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Biomedical subjects

T Di Perri

Publications and source records attributed to T Di Perri.

At least 55 records · Page 3Linked to original sources
PubMed1991

Nitroprusside in vitro inhibits platelet aggregation and intracellular calcium translocation. Effect of haemoglobin.

The biologically final active compound of nitrovasodilators is now supposed to be nitric oxide (NO), a labile substance identical to EDRF. The effects of nitroprusside on platelet functions were studied in vitro. Platelet aggregation induced by several stimuli (ADP, collagen, arachidonic acid and PAF) was inhibited by increasing concentrations of the drug (1-50 uM); interestingly, the potency of nitroprusside is higher when PAF is employed as stimulating agent in comparison with the other agonists (ED50 = 2 uM for ADP, 2.5 uM for A.A., 4.5 uM for collagen and 0.3 uM for PAF-induced aggregations). The concomitant addition of haemoglobin is able to reverse the inhibitory effect of nitroprusside, according to the view that haemoglobin possesses a high affinity for NO, thus antagonizing the effect of this compound. Nitroprusside was also able to inhibit intracellular calcium translocation, as studied with the Quin 2 technique, induced by PAF and arachidonic acid. Fron these observations the hypothesis may be suggested that nitroprusside inhibits platelet functions by mimicking the endogenous NO, and that the intracellular calcium metabolism is involved in the inhibitory activity of the drug.

Adenosine Diphosphate↗
PubMed1991

Hemodynamic and hemorheologic effects of i.v. Dilevalol in hypertensive patients.

The authors evaluated the effect of Dilevalol infusion on blood pressure, heart rate, central hemodynamics, and rheologic parameters in hospitalized inpatients affected with mild or moderate hypertension. After a dose-finding phase and a washout period of one week, 10 patients aged fifty to seventy-two-years (median 61.5) were given either a single dose of Dilevalol 60 mg or placebo, and seven days later they underwent the other treatment, according to a single-blind, crossover design. Central hemodynamic measurements were performed by means of M-mode echocardiography, and hemorheologic parameters were evaluated by means of strain-gauge plethysmography. The maximal increase in lower extremity flow at rest had been obtained with the infusion of 60 mg Dilevalol during dose-finding, and so this dose was chosen for the second part of the study. The infusion of Dilevalol significantly increased rest flow and decreased blood viscosity, but the changes in central, parameters were not considered clinically relevant, although statistically significant. Blood pressure decreased without significant changes in heart rate. Thus, the acute administration of Dilevalol reduced blood pressure, without affecting heart rate and central hemodynamics, confirming the vasodilating effect of the drug. A significant improvement was also shown on blood viscosity in these hypertensive patients.

Blood Viscosity↗
PubMed1991

Defibrotide inhibits Ca2+ dependent neutrophil activation: implications for its pharmacological activity in vascular disorders.

Defibrotide (DEF) is a polydeoxyribonucleotide agent provided with profibrinolytic and antithrombotic properties. Moreover, an antiischemic, cardioprotective effect of the drug has recently been demonstrated in experimental animals. Increasing evidence exists of the important role played by neutrophils in the development of tissue damage during chronic and acute ischemia and in the early phases of reperfusion. In order to evaluate whether the overall cytoprotective effect of DEF could be based, at least in part, on a neutrophil-involving mechanism, the authors studied the in vitro effects of the drug on human neutrophil activation triggered by several specific stimuli. The drug dose-dependently (10-100 microM) inhibited enzyme release, superoxide anion generation, and chemiluminescence induced in neutrophils by the chemoattractant oligopeptide fMLP and by the divalent cation ionophores A23187 and ionomycin. The increase of extracellular calcium concentration from 0.5 to 2.0 mM antagonized the inhibitory effect of DEF. The use of the fluorescent probe Fura 2/AM led them to show that DEF is able to reduce the cytosolic free calcium increase following specific stimulation by affecting extracellular calcium entrance. Such a behavior resembles that of calcium-antagonistic drugs, thus suggesting that DEF works, at least in part, similarly to calcium entry blockers. Such an activity on cell calcium translocation could represent the underlying molecular mechanism of cytoprotection. Finally, the inhibitory action on neutrophil functions may play a role in tissue protection during ischemic injury.

Calcium↗
PubMed1991

[Ridogrel, a new platelet antiaggregant molecule with a double mechanism of action. A pharmacological and clinical profile].

Ridogrel has a double mechanism of action: it is a combined thromboxane A2 synthetase inhibitor and thromboxane A2/prostaglandin endoperoxide receptor blocker, demonstrated in vitro, as well as in vivo in animals and in man. In man, ridogrel is quickly absorbed after oral administration (30-60 min). The half-life is about 6-9 hours. At the oral dose of 300 mg b.i.d., the steady state has been reached at the third day of administration. Pharmacodynamic studies in healthy volunteers as well as in patients demonstrate a marked decrease in TXB2 serum level and an increase in 6ketoPGF1 alpha level. Moreover ridogrel inhibits the human platelet aggregation induced by U46619, collagen and arachidonic acid (thromboxane A2/prostaglandin endoperoxide receptor blocker). During the ridogrel treatment there have been neither variations of coagulative parameters (PTT, APTT, plasmatic fibrinogen) nor variations of other metabolic parameters except for those concerning the antiaggregant activity. To conclude, the preliminary data on about 100 healthy volunteers and more than 100 patients show that pharmacologic combined actions on enzyme and on receptors could be more efficacious than one single activity in eliminating circulatory flux resistance, in potentiating thrombolysis and in preventing or postponing vessels reocclusions. According to the above-mentioned results, ridogrel could have a good application in correction of thrombotic disorders due to platelet activation.

Animals↗
PubMed1991

Pharmacokinetics and pharmacodynamics of slow-release theophylline during treatment with nimesulide.

The pharmacodynamic and pharmacokinetic interactions were studied between nimesulide, a recently introduced non-steroidal anti-inflammatory drug, and theophylline, another highly protein-bound drug, in patients who were receiving slow-release theophylline for a chronic airflow-obstruction and who also needed anti-inflammatory treatment. A good tolerability was demonstrated of the two drugs association and there was an absence of pharmacodynamic interaction, as shown by lung function parameters, assayed before and after the coinciding nimesulide association. The pharmacokinetics of nimesulide and 4-hydroxy-nimesulide (its active metabolite) were not modified, in agreement with data shown by other authors. On the contrary, there was a slight alteration of theophylline pharmacokinetics, yet neither clinically nor biologically significant, probably due to an enzymatic induction.

Adolescent↗
PubMed1991

Clinical study on pharmacological interaction between nimesulide and warfarin.

This article describes the pharmacological interaction between nimesulide, a recently introduced non-steroidal anti-inflammatory drug, and warfarin, an indirect anticoagulant. The aim of the study was to demonstrate if nimesulide could potentiate the activity of this anticoagulant drug, as previously shown by some authors. Ten patients, who were taking 5 mg/day of warfarin, were treated with nimesulide 100 mg twice a day, for seven days: the association of the two drugs did not alter, in a statistical way, neither prothrombin time, nor partial thromboplastin time, nor fibrinogenemia, nor bleeding time. The findings showed that, in a short-term treatment, there was no bleeding risk in combining warfarin with nimesulide.

Adolescent↗
PubMed1991

Effect of cefodizime (HR 221) on immunological defects induced by surgical stress.

Cefodizime, a new aminothiazolylcephalosporin, has been shown to possess immunomodulating activity in many experimental models in vivo and in vitro. The in-vivo effect of the drug was evaluated in a model represented by the surgical patient, being surgical practices usually associated with an immunological impairment involving many aspects of the immune response. Two groups of ten subjects were treated respectively with cefodizime (2 g i.v. daily) and another cephalosporin (ceftriaxone) at the same dosage. Aspecific immunity (complement activity, neutrophil phagocytosis, chemiluminescence and superoxide anion production) and cell-mediated reactivity (lymphocyte subpopulations and E-rosette-forming cells) were evaluated before, and at predetermined intervals after, surgery and antibiotic treatment. In the control group an important immunological derangement is observed, involving both lymphocytes and neutrophil functions and complement system. The treatment with cefodizime displays a positive effect with a significant improvement of impaired functions. The effect of the drug particularly influences neutrophil phagocytosis, explored with both the NBT test and determinations of chemiluminescence, and the complement system, through both the classic and the alternative pathways. A slight effect is observed on lymphocyte functions.

Adolescent↗
PubMed1990

Selective 1H-NMR relaxation investigations of membrane-bound drugs in vitro. 3. Calcium-entry blockers and adenosine.

Selective proton relaxation rates (SPRR) were measured for selected protons of nimodipine or diltiazem in the presence of neutrophils, allowing detection of binding to the cell membrane. Fast exchange exchange of drug molecules between bound and free environments was shown to be the main factor determining the enhancement of SPRR, whereas viscosity effects could be neglected. The SPRR enhancement was almost completely cancelled out by the presence of adenosine as a cosolute in a dose-dependent fashion, leading to the suggestion that the endogenous mediator 'adenosine' affects binding of calcium-entry blockers to the neutrophil surface.

Adenosine↗
PubMed1990

[Calcium dobesilate in the treatment of primary venous insufficiency of the lower limbs. A controlled clinical study].

Fourty patients with lower limb chronic venous insufficiency entered a randomised placebo controlled study with calcium dobesilate for one month. Clinical symptoms and plethysmographic parameters were evaluated before and after therapy in all patients. In the group of patients treated with calcium dobesilate we observed an improvement of clinical and instrumental parameters; no changes were found in the placebo group. We observed good tolerance to the drug and no side effects required withdrawal of treatment.

Aged↗
PubMed1990

Adenosine system and cell calcium translocation: interference of calcium channel blockers.

Adenosine is able to inhibit in vitro neutrophil functions induced by formyl-methionyl-leucyl-phenylalanine (FMLP) and A23187, but not phorbol 12-myristate 13-acetate (PMA). The inhibiting activity on A23187 is reversed by increasing extracellular Ca2++ concentration. The calcium entry blocker flunarizine shows an activity very similar to that of adenosine. Both adenosine and flunarizine prevent Ca++ influx into activated neutrophils as detected by the fluorescent Ca++ chelator Quin-2. Finally, flunarizine binds to the neutrophil membrane and adenosine competitively inhibits flunarizine binding as assessed by 1H-Nuclear Magnetic Resonance (1H-NMR) technique, thus indicating that the two agents share a common binding site on the cell membrane.

Adenosine↗
PubMed1990

Adenosine blocks calcium entry in activated neutrophils and binds to flunarizine-sensitive calcium channels.

Adenosine is able to prevent Ca+(+) influx into activated neutrophils as detected by the specific fluorescent indicator Quin 2. Such an effect is shown in a similar fashion by the calcium entry blocker flunarizine. The binding interaction between flunarizine and the neutrophil membrane as well as the flunarizine-adenosine antagonism are shown by the 1H-NMR technique, thus supporting evidence of a competition between the agents at the same or a nearby site on the cell membrane.

Adenosine↗
PubMed1990

[The effects of vinburnine on the blood rheology parameters and on the oxyhemoglobin dissociation curve and 2,3-diphosphoglycerate. In vitro research].

The authors investigate the protective action of vinburnine on impairment of blood haemorheology and on metabolic parameters due to in vitro ageing of blood samples. In each sample the following parameters were measured: blood viscosity and filterability, p50 and 2,3-DPG. Vinburnine is able to induce a slight improvement of haemorheological parameters and of p50 compared to controls. After incubation for 4 hr, a reduced impairment of the mentioned parameters was observed in comparison with controls. Some hypotheses are discussed about the mechanisms of action of the drug.

2,3-Diphosphoglycerate↗
PubMed1990

[The effects of the acute administration of vinburnine on blood rheology, oxygen transport and regional circulation under normal conditions and in hypoxemia. In vivo research].

Vinburnine has been shown to be effective in avoiding chronic ischaemic tissue injury. Many studies have demonstrated the antihypoxic and oxygenation properties of this drug. In our study we have evaluated in two groups of patients the effects on blood rheology, oxygen transport, regional circulation and ergospirometric data of 40 mg vinburnine infused in a systemic vein. We have selected in the first group 10 patients with low hemoglobin oxygen affinity (p50 28.6 +/- 1.37 mmHg), in the second one 7 patients with normal values (p50 26.6 +/- 0.84 mmHg). In the two groups of the study we evaluated nutritional blood flow by a plethysmographic method, blood gas analysis [correction of hemogasanalitic] parameters in arterial and venous blood, haemoglobin oxygen affinity expressed as p50 and erythrocytic 2,3-DPG, hemorheologic and ergospirometric parameters. Data were evaluated in basal conditions and at the end of the infusion. The improvement of rheological properties, hemodynamic and metabolic data in the two groups of the study seems to confirm the oxyphoretic properties of this drug.

Adult↗
PubMed1989

[Use of a new preparation of flunarizine in patients with peripheral obliterating arteriopathy at the second stage. Controlled clinical study].

The authors report a randomised double-blind clinical study on the efficacy and tolerability of flunarizine. Two groups of patients with obliterating peripheral arterial disease (stage II) were treated for 3 months either with 10 mg flunarizine or with placebo and were examined monthly as to subjective symptoms, laboratory and instrumental parameters. Findings were evaluated by analysis of variance and Student's t-test. After three months, the flunarizine group had a greater increase of the distance walked before the onset of claudication and of maximum post-ischemic blood flow. No changes were observed in laboratory tests and central hemodynamics. The score of subjective symptoms was improved in the flunarizine treated group. Tolerance was good, side effects requiring withdrawal of treatment were not observed.

Aged↗
PubMed1989

New in vivo model to assess venous endothelial cell functions. Effect of defibrotide.

In the past few years there has been increasing interest in the role of the vascular endothelium as an active modulator of biological responses. Endothelial cells exert antithrombotic activity by the release of prostacyclin [23] and adenine nucleotides [16], the availability on the cell surface of heparin-like substances [3], and thrombomodulin-mediated activation of protein C [8]. In addition, endothelium is involved in the regulation of fibrinolysis by releasing soluble factors, such as tissue plasminogen activator (tPA; [10]) and plasminogen activator inhibitor (PAI; [22, 11]), as well as in the control of vascular responsiveness by the production of smooth muscle relaxing and contracting factors. Endothelial cells have also been shown to synthesize and to express procoagulant activities [18]. Many data on endothelial cell functions has been obtained from two experimental models, namely endothelial cell cultures and perfused segments of animal and human vessels. Both are subject to methodological criticism since they only represent in part in vivo conditions, and the necessary experimental manipulations and laboratory procedures greatly modify the naturally occurring cellular functions. In order to overcome such difficulties as far as possible, a new in vivo model has been employed to provide easily assessable and reliable data on the properties of endothelial cells in man. A venous segment was isolated functionally by cannulating a dorsal vein in the hand and a cubital vein in the same arm. Changes observed ex vivo in blood from the cubital vein following infusion into the hand vein of an active drug, can mainly be attributed to its local effect on the venous wall. At the same time, a cubital vein in the other arm was cannulated in order to provide information to distinguish systemic from regional effects.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

In vivo and in vitro evidence of an adenosine-mediated mechanism of calcium entry blocker activities.

Drugs such as dipyridamole (200 micrograms/kg/min), an adenosine uptake inhibitor, and theophylline (300 micrograms/kg/min), an adenosine receptor antagonist, respectively increased and decreased postischemic hyperemia in normal subjects, as well as in POAD patients. Moreover, dipyridamole pretreatment was able to antagonize the reduction of peak flow induced by nifedipine, and the potentiating effect of flunarizine on postischemic hyperemia was affected significantly by theophylline, thus suggesting a possible interference of calcium entry blocker drugs with the endogenous adenosine system. In a cellular model (polymorphonuclear leukocytes--PMN) the inhibitory effect of calcium entry blockers on stimulated functions (degranulation and free radical production) was highly antagonized by theophylline. Finally, a 1H-NMR spectroscopy study showed a binding interaction between adenosine and flunarizine on the cell membrane. An adenosine-receptor coupling to the calcium entry blocker channels is suggested.

Adenosine↗