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PubMed1995

Comparing a high-dose dipyridamole SPECT imaging protocol with dobutamine and exercise stress testing protocols.

OBJECTIVE: To determine the safety, sensitivity, specificity, and accuracy of high-dose dipyridamole compared with treadmill and dobutamine stress imaging protocols. BACKGROUND: Nuclear imaging studies using standard dose dipyridamole provide similar results to those obtained when treadmill stress is used. Recently dobutamine tomography and planar imaging with high-dose dipyridamole have been shown no improve nuclear imaging results. METHODS: One hundred fifty-nine patients were imaged with thallium, teboroxime, or sestamibi per standard single photon emission computed tomography (SPECT) protocols. Pharmacologic stress was performed in 85 people with the remainder undergoing exercise testing by Bruce protocol. In this study, 0.852 mg dipyridamole was used per kilogram body weight and was infused over a four-minute period. Results from nuclear imaging were compared with those from coronary arteriograms. RESULTS: The sensitivity and specificity of high-dose dipyridamole was 100% and 88.9%, respectively, which is statistically greater (P < 0.005) than that achieved when patients were stressed by treadmill. Side effects with the higher dose of dipyridamole were easily reversed with aminophylline. The sensitivity and specificity of intravenous dobutamine was 100%, but it was used in a limited number of subjects. When patients were stressed by Bruce protocol the sensitivity was 92.5% and specificity was 42.8%. The differences were not attributable to inadequate exercise duration. CONCLUSIONS: High-dose dipyridamole is safe and easily reversed with intravenous aminophylline. The sensitivity and specificity of dipyridamole and dobutamine stress testing were statistically more accurate than results obtained with treadmill protocols when SPECT is used to image the heart. High-dose dipyridamole resulted in greater changes in heart rate and blood pressure response than seen with standard-dose dipyridamole. Associated side effects can be easily reversed with the administration of intravenous aminophylline without significant complications. The sensitivity, specificity, and accuracy of single photon emission computed tomography using high-dose dipyridamole are 100%, 88.9%, and 97.9%, respectively, for the overall presence or absence of disease when compared with coronary arteriography. This is significantly (P < 0.005) greater than that obtained by treadmill nuclear imaging protocols, independent imaging agent.

Aged↗

PubMed1997

Cost-minimization analysis of intravenous adenosine and dipyridamole in thallous chloride TI 201 SPECT myocardial perfusion imaging.

OBJECTIVE: To conduct a cost-minimization analysis of intravenous adenosine and intravenous dipyridamole in thallous chloride TI 201 single-photon emission computed tomography (SPECT) myocardial perfusion imaging. DESIGN: A retrospective, open-label, cost-minimization analysis. SETTING: University hospital, outpatient nuclear medicine department. PATIENTS: Eighty-three patients undergoing dipyridamole TI 201 SPECT and 166 patients undergoing adenosine TI 201 SPECT. MAIN OUTCOME MEASURES: A cost-minimization analysis was conducted using a direct cost accounting approach estimating institutional costs. For the purpose of this study, sensitivity and specificity between adenosine SPECT and dipyridamole SPECT were assumed to be identical. Key costs evaluated included acquisition, administration, monitoring, treatment of adverse effects, follow-up care, and repeat tests. RESULTS: Adenosine increased heart rate and lowered blood pressure to a significantly greater extent than dipyridamole. The frequency of adverse reactions was not significantly different (p = 0.103) between adenosine (1.64 +/- 1.32 per patient) and dipyridamole (1.36 +/- 1.23 per patient). The frequency of prolonged and late-onset adverse effects was significantly greater for dipyridamole than for adenosine (p < 0.001). The frequency of adverse events requiring medical intervention was statistically greater for dipyridamole (24%) compared with adenosine (5%) (p < 0.00001). Total cost was significantly less for adenosine ($378.50 +/- $128.20 per patient) compared with dipyridamole ($485.60 +/- $230.40). Although adenosine had a significantly greater acquisition cost than dipyridamole (p < 0.0001), administration, monitoring, and adverse reaction costs were significantly less for adenosine than for dipyridamole. CONCLUSIONS: The cost of using dipyridamole is significantly greater than the cost of using adenosine despite adenosine's high acquisition cost. Adenosine is less expensive to use because of lower administration costs, monitoring costs, and adverse effect costs. Adenosine should be the agent of choice for pharmacologic vasodilation in the setting of myocardial perfusion imaging.

Adenosine↗

PubMed1995

Hemodynamic responses and adverse effects associated with adenosine and dipyridamole pharmacologic stress testing: a comparison in 2,000 patients.

OBJECTIVE: To compare the hemodynamic responses and the adverse effects associated with two coronary vasodilators used for pharmacologic stress testing. DESIGN: We retrospectively studied the results of adenosine and dipyridamole perfusion imaging in a large group of patients who underwent pharmacologic stress radionuclide perfusion imaging. MATERIAL AND METHODS: One thousand patients given dipyridamole between April 1989 and April 1991 (before adenosine became available) were compared with 1,000 patients given adenosine between April 1991 and October 1992. A standard protocol was used to infuse the drugs before myocardial perfusion imaging with 201Tl or 99mTc sestamibi. RESULTS: Peak heart rate was higher (85 versus 83 beats/min; P = 0.02) and systolic blood pressure was lower (129 versus 133 mm Hg; P < 0.0001) with adenosine than with dipyridamole. More patients had a decrease in systolic blood pressure of 30 mm Hg or more with adenosine than with dipyridamole (P = 0.002). Horizontal or downsloping ST-segment depression of 1 mm or more occurred in 9% of patients who received adenosine and in 8% of those who received dipyridamole. Adverse effects occurred in 78% of the adenosine study group and in 50% of the dipyridamole group (P < 0.0001). Chest pain was the most common symptom with both drugs. Atrioventricular block occurred in 76 patients who received adenosine but in none who received dipyridamole. Because of adverse effects, 28% of patients who received dipyridamole required extra monitoring time (mean, 6 +/- 5 minutes beyond the standard protocol). Aminophylline was administered to 163 and 6 patients, respectively, in the dipyridamole and adenosine study groups. CONCLUSION: Adenosine causes slightly greater systemic vasodilation than does dipyridamole. Adverse effects occur less often with dipyridamole but, in comparison with adenosine, are more difficult to manage and necessitate more monitoring time as well as fairly frequent intravenous use of aminophylline for reversal.

Adenosine↗

PubMed1992

Azidothymidine and dipyridamole as biochemical response modifiers: synergism with methotrexate and 5-fluorouracil in human colon and pancreatic carcinoma cells.

Azidothymidine (AZT), inhibiting thymidine kinase (EC 2.7.1.21) (Weber, G. et al., Cancer Commun. 2:129-133, 1990) and dipyridamole, inhibiting nucleoside transport (Zhen, Y.-s. et al., Cancer Res. 43:1616-1619, 1983) exert blocking action on the activities of salvage pathways of nucleotide biosynthesis. Determined by clonogenic assay in human colon cancer HT-29 cells, the cell survivals for AZT, 10 microM, dipyridamole, 5 microM, and methotrexate (MTX), 0.025 microM, were 90, 82, and 62%, respectively; while the combinations of AZT + MTX, dipyridamole + MTX and AZT + dipyridamole + MTX, reduced survivals to 36, 4.3, and 0.7%. AZT or dipyridamole was synergistic with MTX, whereas AZT plus dipyridamole showed an even more marked potentiation of MTX activity. The survivals for 5-fluorouracil (5-FU), 0.5 microM, alone, AZT + 5-FU, dipyridamole + 5-FU, and AZT + dipyridamole + 5-FU were 86, 47, 29 and 5.1%, respectively. Similar results were observed in human pancreatic carcinoma BxPC-3 and PANC-1 cells. AZT markedly enhanced the inhibitory effect of dipyridamole in reversing the thymidine-hypoxanthine rescue from MTX cytotoxicity. AZT inhibited [14C]thymidine incorporation into DNA in HT-29 cells and strongly enhanced the effect of dipyridamole. The results indicate that combinations composed of AZT, dipyridamole, and antimetabolites, such as MTX and 5-FU, are potentially effective in the chemotherapy of human neoplasias.

Adenocarcinoma↗

PubMed1987

Interaction of [3H]dipyridamole with the nucleoside transporters of human erythrocytes and cultured animal cells.

Equilibrium binding of [3H]dipyridamole identified high-affinity (Kd approximately 10 nM) binding sites on human erythrocytes (approximately 5 X 10(5) sites/cell) and on HeLa cells (approximately 5 X 10(6) sites/cell). The equilibration of dipyridamole with these sites on human erythrocytes was compatible with a second-order process which proceeded at 22 degrees C with a rate constant of about 6 X 10(6) M-1 sec-1. Binding of dipyridamole to these sites correlated kinetically with the inhibition of the equilibrium exchange of 500 microM uridine in these cells and was inhibited in a concentration-dependent manner by nucleosides and other inhibitors of nucleoside transport, such as nitrobenzylthioinosine, dilazep and lidoflazine, but not by hypoxanthine, which is not a substrate for the nucleoside transporter of human erythrocytes. The results indicate that the substrate binding site of the transporter is part of the high-affinity dipyridamole binding site. Bound [3H]dipyridamole became displaced from these sites on human erythrocytes by incubation with an excess of unlabeled dipyridamole or high concentrations of nucleosides and inhibitors of nucleoside transport, but neither by hypoxanthine nor sugars. Dissociation of [3H]dipyridamole behaved as a simple first-order process, but the rate constant was about one order of magnitude lower (about 3 X 10(-3) sec-1) than anticipated for typical ligand-protein binding on the basis of the measured association rate and equilibrium constants. The reason for this discrepancy has not been resolved. No high-affinity dipyridamole binding sites were detected on Novikoff rat hepatoma cells, P388, L1210 and S49 mouse leukemia cells or Chinese hamster ovary cells, and their absence correlated with a greater resistance of nucleoside transport in these cells to inhibition by dipyridamole. All cells expressed considerable low affinity (Kd greater than 0.5 microM) and nonspecific binding of dipyridamole.

Animals↗

PubMed1986

The effect of the nucleoside transport inhibitor dipyridamole on the incorporation of [3H]thymidine in the rat.

Dipyridamole is a non-specific inhibitor of nucleoside transport into mammalian cells. It is currently undergoing clinical evaluation in combination with various antimetabolites in an attempt to enhance the activity of these anticancer drugs by blocking the salvage of extracellular nucleosides, an important determinant of their cytotoxicity. In the present study, the effect of i.v. infusions of dipyridamole on [3H]thymidine incorporation into DNA has been examined in the anaesthetized rat. The tissues studied were bone marrow, gastrointestinal tract epithelium and the ascitic form of the Walker carcinosarcoma. Dipyridamole at 10 mg/kg, given over 3 hr, led to plasma levels of less than 5 microM and did not reduce [3H]thymidine incorporation into any of the tissues studied. At 40 mg/kg dipyridamole (plasma levels 10-15 microM) [3H]thymidine incorporation into the DNA of bone marrow and gastrointestinal tract epithelium was reduced to 20-30% of control values. Increasing the dose to 100 mg/kg did not lead to a further suppression of incorporation. Measurement of [3H]thymidine plasma pharmacokinetics and the intracellular distribution of tritium suggested that the inhibition of [3H]thymidine incorporation was due to reduced cellular uptake. In contrast to the effects on normal tissues, even at a lethal dose (200 mg/kg) dipyridamole did not significantly inhibit [3H]thymidine incorporation into Walker tumour cells. The levels of dipyridamole found in the ascitic fluid, at 100 mg/kg approximately half those in plasma, argue against a pharmacokinetic basis for this difference. Dipyridamole was found to bind extensively (97%) to rat plasma proteins, which may explain the discrepancy between the concentrations of dipyridamole required to inhibit nucleoside incorporation in vitro, in serum-free media, and those needed in vivo. From a comparison of the plasma levels of dipyridamole which cause an inhibition of [3H]thymidine incorporation in the rat with those which can be achieved safely in patients, it is concluded that dipyridamole is unlikely to markedly reduce nucleoside salvage in man.

Animals↗

PubMed1987

Augmentation of methotrexate cytotoxicity in human colon cancer cells achieved through inhibition of thymidine salvage by dipyridamole.

In HCT 116 cells, a human colon cancer cell line, the levels of thymidine (0.6 microM) and hypoxanthine (9 microM) contributed to the tissue culture medium by the fetal bovine serum significantly reduced the growth inhibition and lethality produced by 0.1 microM methotrexate. Dipyridamole, an inhibitor of nucleoside transport, potentiated the growth inhibitory effects of methotrexate when the cells were grown in medium that was changed daily. However, when the medium was supplemented with dialyzed serum, methotrexate cytotoxicity was not increased by dipyridamole. Similarly, in cloning experiments, dipyridamole increased the cell killing produced by methotrexate. The potentiation of methotrexate toxicity produced by dipyridamole was mediated through inhibition of thymidine uptake. The uptake of 1 microM thymidine was inhibited 50% by 0.12 microM dipyridamole but neither hypoxanthine nor guanine uptake was decreased by dipyridamole (5 microM). As a result, the decrease in dTTP pools produced by methotrexate was augmented by dipyridamole. In contrast, dipyridamole did not influence the effect of methotrexate on ribonucleoside triphosphate pools. HCT 116 cells avidly salvaged low concentrations of thymidine, and methotrexate increased this capacity. Conversion of 0.11 microM thymidine to thymidine triphosphate was increased by 55%, from 16.6 to 25.7 pmoles/10(6) cells, following exposure to 1.0 microM methotrexate. Dipyridamole blocked this pool expansion. This study suggests that the salvage of physiological levels of thymidine may diminish the cytotoxic effects of methotrexate on human colon cancer cells. Inhibition of thymidine uptake by dipyridamole may be an effective strategy to increase the cytotoxicity of methotrexate.

Cell Line↗

PubMed1990

Evaluation of coronary arterial disease by oral dipyridamole stress testing using 12-lead electrocardiography.

We studied the values of oral dipyridamole needed to detect coronary arterial disease using 12-lead electrocardiography. The relationship between dipyridamole-induced ST segment depression and coronary arterial lesions, coronary collaterals and myocardial infarction was investigated. 375 mg oral dipyridamole was given to 31 patients (22 with coronary arterial disease, 9 controls). 12-lead electrocardiogram was recorded before and 45 minutes after the test. The control group and the patients, who had no ST segment depression after dipyridamole, performed isometric contraction (handgrip) for 5 minutes and then the 12-lead electrocardiogram was recorded. All patients had coronary angiography. We also performed treadmill stress testing in 28 patients. Dipyridamole testing was positive (greater than or equal to 1 mm ST depression on electrocardiogram) in 7 of 22 patients with coronary arterial disease, of whom 6 had positive treadmill stress testing. Only 2 patients had previous myocardial infarction in the group with positive dipyridamole tests. Of the 15 in whom dipyridamole testing was negative, 5 had positive treadmill stress testing, while 13 of them had had previous myocardial infarction. All patients in the control group had negative dipyridamole stress testing and normal coronary angiograms. No additional ST segment changes were observed in the group who had performed isometric contraction test (both dipyridamole test negative and control groups). Sensitivity and specificity of the test were 32 and 100%, respectively. Comparison of collateral vessels between the groups positive and negative for dipyridamole revealed no difference. But the number of patients with old myocardial infarction was higher in those testing negative than in those who proved positive.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1989

Dipyridamole radionuclide ventriculography: a test with high specificity for severe coronary artery disease.

Ventricular dysfunction induced by dipyridamole would be evidence of myocardial ischemia in patients with limited ability to undergo standard exercise testing. Radionuclide ventriculography before and after intravenous dipyridamole infusion was compared with the results of exercise radionuclide ventriculography in a prospective study of 31 patients undergoing coronary angiography. Among these patients, 21 (68%) had significant coronary artery disease (greater than or equal to 50% stenosis), 19 (61%) had severe coronary disease (greater than or equal to 70% stenosis) and 10 (32%) were "normal" (less than 50% stenosis). The left ventricular ejection fraction was calculated, and regional wall motion was scored on a 6 unit scale. In the normal patients, the ejection fraction (+/- SEM) increased 5.6 +/- 2% (units) during exercise and 7.9 +/- 1 units after dipyridamole (both p less than or equal to 0.004 compared with that during rest). However, in patients with coronary artery disease, the ejection fraction failed to increase during exercise or after dipyridamole. In the patients with coronary artery disease, regional wall motion decreased by 4.1 +/- 0.5 units during exercise (p less than 0.003) and by 1.8 units after dipyridamole (p less than 0.02). Receiver operating characteristic analysis demonstrated general comparability between the sensitivity and specificity of exercise and dipyridamole ventriculography, with "optimal" operating points that favored choosing high sensitivity for the former and high specificity for the latter. Specific subsets of patients with severe coronary atherosclerosis were analyzed with use of these criteria. In patients with severe stenosis (greater than or equal to 70%), the sensitivity of dipyridamole ventriculography was 67% compared with 89% for exercise ventriculography. However, at these levels of sensitivity, the specificity of dipyridamole ventriculography was 92% compared with 67% for exercise ventriculography. In this and other subsets of patients, the specificity of dipyridamole ventriculography exceeded that of exercise ventriculography. Thus, it is concluded that dipyridamole radionuclide ventriculography is moderately sensitive and highly specific for detecting severe coronary atherosclerosis. This technique provides a widely applicable, useful alternative to exercise ventriculography in the diagnosis of coronary atherosclerosis in patients who have limited exercise tolerance.

Adult↗

PubMed1995

Prognostic value of high dose dipyridamole echocardiography in patients with chronic coronary artery disease and preserved left ventricular function.

OBJECTIVES: The prognostic value of dipyridamole echocardiography was assessed in patients with chronic coronary artery disease and preserved left ventricular function. BACKGROUND: Few data are available on the prognostic value of dipyridamole echocardiography in patients with a low risk of cardiac events. METHODS: Two hundred sixty-eight consecutive patients with stable, proven or suspected coronary artery disease and ejection fraction > or = 0.40 underwent high dose (up to 0.84 mg/kg body weight) dipyridamole echocardiography. In 204 patients definite exercise electrocardiographic (ECG) results were also available. RESULTS: During a mean (+/- SD) follow-up period of 16 +/- 8 months (range 6 to 36), 33 spontaneous events occurred: 15 "hard" events (cardiac death [n = 6], myocardial infarction [n = 9]) and 18 "soft" events (unstable angina). Events occurred more frequently in patients with positive findings on dipyridamole echocardiography (59% vs. 3%, p < 0.001; hard events 24% vs. 2%, p < 0.01). A positive response at the low dose (up to 0.56 mg/kg) identified patients with a high incidence of hard events (7 of 16 patients, sensitivity 50%, specificity 96%). In patients with an exercise ECG, a comparable sensitivity for cardiac events was found (89% vs. 93%, p = NS), but dipyridamole echocardiography was more specific (91% vs. 61%, p < 0.01). A positive response on the low work load exercise ECG (< 8 min) and a positive response to low dose dipyridamole echocardiography had similar accuracy (82% vs. 90%, p = NS). Cox analysis identified dipyridamole echocardiography as the best predictor of cardiac events (odds ratio [OR] 20.9, 95% confidence interval [CI] 10.8 to 37.9); the highest risk of hard events was found in patients with a positive response to low dose dipyridamole echocardiography (OR 25.4, 95% CI 12.2 to 54.1). CONCLUSIONS: In patients with chronic coronary artery disease and a low incidence of cardiac events, dipyridamole echocardiography was effective in prognostic stratification, and positive low work load exercise ECG results were a reliable predictor of subsequent events. Consequently, dipyridamole echocardiography should be considered a complementary tool in the presence of high work load positivity or ambiguous exercise ECG results.

Coronary Disease↗

PubMed2003

Effects of acute myocardial ischemia on QT dispersion by dipyridamole stress echocardiography.

Increased dispersion of the QT interval has been observed during pacing or exercise stress testing in patients with coronary artery disease (CAD). It has not been established whether this phenomenon is a consequence of ischemia. Therefore, we sought to evaluate whether dipyridamole-induced myocardial ischemia, as directly detected by echocardiographic monitoring of regional contractile function, would affect QT dispersion. Twenty-four patients with nonsignificant and 34 patients with significant CAD but no previous myocardial infarction underwent dipyridamole stress echocardiography while not taking medications. QT dispersion was measured on a 12-lead electrocardiogram at baseline and at various times after dipyridamole infusion. Dipyridamole infusion did not influence QT dispersion in patients without CAD. QT dispersion was similarly unaffected in patients with CAD in whom dipyridamole did not induce wall motion abnormalities. In contrast, in patients with positive dipyridamole stress test findings, QT dispersion increased from 60 +/- 17 ms at baseline to 94 +/- 25 ms during peak infusion (p <0.0001), with a time course mirroring that of development of contractile abnormalities. QT dispersion returned to 63 +/- 25 ms upon relief of ischemia by administration of aminophylline. The increase in QT dispersion was significantly related to the extent of contractile dysfunction induced by dipyridamole. Although ST-segment depression occurred in only 40% of patients with positive dipyridamole stress test findings, 88% of such patients had an increase in QT dispersion. Analysis of the receiver-operating characteristic curve showed that a QT dispersion increase of > or =20 ms identified positive findings for dipyridamole stress echocardiography with 68% sensitivity and 91% specificity. Thus, QT dispersion is acutely affected by myocardial ischemia induced by the administration of dipyridamole. Measurement of QT dispersion may improve detection of stress-induced ischemia on surface electrocardiograms.

Aged↗

PubMedDate not supplied

Outcomes and costs of positron emission tomography: comparison of intravenous adenosine and intravenous dipyridamole.

The objective of this study was to compare the cost of intravenous adenosine and intravenous dipyridamole in positron emission tomography (PET) in patients with coronary artery disease. A retrospective, open-label, case-control, cost-effectiveness analysis was performed in the out-patient nuclear medicine department of a university hospital. Thirty-six patients underwent dipyridamole PET, and 72 matched patients underwent adenosine PET. A cost-effectiveness analysis was conducted using a direct cost accounting approach to estimate institutional costs. Key costs evaluated included acquisition cost, administration cost, monitoring cost, cost of management of side effects, and cost of follow-up care. The total cost of adenosine PET and dipyridamole PET was divided by their respective predictive accuracies to provide a total cost adjusted for efficacy. Adenosine increased heart rate and lowered systolic blood pressure to a significantly greater extent than dipyridamole. The number of patients experiencing adverse drug reactions was significantly greater for adenosine (82%) than for dipyridamole (67%), but the frequency of prolonged (> 5 minutes) and late-onset side effects was significantly greater for dipyridamole than for adenosine. The frequency of side effects requiring medical intervention was also significantly greater for dipyridamole (53%) than for adenosine (6%). Although adenosine had a significantly greater acquisition cost than dipyridamole, costs of monitoring, management of side effects, and follow-up care were significantly less for adenosine than for dipyridamole. As a result, the total cost of using dipyridamole is significantly greater ($928.00 per patient) than the total cost of using adenosine ($672.00 per patient). Based on these results, adenosine may be the drug of choice for pharmacologic vasodilation for PET.

Adenosine↗

PubMedDate not supplied

Comparison between dipyridamole and adenosine as pharmacologic coronary vasodilators in detection of coronary artery disease with thallium 201 imaging.

BACKGROUND: Both dipyridamole and adenosine are widely used as pharmacologic stressors with 201Tl imaging for detection of coronary artery disease. The purpose of this study was to compare dipyridamole and adenosine 201Tl imaging directly in patients with angiographically proved coronary artery disease. METHODS AND RESULTS: Fifty-four patients were submitted to two planar 201Tl studies: one with dipyridamole and the other with adenosine. The interval between the two studies varied from 2 to 7 days and the order was assigned randomly. Three standard planar views were obtained 10 minutes and 4 hours after the injection of 3.0 mCi 201Tl. Administration of dipyridamole was as follows: 0.142 mg/kg/min during 4 minutes, followed by a slight exercise and 201Tl injection. The infusion of adenosine was as follows: 0.140 mg/kg/min during 6 minutes with injection of 201Tl after the third minute of infusion. Patients were asked to give their preference considering the number, type, severity, and duration of side effects on a scale from 0 (worst) to 5 (best). Reading was done by two experienced observers. The heart was divided into three segments per view. The change in systolic blood pressure was -12 +/- 11 mm Hg for adenosine and -5 +/- 10 mm Hg for dipyridamole (p < 0.001), and the change in heart rate was 18 +/- 10 beats/min for adenosine and 8 +/- 7 beats/min for dipyridamole (p < 0.001). With regions of interest, ischemic/normal wall ratios were determined: 0.78 +/- 0.06 for adenosine and 0.83 +/- 0.08 for dipyridamole (p < 0.001). Adenosine detected 295 normal, 170 ischemic, and 21 scar segments, whereas dipyridamole detected 326, 135, and 25 segments, respectively. Patients preferred adenosine (4.3 +/- 1.0 for adenosine vs 3.8 +/- 1.5 for dipyridamole; p < 0.04) mainly because of the short duration of side effects. CONCLUSION: This study shows that the use of adenosine with 201Tl imaging may have some advantages over dipyridamole.

Adenosine↗

PubMed1997

Dipyridamole inhibits PDGF- and bFGF-induced vascular smooth muscle cell proliferation.

Dipyridamole is the only pharmacologic agent demonstrated to reduce polytetrafluoroethylene (PTFE) graft occlusion in hemodialysis patients. However, the mechanism of action of dipyridamole in preventing graft occlusion is unknown. The purpose of this study was to examine the direct effects of dipyridamole on both platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF)-induced vascular smooth muscle cell (VSMC) proliferation. Human aortic smooth muscle cells were grown to confluence in 96 well plates. A total of 5 x 10(-6) molar dipyridamole, PDGF 10 ng/ml, or bFGF 10 ng/ml were added to appropriate wells at the start of each experiment. Cell proliferation at 48 hours was determined using tritiated thymidine uptake. Intracellular cyclic AMP (cAMP) was measured using a competitive enzyme immunoassay. Treatment of VSMC with 5 microM dipyridamole dramatically reduced basal proliferation rates compared to controls [5229 +/- 1131 counts per minute (CPM) versus 387 +/- 68 CPM, P < 0.001]. Treatment with dipyridamole also reduced PDGF-stimulated VSMC proliferation (7311 +/- 1655 CPM vs. 593 +/- 110 CPM, P < 0.001) as well as the response to bFGF (5632 +/- 1270 CPM vs. 310 +/- 31 CPM, P < 0.001). Treatment of VSMC with either 5 or 20 microM dipyridamole did not change intracellular cAMP levels. Furthermore, the addition of dibutyryl cAMP to VSMC demonstrated only a modest inhibitory effect on proliferation. We conclude that dipyridamole inhibits both PDGF- and bFGF-stimulated VSMC proliferation. The effects of dipyridamole on VSMC proliferation do not appear to be entirely mediated by changes in intracellular cAMP concentrations. The direct effect of dipyridamole on VSMC proliferation may account for its efficacy in reducing PTFE graft thrombosis in hemodialysis patients.

Aorta↗

PubMed1999

Potentiation of the cytotoxicity of thymidylate synthase (TS) inhibitors by dipyridamole analogues with reduced alpha1-acid glycoprotein binding.

Dipyridamole has been shown to enhance the in vitro activity of antimetabolite anticancer drugs through the inhibition of nucleoside transport. However, the clinical potential of dipyridamole has not been realized because of the avid binding of the drug to the plasma protein alpha1-acid glycoprotein (AGP). Dipyridamole analogues that retain potent nucleoside transport inhibitory activity in the presence of AGP are described and their ability to enhance the growth inhibitory and cytotoxic effects of thymidylate synthase (TS) inhibitors has been evaluated. Three dipyridamole analogues (NU3026, NU3059 and NU3060) were shown to enhance the growth inhibitory activity of the TS inhibitor CB3717 and block thymidine rescue in L1210 cells. The extent of potentiation at a fixed analogue concentration (10 microM) was related to the potency of inhibition of thymidine uptake. A further analogue, NU3076, was identified, which was more potent than dipyridamole with a Ki value for inhibition of thymidine uptake of 0.1 microM compared to 0.28 microM for dipyridamole. In marked contrast to dipyridamole, inhibition of thymidine uptake by NU3076 was not significantly affected by the presence of AGP (5 mg ml(-1)). NU3076 and dipyridamole produced equivalent potentiation of the cytotoxicity of the non-classical antifolate TS inhibitor, nolatrexed, in L1210 cells with both compounds significantly reducing the LC90, by > threefold in the absence of salvageable thymidine. Thymidine rescue of L1210 cells from nolatrexed cytotoxicity was partially blocked by both 1 microM NU3076 and 1 microM dipyridamole. NU3076 also caused a significant potentiation of FU cytotoxicity in L1210 cells. These studies demonstrate that nucleoside transport inhibition can be maintained in the absence of AGP binding with the dipyridamole pharmacophore and that such analogues can enhance the cytotoxicity of TS inhibitors.

Animals↗

PubMed2003

Dipyridamole enhances digoxin bioavailability via P-glycoprotein inhibition.

BACKGROUND: On the basis of in vitro studies indicating that dipyridamole is an inhibitor for the MDR1 efflux membrane transporter P-glycoprotein, we postulated that dipyridamole could increase the bioavailability of digoxin, a P-glycoprotein substrate. OBJECTIVES: The main objective was to determine whether dipyridamole alters the bioavailability of digoxin. The secondary objective was to determine whether the magnitude of the pharmacokinetic interaction was influenced by MDR1 genetic polymorphism in exon 26 (C3435T). MATERIAL AND METHODS: (1) The effect of dipyridamole on in vitro P-glycoprotein-mediated, polarized transport of tritium-labeled digoxin was investigated in Caco-2 cell monolayers. (2) Twelve healthy volunteers participated in this open, randomized, 2-period crossover study, in which the effects of dipyridamole (300 mg/d for 3 days) versus placebo on the pharmacokinetics of a single oral dose of digoxin (0.5 mg) were compared. MDR1 genotyping (exon 26, C3435T) was determined before the study to include 6 homozygous CC and 6 homozygous TT subjects. RESULTS: Dipyridamole inhibited [(3)H]digoxin transport in Caco-2 cells with a 50% inhibitory concentration value of 1.5 +/- 1.5 micromol/L. We observed a 20% and 13% increase in digoxin area under the plasma concentration-time curve (AUC) from 0 to 4 hours and AUC from 0 to 24 hours (P <.05), respectively, during dipyridamole administration, which was consecutive to an increase in digoxin absorption. Digoxin AUC from 0 to 4 hours and AUC from 0 to 24 hours were significantly higher among subjects harboring the TT compared with the CC MDR1 genotype: 7.5 +/- 1.2 ng x h x mL(-1) versus 6.1 +/- 0.8 ng x h x mL(-1) and 20.2 +/- 2.1 ng x h x mL(-1) versus 16.8 +/- 1.7 ng x h x mL(-1), respectively (P <.05). Digoxin pharmacokinetic modifications during the dipyridamole period were similar in both genotypes. CONCLUSION: Dipyridamole is an in vitro and in vivo P-glycoprotein inhibitor that increases intestinal digoxin absorption and digoxin plasma concentrations. In light of the modest changes in digoxin pharmacokinetics in the presence of dipyridamole, this drug interaction is probably clinically irrelevant.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1999

Stimulation of long-chain fatty acid uptake by dipyridamole in isolated myocytes.

This study was designed to investigate the effects of the cardiovascular drug dipyridamole on fatty acid metabolism in isolated cardiac myocytes. Effects of dipyridamole on the oxidation of long-chain (palmitate) fatty acid, medium-chain (octanoate) fatty acid, and the carbohydrate intermediate (pyruvate) were determined by using isolated cardiac myocytes from both normal and diabetic rats. Dipyridamole increased palmitate oxidation in a concentration-dependent manner in both normal and diabetic myocytes. Maximal stimulation of palmitate oxidation (175% of control) was observed with 100 microM dipyridamole. In contrast, oxidation of octanoate and pyruvate was not affected. The stimulation of palmitate oxidation by dipyridamole persisted despite its removal from the incubation medium. In contrast to the effect in myocytes, palmitate oxidation was not affected by dipyridamole in isolated rat heart mitochondria. Palmitate uptake was increased by 2.5- and 1.6-fold when palmitate concentration was adjusted to 0.05 and 0.2 mM, respectively. Dipyridamole did not affect lipolysis in isolated myocytes. When dipyridamole (100 microM) and L-carnitine (5 mM) were added together to the incubation medium, palmitate oxidation was further increased to 223% of the control. The nucleoside transport inhibitor nitrobenzylthioinosine (NBMPR) failed to increase palmitate oxidation in isolated myocytes. Although palmitate oxidation in diabetic cells is much higher than that in normal myocytes, dipyridamole increased palmitate oxidation by 243% in diabetic myocytes over its baseline oxidation rate in normal cells. These results suggest that increased palmitate oxidation in isolated cardiac myocytes after dipyridamole administration occurs independent of effects on either the phosphodiesterase enzyme or nucleoside transport protein, but it may result from increased palmitate transport across the plasma membrane.

Animals↗

PubMed1989

Potentiation of some anticancer agents by dipyridamole against drug-sensitive and drug-resistant cancer cell lines.

In this study, we have used two different vincristine (VCR)-resistant variants, VJ-300 and HC-7-5/VCR. VJ-300 was isolated from a human cancer KB cell line and HC-7-5/VCR from a human cancer HC-7-5 cell line. VJ-300 and HC-7-5/VCR are both multidrug-resistant (MDR) variants, showing resistance to multiple anticancer drugs such as VCR, adriamycin, actinomycin D and daunomycin. Dipyridamole, a specific inhibitor of nucleoside transport, potentiated these anticancer drugs about 2- to 10-fold against KB and VJ-300. Dipyridamole almost completely reversed drug resistance to actinomycin D in VJ-300 cells with about a 70-fold higher resistance to actinomycin D. Dipyridamole inhibited the efflux of actinomycin D and VCR from VJ-300 cells. Dipyridamole enhanced the uptake of VCR but not that of actinomycin D in VJ-300 and KB. Dipyridamole at 10-100 microM inhibited photoaffinity labeling with [3H]azidopine of the cell-surface protein P-glycoprotein in VJ-300 cells. Dipyridamole potentiated 5-fluorouracil and hexylcarbamoyl-5-fluorouracil in cultured KB and VJ-300, but it annihilated the cytotoxic action of 5-fluorouridine. Potentiation of 5-fluorouracil by dipyridamole against HC-7-5 and HC-7-5/VCR was also observed, but appeared to be less than in VJ-300 and KB cells. Dipyridamole almost completely inhibited the cellular accumulation of 5-fluorouridine, but not that of 5-fluorouracil. Thus, dipyridamole appeared to potentiate anticancer agents through pleiotropic action sites, one of which is inhibition of enhanced efflux of MDR cell lines and the other of which is inhibition of nucleoside transport. Dipyridamole might be a useful and potent agent to potentiate anticancer agents and reverse drug-resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗