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PubMed2003

Dipyridamole for preventing stroke and other vascular events in patients with vascular disease.

BACKGROUND: Patients with transient ischaemic attacks (TIA) and minor ischaemic strokes are at risk of serious vascular events (death from all vascular causes, non-fatal stroke, or non-fatal myocardial infarction). Their risk of vascular events lies between 4 and 11 percent per year. Aspirin only, in a daily dose of 30 mg or more, offers only modest protection in such patients: it reduces the incidence of major vascular events by 13 percent. In a single trial, adding dipyridamole (an alternative antiplatelet agent) to aspirin was associated with a 22 percent reduction in the risk of major vascular events compared with aspirin alone. However, a systematic review of all trials of antiplatelet agents by the Antithrombotic Trialists' Collaboration showed that, in high risk patients, there was virtually no difference between the aspirin-dipyridamole combination and aspirin alone. We therefore sought to assess the effects of dipyridamole in more detail. OBJECTIVES: 1) To assess the efficacy of dipyridamole versus control in the secondary prevention of vascular events in patients with vascular disease in the presence and absence of other antiplatelet drugs. 2) To assess the safety of dipyridamole versus control in the secondary prevention of vascular events in patients with vascular disease in the presence and absence of other antiplatelet drugs. SEARCH STRATEGY: The Cochrane Stroke Group Trials Register was searched and other relevant Cochrane Groups were contacted to search their specialised registers (last search 29 April 2002). In addition the Cochrane Controlled Trials Register, MEDLINE and EMBASE were searched and Dutch manufacturers of dipyridamole were contacted to identify further published and unpublished studies. SELECTION CRITERIA: Randomised long term secondary prevention trials with concealed treatment allocation, treatment for > 1 month, starting within 6 months after presentation of a arterial vascular disease were selected (coronary artery disease, myocardial infarction, angina pectoris, retinopathy, nephropathy, peripheral arterial disease, stroke, TIA, amaurosis fugax). Therapy consisted of dipyridamole in any dose in the presence or absence of other antiplatelet drugs compared with no drug or an antiplatelet drug(s) other than dipyridamole (control group). DATA COLLECTION AND ANALYSIS: Two reviewers selected trials which met the inclusion criteria and extracted details of randomisation methods, blinding of treatments and assessments, whether intention-to-treat analysis was possible from the published data, whether treatment groups were comparable with regard to major prognostic factors, the number of patients who were excluded or lost to follow-up, definition of outcome events, and entry and exclusion criteria. The methodological quality of each trial was assessed by the two reviewers on the basis of these extracted data. In addition, dose and type of antiplatelet treatments, duration of follow-up and the numbers of defined outcome events were recorded. Data published by the Antithrombotic Trialists' Collaboration were used. The remaining data were independently extracted by the same two reviewers and cross checked. Data were analysed according to the intention-to-treat principle. Relative and absolute risk reductions were calculated by means of the statistical software provided by the Cochrane Collaboration (RevMan). MAIN RESULTS: Twenty-six trials were included, with a total of 19842 patients, among whom 1399 vascular deaths and 3085 fatal and non-fatal vascular events occurred during follow-up. Compared with control, dipyridamole had no clear effect on vascular death (RR 1.02, 95% CI 0.90 to 1.17). This result was not influenced by the dose of dipyridamole or type of presenting vascular disease. Compared with control, dipyridamole appeared to reduce the risk of vascular events (RR 0.90, 95% CI 0.83 to 0.98), but this effect was only statistically significant due to a single large trial in patients presenting with cerebral ischaemia (6602 patients). Comparing dipyridamole plus aspirin with aspirin alone: there was no clear difference in vascular death, the RR was 1.03 (95% CI 0.87 to 1.22); the combination was associated with fewer vascular events with an RR of 0.90 (95% CI 0.80 to 1.00). Combination treatment of dipyridamole and aspirin compared with placebo had an RR of 0.89 (95% CI 0.79 to 1.01) for vascular death and an RR of 0.74 (95% CI 0.68 to 0.80) for vascular events. REVIEWER'S CONCLUSIONS: This review found that, for patients who presented with arterial vascular disease, there was no evidence that dipyridamole, in the presence or absence of an other antiplatelet drug (chiefly aspirin) reduced the risk of vascular death, though it may reduce the risk of further vascular events. However, this benefit was found in only a single large trial and only in patients presenting after cerebral ischaemia. There was no evidence that dipyridamole alone was more efficacious than aspirin. Further trials comparing the effects of the combination of dipyridamole with aspirin with aspirin alone are justified.

Anticoagulants↗

PubMed1996

Combined low dose dipyridamole-dobutamine stress echocardiography to identify myocardial viability.

OBJECTIVES: We sought to evaluate the effects of combined administration of infra-low dose dipyridamole and low dose dobutamine on assessment of myocardial viability. BACKGROUND: Low dose pharmacologic stress echocardiography with either dobutamine or dipyridamole infusion has been proposed for the recognition of myocardial viability. METHODS: Thirty-four patients with rest wall motion dyssynergy by two-dimensional echocardiography and with angiographically proved coronary artery disease underwent in combination with two-dimensional echocardiographic monitoring: 1) low dose (5 to 10 microgram/kg per min over 3 min) dobutamine infusion; 2) infra-low dose (0.28 mg/kg over 4 min) dipyridamole infusion; 3) combination of infra-low dose dipyridamole infusion immediately followed by low dose dobutamine infusion (combined dipyridamole-dobutamine). RESULTS: Follow-up rest echocardiography was available in 30 patients. After revascularization, 82 segments showed a contractile improvement of > or = 1 grade, whereas 63 segments remained unchanged. The sensitivity of dobutamine, dipyridamole and combined dipyridamole-dobutamine for predicting recovery was 72% (95% confidence interval [CI] 60.9% to 81.3%), 67% (CI 55.8% to 77%) and 94% (CI 86.3% to 97.9%), respectively. The specificity of dipyridamole, dobutamine and combined dipyridamole-dobutamine was 95% (CI 86.7% to 99%), 92% (CI 82.4% to 97.3%) and 89% (CI 78.4% to 95.4%), respectively. The accuracy of the dobutamine, dipyridamole and combined dipyridamole-dobutamine test was 80%, 79% and 92%, respectively (combined dipyridamole-dobutamine vs. dobutamine, p < 0.05; combined dipyridamole-dobutamine vs. dipyridamole, p < 0.01). CONCLUSIONS: Infra-low dose dipyridamole added to low dose dobutamine recruits an inotropic reserve in asynergic segments that were nonresponders after either dobutamine or dipyridamole alone and destined to recover after revascularization.

Adult↗

PubMed1994

[Adding atropine improves the diagnostic accuracy of dipyridamole-echo test].

BACKGROUND: The clinical experience with dipyridamole stress echocardiography for the diagnosis of coronary artery disease (CAD) revealed that patients with less severe extent of CAD and limited impairment of coronary reserve are frequently not recognized by the test. Increasing myocardial oxygen consumption adding atropine to dipyridamole may improve the diagnostic accuracy of dipyridamole for the detection of CAD. METHODS: Fifty-two patients (48 men, aged 53 +/- 7 years) underwent a high-dose dipyridamole-echo stress test (0.84 mg/kg over 10 minutes) and coronary arteriography within 15 days from the test. Eighteen out of 52 patients were referred for chest pain; 11 suffered from a previous myocardial infarction (MI) and 23 were studied in the early phase after a first acute MI. Starting after 4 minutes from the end of dipyridamole infusion, atropine was added, in 2 doses of 0.5 mg each, at 1-minute interval in those patients with no echocardiographic evidence of myocardial ischemia after dipyridamole alone. Left ventricular wall motion was analyzed on a 11-segment left ventricular model in a qualitative manner. RESULTS: Dipyridamole-echo stress test was positive in 23/52 (44%) and negative in 29/52 (56%) patients. In these patients atropine was added resulting in an additional echo positivity in 14/29 patients. Coronary arteriography was normal in 6 patients (12%); 1-vessel CAD was diagnosed in 23 (44%), 2-vessel CAD in 13 (25%) and 3-vessel CAD in 10 (19%) cases. The sensitivity for CAD diagnosis was 48% (22/46) for dipyridamole alone and 76% (35/46) for dipyridamole-atropine echo (p < .005), while the specificity was 83% (5/6) and 80% (4/5) respectively. Diagnostic accuracy increased from 52% (27/52) to 75% (39/52) (p < .001). The better diagnostic accuracy of dipyridamole-atropine echo stress test was mainly related to the increased sensitivity of the combined test in patients with 1-vessel CAD (from 39% to 70%) (p < .005). Peak heart rate was significantly higher after the addition of atropine (100 +/- 17 beats/min) compared to basal (64 +/- 10) and dipyridamole (85 +/- 12) in those patients with a positive dipyridamole-atropine echo stress test. No limiting side effects were elicited with the addition of atropine to dipyridamole. CONCLUSIONS: The combination of atropine and dipyridamole induces a chronotropic stress adjunctive to flow maldistribution phenomena that permits to increase diagnostic accuracy of dipyridamole-echo stress test particularly in patients with less severe extent of CAD; it is usually well tolerated and safe and may be considered as a useful procedure for optimizing diagnostic value of dipyridamole-echo stress test.

Aged↗

PubMed1992

Dipyridamole echocardiography.

Intravenous dipyridamole is a potent coronary vasodilator that has been extensively investigated over the past several years in the noninvasive assessment of patients with suspected coronary artery disease when exercise cannot be performed or is suboptimal. As an alternative to exercise studies, dipyridamole has been used in combination with different cardiac imaging techniques such as echocardiography, thallium scintigraphy, and radionuclide ventriculography. Extensive experience has been obtained with dipyridamole thallium-201 imaging for coronary artery disease screening, risk stratification, and prognosis after an acute coronary event. However, experience with the use of dipyridamole in combination with two-dimensional echocardiography has been limited. Dipyridamole increases coronary blood flow in nondiseased coronary vessels relative to coronary vessels with significant luminal narrowings. These provide the basis for detecting regional differences in flow by using different cardiac imaging techniques. Two-dimensional echocardiography would show regional wall-motion abnormalities in response to those regional differences in coronary blood flow. In this article, the most commonly used protocols, safety, and practicability of dipyridamole echocardiography are reviewed. As an alternative to exercise, dipyridamole echocardiography shares all the indications of a standard exercise test. Clinical applications of dipyridamole echocardiography include coronary artery disease screening, suspected coronary artery spasm, postmyocardial infarction risk stratification, evaluation of percutaneous transluminal coronary angioplasty results, and prognosis following an acute coronary event. Compared to conventional (ECG) exercise testing, dipyridamole echocardiography appears to be equally sensitive but more specific. Compared to atrial pacing, dipyridamole provokes ischemia at a lower rate pressure product and results in a greater ST segment depression suggesting that dipyridamole induces more profound myocardial ischemia than atrial pacing. Dipyridamole thallium and exercise thallium have shown to be equally sensitive and specific in the assessment of coronary artery disease. High dose dipyridamole echocardiography appeared to be equally sensitive and more specific. Experimental studies have demonstrated that dobutamine appears to be a more powerful pharmacological agent in inducing wall-motion abnormalities. Dipyridamole echocardiography as compared to stress echocardiography offers the advantage of obtaining better quality postintervention images. With regard to sensitivity and for coronary artery disease diagnosis, both techniques appear to render similar results. Although further studies are needed, the available data indicates that cardiac ultrasound imaging prior to and following the intravenous administration of dipyridamole may be an attractive alternative to thallium perfusion imaging in the clinical setting, particularly when radionuclide capabilities are not present.

Angioplasty, Balloon, Coronary↗

PubMed1992

Oral vs intravenous dipyridamole echocardiography for detecting coronary artery disease.

The usefulness of the intravenous dipyridamole-echocardiography test (12-lead and two-dimensional [2-D] echo monitoring during dipyridamole infusion) in the diagnosis of coronary artery disease recently has been suggested. However, the intravenous form of dipyridamole is not available for clinical use in some countries and therefore the administration of oral dipyridamole has been employed in combination with echocardiography. In order to evaluate the relative usefulness of the oral (300 mg of pulverized tablets) vs the intravenous (up to 0.84 mg/kg in 10 min) dipyridamole-echocardiography test, we performed the two tests, on different days and in random order, in 28 inhospital patients: 21 had coronary artery disease (seven had one-vessel disease, eight had two-vessel disease, and six had three-vessel disease); seven patients had no significant coronary artery disease. For both tests, the diagnostic end-point was the development of a transient dyssynergy of contraction. Sensitivity was 95 percent for the intravenous and 52 percent for the oral dipyridamole-echocardiography test (p < 0.01); in positive cases, the dyssynergy after the dipyridamole administration appeared at 6.5 +/- 2.5 min for the intravenous and at 27.8 +/- 12.4 min for the oral test (p < 0.01). Specificity was 100 percent for both the intravenous and oral dipyridamole-echocardiography test. One or more extracardiac side effects (headache, gastrointestinal upset, flushing, etc) occurred in 61 percent of the intravenous and 68 percent of the oral tests (p = ns). Nine patients with a positive intravenous and oral dipyridamole-echocardiography test also had a positive exercise-electrocardiography test. A significant correlation between exercise time (ie, the time from onset of exercise and 0.1 m V of ST segment shift) and dipyridamole time (ie, the time from onset of dipyridamole administration and the development of frank dyssynergy) was present for the intravenous (r = 0.6, p < 0.05) but not for the oral test. We conclude that the oral dipyridamole-echocardiography test, in comparison with the intravenous dipyridamole-echocardiography test, has a lower sensitivity and requires a substantially longer imaging time. The dipyridamole time is related to exercise time for intravenous but not for the oral dipyridamole-echocardiography test.

Administration, Oral↗

PubMed1990

Phase I trial of dipyridamole with 5-fluorouracil and folinic acid.

We have performed two Phase I trials of the combination of dipyridamole, 5-fluorouracil (5-FU), and folinic acid in patients with advanced refractory malignancy, based upon in vitro evidence that dipyridamole can modulate the cytotoxicity of 5-FU. In the first trial, patients were treated every 4 wk with dipyridamole (50 mg/m2) p.o. every 6 h on Days 0 to 6, beginning 24 h prior to the i.v. administration of folinic acid (200 mg/m2) and escalating doses of i.v. 5-FU on Days 1 to 5. The maximum tolerated daily dose of 5-FU that could be given with this combination was 375 mg/m2. Because dipyridamole is extensively bound to plasma proteins, it was hypothesized that the concentrations of free dipyridamole achieved with a dose of 50 mg/m2 were inadequate to modulate the cytotoxicity of 5-FU and folinic acid. Therefore, a second Phase I trial of escalating dose of p.o. dipyridamole was performed. Folinic acid (200 mg/m2) and 5-FU (375 mg/m2) were given i.v. on Days 1 to 5 every 4 wk, beginning 24 h after the start of therapy with dipyridamole; dipyridamole was administered p.o. on Days 0 to 6 at doses of 75, 100, 125, 150, 175, or 200 mg/m2/dose to successive cohorts of patients. Dose-limiting neutropenia, mucositis, and nausea were produced at a dose of 200 mg/m2/dose; the recommended dose of dipyridamole for use in Phase II studies is 175 mg/m2 p.o. every 6 h, or 700 mg/m2/day. At this dose, a mean peak plasma concentration of total dipyridamole of 16.32 mumol and a mean peak plasma concentration of free dipyridamole of 38.30 nmol were observed. Trough concentrations of free dipyridamole averaged 60% of the peak concentrations. Objective antitumor responses were seen in a number of tumor types; five of 13 patients with breast cancer treated with high-dose p.o. dipyridamole, 5-FU, and folinic acid responded. High-dose p.o. dipyridamole can produce plasma concentrations of free dipyridamole within the range shown to modulate the cytotoxicity of 5-FU and other agents. Phase II trials of this combination are justified.

Adult↗

PubMed1986

Alteration of fluorouracil metabolism in human colon cancer cells by dipyridamole with a selective increase in fluorodeoxyuridine monophosphate levels.

The nucleoside transport inhibitor dipyridamole can increase the cytotoxicity of 5-fluorouracil in a human colon cancer cell line (HCT 116) without affecting the total amount of fluorouracil incorporated into the acid soluble and insoluble fractions (J. L. Grem and P. H. Fischer, Cancer Res., 45: 2967-2972, 1985). We now report that dipyridamole altered the pattern of fluorouracil metabolism and provided a selective increase in intracellular fluorodeoxyuridine monophosphate (FdUMP) levels. At 2 and 4 h after exposure to fluorouracil and dipyridamole, FdUMP levels were approximately 5-fold higher in the presence of dipyridamole. The ratio of FdUMP to fluorouridine triphosphate at 4 h was substantially increased in the presence of dipyridamole (0.4 +/- 0.05) compared to fluorouracil alone (0.08 +/- 0.03). In cells preloaded with fluorodeoxyuridine (FdUrd), dipyridamole potently inhibited the efflux of FdUrd, leading to an increased retention of intracellular FdUMP. One h following removal of [6-3H]FdUrd, the FdUMP levels were increased 8-fold in the presence of dipyridamole, and the half-life of intracellular FdUMP was increased from 24 to 78 min. We have previously shown that the addition of sufficient thymidine (25 microM) can prevent the augmentation of fluorouracil toxicity produced by dipyridamole. In these studies, the addition of 25 microM thymidine reduced the FdUMP levels to less than half of those measured in the presence of fluorouracil plus dipyridamole for the first 8 h of exposure, and reduced the FdUMP levels to 6% of the FdUMP levels seen with fluorouracil and dipyridamole after 24 h of exposure. Thymidine prevented the enhanced intracellular retention of FdUMP produced by dipyridamole in cells preloaded with FdUrd. In addition, thymidine inhibited the accumulation of FdUMP in cells exposed to FdUrd. In cancer cells which significantly catabolize FdUMP, the ability of dipyridamole to block the efflux of FdUrd may provide an effective means of selectively increasing FdUMP levels and enhancing the toxicity of fluorouracil. Furthermore, dipyridamole blocked the efflux of deoxyuridine and prolonged the intracellular half-life of deoxyuridine monophosphate. In cells prelabeled with [2'-3H]dUrd, transfer of tritium to FdUrd and FdUMP occurred in cells exposed to fluorouracil and dipyridamole. These data suggest that blockade of nucleoside efflux can enhance the availability of deoxyribose-1-phosphate donors for the synthesis of FdUrd. Thus, dipyridamole's ability to inhibit nucleoside transport can perturb the metabolism of a nucleobase, fluorouracil.

Cells, Cultured↗

PubMed1989

Inhibition of inorganic anion transport across the human red blood cell membrane by chloride-dependent association of dipyridamole with a stilbene disulfonate binding site on the band 3 protein.

The inhibition of inorganic anion transport by dipyridamole (2,6-bis(diethanolamino)-4,8-dipiperidinopyrimido[5,4-d] pyrimidine) takes place only in the presence of Cl-, other halides, nitrate or bicarbonate. At any given dipyridamole concentration, the anion flux relative to the flux in the absence of dipyridamole follows the equation: Jrel = (1 + alpha 2[Cl-])/(1 + alpha 4[Cl-]) where alpha 2 and alpha 4 are independent of [Cl-] but dependent on dipyridamole concentration. At high [Cl-] the flux approaches alpha 2/alpha 4, which decreases with increasing dipyridamole concentration. Even when both [Cl-] and dipyridamole concentration assume large values, a small residual flux remains. The equation can be deduced on the assumption that Cl- binding allosterically increases the affinity for dipyridamole binding to band 3 and that the bound dipyridamole produces a non-competitive inhibition of sulfate transport. The mass-law constants for the binding of Cl- and dipyridamole to their respective-binding sites are about 24 mM and 1.5 microM, respectively (pH 6.9, 26 degrees C). Dipyridamole binding leads to a displacement of 4,4'-dibenzoylstilbene-2,2'-disulfonate (DBDS) from the stilbenedisulfonate binding site of band 3. The effect can be predicted quantitatively on the assumption that the Cl- -promoted dipyridamole binding leads to a competitive replacement of the stilbenedisulfonates. For the calculations, the same mass-law constants for binding of Cl- and dipyridamole can be used that were derived from the kinetic studies on Cl- -promoted anion transport inhibition. The newly described Cl- binding site is highly selective with respect to Cl- and other monovalent anion species. There is little competition with SO4(2-), indicating that Cl- binding involves other than purely electrostative forces. The affinity of the binding site to Cl- does not change over the pH range 6.0-7.5. Dipyridamole binds only in its deprotonated state. Binding of the deprotonated dipyridamole is pH-independent over the same range as Cl- binding.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1993

Prognostic value of dipyridamole echocardiography early after myocardial infarction in elderly patients. Echo Persantine Italian Cooperative (EPIC) Study Group.

OBJECTIVES: This study was conducted to assess the feasibility, safety and prognostic value of dipyridamole echocardiography in elderly patients recovering from an uncomplicated acute myocardial infarction in a subset analysis performed on the patients entered in the subproject "residual ischemia" of the Echo Persantine Italian Cooperative Study (EPIC). BACKGROUND: Coronary heart disease accounts for two thirds of all deaths in the age group > 65 years, and > 50% of all patients admitted to the hospital with acute myocardial infarction are > 65 years old. The prognostic value of dipyridamole-induced left ventricular dysfunction was clearly established in patients evaluated early after acute infarction. METHODS: In a subgroup analysis of the Echo Persantine Italian Cooperative Study (EPIC), we assessed the value of dipyridamole echocardiography in predicting cardiac events in 190 elderly (> or = 65 years) patients (age 68.4 +/- 3.3 years, range 65 to 78; 147 men and 43 women) evaluated early (mean 10 days) after uncomplicated acute myocardial infarction and followed up for 14 +/- 9.8 months. RESULTS: There was no major side effect during dipyridamole echocardiography. A positive test result occurred in 85 patients (44.7%). During follow-up, there were 62 events (14 cardiac deaths, 7 nonfatal reinfarctions, 21 cases of class III or IV angina and 20 revascularization procedures). Of these 62 events, 44 occurred among 85 patients with positive dipyridamole echocardiography and 18 among 105 patients with negative dipyridamole echocardiography (52% vs. 17%, p < 0.001). Spontaneous events (death, reinfarction, angina) occurred in 31 patients with positive and in 11 with negative dipyridamole echocardiography (36% vs. 10%, p < 0.001). Hard events (myocardial infarction or death) occurred in 14 patients with positive and 7 with negative dipyridamole echocardiography (16% vs. 6%, p < 0.05). Death occurred in 11 patients with positive and in 3 with negative dipyridamole echocardiography (13% vs. 3%, p < 0.01). The positive predictive value of positive dipyridamole echocardiography and negative predictive value of negative dipyridamole echocardiography as related to the occurrence of all events in the follow-up period (death, reinfarction, angina, revascularization procedures) were 52% and 83%, respectively. The relative risk (that is, the relative risk of occurrence of future cardiac events in the group with positive dipyridamole echocardiography compared with that in those with negative dipyridamole echocardiography) was 3 for all events and 4.4 for death. CONCLUSIONS: Dipyridamole echocardiography was well tolerated by elderly patients and proved to be very effective in prognostic stratification early after uncomplicated acute myocardial infarction, even when only survival was considered.

Aged↗

PubMed1994

Effect of dipyridamole on zidovudine pharmacokinetics and short-term tolerance in asymptomatic human immunodeficiency virus-infected subjects.

Zidovudine delays the progression of infection and prolongs the survival of human immunodeficiency virus (HIV)-infected patients, but these benefits are limited by dose-related toxicity and the cost of the drug. Dipyridamole, in micromolar concentrations, acts synergistically with zidovudine, reducing the anti-HIV 95% inhibitory concentration of zidovudine 5- to 10-fold in vitro. We sought to establish a well-tolerated dose of dipyridamole for use in combination with zidovudine and to detect clinically significant pharmacokinetic interactions. Both objectives are essential for planning studies of the efficacy of the zidovudine-dipyridamole combination. Eleven asymptomatic HIV-infected subjects (median CD4+ cell count, 311 cells per mm3), 10 of whom had been on zidovudine at 500 mg/day for at least 6 months, were admitted to the study. Zidovudine pharmacokinetics were measured on day 1. Dipyridamole was then begun at 600 mg/day (subjects 1 to 3) or 450 mg/day (subjects 4 to 11), and zidovudine and dipyridamole pharmacokinetics were measured on day 5. All subjects given 600 mg of dipyridamole per day developed headache or nausea, or both. Six of eight subjects given dipyridamole at 450 mg/day developed headache or mild nausea that resolved after a median of 2 days. The area under the zidovudine concentration-time curve was not significantly different on day 1 in comparison with that on day 5 (P = 0.11). Symptoms were significantly correlated with the maximum zidovudine concentrations, which were achieved when dipyridamole was dosed concomitantly (p = 0.03). Total (free and protein-bound) dipyridamole trough concentrations were near those demonstrating synergy with zidovudine against HIV in vitro. Dipyridamole was highly protein bound, with a median free/total dipyridamole ratio of 0.7%; the percent free/total dipyridamole ratio was inversely correlated with alpha 1 acid glycoprotein concentrations (r2 =0.66). Results of the study indicate that adjustment of the zidovudine dose was not required to achieve equivalent zidovudine concentrations when zidovudine was administered in combination with dipyridamole at the doses studied. In the short study described here, the zidovudine-dipyridamole combinations was well tolerated in asymptomatic HIV-infected subjects after the occurrence of mild transient symptoms.

Adult↗

PubMed1988

Phase I clinical trial of a combination of dipyridamole and acivicin based upon inhibition of nucleoside salvage.

A Phase I clinical trial of simultaneous 72-h infusions of dipyridamole and acivicin was carried out in patients with advanced malignancies. The objective of this trial was to determine the maximum tolerated dose of dipyridamole when administered as a 72-h infusion in combination with acivicin. The development of this combination is of interest because of in vitro observations which demonstrate that dipyridamole potentiates the cytotoxic action of acivicin by blocking nucleoside salvage. Patients were treated with concomitant i.v. infusions of dipyridamole and acivicin for 72 h. The acivicin dose infused remained constant during the trial at 60 mg/m2/72 h. The maximum tolerated dose (MTD) of dipyridamole was 23.1 mg/kg/72 h. Limiting toxicities at the MTD of dipyridamole with acivicin were severe gastrointestinal and constitutional symptoms which appeared to be caused by the high doses of dipyridamole administered. Escalation of dipyridamole did not potentiate the mild myelosuppression or the neurotoxicity which occurs with acivicin alone. At a dose of dipyridamole which was well below the MTD, one patient experienced symptomatic orthostatic hypotension, and another patient with coronary artery disease developed dizziness and transient electrocardiogram abnormalities. However, no other hypotensive or cardiovascular events occurred as dipyridamole was escalated to the MTD. Phlebitis occurred at the site of infusion when the dose of dipyridamole exceeded 13.5 mg/kg/72 h. Because of this local toxicity, it was necessary to administer dipyridamole through a central venous catheter to achieve maximum plasma levels. At the MTD of dipyridamole, steady-state total and free plasma levels of 11.9 microM and 27.8 nM, respectively, were attained by 24 h. These are free dipyridamole levels which in vitro were sufficient to block cytidine salvage and to potentiate the biochemical and cytotoxic effects of acivicin against human colon cancer cells (P.H. Fischer et al., Cancer Res., 44:3355-3359, 1984).

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1994

Dipyridamole directly inhibits vascular smooth muscle cell proliferation in vitro and in vivo: implications in the treatment of restenosis after angioplasty.

OBJECTIVES: The effect of dipyridamole on smooth muscle cell proliferation and prevention of intimal thickening after arterial injury was investigated. BACKGROUND: In addition to antiplatelet activity, dipyridamole also inhibits cell proliferation. We examined whether the antiproliferative action of dipyridamole on smooth muscle cells, as demonstrated here, has a direct effect on intimal thickening after vascular injury. METHODS: Cell proliferation was determined by measuring deoxyribonucleic acid (DNA) synthesis and by cell counting. The in vivo effect of locally delivered dipyridamole was determined in a rabbit model with carotid or femoral artery injury. RESULTS: Dipyridamole produced a dose-dependent inhibition of smooth muscle cell proliferation, producing 50% inhibition at 7 micrograms/ml. Structural analogues SH-869 and mopamidol were 10 to 100 times less effective than dipyridamole, suggesting that cell growth inhibition may be unrelated to the antiplatelet activity of dipyridamole. Inhibition of cell proliferation by dipyridamole was attenuated by increasing the serum concentration in the culture medium. Bypassing serum by local delivery of dipyridamole at the periadventitial site produced 63% inhibition (p < 0.05) of cell replication in balloon-injured arteries. Locally delivered dipyridamole also inhibited intimal thickening (20%, p < 0.05) after balloon injury. CONCLUSIONS: Dipyridamole inhibited smooth muscle cell proliferation in vitro. This activity was attenuated by serum proteins. Locally delivered dipyridamole inhibited cell replication in arteries and intimal thickening after balloon injury. These results suggest that although systemic treatment with dipyridamole may not be efficacious because of inadequate serum levels, its antiproliferative action on smooth muscle cells may reduce restenosis when the drug is delivered locally after coronary angioplasty.

Angioplasty, Balloon↗

PubMed1999

Comparison of combination of dipyridamole and dobutamine during echocardiography with thallium scintigraphy with thallium scintigraphy to improve viability detection.

The aim of this study was to investigate the relation between radioisotopic and echocardiographic markers of myocardial viability and their correlation with functional recovery after coronary revascularization. Myocardial viability can be detected by techniques exploring various aspects of cell physiology: thallium-201 scintigraphy and dobutamine and dipyridamole echocardiography focus on cell membrane integrity, beta-1 and adrenoceptor, and A2-adenosine receptor-mediated inotropic response, respectively. Fifty-seven patients (mean age 60+/-8 years) with previous myocardial infarction (>3 months), angiographically assessed coronary artery disease, and resting regional dysfunction underwent rest-redistribution 201-thallium scintigraphy and low-dose pharmacologic stress echo with dobutamine (up to 10 microg/kg/min), very low dose regimen of dipyridamole (0.28 mg/kg over 4 minutes), and combined dipyridamole-dobutamine. Criteria for viability in a 13-segment model for both techniques were percent peak activity in redistribution images >55% for thallium-201 and a decrease in wall motion score >1 grade (1 [normal] to 4 [dyskinetic]) for stress echo. Thirty patients underwent coronary revascularization (bypass surgery in 8, angioplasty in 22) and were followed up at 4 weeks from intervention with a resting echocardiogram. The rate of agreement between thallium-201 and stress echo was 63% for dipyridamole, 66% for dobutamine, and 74% for combined dipyridamole-dobutamine (p <0.05 vs dipyridamole and dobutamine). In the 30 patients who underwent revascularization, a regional resting dyssynergy was observed in 225 segments, assuming that postrevascularization functional recovery (which occurred in 126 segments) was the gold standard; combined dipyridamole-dobutamine showed a higher sensitivity (90% confidence interval [CI] 85% to 95%) than thallium-201, dobutamine, or dipyridamole (87%, CI 81% to 92%; 82%, CI 76% to 89%; and 82%, CI 76% to 89%, respectively). Specificity was lower for viability recognition with thallium-201 (61%, CI 51% to 71%) than with dobutamine (93%, CI 88% to 98%), dipyridamole (95%, CI 91% to 99%), and combined dipyridamole-dobutamine (92%; CI 87% to 97%). Combined adrenergic and adenosinergic stimulation recruits an inotropic reserve in a significant proportion of segments with preserved thallium uptake that were nonresponders after either dipyridamole or dobutamine. When functional recovery after successful revascularization is considered as the postoperative gold standard, thallium has a higher sensitivity than dipyridamole or dobutamine; this sensitivity gap is filled with combined dipyridamole-dobutamine. The specificity of all forms of pharmacologic stress echo is better than thallium-201.

Cardiotonic Agents↗

PubMed1991

Effect of dipyridamole alone and in combination with aspirin on whole blood platelet aggregation, PGI2 generation, and red cell deformability ex vivo in man.

STUDY OBJECTIVE: The aim was to investigate the effects of dipyridamole, aspirin, and a combination of dipyridamole plus aspirin on platelet aggregation in whole blood, PGI2 generation, and red cell deformability ex vivo. SUBJECTS: were 16 male volunteers, aged 22-39 years, mean age, 26.6 years. DESIGN: This was a randomised, double blind, placebo controlled trial. The volunteer received each of the following treatments 10 days apart: dipyridamole 200 mg; aspirin 300 mg; dipyridamole 200 mg plus aspirin 300 mg; matched placebos. MEASUREMENTS AND MAIN RESULTS: Blood was taken for platelet function tests, PGI2 metabolite assay, and red cell deformability before and 2 h after the trial dose was taken. Platelet aggregation was quantified by measuring the fall in single platelet count after stimulation with 2 micrograms.ml-1 collagen or 50 nM platelet activating factor (PAF), or by rollermixing aliquots of blood to initiate spontaneous aggregation. The platelet function tests were completed at 37 degrees C within 10 min of venepuncture. The stable metabolite of PGI2, 6-keto PGF1 alpha, was measured in serum. There was inhibition of spontaneous platelet aggregation by dipyridamole (p less than 0.004), aspirin (p less than 0.005), and the combination of dipyridamole plus aspirin (p less than 0.0001) as compared with placebo. PAF induced platelet aggregation was inhibited by dipyridamole (p less than 0.002) and the combination of dipyridamole plus aspirin (p less than 0.0001) but aspirin alone had no inhibitory effect. Collagen induced platelet aggregation was inhibited by all three treatments: dipyridamole (p less than 0.06), aspirin (p less than 0.0001), and the combination of dipyridamole plus aspirin (p less than 0.0001). PGI2 generation was markedly inhibited by aspirin (p less than 0.0001) and the combination doses (p less than 0.0001) but was unaffected by dipyridamole alone. Of the three active treatments, only dipyridamole alone significantly (p less than 0.001) increased red cell deformability; there was a modest decrease in red cell deformability with aspirin. CONCLUSIONS: The results with PAF support the view that dipyridamole inhibits platelet activation by more than one mechanism; the effect on collagen induced and spontaneous platelet aggregation suggests that the effect of the combination doses is additive and that on red cell deformability the synergy is negative.

6-Ketoprostaglandin F1 alpha↗

PubMed1996

Infra-low dose dipyridamole test. A novel dose regimen for selective assessment of myocardial viability by vasodilator stress echocardiography.

Low (0.56 mg.kg-1 over 4 min) and high (0.84 mg.kg-1 over 10 min) doses of dipyridamole can identify viable myocardium through the contractile recovery of basally dyssynergic regions; however, it also induces ischaemia in susceptible patients. The aim of this study was to assess the potential of an "infra-low' dose of dipyridamole to selectively identify myocardial viability, independently evaluated by low dose dobutamine. Forty patients with resting dyssynergy and angiographically assessed coronary artery disease (1-vessel in 18, 2-vessel in 12, and 3-vessel in 10 patients) separately underwent a low dose dobutamine (5-10 micrograms.kg-1.min-1 for 3 min) echo test and an infralow dose (0.28 mg.kg-1 over 4 min) dipyridamole echo test. Systolic blood pressure (rest: 131 +/- 19 mmHg) changed slightly after dobutamine (137 +/- 21, P < 0.05 vs rest) and remained stable after dipyridamole (130 +/- 17, P = ns vs rest). Heart rate (rest: 68 +/- 13 beats.min-1) was also unchanged after dipyridamole (69 +/- 12, P = ns vs rest) and increased slightly after dobutamine (71 +/- 15, P < 0.05 vs rest and vs dipyridamole). No patient developed echocardiographic or electrocardiographic signs of ischaemia after either dipyridamole or dobutamine. Of the 243 segments with baseline dyssynergy, 70 were responders (i.e. they showed an improvement of 1 grade or more, from 1 = normal/hyperkinetic to 4 = dyskinetic in a 16-segment model of the left ventricle) by both dipyridamole and dobutamine, 157 were non-responders (i.e. they showed no change) by both dipyridamole and dobutamine, and 16 showed discordant results (five responders by dipyridamole only; 11 by dobutamine only). The overall concordance of dipyridamole and dobutamine was 93%. An echocardiographic follow-up could be obtained > 6 weeks after successful revascularization (achieved with angioplasty in 17, with by pass surgery in 3) in 19 patients and showed an improvement of one grade or more in 50 segments (viable) and no improvement in 50 segments (necrotic). The sensitivity of dobutamine and dipyridamole for predicting recovery was 76 and 78% respectively (P = ns); the specificity of both tests was 94%. In conclusion, infra-low dose dipyridamole is a haemodynamically neutral stress test which does not affect either heart rate or systolic blood pressure; it allows myocardial viability to be explored selectively, without eliciting ischaemia; it shows excellent overall concordance with low dose dobutamine and has good sensitivity and excellent specificity for predicting functional recovery following successful revascularization.

Adult↗

PubMed1998

Effects of dipyridamole and inhaled nitric oxide in pediatric patients with pulmonary hypertension.

Inhaled nitric oxide (iNO) causes selective pulmonary vasodilation by increasing pulmonary vascular levels of cyclic guanosine monophosphate (cGMP). Dipyridamole, a drug with several putative vasodilator mechanisms, is an inhibitor of cGMP-specific phosphodiesterases (PDE5); it therefore has the potential to increase pulmonary vascular cGMP levels, lower pulmonary vascular resistance, augment iNO-induced pulmonary vasodilation, and attenuate excessive pulmonary vasoreactivity. To test dipyridamole in the pulmonary circulation, we studied pediatric patients undergoing cardiac catheterization who had severe resting pulmonary hypertension (Group 1; n = 11) or exaggerated acute hypoxia-induced pulmonary vasoconstriction (Group 2; n = 4). In Group 1, we compared the effects of iNO (20 ppm), dipyridamole (0.6 mg/kg), and combined treatments (iNO + dipyridamole) on pulmonary and systemic hemodynamics. In Group 2 we measured the pulmonary and systemic effects of dipyridamole while the patients were breathing room air and hypoxic gas mixtures (FIO2 = 0.16). One patient in Group 1 had a hypotensive response to dipyridamole and was exluded from study. In the remaining 12 studies done on 10 patients, iNO caused a selective decrease in mean pulmonary artery pressure (Ppa) and indexed pulmonary vascular resistance (PVRI) without affecting mean aortic pressure (Pao) or indexed systemic vascular resistance (SVRI). Dipyridamole decreased PVRI to similar values as did iNO, but this effect was primarily due to an increase in cardiac index (CI), and was not associated with any change in Ppa, and was associated with a decrease in Pao and SVRI. In comparison with individual treatments, combined therapy (iNO + dipyridamole) did not augment pulmonary vasodilation in the group as a whole; however, in 50% of patients, combined therapy decreased PVRI by 20% more than did iNO or dipyridamole alone. In Group 2, Ppa and the pulmonary-to-systemic resistance ratio (Rp/Rs) increased to suprasystemic levels during acute hypoxia. Pretreatment with dipyridamole blunted the increase in Ppa and Rp/Rs during repeat hypoxia, keeping Ppa at a subsystemic level and Rp/Rs < 1. We conclude that: (1) dipyridamole nonselectively reduces PVRI, primarily through an increase in CI; (2) in combination with iNO, dipyridamole augments the decrease in PVRI in some patients; and (3) dipyridamole blunts the severity of acute hypoxic pulmonary vasoconstriction in children with exaggerated hypoxic pressor responses.

Administration, Inhalation↗

PubMed1988

Biochemical assessment of the effects of acivicin and dipyridamole given as a continuous 72-hour intravenous infusion.

Since this Phase I trial was based on a strategy of biochemical modulation, namely, the inhibition of nucleoside uptake by dipyridamole, a biochemical assessment of the actions of acivicin and dipyridamole was undertaken in order to aid our interpretation of the clinical findings. The primary biochemical objectives of this trial were: (a) to determine whether plasma levels of dipyridamole sufficient to inhibit nucleoside uptake could be achieved with a 72-h continuous i.v. infusion; (b) to monitor the effects of acivicin on two key enzymatic targets, CTP synthetase and GMP synthetase; and (c) to evaluate changes in cellular ribonucleoside triphosphate pools during therapy. Since peripheral blood mononuclear cells have relevant biochemical targets and can be serially obtained during the course of therapy, the biochemical effects of acivicin and dipyridamole were determined in these cells. At the maximally tolerated dose of dipyridamole (23.1 mg/kg/72 h), the steady-state concentrations of total and free dipyridamole averaged 11.9 microM and 27.8 nM, respectively. These levels were sufficient to inhibit cytidine (1 microM) uptake by greater than 50% in the lymphocytes of five of six patients so treated. Using lymphocytes obtained from 14 normal volunteers the concentration of free dipyridamole needed to inhibit the uptake of 1 microM cytidine by 50% averaged 13.8 +/- 1.1 nM. The plasma levels of alpha 1-acid glycoprotein, which tightly binds dipyridamole, ranged from 60 to 300 mg/dl in the patients in this study. As a consequence there were wide variations in the percentage of dipyridamole present as the unbound, pharmacologically active form and in the rates of dipyridamole clearance. The decreased rate of dipyridamole clearance seen in patients with high levels of alpha 1-acid glycoprotein resulted in higher plasma concentrations of total dipyridamole and compensated for the reduced fraction of free drug. Therefore, the plasma concentration of free dipyridamole varied much less than the total drug concentration in these patients. CTP synthetase and GMP synthetase activities were measured in patients' peripheral mononuclear cells prior to and at various times during therapy. CTP synthetase activity was inhibited in a time-dependent fashion by greater than 75% in seven of 13 evaluable courses; GMP synthetase was similarly inhibited in only three of ten cases. Ribonucleoside triphosphate pools were also measured in the patient's lymphocytes. CTP pool reductions of 30 to 50% were seen in nine of 19 courses, but in only four cases was the inhibition greater than 50%.(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1993

Identification of hemodynamically significant coronary artery stenoses by dipyridamole-magnetic resonance imaging and 99mTc-methoxyisobutyl-isonitrile-SPECT.

Magnetic resonance imaging (MRI) has been used in conjunction with dipyridamole induced wall motion abnormalities for the noninvasive detection of coronary artery disease (CAD). To assess the clinical usefulness of dipyridamole-MRI for the localization of CAD and to evaluate the relation between dipyridamole induced wall motion abnormalities and myocardial perfusion 33 patients with severe CAD (> 70% diameter reduction) underwent MRI at rest and after dipyridamole infusion (0.75 mg dipyridamole/kg over a period of 10 minutes). All patients performed exercise stress testing and 20 patients of the study group additionally had rest and exercise stress 99mTc-methoxyisobutyl-isonitrile-SPECT (MIBI-SPECT). Two patients (6%) could not be evaluated due to severe motion artifacts during dipyridamole MRI. Segmental wall motion and perfusion of corresponding short axis planes were related to the major coronary arteries using a standardized segmental coronary artery perfusion pattern. Detection of wall motion abnormalities or perfusion defects by 2 blinded observers in consensus was the criterion for grading a segment normal or pathologic. For localization of CAD, segmental gradings were related to the presumed coronary artery territories. Stress-ECG was pathologic in 19/31 patients yielding a sensitivity of 61% and dipyridamole induced angina was present in 68% (21/31) of patients. Dipyridamole-MRI detected coronary artery disease with a sensitivity of 84% (26/31 patients) and all patients with new wall motion abnormalities also had dipyridamole induced angina. For the subgroup of 20 patients with MIBI-SPECT images, CAD was detected by both MIBI-SPECT and Dipyridamole-MRI in 90% (18/20) of patients. Dipyridamole-MRI and MIBI-SPECT gradings agreed in 55/60 (92%) coronary artery perfusion territories. There were no significant differences with respect to the sensitivities of Dipyridamole-MRI/MIBI-SPECT for the localization of individual coronary artery stenoses yielding 81%/78% for left anterior descending, 80%/80% for left circumflex and 92%/89% for right coronary artery stenoses. However, specificity of Dipyridamole-MRI (89%) for the detection of RCA stenoses was slightly better than for MIBI-SPECT (80%).

Coronary Angiography↗