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CILOSTAZOL

Cilostazol is a medication that has been studied for various medical conditions across multiple clinical trials. As a phosphodiesterase type 3 (PDE3) inhibitor, it works by preventing the breakdown of cyclic adenosine monophosphate (cAMP), which leads to vasodilation (widening of blood vessels) and inhibition of platelet aggregation (preventing blood clots). This article examines how cilostazol has been investigated in clinical trials for different conditions, from cardiovascular diseases to reproductive health and neurological disorders. Understanding these research efforts can provide valuable insights into the potential therapeutic applications of this medication.

Table of Contents

What is Cilostazol?

Cilostazol is a medication primarily used to treat the symptoms of intermittent claudication, which is a type of leg pain caused by poor blood circulation during walking or exercise. It belongs to a class of drugs known as phosphodiesterase inhibitors. The drug is marketed under various brand names including Pletal and Pletaal[1].

Cilostazol works by improving blood flow in the legs and reducing blood clotting. It helps widen blood vessels and prevents platelets (a type of blood cell) from sticking together and forming clots[2].

How Does Cilostazol Work?

Cilostazol is a selective inhibitor of phosphodiesterase type 3 (PDE3). This enzyme normally breaks down cyclic adenosine monophosphate (cAMP), an important cellular signaling molecule. By inhibiting PDE3, cilostazol increases the amount of cAMP in blood vessels and platelets[2].

The increased cAMP levels result in several important effects:

  • Vasodilation: Cilostazol causes blood vessels to widen, which improves blood flow[3].
  • Inhibition of platelet aggregation: The drug prevents platelets from clumping together, reducing the risk of blood clots[4].
  • Improvement in blood lipid levels: Cilostazol can decrease triglyceride levels and increase HDL (good) cholesterol levels[2].

Medical Uses

Cilostazol has been approved and studied for various medical conditions, primarily related to blood vessel and circulation problems:

Peripheral Artery Disease and Intermittent Claudication

The primary FDA-approved use of cilostazol is for the treatment of intermittent claudication symptoms in people with peripheral arterial disease (PAD). PAD is a condition where narrowed arteries reduce blood flow to the limbs, usually the legs[5].

Intermittent claudication causes pain, cramping, or aching in the calves, thighs, or buttocks during walking or exercise, which typically subsides with rest. Cilostazol helps to increase walking distance and reduce claudication symptoms in these patients[5].

Research has shown that cilostazol is also effective in preventing restenosis (re-narrowing of blood vessels) after endovascular procedures such as angioplasty or stent placement in peripheral arteries. Several studies conducted in Japan demonstrated that cilostazol improves patency (openness) of treated blood vessels following these interventions[6].

Stroke Prevention and Treatment

Cilostazol has shown promising results in preventing the recurrence of cerebral infarction (ischemic stroke). In the Cilostazol Stroke Prevention Study, a double-blind, placebo-controlled trial, cilostazol was assessed for its long-term safety and efficacy in preventing the recurrence of cerebral infarction in patients who had suffered a stroke 1 to 6 months prior to entering the trial[7].

Studies have also examined cilostazol’s effectiveness in treating symptomatic intracranial arterial stenosis (narrowing of arteries inside the brain), which is a major cause of stroke. Research has compared cilostazol to other antiplatelet medications like clopidogrel for preventing the progression of this condition[8].

Additionally, cilostazol has been studied for use in acute minor stroke and transient ischemic attack (TIA), comparing its effectiveness when combined with aspirin versus other antiplatelet combinations[9].

Heart and Blood Vessel Conditions

Cilostazol has been investigated for its effects on various heart and blood vessel conditions:

  • Carotid artery stenting: Research suggests that cilostazol may reduce in-stent restenosis following carotid artery stenting procedures, which are performed to open narrowed carotid arteries (the main blood vessels that supply blood to the brain)[10].
  • Coronary artery disease: Studies have examined cilostazol’s effects when added to standard antiplatelet therapy after drug-eluting stent implantation in coronary arteries[11].
  • Vasospastic angina: Cilostazol has been studied for treating vasospastic angina, a type of chest pain caused by spasm of the coronary arteries[12].

Potential Emerging Uses

Ongoing research is exploring several other potential uses for cilostazol:

  • Diabetic polyneuropathy: Some studies are investigating cilostazol’s effectiveness in treating nerve damage caused by diabetes[13].
  • Tinnitus: Research has examined whether cilostazol can improve chronic tinnitus (ringing in the ears) by enhancing blood flow to the inner ear[14].
  • Raynaud’s phenomenon: Cilostazol has been studied for treating Raynaud’s phenomenon, a condition where blood vessels in the fingers and toes spasm in response to cold or stress[15].
  • Alzheimer’s disease: Some research is exploring cilostazol’s potential for treating Alzheimer’s disease, particularly in patients with subcortical white matter hyperintensities (areas of damage in the brain’s white matter)[16].
  • Cerebral small vessel disease: Studies are investigating whether cilostazol can slow the progression of cerebral small vessel disease, which increases the risk of stroke and dementia[17].
  • Contraception: Interestingly, cilostazol has been studied for its potential as a non-hormonal contraceptive method. Research has explored its effects on human oocyte (egg cell) maturation[2].

Dosage and Administration

Cilostazol is typically taken orally in tablet form. The standard dosage for adults is usually 100 mg twice daily, taken at least 30 minutes before or 2 hours after breakfast and dinner. This timing is important because food, especially high-fat meals, can increase the absorption of cilostazol[2].

For some patients, particularly those taking medications that may interact with cilostazol or those with certain health conditions, a lower dose of 50 mg twice daily may be recommended[17].

It’s important to note that the full beneficial effects of cilostazol may take 2-4 weeks or longer to become noticeable[5].

Side Effects

Common side effects of cilostazol may include:

  • Headache
  • Diarrhea
  • Abnormal stools
  • Increased heart rate (tachycardia)
  • Palpitations
  • Dizziness
  • Nausea

Most of these side effects are mild to moderate and often improve as your body adjusts to the medication[5][12].

More serious but less common side effects may include:

  • Significant drop in blood pressure
  • Bleeding complications
  • Heart rhythm abnormalities
  • Severe headaches

Cilostazol should not be used in patients with heart failure, as PDE3 inhibitors have been associated with increased mortality in these patients[2].

Drug Interactions

Cilostazol may interact with various medications, including:

  • Other antiplatelet drugs or anticoagulants: Combining cilostazol with aspirin, clopidogrel, or blood thinners may increase the risk of bleeding[4].
  • CYP3A4 and CYP2C19 inhibitors: Medications that inhibit these liver enzymes can increase cilostazol levels in the blood. These include certain antibiotics, antifungals, and grapefruit juice[2].
  • Statins: Some interactions with cholesterol-lowering medications have been reported[18].

Always inform your healthcare provider about all medications, supplements, and herbal products you are taking before starting cilostazol[2].

Special Populations

Elderly Patients

Older adults may be more sensitive to the side effects of cilostazol, particularly dizziness or heart-related effects. Careful monitoring may be needed[5].

Patients with Kidney or Liver Problems

Dosage adjustments may be necessary for patients with kidney or liver impairment, as these conditions can affect how the body processes cilostazol[2].

Pregnant or Breastfeeding Women

The safety of cilostazol during pregnancy and breastfeeding has not been well established. Animal studies have shown some potential risks. Women who are pregnant, planning to become pregnant, or breastfeeding should discuss the potential risks and benefits with their healthcare provider[2].

Ongoing Research

Several clinical trials are currently underway to explore additional uses and effects of cilostazol:

  • Comparing cilostazol to clopidogrel in type 2 diabetes patients with carotid atherosclerosis[19].
  • Evaluating cilostazol’s effect on wound healing in diabetic foot ulcer patients[20].
  • Assessing cilostazol versus aspirin in acute non-cardioembolic stroke patients with cerebral microbleeds[21].
  • Investigating cilostazol’s potential for preventing dementia compared to other medications[22].

These ongoing studies may expand our understanding of cilostazol’s therapeutic potential and lead to new approved uses in the future.

Clinical Application Trial Information Key Findings/Objectives
Contraception Cilostazol’s effects on human oocyte maturation Investigating whether cilostazol can impair egg maturation following ovarian follicle stimulation as a potential non-hormonal contraceptive method. Based on evidence that high cAMP levels inhibit resumption of meiosis in oocytes.
Peripheral Arterial Disease Cilostazol After Lower Extremity Arterial Revascularization Trial (CLEAR) Evaluating the impact of cilostazol 100mg twice daily on quality of life after peripheral revascularization. Secondary outcomes included graft patency and cardiovascular events.
Carotid Artery Stenosis Carotid Artery Stenting With Cilostazol Addition for Restenosis (CAS-CARE) Multi-center study of cilostazol’s effect on preventing in-stent restenosis following carotid artery stenting, with a primary endpoint of restenosis within 2 years.
Drug Interactions Interactions of Clopidogrel and Cilostazol in Healthy Volunteers Examining how genetic polymorphisms affect pharmacokinetic and pharmacodynamic interactions between these two medications.
Diabetic Neuropathy Asian Study on Cilostazol Effectivity in Neuropathies of Diabetes Mellitus Evaluating changes in subjective, objective, and electrophysiologic parameters of diabetic polyneuropathies after cilostazol therapy.
Vasospastic Angina Safety and Efficacy Study of Cilostazol to Treat Vasospastic Angina One-group, open-label study to evaluate safety and efficacy of cilostazol for 24 weeks in patients with vasospastic angina.
Cerebral Small Vessel Disease Retina is a Marker for Cerebrovascular Heath Investigating whether cilostazol can slow progression of cerebral small vessel disease, with outcomes including white matter disease volume and cognitive function.
Stroke Prevention Cilostazol Stroke Prevention Study Double-blind, placebo-controlled trial assessing long-term safety and efficacy in preventing recurrent cerebral infarction.
Raynaud’s Phenomenon Safety and Efficacy for Juvenile Primary and Secondary Raynaud’s Testing cilostazol’s ability to lessen severity of symptoms and decrease number of Raynaud’s episodes in juvenile patients.
Alzheimer’s Disease Cilostazol Augmentation Study in Dementia (CASID) Examining the effects of cilostazol augmentation in mild to moderate Alzheimer’s disease patients with subcortical white matter hyperintensities already treated with donepezil.
Tinnitus Effect of Cilostazol in Patients With Chronic Tinnitus Randomized, double-blind pilot study evaluating if cilostazol improves subjective symptoms of chronic tinnitus through increased blood flow to cochlear cells.
Diabetic Foot Ulcers Impact of Cilostazol Versus Cilostazol and Selenium Combination Comparing standard care, cilostazol alone, and cilostazol with selenium for healing diabetic foot ulcers.

FAQ

  • What is cilostazol and how does it work? Cilostazol is a medication that belongs to a class of drugs called phosphodiesterase type 3 (PDE3) inhibitors. It works by preventing the breakdown of cyclic adenosine monophosphate (cAMP), which increases the active form of protein kinase A (PKA). This leads to two main effects: vasodilation (widening of blood vessels) and inhibition of platelet aggregation (preventing blood clots). These actions improve blood flow to various tissues and prevent blood clot formation, which explains why cilostazol is used in conditions involving poor circulation or risk of clotting.
  • What medical conditions has cilostazol been studied for in clinical trials? Clinical trials have investigated cilostazol for a wide range of conditions. These include peripheral artery disease (specifically for intermittent claudication or leg pain when walking), stroke prevention, carotid artery stenosis, coronary artery disease, diabetic complications, tinnitus, and even as a potential non-hormonal contraceptive. Research has also examined its potential benefits in Alzheimer's dementia, cerebral small vessel disease, vasospastic angina, diabetic foot ulcers, and Raynaud's phenomenon. This diversity of applications reflects cilostazol's effects on blood flow and clotting mechanisms.
  • How effective is cilostazol for stroke prevention compared to other medications? Several clinical trials have compared cilostazol to other antiplatelet medications for stroke prevention. The Cilostazol Stroke Prevention Study was a double-blind, placebo-controlled trial that assessed cilostazol's long-term safety and efficacy in preventing recurrent cerebral infarction. Other studies have compared cilostazol to medications like aspirin and clopidogrel. For instance, one trial examined cilostazol plus aspirin versus clopidogrel plus aspirin in patients with minor ischemic stroke or transient ischemic attack. These studies suggest cilostazol may be effective for secondary stroke prevention, particularly in patients with specific risk factors like cerebral microbleeds, though effectiveness varies based on patient characteristics.
  • What are the common side effects of cilostazol observed in clinical trials? Clinical trials have documented several side effects associated with cilostazol. The most commonly reported ones include headache, diarrhea, dizziness, and heart palpitations or increased heart rate. Some patients also experience nausea, stomach discomfort, or weakness. Most side effects are related to the drug's vasodilatory effects. In some trials, these side effects led to discontinuation of the medication. Safety monitoring in clinical trials typically includes assessments of bleeding complications, which is important since cilostazol affects platelet function. However, compared to some other antiplatelet medications, cilostazol may have a lower risk of serious bleeding events.
  • What is one of the most surprising potential uses of cilostazol being studied? One of the most surprising potential uses of cilostazol being studied is as a non-hormonal contraceptive. Research has shown that cilostazol may affect oocyte (egg) maturation in women. In a clinical trial titled 'Cilostazol and Its Effects on Resumption of Meiosis in the Human Ovary,' researchers investigated whether cilostazol could impair egg maturation following ovarian follicle stimulation. This approach is based on findings that high concentrations of cAMP (which cilostazol helps maintain by inhibiting PDE3) can prevent eggs from maturing properly. This research could potentially lead to a new non-hormonal contraceptive option, which would be beneficial for women who experience side effects from hormonal contraceptives or have medical conditions that make hormonal options unsafe.

Ongoing Clinical Trials on CILOSTAZOL

  • Study on the Effects of Cilostazol on Headaches in Men and Women with Migraine Without Aura

    Recruiting

    1 1
    Investigated drugs:
    Denmark

  • Study of cilostazol and nimodipine combination to improve outcomes in patients with aneurysmal subarachnoid hemorrhage

    Recruiting

    1 1 1
    Investigated diseases:
    Investigated drugs:
    France

Glossary

  • Phosphodiesterase type 3 (PDE3) inhibitor: A class of medications that block the enzyme phosphodiesterase type 3, which normally breaks down cyclic adenosine monophosphate (cAMP). By inhibiting this enzyme, these drugs increase cAMP levels, leading to vasodilation and decreased platelet aggregation.
  • Cyclic adenosine monophosphate (cAMP): An important second messenger in many biological processes, including cell signaling. In the context of cilostazol, increased cAMP levels lead to blood vessel dilation and reduced platelet clumping.
  • Protein kinase A (PKA): An enzyme activated by cAMP that regulates numerous cellular processes. In blood vessels, PKA activation leads to relaxation of smooth muscle cells causing vasodilation. In platelets, it suppresses aggregation.
  • Peripheral artery disease (PAD): A circulatory condition where narrowed arteries reduce blood flow to the limbs, particularly the legs, causing symptoms like leg pain when walking (claudication).
  • Intermittent claudication: Pain, cramping, or aching in the calves, thighs, or buttocks that occurs during walking or exercise and is relieved by rest. It's a common symptom of peripheral artery disease.
  • Cerebral infarction: Also known as ischemic stroke, it occurs when blood flow to a part of the brain is blocked, leading to tissue damage and death in that area.
  • Carotid artery stenting (CAS): A procedure that opens narrowed carotid arteries (the main blood vessels carrying blood to the brain) using a small wire mesh tube called a stent.
  • In-stent restenosis: The recurrence of narrowing in a blood vessel after it has been treated with a stent. This happens due to tissue growth within or around the stent.
  • Ankle-Brachial Index (ABI): A test that compares blood pressure measured at the ankle with blood pressure measured at the arm to determine arterial blood flow to the legs and diagnose peripheral artery disease.
  • Cerebral small vessel disease: A condition affecting the small blood vessels in the brain, which can lead to stroke, cognitive impairment, and dementia.
  • White matter hyperintensities (WMHI): Areas of the brain that appear bright on certain types of MRI scans, indicating small vessel damage in the brain's white matter. They are associated with increased risk of stroke and cognitive decline.
  • Vasospastic angina: A type of chest pain caused by spasm of the coronary arteries rather than blockages, leading to temporary reduction in blood flow to the heart.
  • Oocyte maturation: The process by which an immature egg cell (oocyte) develops to become ready for fertilization. This involves resumption of meiosis, a type of cell division.
  • Germinal vesicle breakdown (GVBD): An early marker of oocyte maturation where the nucleus of the immature egg (called the germinal vesicle) breaks down as part of the process toward becoming a mature egg.
  • Transient ischemic attack (TIA): Often called a 'mini-stroke,' it's a temporary period of symptoms similar to a stroke that doesn't cause permanent damage. It's often a warning sign of future stroke risk.
  • Cerebral microbleeds: Small chronic brain hemorrhages that can be detected on specialized MRI sequences. They are markers of small vessel disease and may indicate higher risk for future brain bleeding.
  • Bioequivalence: The relationship between two preparations of the same drug in the same dosage form that have similar bioavailability and produce the same effect at the site of action.
  • Endothelial function: How well the inner lining of blood vessels (endothelium) works to control blood vessel relaxation and contraction, blood clotting, immune function, and platelet adhesion.
  • Flow-mediated dilation (FMD): A non-invasive method to assess endothelial function by measuring how a blood vessel dilates in response to increased blood flow.
  • Intima-media thickness (IMT): A measurement of the thickness of the inner two layers of the arterial wall, used as an indicator of atherosclerosis and cardiovascular risk.

References

  1. https://clinicaltrials.gov/study/NCT00773630
  2. https://clinicaltrials.gov/study/NCT01915069
  3. https://clinicaltrials.gov/study/NCT02374957
  4. https://clinicaltrials.gov/study/NCT01482117
  5. https://clinicaltrials.gov/study/NCT00912756
  6. https://clinicaltrials.gov/study/NCT02770274
  7. https://clinicaltrials.gov/study/NCT00766545
  8. https://clinicaltrials.gov/study/NCT00130039
  9. https://clinicaltrials.gov/study/NCT06522113
  10. https://clinicaltrials.gov/study/NCT01261234
  11. https://clinicaltrials.gov/study/NCT00776828
  12. https://clinicaltrials.gov/study/NCT02094469
  13. https://clinicaltrials.gov/study/NCT01076478
  14. https://clinicaltrials.gov/study/NCT01378650
  15. https://clinicaltrials.gov/study/NCT00048763
  16. https://clinicaltrials.gov/study/NCT01409564
  17. https://clinicaltrials.gov/study/NCT04753970
  18. https://clinicaltrials.gov/study/NCT00886574
  19. https://clinicaltrials.gov/study/NCT06402747
  20. https://clinicaltrials.gov/study/NCT06117436
  21. https://clinicaltrials.gov/study/NCT06530537
  22. https://clinicaltrials.gov/study/NCT05635370