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PubMed1989

Interaction of deoxyuridine with fluorouracil and dipyridamole in a human colon cancer cell line.

We have reported previously that dipyridamole increases the toxicity of 5-fluorouracil and alters fluorouracil metabolism in HCT 116 cells, producing a selective increase in fluorodeoxyuridine monophosphate (FdUMP) levels by blocking the efflux of fluorodeoxyuridine. Dipyridamole also blocks deoxyuridine efflux and prolongs the intracellular half-life of deoxyuridine monophosphate (dUMP). The significance of the effect of dipyridamole on FdUMP and dUMP levels was explored further. In cell growth experiments, 1-50 microM deoxyuridine enhanced the cytotoxicity of 5 microM fluorouracil in a dose-dependent manner, and greater than or equal to 10 microM deoxyuridine increased the augmentation of fluorouracil toxicity produced by 0.5 microM dipyridamole. The effect of deoxyuridine on [6-3H]fluorouracil metabolism was studied. After 4 hr, 25 microM deoxyuridine increased the amount of [3H]FdUMP formed 2- to 4-fold relative to that of fluorouracil +/- dipyridamole alone. The mechanism by which deoxyuridine increased FdUMP was examined by measuring the distribution of [2'-3H]deoxyuridine metabolites following exposure of 25 microM deoxyuridine +/- 5 microM fluorouracil. Tritium appeared in the FdUMP peak at 4 and 24 hr in cells exposed to fluorouracil and deoxyuridine, indicating that [3H]deoxyribose was transferred to fluorouracil. A large buildup of [3H]dUMP was seen in cells exposed to fluorouracil plus deoxyuridine for 4 and 24 hr compared to exposure to [3H]deoxyuridine alone, suggesting that dUMP may also inhibit catabolism of FdUMP. Since the increased FdUMP levels produced by dipyridamole did not appear to correlate with further depletion of thymidine triphosphate pools, the incorporation of [3H]fluorouracil metabolites into nucleic acids was monitored by cesium sulfate density centrifugation. Fluorouracil-RNA increased as a function of time (1, 2 and 13 pmol/10(6) cells after 4, 8 and 24 hr), but fluorouracil-DNA was detected only after 24 hr (0.5 pmol/10(6) cells). Dipyridamole however, did not appear to alter the pattern of incorporation of fluorouracil into either RNA or DNA. Perturbations of endogenous dUMP levels by fluorouracil and dipyridamole were then studied. In cells exposed to fluorouracil alone, dUMP pools were unchanged from control at 2 hr, but they had increased 9-fold by 4 hr (3362 pmol/10(6) cells). Simultaneous exposure to fluorouracil and dipyridamole resulted in a 1.5-fold (566 pmol/10(6) cells) and 13.6-fold (5049 pmol/10(6) cells) increase over control dUMP levels after 2 and 4 hr respectively. The dUMP pools continued to enlarge through 24 hr. The effect of fluorouracil on DNA fragility was examined.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell Survival↗

PubMed1990

Role of hypoxanthine and thymidine in determining methotrexate plus dipyridamole cytotoxicity.

The nucleoside transport inhibitor dipyridamole can potentiate the cytotoxicity of methotrexate by a mechanism that was thought to be related to the inhibition of thymidine salvage. In human ovarian carcinoma cells thymidine only partly reversed the in vitro cytotoxicity of methotrexate plus dipyridamole at sub-millimolar concentrations, above which the cytotoxicity of thymidine itself became evident. Hypoxathine with thymidine, or hypoxanthine alone at a higher concentration, completely reversed methotrexate and methotrexate plus dipyridamole cytotoxicity. The effects of dipyridamole on cellular cyclic adenosine monophosphate (cAMP) levels and on 3H-methotrexate efflux in 2008 cells were examined. At 10 mumol/l, dipyridamole did not alter cAMP content or methotrexate influx in ovarian carcinoma cells, but reduced the rate of efflux of 3H-methotrexate by 25%. In Chinese hamster ovary cells and their folylpolyglutamyl synthase-deficient variant AUX B1, the reduced methotrexate efflux by dipyridamole was not due to increased polyglutamation, since increased retention was observed in both cell lines. The data support the hypothesis that dipyridamole potentiated the activity of methotrexate by inhibiting the salvage of hypoxanthine, and to a lesser extent, that of thymidine. The ability of dipyridamole to increase the cellular retention of methotrexate was probably a non-specific action of dipyridamole on the cell membrane, and may have a role in the observed synergy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1989

High dose dipyridamole echocardiography early after uncomplicated acute myocardial infarction: correlation with exercise testing and coronary angiography.

The feasibility, safety and usefulness of dipyridamole echocardiography (two-dimensional echocardiography and 12 lead electrocardiographic monitoring during dipyridamole infusion, up to 0.84 mg/kg over 10 min) were evaluated in 94 asymptomatic patients 8 to 10 days after uncomplicated acute myocardial infarction. The results were compared with those of symptom-limited treadmill exercise testing and correlated with coronary angiography. Two mechanical patterns of positivity of dipyridamole echocardiography could be identified: 1) a new wall motion abnormality confined to the infarct zone or to the adjacent segments (24 patients), and 2) transient remote asynergy (33 patients). The success rate in recording adequate images during dipyridamole infusion was 100%. Interobserver agreement concerning diagnosis occurred in 89 (93%) of 94 patients. Dipyridamole echocardiography was well tolerated; no complication was observed during or after the test. Seventy-three patients underwent coronary angiography within 6 weeks after acute myocardial infarction. Transient remote asynergy on echocardiography was present in 27 of 40 patients with multivessel disease and in none of 33 patients without multivessel disease. Results of treadmill exercise testing were positive in 28 patients with multivessel disease and 8 patients without multivessel disease. Thus, the sensitivity of dipyridamole-induced transient remote asynergy was 68% compared with 52% for treadmill testing (p less than 0.05); specificity was 100% and 72%, respectively (p less than 0.005). The overall accuracy of dipyridamole echocardiography (81%) was higher than that of dipyridamole stress electrocardiography (63%) or exercise electrocardiography (60%) (p less than 0.02). It is concluded that dipyridamole echocardiography is a useful, feasible and inexpensive nonexercise-dependent test for detecting the extent of coronary artery disease early after acute myocardial infarction.

Adult↗

PubMed1992

Inhibition of active oxygen generation by dipyridamole in human polymorphonuclear leukocytes.

The effect of dipyridamole on active oxygen generation by human polymorphonuclear leukocytes (PMN) was investigated. Dipyridamole inhibited the production of oxidative metabolites from human PMN stimulated by opsonized zymosan and formyl-methionyl-leucyl-phenylalanine dose and time dependently. To determine whether dipyridamole directly inhibits the production of oxygen metabolites by human PMN, human PMN were preincubated with dipyridamole washed prior to stimulation. Dipyridamole was found to directly inhibit human PMN from generated active oxygen metabolites at therapeutic concentrations. Dipyridamole may possibly be a potential scavenger of active oxygen metabolites since it inhibited active oxygen metabolite production from human PMN very rapidly. Dipyridamole was also found to directly affect the scavenging of active oxygen metabolites generated by opsonized zymosan-stimulated human PMN at therapeutic concentrations. This action of dipyridamole was also noted to be exerted against hydroxyl radicals and superoxide anions produced biochemically by an electron spin resonance spectrometer. It thus follows that dipyridamole may inhibit human PMN active oxygen metabolite generation and affect directly the scavenging of active oxygen metabolites at therapeutic concentrations.

Dipyridamole↗

PubMed2006

Dipyridamole activation of mitogen-activated protein kinase phosphatase-1 mediates inhibition of lipopolysaccharide-induced cyclooxygenase-2 expression in RAW 264.7 cells.

Dipyridamole is a nucleoside transport inhibitor and a non-selective phosphodiesterase inhibitor. However, the mechanisms by which dipyridamole exerts its anti-inflammatory effects are not completely understood. In the present study, we investigated the role of mitogen-activated kinase phosphatase-1 (MKP-1) in dipyridamole's anti-inflammatory effects. We show that dipyridamole inhibited interleukin-6 and monocyte chemoattractant protein-1 secretion, inducible nitric oxide synthase protein expression, nitrite accumulation, and cyclooxygenase-2 (COX-2) induction in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Dipyridamole inhibited the nuclear factor kappa B (NF-kappaB) signaling pathway as demonstrated by inhibition of the inhibitor of NF-kappaB (IkappaB) phosphorylation, IkappaB degradation, p65 translocation from the cytosol to the nucleus, and transcription of the reporter gene. Dipyridamole also inhibited LPS-stimulated p38 mitogen-activated protein kinase (p38 MAPK) and IkappaB kinase-beta (IKK-beta) activities in RAW 264.7 cells. A p38 MAPK inhibitor, SB 203580, inhibited LPS-stimulated COX-2 expression and IKK-beta activation suggesting that LPS may activate the NF-kappaB signaling pathway via upstream p38 MAPK activation. Furthermore, dipyridamole stimulated transient activation of MKP-1, a potent inhibitor of p38 MAPK function. Knockdown of MKP-1 by transfecting MKP-1 siRNA or inhibition of MKP-1 by the specific inhibitor, triptolide, significantly reduced the inhibitory effects of dipyridamole on COX-2 expression induced by LPS. Taken together, these data suggest that dipyridamole exerts its anti-inflammatory effect via activation of MKP-1, which dephosphorylates and inactivates p38 MAPK. Inactivation of p38 MAPK in turn inhibits IKK-beta activation and subsequently the NF-kappaB signaling pathway that mediates LPS-induced cyclooxygenase-2 expression in RAW 264.7 cells.

Animals↗

PubMed2000

Effect of dipyridamole and aspirin on the platelet-neutrophil interaction via the nitric oxide pathway.

This study was designed to determine the influence of the combination of aspirin and dipyridamole on the interaction in vitro between neutrophils and platelets through the nitric oxide (NO) pathway. Collagen-induced platelet aggregation (impedance method) was determined in platelet-rich plasma and in platelet-rich plasma+neutrophils, and cGMP (enzyme immunoanassay) and NO levels (electrochemical method, with a ISO-200 electrode) were also measured. The 50% inhibitory concentration (IC(50)) of aspirin was 139+/-11 microM in platelet-rich plasma, 367+/-21 microM in platelet-rich plasma+L-N(G)-nitro-arginine-methyl-ester (L-NAME), and 42+/-3 microM in platelet-rich plasma+L-arginine. The IC(50) for dipyridamole in platelet-rich plasma was not affected by L-NAME or L-arginine; the combination of aspirin with 20 microM dipyridamole (which has no effect per se) led to an IC(50) of 51+/-2 microM in platelet-rich plasma, 101+/-7 microM in platelet-rich plasma+L-NAME, and 13+/-2 microM in platelet-rich plasma+L-arginine. The cGMP levels showed the greatest increases in the aspirin plus dipyridamole group. Dipyridamole and aspirin increased the leukocyte production of NO: 50% increases were obtained at concentrations of 285+/-31 microM aspirin, 110+/-9 microM dipyridamole, and 16+/-2 microM aspirin+dipyridamole. Dipyridamole alone at a concentration of 20 microM had no significant effect on NO levels. We conclude that the combination of aspirin and dipyridamole significantly increases the antiplatelet effect of leukocytes, through an increase of NO, and that this effect is further evidence of the therapeutic benefits of this combination of drugs.

Adult↗

PubMed1996

European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke.

In 1988, we undertook a randomized, placebo-controlled, double-blind trial to investigate the safety and efficacy of low-dose acetylsalicylic acid (ASA), modified-release dipyridamole, and the two agents in combination for secondary prevention of ischemic stroke. Patients with prior stroke or transient ischemic attack (TIA) were randomized to treatment with ASA alone (50 mg daily), modified-release dipyridamole alone (400 mg daily), the two agents in a combined formulation, or placebo. Primary endpoints were stroke, death, and stroke or death together. TIA and other vascular events were secondary endpoints. Patients were followed on treatment for two years. Data from 6,602 patients were analysed. Factorial analysis demonstrated a highly significant effect for ASA and for dipyridamole in reducing the risk of stroke (p < or = 0.001) and stroke or death combined (p < 0.01). In pairwise comparisons, stroke risk in comparison to placebo was reduced by 18% with ASA alone (p = 0.013); 16% with dipyridamole alone (p = 0.039); and 37% with combination therapy (p < 0.001). Risk of stroke or death was reduced by 13% with ASA alone (p = 0.016); 15% with dipyridamole alone (p = 0.015); and 24% with the combination (p < 0.001). The treatment had no statistically significant effect on the death rate alone. Factorial analysis also demonstrated a highly significant effect of ASA (p < 0.001) and dipyridamole (p < 0.01) for preventing TIA. The risk reduction for the combination was 36% (p < 0.001) in comparison with placebo. Headache was the most common adverse event, occurring more frequently in dipyridamole-treated patients. All-site bleeding and gastrointestinal bleeding were significantly more common in patients who received ASA in comparison to placebo or dipyridamole. We conclude that (1) ASA 25 mg twice daily and dipyridamole, in a modified-release form, at a dose of 200 mg twice daily have each been shown to be equally effective for the secondary prevention of ischemic stroke and TIA; (2) when co-prescribed the protective effects are additive, the combination being significantly more effective than either agent prescribed singly; (3) low-dose ASA does not eliminate the propensity for induced bleeding.

Adult↗

PubMed1997

Selective potentiation of lometrexol growth inhibition by dipyridamole through cell-specific inhibition of hypoxanthine salvage.

The novel antifolate lometrexol (5,10-dideazatetrahydrofolate) inhibits de novo purine biosynthesis, and co-incubation with hypoxanthine abolishes its cytotoxicity. The prevention of hypoxanthine rescue from an antipurine antifolate by the nucleoside transport inhibitor dipyridamole was investigated for the first time in nine human and rodent cell lines from seven different tissues of origin. In A549, HeLa and CHO cells, dipyridamole prevented hypoxanthine rescue and so growth was inhibited by the combination of lometrexol, dipyridamole and hypoxanthine, but in HT29, HCT116, KK47, MDA231, CCRF CEM and L1210 cells dipyridamole had no effect and the combination did not inhibit growth. Dipyridamole inhibited hypoxanthine uptake in A549 but not in CCRF CEM cells. Dipyridamole prevented the hypoxanthine-induced repletion of dGTP pools, depleted by lometrexol, in A549 but not in CCRF CEM cells. Thus, the selective growth-inhibitory effect of the combination of lometrexol, dipyridamole and hypoxanthine is apparently due to the dipyridamole sensitivity (ds) or insensitivity (di) of hypoxanthine transport. Both the human and murine leukaemic cells are of the di phenotype. If this reflects the transport phenotype of normal bone marrow it would suggest that the combination of lometrexol, dipyridamole and hypoxanthine might be selectively toxic to certain tumour types and have reduced toxicity to the bone marrow.

Antimetabolites, Antineoplastic↗

PubMed2000

Selective protection of RBCs against photodynamic damage by the band 3 ligand dipyridamole.

BACKGROUND: All studied photosensitizers for virus inactivation impair RBCs. To reduce damage to the RBCs without affecting virucidal activity, selective protection of the RBCs is necessary. The ability of the band 3 ligand, dipyridamole, to react with singlet oxygen and to increase the selectivity of photosterilization was investigated. STUDY DESIGN AND METHODS: Solutions of dipyridamole were illuminated in the presence of tetrasulfonated aluminum phthalocyanine (AlPcS(4)) and dimethylmethylene blue (DMMB). Solutions of amino acids, RBCs, and vesicular stomatitis virus (VSV) in RBC suspensions were photodynamically treated in the presence or absence of dipyridamole. RESULTS: Illumination of a solution of dipyridamole in the presence of AlPcS(4) or DMMB resulted in changes in the optical spectrum of dipyridamole. The photooxidation of dipyridamole was inhibited by azide and augmented by D(2)O, which suggests the involvement of singlet oxygen. Photooxidation of amino acids and photodamage to RBCs was strongly reduced in the presence of dipyridamole. In contrast, photoinactivation of VSV in RBC suspensions was only slightly affected by dipyridamole. CONCLUSION: Dipyridamole can improve the specificity of photodynamic sterilization of RBC concentrates, thereby increasing the practical applicability of this photodecontamination method.

Antiviral Agents↗

PubMed2002

Dipyridamole inhibits in vitro renal fibroblast proliferation and collagen synthesis.

Fibroblasts are universally recognized in situations of tubulointerstitial injury, where their presence has been shown to be a marker of disease progression. The objective of this study was to determine whether the functions of fibroblasts relevant to fibrogenesis can be modified in vitro with dipyridamole. Cells were obtained from obstructed rat renal tissue and characterized on the basis of immunohistochemical findings. Fibroblasts constituted all of the cells from passage 3. Functional parameters were measured in cells cultured with 1, 5, and 50 micromol/L dipyridamole and compared to basal parameters of cells grown in Dulbecco's modified Eagle's medium plus 10% fetal calf serum (control). Northern-blot analysis indicated that dipyridamole decreased procollagen alpha1(I) messenger ribonucleic acid expression (P <.05, 50 micromol/L vs control), results that were reflected in a reduction in total collagen secretion as measured on the basis of hydroxyproline incorporation (P <.001, 50 micromol/L vs control). Mitogenesis, as measured on the basis of incorporation of tritiated thymidine, was decreased in a dose-dependent fashion by dipyridamole. Likewise, 50 micromol/L dipyridamole reduced cell-population growth to 16.8% +/- 2.1% of basal growth over 3 days (P <.001 vs control). Effects of dipyridamole on population growth were prevented by coincubation with a protein kinase G inhibitor peptide (P <.001 vs 50 micromol/L dipyridamole; P = not significant vs control). No such effect was observed with inhibitors for protein kinase A (H-89) and protein kinase C (bisindolylmaleimide I). Consistent with a protein kinase G-dependent mechanism, immunofluorescence staining indicated that dipyridamole increased basal expression of the inducible form of nitric oxide synthase. In conclusion, the results of this study demonstrate that at clinically relevant concentrations, dipyridamole inhibits profibrotic activities of renal fibroblasts. Effects on mitogenesis are mediated through a cyclic guanosine monophosphate-protein kinase G effector pathway.

Animals↗

PubMed2005

Identification and mutational analysis of amino acid residues involved in dipyridamole interactions with human and Caenorhabditis elegans equilibrative nucleoside transporters.

The equilibrative nucleoside transporters, hENT1 and CeENT1 from humans and Caenorhabditis elegans, respectively, are inhibited by nanomolar concentrations of dipyridamole and share a common 11-transmembrane helix (TM) topology. Random mutagenesis and screening by functional complementation in yeast for clones with reduced sensitivities to dipyridamole yielded mutations at Ile429 in TM 11 of CeENT1 and Met33 in TM 1 of hENT1. Mutational analysis of the corresponding residues of both proteins suggested important roles for these residues in competitive inhibition of hENT1 and CeENT1 by dipyridamole. To verify the roles of these residues in dipyridamole interactions, hENT2, which naturally exhibits low dipyridamole sensitivity, was mutated to contain side chains favorable for high affinity dipyridamole binding (i.e. a Met at the TM 1 and/or an Ile at the TM 11 positions). The single mutants exhibited increased hENT2 sensitivity to inhibition by dipyridamole, and the double mutant was the most sensitive, with an IC50 value that was only 2% of that of wild type. Functional analysis of the TM 1 and 11 mutants of hENT1 and CeENT1 revealed that Ala and Thr in the TM 1 and 11 positions, respectively, impaired uridine and adenosine transport and that Leu442 of hENT1 was involved in permeant selectivity. Mechanistic and structural models of dipyridamole interactions with the TM 1 and 11 residues are proposed. This study demonstrated that the corresponding residues in TMs 1 and 11 of hENT1, hENT2, and CeENT1 are important for dipyridamole interactions and nucleoside transport.

Adenosine↗

PubMed1996

Residual myocardial perfusion in reversibly damaged myocardium by dipyridamole contrast echocardiography.

In patients with previous myocardial infarction and left ventricular asynergy, dipyridamole infusion may have the capacity to unmask myocardial viability through transient recovery of contractile function in asynergic segments. The purpose of this study was to assess simultaneous changes in myocardial perfusion and LV function--elicited by dipyridamole infusion--in infarcted, asynergic segments. The echo contrast agent Albunex was injected into the left coronary artery of 19 patients (17 males, age 49-70 years) with previous myocardial infarction and baseline left ventricular asynergy, both before and after dipyridamole infusion (up to 0.56 mg.kg-1, i.v.). Analysis was not possible in three patients due to inadequate image quality and in two due to weak contrast. There were no major adverse events, or changes in vital signs or demonstrated on the electrocardiogram. After dipyridamole, 7/14 patients, showed an improvement in regional function of asynergic segments ('responders'), whereas seven patients did not ('non-responders'). Among non-responders, five had a myocardial perfusion deficit corresponding to 41% of the total left ventricular area before dipyridamole and to 38% after dipyridamole. No baseline perfusion deficits were observed in the remaining two non-responders; one of these, however, developed transient asynergy and perfusion deficit after dipyridamole. Among responders, five showed a normal perfusion pattern, both before and after dipyridamole, while the remaining two showed a perfusion deficit which markedly decreased after dipyridamole (from 32% to 13% of total left ventricular area). Thus, residual contractile reserve of asynergic, infarcted ventricular segments appears to be associated with myocardial perfusion either preserved at baseline or recruitable by a coronary dilator stimulus.

Aged↗

PubMed1997

Coronary vasodilation without myocardial erection. Simultaneous haemodynamic, echocardiographic and arteriographic findings during adenosine and dipyridamole infusion.

AIM: The aim of this study was to evaluate simultaneously echocardiographic, haemodynamic and angiographic changes that occur during adenosine and dipyridamole infusion, in patients with one-vessel coronary artery stenosis. This would assess whether deterioration in left ventricular haemodynamics during vasodilator agent infusion is influenced by vasodilation per se, or the development of myocardial ischaemia. METHODS AND RESULTS: We performed adenosine (140 micrograms.kg-1.min-1 over 4 min) and dipyridamole (up to 0.84 mg.kg-1 over 10 min) stress echocardiography tests, together with angiographic and haemodynamic assessment, in 26 patients undergoing elective coronary angioplasty. In 12 of 26 patients, adenosine and dipyridamole tests were repeated 24 h after angioplasty. The criterion for echocardiography test positivity was the appearance of a new transient regional wall motion abnormality. Coronary angiograms were analysed with quantitative coronary arteriography. Adenosine and dipyridamole induced regional dysfunction in 18/26 (69%) and 14/26 (54%) patients before angioplasty, respectively (P = ns). In the echocardiography-positive patients, the percent diameter stenosis was significantly (P < 0.05) tighter stenosis than in the echocardiography-negative patients (adenosine, 66.6 +/- 8.3% vs 58.0 +/- 8.9%; dipyridamole, 69.2 +/- 7.1% vs 57.7 +/- 7.6%). During both tests, left ventricular end-diastolic pressure significantly increased (P < 0.05) in echocardiography-positive patients (adenosine, 9.8 +/- 2.7 mmHg to 13.5 +/- 4.1 mmHg; dipyridamole, 10.1 +/- 2.8 mmHg to 14.1 +/- 4.3 mmHg), but not in echocardiography-negative patients. In the patients who had undergone successful angioplasty (reduction to < 50% diameter stenosis), both adenosine and dipyridamole confirmed the arteriographic success of the procedure (echocardiography negative in all patients). In this group of patients, no significant change was observed in left ventricular end-diastolic pressure during adenosine or dipyridamole infusion. CONCLUSIONS: Intravenous infusion of either adenosine or dipyridamole was accompanied by an obvious increase in left ventricular end-diastolic pressure only in patients with induced wall motion abnormalities. Coronary vasodilation per se has no significant effect on left ventricular end-diastolic pressure when no ischaemia is induced, disproving any clinically significant 'erectile' and adverse effects of coronary vasodilation per se.

Adenosine↗

PubMed2000

Dipyridamole dilates large cerebral arteries concomitant to headache induction in healthy subjects.

Dipyridamole is used for secondary prophylaxis in ischemic stroke and as a vasodilator agent in myocardial scintigraphy. An important side effect to administering dipyridamole is headache. The aim of the current study was to investigate the effects of dipyridamole on cerebral blood flow, large artery diameter, and headache induction. Twelve healthy subjects were included in this single-blind placebo-controlled study in which placebo (0.9% NaCl) and dipyridamole 0.142 mg/kg x min were administered intravenously over 4 minutes 1 hour apart. Blood flow velocity in the middle cerebral artery (Vmax) was recorded by transcranial Doppler and regional cerebral blood flow in the middle cerebral artery (rCBFmca) was measured using single photon emission computed tomography and 133Xenon-inhalation. Blood pressure, heart rate, and pCO2 were measured repeatedly. Headache response was scored every 10 minutes on a verbal scale from 0 to 10 (10 = worst). Dipyridamole caused a decrease in pCO2 (P < 0.001). pCO2 corrected rCBFmca was 41.7 +/- 6.9 mL/100 g x min after placebo versus 41.2 +/- 6.9 after dipyridamole (P > or = 0.05). pCO2 corrected Vmca decreased 8.4% +/- 11.7 (P < 0.001) after dipyridamole, indicating a mean 5.6% +/- 6.7 (P = 0.005) relative increase of the arterial diameter. After dipyridamole the median peak headache score was 2 (range 0 to 7) compared with 0 (range 0 to 3) after placebo (P = 0.02). Dilatation of the middle cerebral artery outlasted the headache response. In conclusion, dipyridamole causes a modest pCO2 independent dilatation of the MCA, which is time-linked to the onset, but not to the cessation, of headache.

Adolescent↗

PubMed2002

Safety and feasibility of dobutamine and dipyridamole stress echocardiography in hypertensive patients.

OBJECTIVES: To establish whether safety and feasibility of dobutamine and dipyridamole stress echocardiography are affected by history of hypertension. METHODS: Data on 2200 consecutive pharmacologic stress echocardiography (959 dobutamine and 1241 dipyridamole) performed between October 1990 and February 2001 at a single cardiology centre, were analysed. RESULTS: There were two complications (1/480 tests) during dobutamine (one sustained ventricular tachycardia and one severe asthmatic attack following antidote administration) and two (1/620 tests) during dipyridamole (one non-Q wave myocardial infarction and one sustained ventricular tachycardia) stress. Complications or limiting side effects were observed in 83/959 patients (48/430 hypertensives and 35/529 normotensives) with dobutamine and in 34/1241 patients (17/571 hypertensives and 17/670 normotensives) with dipyridamole stress. Therefore, the overall feasibility was 88.8% in hypertensives and 93.4% in normotensives (P = 0.013) for dobutamine, and 97% in hypertensives and 97.5% in normotensives (P = 0.64) for dipyridamole. Dipyridamole was significantly more feasible than dobutamine in both hypertensive (P < 0.0001) and normotensive (P = 0.0006) subjects. Logistic regression analysis failed to identify clinical or echocardiographic predictors of adverse reactions with dipyridamole, while history of hypertension [odds ratio (OR) = 1.8, 95% confidence interval (CI) 1.1-2.8, P = 0.0138] was the only independent predictor of cumulative adverse reactions with dobutamine stress. In addition, history of hypertension (OR = 3.2, 95% CI, 1.2-8.5, P = 0.0166), resting wall motion abnormalities (OR = 1.8, 95% CI, 1.1-3.1, P = 0.0282), and age over 70 years (OR = 4.8, 95% CI, 1.5-15.3, P = 0.0087) predicted hypertensive response, ventricular tachycardia, and atrial fibrillation, respectively. No covariate was associated with hypotensive response during dobutamine test. CONCLUSIONS: Dipyridamole has a slightly better safety profile and significantly higher feasibility than dobutamine stress both in hypertensives and in normotensives. In addition, the history of systemic hypertension is an independent predictor of cumulative adverse effects during dobutamine but not during dipyridamole stress.

Aged↗

PubMed1989

Dipyridamole potentiates the growth-inhibitory action of methotrexate and 5-fluorouracil in human keratinocytes in vitro.

Human keratinocytes transport extracellular thymidine across the plasma membrane and incorporate it into DNA. Data presented here show that dipyridamole, a well-known inhibitor of facilitated diffusion of nucleosides, blocks the transport of thymidine into human keratinocytes in vitro. Dipyridamole (1.0 microM) inhibited the transport of 3H-thymidine (0.2 microM) into intracellular material by 75% and its subsequent salvage and incorporation into DNA by 48%. Dipyridamole (1 microM) did not affect the growth of keratinocytes in vitro but did potentiate the growth inhibition caused by methotrexate (MTX) or 5-fluorouracil (5-FU). The growth of keratinocytes exposed to 0.1 microM MTX for 8 d was inhibited by 32%. However, in combination with a noninhibitory concentration of dipyridamole (1 microM), this concentration of MTX (0.01 microM) inhibited the growth of keratinocytes by 93%. Thymidine in culture medium reversed the cytotoxicity of MTX. However, in the presence of dipyridamole, thymidine in the culture medium did not reverse the action of MTX. The synergistic interaction between MTX and dipyridamole was also observed with 5-FU and dipyridamole. 5-FU (0.5 microM) inhibited cell growth by 30% but in combination with dipyridamole (1 microM), inhibited cell growth by 86%. These data are consistent with the theory that inhibiting thymidine salvage by blocking transport of extracellular thymidine potentiates the growth inhibitory action of inhibitors of de novo pyrimidine biosynthesis in human keratinocytes. Combination chemotherapy, such as methotrexate plus dipyridamole, might be efficacious in the treatment of hyperproliferative diseases of the epidermis.

Cell Division↗

PubMed1987

Dipyridamole: pharmacokinetics and effects on aspects of platelet function in man.

1. The effect of dipyridamole on platelet function was measured in twelve normal subjects given 150 or 200 mg tablets as single and multiple doses, and in six subjects given single doses of 25, 50 and 100 mg and multiple doses of 50 mg 8 hourly. 2. Platelet aggregation was measured in response to ADP and collagen. In the subjects given 150/200 mg, the platelets were assayed for content of cyclic AMP and for formation of thromboxane after addition of collagen. The responses to ADP and collagen and the cyclic AMP content were assessed in both the presence and absence of added PGE1. The pharmacokinetics of dipyridamole were studied in all subjects. 3. One hour after 150/200 mg single doses of dipyridamole there was significant inhibition of platelet aggregation in response to both collagen and ADP. There was no detectable effect on aggregation at other time points or with lower doses of dipyridamole. The addition of PGE1 to platelets prior to testing did not enhance the effect of dipyridamole on platelet aggregation. 4. In multiple doses, dipyridamole (150/200 mg twice daily for 11 days) had no detectable effect on platelet aggregation. 5. Dipyridamole did not have any effect on platelet cyclic AMP content, whether or not PGE1 was added prior to assay. 6. Dipyridamole did not affect platelet thromboxane formation. 7. Plasma dipyridamole concentrations were maximal 1-2 h after ingestion, at the same time that inhibition of platelet aggregation was detected. The concentrations declined in a biexponential fashion, with a terminal half life of 24.1 +/- 1.9 h (mean +/- s.e. mean). In six of the 17 subjects, the mean steady state plasma concentration was less than 75% of the value predicted from the single dose data.

Adolescent↗

PubMed1990

Dipyridamole magnetic resonance imaging: a comparison with thallium-201 emission tomography.

Limitation of space and motion artefact make magnetic resonance imaging during dynamic exercise difficult. Pharmacological stress with dipyridamole can be used as an alternative to exercise for thallium scanning. Forty patients with a history of angina and an abnormal exercise electrocardiogram were studied by dipyridamole thallium myocardial perfusion tomography and dipyridamole magnetic resonance wall motion imaging with a cine gradient refocused sequence. Images for both scans were obtained in the oblique horizontal and vertical long axis and short axis planes before and after pharmacological stress with dipyridamole. The myocardium was divided into nine segments for direct comparison of perfusion with wall motion. Segments were assessed visually into grades--normal, hypokinesis or reduced perfusion, and akinesis or very reduced perfusion. After dipyridamole there were reversible wall motion abnormalities in 24 (62%) of 39 patients with coronary artery disease and 24 (67%) of 36 patients with reversible thallium defects. The site of wall motion deterioration was always the site of a reversible thallium defect. Thallium defects affecting more than two segments were always associated with wall motion deterioration but most single segment thallium defects were undetected by magnetic resonance imaging. There was a significant correlation between detection of wall motion abnormality, the angiographic severity of coronary artery disease, and the induction of chest pain by dipyridamole. There were no significant differences in ventricular volume or ejection fraction changes after dipyridamole between the groups with and without detectable reversible wall motion changes but the normalised magnetic resonance signal intensity of the abnormally moving segments was significantly less than the signal intensity of the normal segments. In nine patients the change was apparent visually and it was maximal in the subendocardial region. Magnetic resonance imaging of reversible wall motion abnormalities in patients with coronary artery disease is feasible during pharmacological stress with dipyridamole and may be associated with a reduced magnetic resonance signal. The failure to show wall motion abnormalities in all cases of reversible thallium defects may be because the defect was small or because dipyridamole caused perfusion defects in the absence of myocardial ischaemia.

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