Tullio Di Perri

Placebo Controlled Double Blind Study with Pentoxifylline of Walking Performance in Patients with Intermittent Claudication

A double blind placebo-controlled randomised crossover study was performed with Pentoxifylline (Trental 400 tablets with 400 mg active ingredient) in 24 patients (19 males, 5 females, aged between 40 and 71 years) suffering from peripheral occlusive arteriopathy of stage II severity (Fontaines classification). In 12 patients (group I) the treatment was started with placebo, and in another 12 subjects with Pentoxifylline (group II). The dosage was 3 tablets of either formulation t.d.s., the treatment periods were 8 weeks each with a two week washout between. The standardised walking test (120 steps/min under metronome control) was used for the assessment of the walking capacity. There was a significant 60% increase in pain-free walking distance in either Pentoxifylline treatment periods, whereas there were no clinically relevant changes in the placebo periods. When comparing the two starting periods only, there was an increase in the Pentoxifylline group from 223 to 359 m on average and in the placebo group from 208 to 215 m, patients in both groups being comparable at basal level as to the distribution of sex, age, location of occlusion, duration of disease as well as in respect to the walking capacity. No adverse reactions were recorded during the trial.

Nimodipine: drug pharmacokinetics and plasma adenosine levels in patients affected by cerebral ischemia.

Nimodipine is a dihydropyridine calcium channel blocker used in the treatment of ischemic damage in subarachnoid hemorrhage. Recent investigations have shown that it is able to inhibit adenosine transport in human red blood cells and parietal cortex neurons. In this study we investigated the pharmacokinetics of nimodipine and the effect on plasma adenosine levels in patients affected by cerebral ischemia.

Studies of the Clinical Pharmacology and Therapeutic Efficacy of Pentoxifylline in Peripheral Obstructive Arterial Disease

Studies were carried out to investigate the effects of pentoxifylline on various hemorheological (whole blood, plasma and serum viscosity, erythrocyte filtrability, hematocrit), hemostasiological (blood coagulation and fibrinolysis: euglobulin lysis time, fibrinogen, plasminogen, alpha-2-macroglobulin, alpha-1-antitrypsin, antiplasmin; platelet function: β-thromboglobulin), and hemodynamic factors (limb perfusion: rest and peak flow, time to peak flow; systemic blood pressure, heart rate). In addition, clinical efficacy was monitored in claudicants by assessing walking capacity under placebo controlled double blind cross over conditions. The investigations disclosed the positive influence of acute and chronic pentoxifylline administration on hemorheological, hemostasiological and perfusion parameters, most of the changes recorded being statistically significant. The clinical benefit of pentoxifylline (Trental 400) treatment was demonstrated by the significantly superior increase in walking capacity in comparison to placebo in the controlled study.

Experimental Model of Short-Time Exercise-Induced Preconditioning in POAD Patients:

Regular physical exercise improves walking performance in patients affected with periph eral obliterative arterial disease (POAD). The mechanisms underlying the phenomenon are still controversial. In order to verify the hypothesis that physical conditioning of lower limbs on a treadmill and ischemic preconditioning of the heart could share some biolog ical aspects, 14 POAD subjects underwent a training program on the treadmill consisting of five repeated submaximal exercises at five-minute and two-hour intervals preceding the maximal tolerance test. Moreover, a protocol with two daily submaximal walking exercises over one week was also performed. Pain-free and total walking distance were measured before and after they performed the program. Moreover, plasma levels of adenosine and adenosine triphosphate (ATP) were measured and polymorphonuclear (PMN) leukocyte activity was studied together with rheologic parameters. Pain-free distance was prolonged by 15.4% and 14.3%, and total distance was prolonged by 23.1% and 26.9%, in the exercises with five-minute and two-hour intervals, respectively. After one week of daily exercises, the onset of pain and the end of the test were delayed by 24% and 43.7%, respectively. An improvement in blood rheology and a reduced PMN reactivity were also observed with the three protocols, associated with an increase in plasma levels of adenosine and ATP. Similarly to ischemic preconditioning in the heart, the possibility is suggested that an adenosine-mediated mechanism may contribute to the development of physical condi tioning in treadmill-trained POAD patients.

Rheological Factors in Circulatory Disorders

are, according to the law of Hagen-Poiseuille, determined by the pressure gradient, the length of the tube, the radius of the tube, and the viscosity. This equation was originally developed to describe the flow of a fluid in a glass tube and is not completely applicable to arteries and veins. It must be considered, however, as the basis for an understanding of the regulation of the blood flow. According to this law, the flow of a fluid in a tube can be described by a parabolic velocity profile with a velocity gradient that decreases from the wall, where it reaches the maximal values, to the center, where it is zero. Among other determinant variables, the viscosity of the fluid plays an important role in regulating the flow rate, since the viscosity is dependent on the

Pharmacological preconditioning of ischemic heart disease by low-dose dipyridamole

Fourteen patients affected with coronary artery disease underwent two consecutive dipyridamole echocardiographic stress tests, in basal conditions and after repeated low doses of intravenous dipyridamole, following the observation that pulse increases in adenosine plasma levels due to repeated intravenous administration of dipyridamole mimic the mechanism of ischemic preconditioning. Echocardiographic, electrocardiographic, haemodynamic parameters, and adenosine plasma levels were measured. After the second test, six patients were completely negative, and in those eight still positive the onset of dyssynergy was delayed.

Pharmacokinetics and pharmacodynamics of neutrophil‐associated ciprofloxacin in humans

To study the possibility that the penetration of the antibiotic ciprofloxacin into polymorphonuclear leukocytes (PMN) may be associated with some changes in cell reactivity.

Action of Cinnarizine on the Hyperviscosity of Blood in Patients with Peripheral Obliterative Arterial Disease

Cinnarizine, a drug capable of improving blood flow, was studied for its action on blood viscosity and its main components in patients affected by peripheral obliterative arterial diseases (POAD). Both acute and chronic ad ministration of the drug diminished the increased whole-blood viscosity in patients, without affecting plasma and serum viscosity, hematocrit, plasma fibrinogen concentration, and plasma osmolality. Since cinnarizine also led to a significant increase of peripheral muscular blood flow, it was hypothesized that this action may be due to an increased deformability of the red cells, and may play a considerable role in the therapeutic approach to POAD.

QTc interval prolongation during infusion with dipyridamole or adenosine

The aim of our study was to discover whether there was a relationship between the QTc interval prolongation on the standard 12-lead electrocardiogram (ECG) and provoked myocardial ischemia. Since the increase of adenosine plasma levels, obtained either with adenosine or dipyridamole (an adenosine reuptake inhibitor) infusion, has been used to test the coronary artery reserve in patients affected by coronary artery disease, the QTc interval modifications during dipyridamole or adenosine echocardiographic stress test were evaluated. Twenty-five patients admitted to our Institute for evaluation of chest pain of suspected myocardial origin underwent an echocardiographic dipyridamole stress test (0.84 mg/kg over 10 min) after discontinuation of antianginal treatment. Of these patients, 10 underwent an echocardiographic adenosine stress test (scalar doses of 50, 75, 100, 140 micrograms/kg/min) after 48-72 h. The Bazett formula was used to evaluate the QTc interval. After dipyridamole and adenosine administration, a significant prolongation of the QTc interval was observed only in those patients who had positive test results. Our data suggested that QTc interval prolongation during pharmacological stress tests might be considered a marker of myocardial ischemia.

EVIDENCE OF AN ADENOSINE‐DEPENDENT MECHANISM IN THE HYPOTENSIVE EFFECT OF l‐ARGININE IN MAN

1. The hypothesis that endogenous adenosine could play a role in the haemodynamic response to l‐arginine is investigated.