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Biomedical subjects

A L Pasqui

Publications and source records attributed to A L Pasqui.

At least 19 recordsLinked to original sources
PubMed1995

Imipenem and immune response: in vitro and in vivo studies.

Imipenem is a new beta-lactam antibiotic endowed with very high antimicrobial activity; it is used in severe infections which often occur in those conditions characterized by impairment of the immune system. The aim of this study was to evaluate the effect of imipenem on some immune functions, both in vitro and in vivo. The authors studied the effect in vitro of three different drug concentrations (15, 30 and 60 mg/l) on polymorphonuclear leucocyte (PMN) phagocytosis and superoxide anion production, as well as on lymphomonocyte proliferative response and cytokine production. Preincubation of PMN with the highest dosages (30 and 60 mg/l) was found to increase phagocytosis evaluated via both cytofluorimeter and chemiluminescence, while no effect was detected on superoxide anion production or on lymphomonocyte tests. In the in vivo study, the authors administered imipenem/cilastatin (1500 mg/day) to 15 elderly and diabetic patients, in whom both PMN functions (phagocytosis and superoxide anion production) and lymphocyte tests (CD3, CD4, CD8, CD19, IL2 and sIL2R serum levels) were studied before and on the 3rd and 7th days of treatment. The drug assimilation did not modify the lymphocyte parameters, whereas it increased PMN superoxide anion production and phagocytosis which were depressed in basal conditions. In the former case, such increase was slight and insignificant, whereas in the latter it was significant.

Aged↗
PubMed1994

Pharmacodynamics and pharmacokinetics of Veliten (rutine, alpha-tocopherol and ascorbic acid) in patients with chronic venous insufficiency.

The aim of this study was to evaluate the pharmacodynamics and pharmacokinetics of a single oral dose of Veliten in 12 patients affected by chronic venous insufficiency. In particular, the pharmacokinetics of two components of Veliten, namely rutine and alpha-tocopherol, were considered, while with respect to pharmacodynamics, studies were made of venous function, haemocoagulative and fibrinolytic balance, and haemorheological parameters. Correlation between such changes and plasma drug levels was also evaluated. We found a significant increase of venous tone, venous capacity and venous distension after drug intake, as well as a significant activation of fibrinolysis (globally evaluated with euglobulin lysis time), related to a slight increase of plasminogen tissue activator. These changes appeared concomitantly with maximal plasma levels of rutine. We did not find any modifications of coagulative and haemorheological parameters.

Administration, Oral↗
PubMed1992

Pharmacodynamics of salmon calcitonin in humans: new markers of pharmacological activity.

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 pO2 in venous blood, and the cytosolic free calcium level in circulating cells. Different dosages and routes of administration (1.5 IU.kg-1 and 0.75 IU kg-1 IM, and 1.5 IU.kg-1 via nasal spray) were compared. sCT caused an increase in cAMP, adenosine and pO2, 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 pO2 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.

Adenosine↗
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

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

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

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↗
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↗
PubMed1988

Allopurinol prevents ischaemia-dependent haemorheological changes.

Pre-treatment with allopurinol is able markedly to attenuate the deterioration in blood viscosity (BV) and whole blood filterability (WBF) that occurs after ischaemia during exercise. It also reduces the exercise-induced increase in serum oxidase activity, although this action is slightly less effective in peripheral obliterative arterial disease (POAD) patients. Conversely, allopurinol is completely ineffective in modifying haemorheological parameters in vitro, and it does not affect superoxide anion generation or enzyme release from neutrophils stimulated in vitro with formyl-methionyl-leucyl-phenylalanine (FMLP). It is suggested that allopurinol may attenuate changes in BV and WBF by affecting xanthine-oxidase-dependent free radical formation in tissues.

Aged↗
PubMed1987

Benzodiazepines inhibit in vitro free radical formation from human neutrophils induced by FMLP and A23187.

Diazepam (DZP) inhibited in vitro in a concentration-dependent manner superoxide anion generation and chemiluminescence from human neutrophils stimulated by the formylated oligopeptide FMLP and by the calcium ionophore A23187. The dose-dependent inhibitory effect of DZP on A23187-dependent superoxide generation in the presence of Ca++ 0.6 mM was highly antagonized by increasing extracellular Ca++ concentration to 1.5 mM and to 2.0 mM. Ro 5-4864, a specific ligand for peripheral type benzodiazepine (BZ) binding site, inhibited superoxide generation induced by FMLP, while clonazepam (CNZ), which is selective for brain sites, did not possess any activity. Ro 15-1788, a central type BZ receptor antagonist, did not show any antagonistic activity on DZP-dependent inhibition. A new physiological property for substances presenting an affinity for peripheral type BZ binding sites is supposed. The inhibitory effect of BZ on neutrophil functions seemed to be associated with a Ca++-involving mechanism.

Benzodiazepines↗
PubMed1987

Defibrotide in vitro inhibits neutrophil activation by a Ca++-involving mechanism.

Defibrotide, a polydeoxyribonucleotide provided with a pro-fibrinolytic and prostacyclin-like activity, was studied as an inhibitor of polymorphonuclear leucocyte activation in vitro. It was found capable of dose-dependently (1-8 X 10(-5) M) inhibiting FMLP-induced activation, as shown by a decrease of enzyme release and free-radical formation (superoxide anion generation and chemiluminescence). A similar inhibiting activity was observed on A23187-induced activation. An increase in extracellular Ca++ concentration significantly prevented the effect of defibrotide on ionophore stimulation. When PMA was employed as stimulating agent, the drug did not show any inhibiting effect. Finally the pre-treatment of cells with theophylline markedly reduced the inhibition by defibrotide of FMLP- and A23187-dependent activation. Since the stimulation of neutrophils by FMLP and A23187 depends on the increase of cytoplasmic free-calcium availability or extracellular calcium entrance respectively, whereas PMA activation is completely independent from any Ca++ change, the inhibiting effect of defibrotide could be attributed to a Ca++-involving mechanism.

Calcium↗
PubMed1985

Platelet-dependent granulocyte activation in vitro: effect of ticlopidine.

The presence of platelets or platelet release products is known to augment the injury of endothelial cells caused by stimulated neutrophils (PMN leukocytes). In our in vitro studies, platelet-rich or platelet-poor plasma (PRP or PPP) was placed in one compartment and a PMN suspension in the other of a modified Boyden chamber divided by a dialysis membrane. The addition of the aggregating substance (ADP, collagen) to PRP but not to PPP was followed by PMN activation as shown by enzyme release and O-2 generation. The in vivo treatment with ASA completely prevented the platelets from triggering PMN activation. The in vitro addition of a thromboxane synthetase inhibitor (imidazole 10(-3) M) or a lipoxygenase inhibitor (NDGA 10(-6) M) did not show any effect on platelet-dependent PMN activation, thus suggesting that neither TxA2 nor lipoxygenase by-products are involved. Finally, in vitro and in vivo treatment with ticlopidine blunted the stimulating activity of the platelets on PMN. Our data further support the hypothesis that a sequential platelet-PMN interaction may occur, and that the therapeutic effect of some antiplatelet drugs may be partly due to a protective effect against platelet-dependent PMN-mediated vascular damage.

Adenosine Diphosphate↗