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To clarify the mode of action of the vasoactive agent buflomedil, we evaluated plasma levels of adenosine and adenine nucleotides after intravenous (i.v.) infusion in humans of 50, 100, and 200 mg of the drug in 20 min. Buflomedil induced an increase of the same order of magnitude in plasma levels of adenosine and adenine nucleotides. Maximal adenosine increase (84%) was observed at the end of the infusion period, whereas peak plasma levels of ATP and ADP (69 and 55%, respectively) and of AMP (61%) were detected 10 and 5 min after discontinuation of infusion, respectively. Although the exact mode of action of buflomedil at the molecular level remains unclear, some indirect findings suggest that the increase in adenosine may be due to enhanced release rather than to inhibition of cell uptake. Because such activity of buflomedil consists of enhancement of physiologic mechanisms of vasodilation and tissue protection occurring in the course of ischemic events, new pharmacologic perspectives for the drug may arise.

In the first part of the study 5 control subjects were submitted to iv infusion of 0.2 mM/kg of calcium gluconate in 20 min. Total calcium (atomic absorbtion method), ionized calcium (ion-selective electrode method) and adenosine (HPLC technique) were measured at the following times: 0 (baseline), 5, 10, 15, 20 (end of infusion), 25, 30, 35, and 50 min. The increase of total and ionized calcium serum levels was associated with a significant increase of adenosine plasma levels (from 207 +/- 41 to 362 +/- 63 nM, p < 0.001). Since the increase of adenosine plasma levels, obtained either with adenosine or dipyridamole (an adenosine reuptake inhibitor), has been used to test the coronary reserve in patients with coronary artery disease (CAD), in the second part of the study we compared the effects of calcium infusion with dipyridamole in 15 CAD subjects. Pharmacological stress tests were evaluated by monitoring two-dimensional echocardiography, ECG, heart rate, blood pressure and rate-pressure product. Ten patients were positive both to dipyridamole stress test and to calcium infusion, ad demonstrated by the onset of new areas of transient asynergy in the same myocardial regions. Dipyridamole infusion determined a significant increase in heart rate and rate pressure-product in all patients (both in positive and in negative), whereas calcium induced a slight, not significant decrease of these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to define the pharmacodynamic profile of salmon calcitonin (sCT) in humans, several markers of the biological activity of the drug have been studied, namely cAMP, adenosine and pO in venous blood, and the cytosolic free calcium level in circulating cells. Different dosages and routes of administration (1.5 IU. kg and 0.75 IU kg IM, and 1.5 IU. kg via nasal spray) were compared. sCT caused an increase in cAMP, adenosine and pO, and a decrease in cytosolic free calcium in neutrophils, lymphocytes and platelets. The peak times of all these parameters ranged between 109 and 182 min, and 101 and 168 min after IM and nasal spray administration respectively. There was greater variability in the values after IM than nasal spray of administration of sCT. It is concluded that adenosine and p02 in venous blood, and cytosolic free calcium in circulating cells are valuable markers of the activity of sCT and that sCT decreases the cytosolic free calcium level in neutrophils, lymphocytes and platelets. Pharmacodynamic analysis of the biological effects of the drug is highly reliable and valuable in predicting its pharmacological profile. sCT administration via a nasal spray is able to produce significant biological effects, although they are less marked than after IM dosing. [ABSTRACT FROM AUTHOR]