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PubMed1999

Chronic dipyridamole therapy produces sustained protection against cardiac ischemia-reperfusion injury.

Sustained protection against ischemia-reperfusion injury is not available for patients at risk for myocardial infarction who may require emergent reperfusion therapy. Whereas ischemic preconditioning and adenosinergic agents reduce myocardial injury, they are only effective when given immediately before ischemia or reperfusion. We recently found chronic ethanol exposure, an adenosine uptake inhibitor, produced sustained cardioprotection against ischemia-reperfusion injury. We now ask whether chronic dipyridamole therapy, a clinically usable nucleoside transport inhibitor, induces similar cardioprotection. Perfused hearts from guinea pigs, given dipyridamole (4 mg. kg(-1). day(-1)) in their water for 2-6 wk (n = 10 for each group), underwent ischemia-reperfusion. Injury was assessed by recovery of left ventricular developed (LVDP) and end-diastolic (LVEDP) pressures and creatine kinase release. During reperfusion, hearts from dipyridamole-treated animals (6 wk) had 74% higher LVDP, 28% lower LVEDP, and 61% lower creatine kinase release versus controls. Adenosine A(1)-receptor antagonism (8-cyclopentyl-1, 3-dipropylxanthine; 200 nM) abolished the protection of dipyridamole but A(2) antagonism (3,7-dimethyl-1-propargylxanthine; 10 mM) did not. Dipyridamole therapy produces sustained protection against ischemia-reperfusion injury in guinea pigs. This cardioprotection requires adenosine A(1) receptor signaling at the time of ischemia.

Animals↗
PubMed2005

Enhanced antiplatelet effects of clopidogrel plus acetylsalicylic acid compared with acetylsalicylic acid alone or combined with extended-release dipyridamole in healthy volunteers.

BACKGROUND: Previous studies have shown the potential benefit of using antiplatelet agents with complementary modes of action. METHODS: Using a crossover design, the ex vivo antiplatelet effects of 10 days' treatment with clopidogrel 75 mg + acetylsalicylic acid (ASA) 75 mg daily, ASA 75 mg/day, or extended-release dipyridamole 200 mg/low-dose ASA 25 mg twice daily were compared, using various platelet agonists. RESULTS: Clopidogrel + ASA was significantly more effective than dipyridamole + ASA in inhibiting collagen-induced platelet aggregation in whole blood (mean 44.9 +/- 5.6% inhibition vs. 16.5 +/- 6.7%; p = 0.0009). Clopidogrel + ASA was significantly more effective than ASA or dipyridamole + ASA in inhibiting ADP-induced platelet aggregation in whole blood (p < or = 0.0001) and platelet-rich plasma (PRP) (p < or = 0.0001), and in inhibiting collagen-induced aggregation in PRP (p < or = 0.0001). ASA alone and clopidogrel + ASA were significantly more effective than dipyridamole + ASA in inhibiting arachidonic acid-induced platelet aggregation in whole blood (p < or = 0.0001). CONCLUSIONS: Based on ex vivo platelet aggregometry, clopidogrel + ASA is a more potent antiplatelet regimen than either ASA alone or the marketed combination of dipyridamole + ASA. However, the clinical significance of this finding remains to be confirmed.

Adult↗
PubMed1990

Enhancement of specific biological activity of dipyridamole by complexation with beta-cyclodextrin.

Dipyridamole forms an inclusion complex with beta-cyclodextrin (dip-beta-CD) which shows better solubility and bioavailability than the uncomplexed compound. The present studies have demonstrated that dip-beta-CD is more effective than dipyridamole either as base or HCl (dispersed or not in lactose) on some important cardiovascular parameters when orally administered to conscious animals. In particular, dip-beta-CD causes a stronger and prompter coronary and carotid vasodilatation in dogs, at doses which weakly influence the systemic arterial pressure and the heart rate. In addition, platelets collected from treated rabbits at various intervals appear to be protected from sodium adenosine diphosphate-induced aggregation in vitro more effectively and rapidly by dip-beta-CD than by dipyridamole. Studies on tail bleeding time have confirmed that dip-beta-CD is more active than dipyridamole when given orally to mice. These biological findings are fully in agreement with other oral bioavailability studies in dogs and men indicating that dip-beta-CD gives quicker and higher blood levels with smaller interindividual variability than dipyridamole.

Adenosine Diphosphate↗
PubMed1986

Effect of the antiplatelet agents ticlopidine and dipyridamole on experimental immune complex glomerulonephritis in rats.

The effect of the antiplatelet agents ticlopidine and dipyridamole on immune complex glomerulonephritis in rats was evaluated. Bovine serum albumin (BSA) nephritis was induced in rats with subcutaneous immunization and intravenous dosage of BSA. Ticlopidine and dipyridamole were administered for 4 weeks before and for 7 days after onset of proteinuria. It was shown that both ticlopidine and dipyridamole could reduce the development of proteinuria when administered before the onset of proteinuria. Ticlopidine also reduced the amount of urinary protein after onset of proteinuria, and may thus be more effective against urinary protein excretion. When the antiplatelet agents were administered before onset of glomerulonephritis, blood urea nitrogen and serum creatinine levels were significantly lower, and glomerular hypercellularity and mesangial widening were milder in animals treated with ticlopidine than in controls. Glomerular deposition of BSA was less intense in treated animals than in nontreated controls. Thus, ticlopidine as well as dipyridamole was found to inhibit the development of proteinuria and glomerular alteration. It is suggested that ticlopidine could be more effective than dipyridamole against the development of immune complex glomerulonephritis in rats.

Animals↗
PubMed1988

Effects of dipyridamole on the hypoxemic pulmonary hypertension of patients with chronic obstructive pulmonary disease.

Based on the hypothesis that blood platelets contribute to the pathogenesis of hypoxemic pulmonary hypertension in patients with chronic obstructive pulmonary disease (COPD), the effect of a prolonged treatment with dipyridamole, a platelet-inhibiting drug, on hypoxemic pulmonary hypertension was evaluated in a double-blind cross-over study. Eight patients with COPD, pulmonary hypertension [mean systolic pressure 52.2 +/- (SD) 9.7 mm Hg; mean diastolic pressure 25.8 +/- (SD) 6.8 mm Hg] and shortened platelet regeneration time [mean 5.2 +/- (SD) 1.2 days] received, in a cross-over random sequence, the following two 3-month treatments: (a) dipyridamole 100 mg and acetylcysteine 100 mg every 6 h; (b) acetylcysteine, 100 mg every 6 h. Dipyridamole significantly prolonged the platelet regeneration time [mean 6.5 +/- (SD) 1.0 days; p less than 0.05]. There was no significant effect on diastolic pulmonary pressure. However, systolic pressure was significantly (p less than 0.05) lower after dipyridamole [46.8 +/- (SD) 16 mm Hg] than after placebo [56.1 +/- (SD) 14 mm Hg]. These results suggest that dipyridamole can slow the progression of hypoxemic pulmonary hypertension in patients with COPD.

Aged↗
PubMedDate not supplied

Dipyridamole decreases platelet-derived growth factor levels in human serum.

Mitogenic activities on confluent fibroblasts by sera from patients with scleroderma and normal controls were studied. In experiments using eight different fibroblast strains (one human fetal lung fibroblast, one foreskin fibroblast, three adult skin fibroblast, and three scleroderma fibroblast), pooled scleroderma serum showed lower mitogenic activity by 3H-thymidine incorporation assay than pooled normal serum. Individual serum investigations revealed that 11 of 33 patients (33%) showed low mitogenic activities; all 11 patients were receiving dipyridamole. Of 15 patients, 11 (73%) receiving dipyridamole showed low mutagenic activities; none of 18 patients not receiving dipyridamole showed low mitogenic activities. Approximately 70% of this serum activity was inhibited by the addition of anti-platelet-derived growth factor (PDGF) antibody indicating that most of this serum activity seemed to be derived from PDGF. Western blot analysis of extracts of normal sera before and after administration of dipyridamole with antihuman PDGF antibody showed a large decrease in the amount of immunoreactive PDGF present. These data indicate that dipyridamole is an effective drug to lower release of PDGF during blood clotting.

Adult↗
PubMed1999

Early dipyridamole (99m)Tc-sestamibi single photon emission computed tomographic imaging 2 to 4 days after acute myocardial infarction predicts in-hospital and postdischarge cardiac events: comparison with submaximal exercise imaging.

BACKGROUND: Because of its brief hemodynamic effects and minor effect on determinants of myocardial oxygen demand, vasodilator stress myocardial perfusion imaging (MPI) can be applied very early after acute myocardial infarction (AMI) for risk stratification, allowing management decisions to be made earlier and thus potentially shortening hospitalization stays, reducing costs, and preventing early cardiac events. This multicenter randomized trial compared the prognostic value of early dipyridamole MPI and standard predischarge submaximal exercise MPI in patients who presented with AMI. METHODS AND RESULTS: Patients who presented with their first AMI (n=451) were randomized in a 3:1 ratio to undergo either both an early (day 2 to 4) dipyridamole (99m)Tc-sestamibi MPI study and a predischarge (day 6 to 12) submaximal exercise (99m)Tc-sestamibi MPI study or only the predischarge study. Multivariate predictors of in-hospital cardiac events included nuclear imaging summed stress and summed reversibility scores and peak creatine kinase. For postdischarge cardiac events, multivariate predictors in patients undergoing dipyridamole MPI included only the summed stress, reversibility, and rest imaging scores and anterior MI. For a given summed stress score, the interaction of reversibility score further improved the predictive value. Dipyridamole MPI showed better risk stratification than submaximal exercise MPI. CONCLUSIONS: Dipyridamole MPI very early after MI predicts early and late cardiac events, with superior prognostic value compared with submaximal exercise imaging. The extent and severity of the stress defect and reversibility of the defect were the most important predictors of cardiac death and recurrent MI. This technique can allow management decisions to be made earlier with regard to AMI patients and could have important economic impact if applied widely.

Dipyridamole↗
PubMed1981

Acute effect of intravenous dipyridamole on regional coronary hemodynamics and metabolism.

The acute coronary hemodynamic and metabolic effects of intravenous dipyridamole were studied in 13 patients. Total left ventricular (LV), anterior (supplied by the left anterior descending coronary artery) and inferior (supplied by circumflex and right coronary arteries) regional flows and metabolic responses were assessed from the coronary sinus and great cardiac vein. Perfusion to LV regions was classified as potentially "normal" or "abnormal," based on coronary angiographic findings. Before dipyridamole, coronary flow, LV oxygen delivery and lactate extraction in both the normal and abnormal regions were similar. Within 1 minute after injection of 20 mg of dipyridamole by i.v. bolus, total coronary flow increased 51% (p less than 0.05). Fifteen minutes after injection the flow increase persisted. Flow decreased to approximately control level by 20 minutes. The major component of this increased total coronary flow resulted from increased flow in normal regions (75% at 1 minute, p less than 0.05). Mean regional LV oxygen delivery and lactate extraction were not changed significantly in either normal or abnormal regions. However, lactate production occurred more often after dipyridamole in abnormal regions. These results suggest that during dipyridamole-induced hyperemia, regional coronary flow and metabolic responses depend upon the status of the arteries supplying the LV region. Regional differences in flow and metabolism occur independent of major changes in heart rate and aortic and LV pressures.

Adult↗
PubMed1987

The physiologic basis of dobutamine as compared with dipyridamole stress interventions in the assessment of critical coronary stenosis.

Noninvasive cardiac imaging with echocardiography or thallium-201 scintigraphy utilizing pharmacologic agents as alternatives to exercise is gaining popularity. We investigated the physiologic rationale underlying the optimal choice of pharmacologic stress for functional versus perfusion imaging. With the use of an open-chest dog model, a critical stenosis of the left circumflex coronary artery was produced with total ablation of hyperemic response to a 15 sec period of complete occlusion. Regional left ventricular wall thickening was assessed by quantitative two-dimensional echocardiography. Regional myocardial blood flow was determined by microspheres in both the flow-restricted left circumflex area and the control area supplied by the left anterior descending artery. Eight dogs received 15 micrograms/kg/min dobutamine intravenously for 10 min, and nine dogs received 0.14 mg/kg/min dipyridamole intravenously for 4 min. Dobutamine induced wall thickening abnormalities in all dogs while dipyridamole induced dysfunction in only 55% of the animals studied (p less than .01). Subendocardial blood flow to the left circumflex area was unchanged after both dobutamine and dipyridamole when compared with baseline blood flow. However, subendocardial blood flow increased markedly after dipyridamole in the control area. Regional subendocardial blood flow ratio (left anterior descending/left circumflex) was 3.74 +/- 0.09 (mean +/- SEM) after dipyridamole versus 1.27 +/- 0.09 after dobutamine (p less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Dipyridamole potentiates the myocardial infarct size-limiting effect of ischemic preconditioning.

BACKGROUND: Recent studies implicated a key role for adenosine (ADO) receptor activation in the enhancement of ischemic tolerance by ischemic preconditioning. In this study, we aimed to test the hypothesis that dipyridamole, an ADO transport inhibitor, enhances the preconditioning effect. METHODS AND RESULTS: Six groups of rabbits underwent 30-minute coronary occlusion and 72-hour reperfusion. Infarct size (IS) and the area-at-risk (AR) were determined by histology and by use of fluorescent particles, respectively. IS expressed as the percentage of AR (%IS/AR) was 46.5 +/- 3.4% (n = 13) in control rabbits. Preconditioning with 2-minute ischemia tended to limit %IS/AR (%IS/AR, 35.5 +/- 3.5%, n = 9), and that possible protection was abolished by pretreatment with 10 mg/kg 8-phenyltheophylline (8-PT), an ADO receptor antagonist (%IS/AR, 43.9 +/- 5.8%, n = 9). Administration of dipyridamole (0.25 mg/kg) before the 2-minute preconditioning markedly limited %IS/AR to 13.8 +/- 2.6% (n = 12), indicating the potentiation of the preconditioning effect by this agent. Furthermore, this enhancement of preconditioning effect by dipyridamole treatment was significantly attenuated by 8-PT (%IS/AR, 27.6 +/- 2.1%, n = 11). Dipyridamole given before the 30-minute ischemia, without preconditioning, did not reduce %IS/AR (55.3 +/- 5.2%, n = 7), and a previous study from this laboratory had demonstrated that the present dose of 8-PT alone did not modify IS in the rabbit. CONCLUSIONS: Dipyridamole significantly potentiated the IS-limiting effect of preconditioning. This finding strongly supports the hypothesis that stimulation of ADO receptors by endogenous ADO, which builds up during preconditioning ischemia, mediates the increased ischemic tolerance afforded by preconditioning.

Adaptation, Physiological↗
PubMed2001

Abnormal renal vascular responses to dipyridamole-induced vasodilation in spontaneously hypertensive rats.

The objective of this study was to determine whether there were differences in hemodynamic responses of different vascular beds to systemic administration of dipyridamole between spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. To this end, systemic hemodynamics and organ blood flows (using labeled microspheres) were determined in conscious rats before and 10 minutes after dipyridamole (4 mg. kg(-1). min(-1)) infusion. In both the normotensive and hypertensive rats, the dipyridamole infusion reduced arterial pressure by approximately 20 mm Hg, associated with a decreased total peripheral resistance and an increased cardiac output. Renal blood flow decreased significantly in SHR after dipyridamole but remained unchanged or increased slightly in the WKY rats. There were no other differences in regional hemodynamics, including those of brain, liver, skin, and muscle, between the WKY and SHR. Antihypertensive treatment completely restored normal renal vascular response to dipyridamole. Previous reports had demonstrated an abnormal coronary hemodynamic response of the SHR. Our data demonstrate that, as with coronary hemodynamics, hypertension selectively induced alterations in renal vasculature. These findings may be of importance in identifying the earliest hemodynamic evidence of developing hypertensive nephrosclerosis.

Animals↗
PubMedDate not supplied

The effect of intravenous dipyridamole on the cerebral and systemic circulations of the dog.

In 7 dogs anesthetized with halothane and nitrous oxide, dipyridamole was administered in a loading dose of 1 mg/kg supplemented with 0.5 mg/kg every 30 minutes. Cardiovascular parameters and organ blood flows (using the radioactive microsphere technique) were measured before and at 30 minute intervals after each administration of dipyridamole, for a total of 105 minutes. The administration of dipyridamole was associated with a 20% reduction in systemic arterial pressure, a 31% reduction in peripheral vascular resistance, and a 13% increase in cardiac index. Cerebrovascular resistance decreased 21%, but regional cerebral blood flow and metabolism were unchanged. Blood flow to the heart increased 355% in the right ventricle and 213% in the left ventricle. Blood flow to the jejunum decreased 52% while blood flow to the kidney and liver decreased slightly. The circulatory effects of dipyridamole are probably related to its interference with the inactivation of endogenous adenosine. The differential effects of dipyridamole on organ flow are similar to those seen following the IV infusion of adenosine.

Animals↗
PubMed1976

Effect of nitroglycerin and dipyridamole on regional left ventricular blood flow during coronary artery occlusion.

Coronary vasodilators have been variously reported to increase, decrease, or have no effect upon blood flow to ischemic myocardium. Consequently, the effects of two different types of dilators, nitroglycerin (TNG) and dipyridamole, were studied with radioactive microspheres in open-chested dogs after coronary artery ligation. Given as a bolus i.v. injection 0.4 mg TNG resulted in an increase in blood flow to nonischemic areas of myocardium and a preservation of flow to ischemic regions, despite a fall in blood pressure. 5 min later blood pressure and nonischemic flow were back to base line, and a small selective increase in flow to ischemic myocardium was found (0.15-0.18 ml/min per g, P less than 0.05). During an 0.2 mg/min infusion of TNG, and also after 1 mg/kg i.v. dipyridamole, ischemic flow was maintained in the face of a 20-30% reduction in blood pressure. In this setting, nonischemic flow was unchanged during TNG and doubled after dipyridamole. With the addition of methoxamine in both dilator groups, blood pressure returned to base line while flow to ischemic areas increased above base-line values (TNG, 0.16-0.20 ml/min per g, P less than 0.01; dipyridamole, 0.18-0.31 ml/min per g, P less than 0.05). Epicardial ST segment elevations increased during TNG infusion and were unchanged after dipyridamole, but with addition of methoxamine, ST segments became less elevated in both drug groups, concomitant with the observed increase in collateral blood flow. These data indicate that both types of coronary vasodilators, when used in conjunction with methoxamine to support blood pressure, reduce collateral resistance, increase collateral flow, and reduce epicardial ST-segment elevations.

Animals↗
PubMed1984

Relationship between regional myocardial blood flow and thallium-201 distribution in the presence of coronary artery stenosis and dipyridamole-induced vasodilation.

This study assesses the relationship between the distribution of thallium-201 and myocardial blood flow during coronary vasodilation induced by intravenous dipyridamole in canine models of partial and complete coronary artery stenosis. 10 dogs were chronically instrumented with catheters in the left atrium and aorta and with a balloon occluder and electromagnetic flow probe on the proximal left circumflex coronary artery. Regional myocardial blood flow was measured during control conditions with radioisotope-labeled microspheres, and the phasic reactive hyperemic response to a 20-s transient occlusion was then recorded. Dipyridamole was then infused intravenously until phasic coronary blood flow increased to match peak hyperemic values. The left circumflex coronary artery was either partially occluded to reduce phasic blood flow to control values (group 1) or it was completely occluded (group 2), and thallium-201 and a second microsphere label were injected. 5 min later, the animals were sacrificed, the left ventricle was sectioned into 1-2-g samples, and thallium-201 activity and regional myocardial blood flow were measured. Curvilinear regression analyses between thallium-201 localization and myocardial blood flow during dipyridamole infusion demonstrated a slightly better fit to a second- as compared with a first-order model, indicating a slight roll-off of thallium activity as myocardial blood flow increases. During the dipyridamole infusion, the increases in phasic blood flow, the distributions of regional myocardial blood flow, and the relationships between thallium-201 localization and regional blood flow were comparable to values previously observed in exercising dogs with similar occlusions. These data provide basic validation that supports the use of intravenous dipyridamole and thallium-201 as an alternative to exercise stress and thallium-201 for evaluating the effects of coronary occlusive lesions on the distribution of regional myocardial blood flow.

Animals↗
PubMed2001

Dipyridamole-induced ST-segment elevation indicative of transmural myocardial ischemia--a case report.

Dipyridamole nuclear myocardial perfusion test is a safe and effective alternative to exercise nuclear perfusion testing for detecting myocardial ischemia. It is the procedure of choice in selected patients who are unable to exercise adequately. Intravenous dipyridamole causes coronary vasodilation with resultant maldistribution and heterogeneity of coronary flow in the presence of significant coronary artery disease. True ischemia, causing symptoms or ST-segment depression, is uncommon, in part because there is no increase in myocardial oxygen demand. A patient in whom myocardial ischemia developed, manifested by ST-segment elevation, during dipyridamole stress testing is described. Scintigraphic images illustrated a myocardial perfusion defect, which was consistent with coronary angiographic findings. This case report addresses the importance of dipyridamole-induced ST-segment elevation, its correlation with angiographic findings, and the need for continued hemodynamic and electrocardiographic monitoring in patients following dipyridamole infusion.

Coronary Angiography↗
PubMed1991

Intravenous dipyridamole: use in thallous chloride TL 201 stress imaging.

An intravenous form of dipyridamole has been approved for cardiac stress testing with thallous chloride Tl 201 (201Tl) imaging. The procedure provides an alternative method for stress testing of patients who cannot perform strenuous physical exercise because of physical limitations or those in the immediate postinfarction period. Dipyridamole simulates the physiologic effects of physical exercise by increasing adenosine concentrations, which in turn increases coronary blood flow. Dipyridamole maximizes the differences in uptake of radioactive thallium in myocardial regions supplied by normal coronary arteries and those distal to stenosed arteries where blood flow is reduced. The sensitivity and specificity of dipyridamole-201Tl stress imaging for the detection of coronary disease are comparable to those of traditional exercise-201Tl stress testing. The intravenous dipyridamole usually is well tolerated, and the majority of adverse effects can be reversed with the administration of aminophylline.

Coronary Disease↗
PubMed2006

Comparison of exercise, dobutamine-atropine and dipyridamole-atropine stress echocardiography in detecting coronary artery disease.

BACKGROUND: Dipyridamole and dobutamine stress echocardiography testing are most widely utilized, but their sensitivity remained suboptimal in comparison to routine exercise stress echocardiography. The aim of our study is to compare, head-to-head, exercise, dobutamine and dipyridamole stress echocardiography tests, performed with state-of-the-art protocols in a large scale prospective group of patients. METHODS: Dipyridamole-atropine (Dipatro: 0.84 mg/kg over 10 min i.v. dipyridamole with addition of up to 1 mg of atropine), dobutamine-atropine (Dobatro: up to 40 mcg/kg/min i.v. dobutamine with addition of up to 1 mg of atropine) and exercise (Ex, Bruce) were performed in 166 pts. Of them, 117 pts without resting wall motion abnormalities were enrolled in study (91 male; mean age 54 +/- 10 years; previous non-transmural myocardial infarction in 32 pts, angina pectoris in 69 pts and atypical chest pain in 16 pts). Tests were performed in random sequence, in 3 different days, within 5 day period under identical therapy. All patients underwent coronary angiography. RESULTS: Significant coronary artery disease (CAD; > or =50% diameter stenosis) was present in 69 pts (57 pts 1-vessel CAD, 12 multivessel CAD) and absent in 48 pts. Sensitivity (Sn) was 96%, 93% and 90%, whereas specificity (Sp) was 92%, 92% and 87% for Dobatro, Dipatro and Ex, respectively (p = ns). Concomitant beta blocker therapy did not influence peak rate-pressure product and Sn of Dobatro and Dipatro (p = ns). CONCLUSION: When state-of-the-art protocols are used, dipyridamole and dobutamine stress echocardiography have comparable and high diagnostic accuracy, similar to maximal post-exercise treadmill stress echocardiography.

Atropine↗
PubMed1991

Pharmacokinetic and pharmacodynamic analysis of fluorouracil during 72-hour continuous infusion with and without dipyridamole.

During a phase I trial of 3-day simultaneous continuous intravenous infusions of varying doses of fluorouracil (5FUra) and 7.7 mg/kg/d of dipyridamole, we examined the relationships between 5FUra dose and steady-state plasma concentration (Css) and the percentage reduction in WBCs, as well as the percentage frequency of stomatitis. The 5FUra was administered at doses ranging from 185 mg/m2/d times three to 3,600 mg/m2/d times three. In 42 patients, 86 cycles of 5FUra plus dipyridamole and 28 cycles of 5FUra alone were analyzed. The Css of 5FUra varied even within the same dose level. When patients receiving the same 5FUra dose were considered, the interpatient coefficient of variation of 5FUra Css in cycles of 5FUra plus dipyridamole was 23% +/- 4.2%. For courses of 5FUra alone, the coefficient of variation of 5FUra was 15.6% +/- 6.5%. When the occurrence of any degree of stomatitis was related to the Css 5FUra, with patients grouped in cohorts of 2-mumol/L increments, the following equations accurately described the frequency of stomatitis: for 5FUra plus dipyridamole, percentage frequency of stomatitis = 100(1-e-0.114Css), r2 = 0.88; for 5FUra alone, percentage frequency stomatitis = 100(1-e0.122Css), r2 = 0.80. When 5FUra dose was substituted for Css, these relationships were as follows: percentage frequency of stomatitis = 100(1-e-0.00031 [dose]), r2 = 0.85; and percentage frequency of stomatitis = 100(1-e-0.00051 [dose]), r2 = 0.80. When the relationship between the percentage reduction in WBC and Css 5FUra was examined, statistically significant relationships were also apparent: for 5FUra plus dipyridamole, percentage reduction in WBC = 100(1-e-0.085Css), r2 = 0.46; for 5FUra alone, percentage reduction in WBC = 100(1-e-0.060Css), r2 = 0.61. When 5FUra dose was substituted for Css, these relatinships were as follows: percentage reduction in WBC = 100(1-e-0.00023 [dose]), r2 = 0.40; percentage reduction in WBC = 100(1-e-0.00024 [dose]), r2 = 0.65. The relationship between either Css 5FUra or dose 5FUra and either stomatitis or myelosuppression were also well described by the modified Hill equation (J Theor Biol 20:171-201, 1968). These analyses indicate that it should be possible to develop therapeutic regimens wherein 5FUra is administered to achieve a targeted Css determined by the risk and severity of toxicity deemed acceptable.

Bone Marrow Diseases↗