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Why Not Dipyridamole: a Review of Current Guidelines and Re-evaluation of Utility in the Modern Era.Cardiovascular Drugs and Therapy Jun 2022Dipyridamole is an old anti-platelet and coronary vasodilator agent that inhibits platelet phosphodiesterase and increases interstitial adenosine levels. Its use in... (Review)
Review
Dipyridamole is an old anti-platelet and coronary vasodilator agent that inhibits platelet phosphodiesterase and increases interstitial adenosine levels. Its use in coronary artery disease (CAD) has fallen out of practice in the modern era with the advent of new anti-platelet agents, and most modern guidelines on the management of CAD either neglect to comment on its utility or outright recommend against it. The majority of the studies used in these guidelines are outdated and took place in an era when high doses of aspirin were used and statins were not widely utilized. There is growing evidence in rat models of dipyridamole's synergy with statins through adenosine modulation resulting in significant myocardial protection against ischemia-reperfusion injury and limitation of infract size. The data in human studies are limited but show a similar potential synergy between dipyridamole and statins. It would thus be prudent to reconsider the recommendations against the use of dipyridamole in CAD and to re-evaluate its possible role and potential benefits through well-designed randomized trials combining it with statins, low-dose aspirin, and/or other anti-platelet agents.
Topics: Adenosine; Animals; Aspirin; Dipyridamole; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Rats; Vasodilator Agents
PubMed: 34245446
DOI: 10.1007/s10557-021-07224-9 -
British Journal of Clinical Pharmacology Oct 2011Inhibition of platelet aggregation can be achieved either by the blockade of membrane receptors or by interaction with intracellular signalling pathways. Cyclic... (Review)
Review
Inhibition of platelet aggregation can be achieved either by the blockade of membrane receptors or by interaction with intracellular signalling pathways. Cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) are two critical intracellular second messengers provided with strong inhibitory activity on fundamental platelet functions. Phosphodiesterases (PDEs), by catalysing the hydrolysis of cAMP and cGMP, limit the intracellular levels of cyclic nucleotides, thus regulating platelet function. The inhibition of PDEs may therefore exert a strong platelet inhibitory effect. Platelets possess three PDE isoforms (PDE2, PDE3 and PDE5), with different selectivity for cAMP and cGMP. Several nonselective or isoenzyme-selective PDE inhibitors have been developed, and some of them have entered clinical use as antiplatelet agents. This review focuses on the effect of PDE2, PDE3 and PDE5 inhibitors on platelet function and on the evidence for an antithrombotic action of some of them, and in particular of dipyridamole and cilostazol.
Topics: Blood Platelets; Cilostazol; Clinical Trials as Topic; Dipyridamole; Humans; Phosphodiesterase Inhibitors; Platelet Aggregation; Platelet Aggregation Inhibitors; Tetrazoles; Thrombosis
PubMed: 21649691
DOI: 10.1111/j.1365-2125.2011.04034.x -
Journal of Medicine and Life Sep 2022Dipyridamole is a platelet inhibitor with antithrombotic properties that can help prevent stroke recurrence. Twenty-eight male rats were divided randomly into four...
Dipyridamole is a platelet inhibitor with antithrombotic properties that can help prevent stroke recurrence. Twenty-eight male rats were divided randomly into four groups (7 rats in each group). Control group: rats received a natural diet and water. Normal saline group: rats received 0.9% normal saline for two weeks. Doxorubicin group (induced group): rats received 2.5 mg/kg three times a week for two weeks. Dipyridamole group (dipyridamole treated group): received dipyridamole (6 mg/kg/daily) orally for two weeks. Doxorubicin caused cardiotoxicity as indicated by a significant increase in tumor necrosis factor-α, interleukin-6, malondialdehyde, and caspase-3 level (P<0.05), while total antioxidant capacity and Bcl-2 levels were significantly reduced in cardiac tissues of rats in the doxorubicin group compared to the normal saline control group (P<0.05). Dipyridamole significantly ameliorates doxorubicin-induced cardiotoxicity, as suggested by a significant decrease in inflammatory markers (tumor necrosis factor-α and interleukin-6) (P<0.05). Moreover, the cardiac tissue level of oxidative marker malondialdehyde was significantly decreased (P<0.05), and total antioxidant capacity significantly increased in the dipyridamole group in comparison to the doxorubicin-only group (P<0.05). Dipyridamole exerted a significant heart-protective effect against doxorubicin-induced cardiotoxicity in rats, probably via interfering with oxidative stress, inflammatory response, and apoptotic pathway. The goal of this study was to investigate the potential protective effect of dipyridamole against doxorubicin-induced cardiotoxicity via interfering with pro-inflammatory, oxidative, and apoptotic pathways.
Topics: Male; Rats; Animals; Cardiotoxicity; Antioxidants; Dipyridamole; Tumor Necrosis Factor-alpha; Interleukin-6; Saline Solution; Myocardium; Apoptosis; Rats, Wistar; Doxorubicin; Malondialdehyde; Biomarkers
PubMed: 36415530
DOI: 10.25122/jml-2021-0199 -
Medicine Sep 2022Studies have shown aspirin decreases the risk of some cancers. However, the evidence reported the association between aspirin and cancer risk in the diabetic population....
Studies have shown aspirin decreases the risk of some cancers. However, the evidence reported the association between aspirin and cancer risk in the diabetic population. In this study, we investigate whether aspirin and dipyridamole decrease the risk of cancer in patients with type 2 diabetes. A total of 5308 patients with type 2 diabetes were identified by the National Health Insurance from 1998 to 2000 and followed up until 2013. The demographic characteristics among nondipyridamole nor aspirin, aspirin, and dipyridamole users were analyzed by using the χ(2) test. Cox proportional hazard regression models were used to determine the independent effects of no aspirin nor dipyridamole, aspirin, and dipyridamole users on the risk of different cancer. After adjustment with multiple covariates, both low and high doses of aspirin and dipyridamole decrease liver cancer with risk ratios of 0.56 (95% CI, 0.37-0.83), 0.14 (95% CI, 0.05-0.39), 0.61 (95% CI, 0.38-0.99), and 0.28 (95% CI, 0.12-0.66), respectively. Both low and high doses of aspirin decrease any types of cancer with risk ratios of 0.79 (95% CI, 0.64-0.98) and 0.49 (95% CI, 0.34-0.70), respectively. Therefore, we conclude aspirin may decrease any types of cancer and liver cancer, and dipyridamole may decrease the risk of liver cancer in patients with type 2 diabetes.
Topics: Aspirin; Carcinoma; Diabetes Mellitus, Type 2; Dipyridamole; Humans; Liver Neoplasms; Platelet Aggregation Inhibitors; Retrospective Studies; Taiwan
PubMed: 36123870
DOI: 10.1097/MD.0000000000030468 -
Stroke Jul 2019Background and Purpose- We assessed the efficacy and safety of antiplatelet agents after noncardioembolic stroke or transient ischemic attack and examined how these vary... (Meta-Analysis)
Meta-Analysis
Background and Purpose- We assessed the efficacy and safety of antiplatelet agents after noncardioembolic stroke or transient ischemic attack and examined how these vary according to patients' demographic and clinical characteristics. Methods- We did a network meta-analysis (NMA) of data from 6 randomized trials of the effects of commonly prescribed antiplatelet agents in the long-term (≥3 months) secondary prevention of noncardioembolic stroke or transient ischemic attack. Individual patient data from 43 112 patients were pooled and reanalyzed. Main outcomes were serious vascular events (nonfatal stroke, nonfatal myocardial infarction, or vascular death), major bleeding, and net clinical benefit (serious vascular event or major bleeding). Subgroup analyses were done according to age, sex, ethnicity, hypertension, qualifying diagnosis, type of vessel involved (large versus small vessel disease), and time from qualifying event to randomization. Results- Aspirin/dipyridamole combination (RR, 0.83; 95% CI, 0.74-0.94) significantly reduced the risk of vascular events compared with aspirin, as did clopidogrel (RR, 0.88; 95% CI, 0.78-0.98), and aspirin/clopidogrel combination (RR, 0.83; 95% CI, 0.71-0.96). Clopidogrel caused significantly less major bleeding and intracranial hemorrhage than aspirin, aspirin/dipyridamole combination, and aspirin/clopidogrel combination. Aspirin/clopidogrel combination caused significantly more major bleeding than aspirin, aspirin/dipyridamole combination, and clopidogrel. Net clinical benefit was similar for clopidogrel and aspirin/dipyridamole combination (RR, 0.99; 95% CI, 0.93-1.05). Subgroup analyses showed no heterogeneity of treatment effectiveness across prespecified subgroups. The excess risk of major bleeding associated with aspirin/clopidogrel combination compared with clopidogrel alone was higher in patients aged <65 years than it was in patients ≥65 years (RR, 3.9 versus 1.7). Conclusions- Results favor clopidogrel and aspirin/dipyridamole combination for long-term secondary prevention after noncardioembolic stroke or transient ischemic attack, regardless of patient characteristics. Aspirin/clopidogrel combination was associated with a significantly higher risk of major bleeding compared with other antiplatelet regimens.
Topics: Aged; Aged, 80 and over; Aspirin; Cerebrovascular Disorders; Clopidogrel; Dipyridamole; Drug Therapy, Combination; Female; Hemorrhage; Humans; Ischemic Attack, Transient; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Risk; Secondary Prevention; Stroke; Ticlopidine; Treatment Outcome
PubMed: 31177983
DOI: 10.1161/STROKEAHA.118.024497 -
Journal of Ocular Pharmacology and... Mar 2016Dipyridamole was introduced decades ago as a treatment for angina, subsequently found to inhibit platelet aggregation. It is most commonly used, and approved for use in... (Review)
Review
Dipyridamole was introduced decades ago as a treatment for angina, subsequently found to inhibit platelet aggregation. It is most commonly used, and approved for use in thromboembolism prevention, following surgery. Some of its recognized effects such as adenosine uptake inhibition, elevation of cAMP and cGMP levels, vasodilation, and tissue perfusion are important in various ocular disorders. For this reason, dipyridamole represents an interesting candidate as a therapeutic target for the treatment of eye disorders affecting different ocular structures. The aim of this article is to review the evidence and current understanding of the mechanisms by which dipyridamole exerts its effects on different ocular tissues, discuss the role of dipyridamole in clinical practice, and highlight areas of use and routes of administration.
Topics: Administration, Ophthalmic; Dipyridamole; Drug Administration Routes; Eye Diseases; Humans; Vasodilation; Vasodilator Agents
PubMed: 26696547
DOI: 10.1089/jop.2015.0128 -
Movement Disorders : Official Journal... Oct 2021New pharmacological targets are needed for restless legs syndrome. Preclinical data suggest that a hypoadenosinergic state plays an important pathogenetic role. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
New pharmacological targets are needed for restless legs syndrome. Preclinical data suggest that a hypoadenosinergic state plays an important pathogenetic role.
OBJECTIVE
The objective of this study was to determine whether inhibitors of equilibrative nucleoside transporters, for example, dipyridamole, could provide effective symptomatic treatment.
METHODS
A 2-week double-blind, placebo-controlled crossover study assessed the efficacy of dipyridamole (possible up-titration to 300 mg) in untreated patients with idiopathic restless legs syndrome. Multiple suggested immobilization tests and polysomnography were performed after each treatment phase. Severity was assessed weekly using the International Restless Legs Rating Scale, Clinical Global Impression, and the Medical Outcomes Study Sleep scale. The primary end point was therapeutic response.
RESULTS
Twenty-eight of 29 patients recruited were included. International Restless Legs Rating Scale scores improved from a mean ± standard deviation of 24.1 ± 3.1 at baseline to 11.1 ± 2.3 at the end of week 2, versus 23.7 ± 3.4 to 18.7 ± 3.2 under placebo (P < 0.001). Clinical Global Impression, Medical Outcomes Study Sleep, and Multiple Suggested Immobilization Test scores all improved (P < 0.001). The mean effective dose of dipyridamole was 217.8 ± 33.1 mg/d. Sleep variables improved. The mean periodic leg movement index at the end of treatment with dipyridamole was 8.2 ± 3.5 versus. 28.1 ± 6.7 under placebo. Side effects (dipyridamole vs placebo) included abdominal distension (18% vs. 7%), dizziness (10.7% vs 7.1%), diarrhea, and asthenia (each 7.1% vs 3.6%).
CONCLUSIONS
Dipyridamole has significant therapeutic effects on both sensory and motor symptoms of restless legs syndrome and on sleep. Our findings confirm the efficacy of dipyridamole in restless legs syndrome predicted from preclinical studies and support a key role of adenosine in restless legs syndrome. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Cross-Over Studies; Dipyridamole; Dopamine Agonists; Double-Blind Method; Humans; Polysomnography; Restless Legs Syndrome; Treatment Outcome
PubMed: 34137476
DOI: 10.1002/mds.28668 -
Handbook of Experimental Pharmacology 2012There are two primary modes of platelet inhibition: blockade of membrane receptors or neutralization of intracellular pathways. Both means of inhibition have proven... (Review)
Review
There are two primary modes of platelet inhibition: blockade of membrane receptors or neutralization of intracellular pathways. Both means of inhibition have proven benefits in the prevention and resolution of atherothrombotic events. With regard to intracellular inhibition, phosphodiesterases (PDEs) are fundamental for platelet function. Platelets possess several PDEs (PDE2, PDE3 and PDE5) that catalyze the hydrolysis of cyclic adenosine 3'-5'-monophosphate (cAMP) and cyclic guanosine 3'-5'-monophosphate (cGMP), thereby limiting the levels of intracellular nucleotides. PDE inhibitors, such as cilostazol and dipyridamole, dampen platelet function by increasing cAMP and cGMP levels. This review focuses on the roles of PDE inhibitors in modulating platelet function, with particular attention paid to drugs that have anti-platelet clinical indications.
Topics: Animals; Blood Platelets; Cilostazol; Dipyridamole; Humans; Phosphodiesterase Inhibitors; Platelet Aggregation Inhibitors; Tetrazoles
PubMed: 22918733
DOI: 10.1007/978-3-642-29423-5_9 -
Arteriosclerosis, Thrombosis, and... Mar 2008Dipyridamole (DP) is a phosphodiesterase inhibitor that increases the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate... (Review)
Review
Dipyridamole (DP) is a phosphodiesterase inhibitor that increases the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP) by preventing their conversion to AMP and GMP, respectively. By increasing cAMP and cGMP levels in platelets, DP reversibly inhibits platelet aggregation and platelet-mediated thrombotic disease. In addition, DP may potentiate some of the vascular protective effects of endothelium-derived nitric oxide (NO), which increases cGMP by stimulating soluble guanylyl cyclase. Endothelium-derived NO is an important regulator of vascular tone, blood flow, and tissue perfusion. Indeed, endothelial NO synthase-deficient (eNOS-/-) mice exhibit elevated systemic blood pressure and have larger myocardial and cerebral infarct size after ischemic injury. Other NO/cGMP-dependent effects that may be potentiated by DP include inhibition of vascular smooth muscle proliferation and prevention of endothelial-leukocyte interaction. In addition, DP increases local concentrations of adenosine and prostacyclin, which could affect vascular tone and inflammation. Finally, DP has antioxidant properties, which could stabilize platelet and vascular membranes as well as prevent the oxidation of low-density lipoprotein. These platelet and nonplatelet actions of DP may contribute to some of its therapeutic benefits in vascular disease.
Topics: Acute Coronary Syndrome; Animals; Cyclic AMP; Cyclic GMP; Dipyridamole; Disease Models, Animal; Endothelium, Vascular; Humans; Mice; Nitric Oxide; Oxidation-Reduction; Phosphodiesterase Inhibitors; Platelet Aggregation; Prognosis; Stroke; Survival Rate; Treatment Outcome
PubMed: 18174451
DOI: 10.1161/ATVBAHA.107.160226 -
American Heart Journal Feb 1988Dipyridamole cardiac imaging is a useful alternative technique to exercise stress testing in the evaluation of patients with ischemic heart disease. Intravenous... (Review)
Review
Dipyridamole cardiac imaging is a useful alternative technique to exercise stress testing in the evaluation of patients with ischemic heart disease. Intravenous dipyridamole is still in the investigational phase, while oral dipyridamole is widely available. The hemodynamic effects of dipyridamole include an increase in coronary blood flow (due to coronary vasodilation) which is in excess of the increase in myocardial oxygen consumption and cardiac output. The disparity in the increase in coronary blood flow relative to the cardiac output results in an increase in myocardial thallium activity and an increase in the myocardial/background activity ratio. The quality of the thallium images is better or similar to that of exercise thallium images. The optimal dose of intravenous dipyridamole is 0.56 mg/kg, and of the oral dose it is 300 to 400 mg, although higher doses may be necessary in some patients. Analysis of the thallium images has been to a large extent based on visual inspection of the planar images. Delayed images are helpful to establish the nature of the perfusion abnormalities (transient or fixed). The process of redistribution is based on disparate rates of washout from the normal and abnormal zones. The sensitivity and specificity of dipyridamole thallium imaging, whether intravenous or oral, have been shown in a number of studies to be quite adequate and comparable to that achieved during exercise thallium imaging. Dipyridamole two-dimensional echocardiography has also been used in the detection of coronary artery disease; transient (new or worsening of preexisting) wall motion abnormalities have been found to be a specific marker of coronary artery disease. Transmural as well as regional coronary steal phenomena have been postulated as the mechanism for dipyridamole-induced regional wall motion abnormalities. Compared to exercise two-dimensional echocardiography, dipyridamole echocardiography provides high-quality studies and in higher proportions of patients. The results of dipyridamole thallium imaging have also been extremely important in identifying high-risk patients after acute myocardial infarction or patients with peripheral vascular disease undergoing elective vascular surgery; the presence of a dipyridamole-induced perfusion abnormality identifies patients at high risk for future cardiac events. Thus, dipyridamole cardiac imaging is helpful in the diagnosis of coronary artery disease and in risk stratification.
Topics: Animals; Coronary Disease; Dipyridamole; Dogs; Echocardiography; Heart; Humans; Radionuclide Imaging; Thallium Radioisotopes
PubMed: 3277361
DOI: 10.1016/0002-8703(88)90492-9