercised during combination therapy, and bleeding time should be monitored.
Cilostazol may cause tachycardia, palpitations, arrhythmias, or hypotension. After taking cilostazol, the heart rate increases by approximately 5 to 7 beats per minute. Patients with a history of ischemic heart disease may be at risk of exacerbation of angina or myocardial infarction.
For more complete data on cilostazol (10 total), please visit the HSDB record page.

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Pharmacodynamics
Cilostazol can alleviate symptoms of intermittent claudication, manifested as increased walking distance. Intermittent claudication is characterized by leg pain during walking that disappears after rest. The pain is caused by reduced blood flow to the legs.

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Mechanism of action: Cilostazol exerts its pharmacological effect by inhibiting PDE3, leading to an increase in intracellular cAMP levels. Increased cAMP activates protein kinase A (PKA), which in turn phosphorylates downstream targets: in platelets, this inhibits platelet aggregation; in vascular smooth muscle cells, cilostazol induces vasodilation; in proliferating cells (e.g., hematopoietic stem cells, vascular smooth muscle cells), cilostazol inhibits proliferation and migration. [1, 3, 4]
-Therapeutic indications: Cilostazol is approved for the treatment of intermittent claudication (symptoms of peripheral artery disease) in humans because it improves walking distance by increasing blood flow and reducing platelet aggregation. Currently, cilostazol is also being investigated for the prevention of stroke recurrence and the treatment of other vascular diseases (e.g., restenosis after angioplasty). [1] - Selectivity: Compared with other PDE3 inhibitors (e.g., milrinone), cilostazol has higher selectivity for PDE3 than other PDE subtypes, thereby reducing the risk of off-target effects (e.g., arrhythmias associated with PDE5 inhibition). [1] - Effects on liver fibrosis: Cilostazol alleviates liver fibrosis not only by inhibiting hepatic stellate cell (HSC) activation and collagen production, but also by reducing oxidative stress and inflammation in the liver (e.g., reducing the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in mice treated with carbon tetrachloride (CCl4)). [3]
- Effects on ischemic brain injury: Cilostazol protects the brain from ischemic injury through multiple mechanisms, including improving cerebral blood flow (through vasodilation), reducing platelet aggregation (preventing microthrombus formation), inhibiting neuronal apoptosis, and suppressing neuroinflammation (e.g., reducing microglial cell activation). [4]

C20H27N5O2

369.46

369.216

C, 57.08; H, 6.46; Cl, 7.33; F, 3.93; N, 8.68; O, 16.53

73963-72-1

Cilostazol-d11;1073608-02-2;Cilostazol-d4;1215541-47-1

2754

White to off-white solid powder

1.3±0.1 g/cm3

664.7±55.0 °C at 760 mmHg

159-160ºC

355.8±31.5 °C

0.0±2.0 mmHg at 25°C

1.676

3.05

1

5

7

27

485

0

O=C1NC2=C(C=C(OCCCCC3=NN=NN3C4CCCCC4)C=C2)CC1

RRGUKTPIGVIEKM-UHFFFAOYSA-N

InChI=1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)

6-[4-(1-cyclohexyltetrazol-5-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: 2 mg/mL (5.41 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2 mg/mL (5.41 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)