Dipyridamole, effect

Mithani SD. Dissolution and Precipitation of Dipyridamole Effect of pH and Bile Salt Concentration. Thesis The University of Michigan, Michigan, 1998. 

Initially, it was beheved that the abiUty of xanthines phosphodiesterase (PDF) led to bronchodilation (Fig. 2). One significant flaw in this proposal is that the concentration of theophylline needed to significantly inhibit PDE in vitro is higher than the therapeutically useful semm values (72). It is possible that concentration of theophylline in airways smooth muscle occurs, but there is no support for this idea from tissue distribution studies. Furthermore, other potent PDE inhibitors such as dipyridamole [58-32-2] are not bronchodilators (73). EinaHy, although clinical studies have shown that neither po nor continuous iv theophylline has a direct effect on circulating cycHc AMP levels (74,75), one study has shown that iv theophylline significant potentiates the increase in cycHc AMP levels induced by isoproterenol (74). 

Administration of dipyridamole-AMP to mice 5—25 min after 1 Gy (100 rad) of TBI y-kradiation is also protective, as indicated by plasma thymidine levels and the amount of saline soluble polynucleotides in the thymus (112). Adding dipyridamole-AMP to in vitro kradiated suspensions of thymocytes enhances the rejoining of DNA strand breaks (112). These post-kradiation effects ate presumably mediated by the activation of extraceUulat adenosine receptors. 

Adenosine is produced by many tissues, mainly as a byproduct of ATP breakdown. It is released from neurons, glia and other cells, possibly through the operation of the membrane transport system. Its rate of production varies with the functional state of the tissue and it may play a role as an autocrine or paracrine mediator (e.g. controlling blood flow). The uptake of adenosine is blocked by dipyridamole, which has vasodilatory effects. The effects of adenosine are mediated by a group of G protein-coupled receptors (the Gi/o-coupled Ai- and A3 receptors, and the Gs-coupled A2a-/A2B receptors). Ai receptors can mediate vasoconstriction, block of cardiac atrioventricular conduction and reduction of force of contraction, bronchoconstriction, and inhibition of neurotransmitter release. A2 receptors mediate vasodilatation and are involved in the stimulation of nociceptive afferent neurons. A3 receptors mediate the release of mediators from mast cells. Methylxanthines (e.g. caffeine) function as antagonists of Ai and A2 receptors. Adenosine itself is used to terminate supraventricular tachycardia by intravenous bolus injection. 

Beyond Viagra, there are a number of other PDE inhibitors that are used clinically. In fact, the classic drugs papaverine and dipyridamole were used clinically before their effects on PDEs were known. Caffeine and theophylline (a compound found in tea) are also PDE inhibitors. However, all of these drugs most likely have multiple targets, making conclusions regarding the roles of PDEs in processes that are sensitive to these agents difficult to interpret. Certainly, some of their effects are due to their actions on adenosine receptors. 

Dipyridamole exerts its effect by inhibition of platelet phosphodiesterase E5, increasing cyclic guanosine monophosphate and cyclic adenosine monophosphate (cAMP). By inhibiting its uptake and metabolism by erythrocytes, dipyridamole also increases the availability of adenosine within blood vessels, promoting inhibition of platelet aggregation and local vasodilatation. " Dipyridamole may also inhibit cAMP phosphodiesterase in platelets, which further increases cAMP levels and may enhance endothelial nitric oxide production, contributing to its antithrombotic effect. Existing trials of dipyridamole in stroke have focused on secondary prevention and will be discussed briefly. 

The European/Australian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) confirmed the finding of ESPS 2, showing that the combination of aspirin and dipyridamole is more effective than aspirin alone in the prevention of new vascular events in patients with nondisabling cerebral ischaemia of presumed arterial origin. Adding the ESPRIT data to the meta-analysis of previous trials resulted in an overall risk ratio for the composite of vascular death, stroke, or MI of 0.82 (95% Cl 0.74-0.91). 

L Landi, D Fiorentini, M Lucarini, E Marchesi, GF Pedulli. Effect of the medium on the antioxidant activity of dipyridamole. In SFRR Europe Summer Meeting, June 26-28, 1997, Abano Terme. Book of Abstracts, p 265. 

Adenosine and inosine can be transported across cell membranes in either direction, facilitated by a membrane-associated nucleoside transport protein. Concentrative transporters have also been identified. Messenger RNA for a pyrimidine-selective Na+-nucleoside cotransporter (rCNTl) and a purine-selective Na+-nucleoside cotransporter (rCNT2) are found throughout the rat brain. Most degradation of adenosine is intracellular, as evidenced by the fact that inhibitors of adenosine transport, such as dipyridamole, increase interstitial levels of adenosine. Dipyridamole is used clinically to elevate adenosine in coronary arteries and produce coronary vasodilation. In high doses, dipyridamole can accentuate adenosine-receptor-mediated actions in the CNS, resulting in sedation and sleep, anticonvulsant effects, decreased locomotor activity and decreased neuronal activity. 

Bohyn, M., Berkenboom, G., Fontaine, J., Effect of nitrate tolerance and dipyridamole on the response to SINj in human isolated saphenous vein. Cardiovasc. Drugs. Then 5 (1991), p. 457-462... 

Torfgard, K. E., Ahlner, )., Effect of a low dose of dipyridamole on glyceryl trinitrate tolerance in healthy volunteers. J. Cardiovasc. Pharmacol. 21 (1993), p. 516-521... 

Adverse reactions at therapeutic doses are usually minimal and transient. With long-term use, initial side effects usually disappear. The following reactions were reported in 2 heart valve replacement trials comparing dipyridamole and warfarin therapy to either warfarin alone or warfarin and placebo dizziness, abdominal distress, headache, and rash. 

Pharmacology Antithrombotic action is the result of the additive antiplatelet effects of dipyridamole and aspirin. 

Coronary artery disease Due to the vasodilatory effect of dipyridamole, use with caution in patients with severe coronary artery disease (eg, unstable angina, recently sustained Ml). Chest pain may be aggravated in patients with underlying coronary artery disease who are receiving dipyridamole. For stroke or transient ischemic attack patients for whom aspirin is indicated to prevent recurrent Ml or angina pectoris, the aspirin in this product may not provide adequate treatment for the cardiac indications. 

The DNA-mediated effects of fluropyrimidines can be modulated by a number of agents, such as leucovorin (LV), levamisole, and interferon-alpha (IFN-alpha). LV prolongs TS inhibition by increasing the availability of the reduced folate cofactor necessary for formation of the inactive TS-FdUMP complex (21) (Fig. 4). Studies show alpha-interferon can potentiate 5-FU-mediated cyotoxicity, but the mechanisms are not yet defined (22,23). Another approach to modulate the activity of fluoropyrimidines is the use of the nucleoside transport inhibitor dipyridamole. Dipyridamole probably permits... 

Fig. 2.11 Effect of vigorous lifestyle and pharmacologic management on stopping progression of CAD. Top row PET scan a year after bypass surgery, showing a severe resting defect of the apex in the distribution of the initial LAD occlusion. Middle row Dipyridamole stress causes more...

Fig. 2.12 Effect of intense medical therapy on progression of non-revascularized CAD. Rest perfusion image upper row) shows a small transmural scar in the distribution of the distal LCx that is more severe and larger after dipyridamole stress...

Aspirin and ticlopidine are used for their antiplatelet effect. They lower the risk of vascular recurrence by 27%. Asasantine (aspirin 50 mg - - dipyridamole 400 mg) lowers the risk by 37% (ESPS2). Clopidro-gel (75 mg) lowers the risk of recurrent vascular events after cerebral, cardiac or lower limb infarction by 8.7%. 

Therapy, in the short term, is with intravenous unfractionated or subcutaneous low molecular weight heparin. Aspirin, given in low doses between 50 and 100 mg per day, is sufficient to diminish platelet-vessel interaction. Alternatives include 100-200 mg of sulphinpyrazone once or twice a day or dipyridamole where 100 mg four times a day can be used on its own or between 25 and 75 mg combined with aspirin three times a day. More recently thiopy-ridines, as a class, has been shown to have equivalence at 250 mg twice a day. In hyperhomocysteinaemia the risk is reduced by 5 mg of folate and 100 mg of vitamin Bg daily, with addition of oral vitamin Bi2 of less clearly defined benefit. The effect of this intervention requires re-assay at 3-monthly intervals, following standard methionine challenge, to ensure that suitable suppression has been achieved in the plasma amino acid level (Table 5). 

Metabolism of adenosine is slowed by dipyridamole, indicating that in patients stabilized on dipyridamole the therapeutically effective dose of adenosine may have to be increased. Methylxanthines antagonize the effects of adenosine via blockade of the adenosine receptors. 

Anon. Clinical trials on AIDS start. Reprowatch 1999 1—28 6—11. Garcia-Fuentes, E., A. Gil-Villarino, M. F. Zafra, and E. Garcia-Peregrin. Changes in plasma lipid composition induced by coconut oil. Effects of dipyridamole. J Physiol Biochem 2002 58(1) 33-41. 

Adenosine is a nucleoside that occurs naturally throughout the body. Its half-life in the blood is less than 10 seconds. Its mechanism of action involves activation of an inward rectifier K+ current and inhibition of calcium current. The results of these actions are marked hyperpolarization and suppression of calcium-dependent action potentials. When given as a bolus dose, adenosine directly inhibits atrioventricular nodal conduction and increases the atrioventricular nodal refractory period but has lesser effects on the sinoatrial node. Adenosine is currently the drug of choice for prompt conversion of paroxysmal supraventricular tachycardia to sinus rhythm because of its high efficacy (90-95%) and very short duration of action. It is usually given in a bolus dose of 6 mg followed, if necessary, by a dose of 12 mg. An uncommon variant of ventricular tachycardia is adenosine-sensitive. The drug is less effective in the presence of adenosine receptor blockers such as theophylline or caffeine, and its effects are potentiated by adenosine uptake inhibitors such as dipyridamole. 

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