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Biomedical subjects

M Falciani

Publications and source records attributed to M Falciani.

At least 19 recordsLinked to original sources
PubMed2001

Nebivolol and airway responsiveness in the rabbit.

Beta-adrenergic receptor antagonists are currently used as first-line therapy in the treatment of hypertension and angina pectoris, but are contraindicated or used with caution in patients with bronchospastic syndromes. In this study we evaluated in vivo the effects of nebivolol on airway responsiveness compared to atenolol, pindolol, and propranolol. In New Zealand white rabbits total lung resistance (R(L)) and dynamic compliance (Cdyn) were calculated. In acute protocol, the animals were intravenously injected with the beta-blockers at different doses while in the chronic protocol, animals were daily injected for 30 days. Furthermore, the changes induced by beta-blockers (higher doses) in R(L) and Cdyn after a treatment with salbutamol were calculated. In acute treatment, airway responsiveness to histamine was not modified by nebivolol at any dosage, but increased significantly following the exposure to the higher doses of the other beta-blockers. In chronic treatment, the thirty-day exposure to nebivolol, did not modify the airway responsiveness to histamine, whereas the other beta-blockers significantly increased airway responsiveness. Moreover, nebivolol affected the salbutamol-induced relaxation less markedly than other beta-blockers do. These data demonstrate that nebivolol respect the other beta-blockers used in this study, does not significantly affect the airway responsiveness, therefore it could be used in patients with both cardiovascular and bronchial diseases more safely than other beta-blockers drugs.

Adrenergic beta-Antagonists↗
PubMed2000

A mutation in the pleckstrin homology (PH) domain of the FGD1 gene in an Italian family with faciogenital dysplasia (Aarskog-Scott syndrome).

Aarskog-Scott Syndrome (AAS) is an X-linked disorder characterised by short stature and multiple facial, limb and genital abnormalities. A gene, FGD1, altered in a patient with AAS phenotype, has been identified and found to encode a protein with homology to Rho/Rac guanine nucleotide exchange factors (Rho/Rac GEF). However, since this original report on identification of a mutated FGD1 gene in an AAS patient, no additional mutations in the FGD1 gene have been described. We analysed 13 independent patients with clinical diagnosis of AAS. One patient presented a mutation that results in a nucleotide change in exon 10 of the FGD1 gene (G2559>A) substituting a Gln for Arg in position 610. The mutation was found to segregate with the AAS phenotype in affected males and carrier females in the family of this patient. Interestingly, Arg-610 is located within one of the two pleckstrin homology (PH) domains of the FGD1 gene and it corresponds to a highly conserved residue which has been involved in InsP binding in PH domains of other proteins. The same residue is often mutated in the Bruton's tyrosine kinase (Btk) gene in patients with an X-linked agammaglobulinemia. The Arg610Gln mutation represents the first case of a mutation in the PH domain of the FGD1 gene and additional evidence that mutations in PH domains can be associated to human diseases.

Abnormalities, Multiple↗
PubMed2000

Effect of tourniquet use on activation of coagulation in total knee replacement.

Total knee replacement often is performed with tourniquet application. The advantages of a dry field, including fixation, are well known, but it still is debatable if tourniquet application increases deep vein thrombosis. Measurement of coagulation markers is a well accepted method of studying thrombogenesis activation intraoperatively and postoperatively. Twenty patients undergoing total knee replacement with subarachnoid anesthesia were assigned randomly to two groups: either with tourniquet application (Group I) or without tourniquet application (Group II). There were no differences between patients in the two groups in terms of age, gender, diagnosis (all had osteoarthritis), operative time, and total (intraoperative and postoperative) blood loss. Markers for thrombin generation and fibrinolysis were measured. Blood samples were drawn at four times: baseline before the operation; after bone cuts; after cement fixation (Group II) or 2 minutes after tourniquet deflation (Group I); and 1 hour after surgery. Markers of thrombin generation and fibrinolysis showed a significant increase from baseline in all the patients. In Group II these markers started to increase during surgery, whereas in Group I the increase occurred at the end of the procedure when the tourniquet was deflated. The total amount of thrombin generation was significantly higher in Group II (without tourniquet), whereas fibrinolysis was significantly greater in Group I. Total knee replacement is accompanied by a hypercoagulative state with or without the use of a tourniquet, but it seems to be higher when the tourniquet is not used. In addition, tourniquet application may increase fibrinolysis.

Aged↗
PubMed2000

[Evidence-based guidelines for prevention and therapy of venous thromboembolism].

UNLABELLED: Recently, evidence-based guidelines for the prevention and therapy of venous thromboembolism have been published. Prophylaxis: in General Surgery patients with moderate to severe risk need to be treated with unfractioned (UFH) or low molecular weight (LMWH) heparin. Non pharmacological methods must be reserved to patients with high hemorrhagic risk and in association to heparin to patients with particularly high thromboembolic risk. In high risk Ortopedic Surgery prophylaxis with high doses LMWH or oral anticoagulants (OA) is indicated. Il Neurosurgical Surgery and in politraumatized patients prophylaxis must be individualized taking account of hemorrhagic risk; patients with acute medullary lesion with paraplegia must be treated with LMWH. In Internal Medicine conditions which determine prolonged bed rest need prophylaxis with UFH or LMWH. In pregnancy, pharmacological prophylaxis is indicated only in cases of preceding thrombotic events or documented congenital risk factors. THERAPY: deep venous thrombosis or sub-massive pulmonary embolism must be treated with anticoagulant doses of UFH or LMWH (100 U antiXa/Kg twice daily). OA must be continued for a time identifiable on the basis of underlying disease. In massive or sub-massive pulmonary embolism with hemodynamic instability thrombolysis is indicated. In heparin induced thrombocytopenia alternative antithrombotic treatments must be employed.

Administration, Oral↗
PubMed1999

Endothelin-1 affects capsaicin-evoked release of neuropeptides from rat vas deferens.

Capsaicin-sensitive neurones release a number of neuropeptides, such as substance P, neurokinin A, somatostatin and calcitonin gene-related peptide (CGRP), which exert a number of effects on smooth muscle tissues. Endothelin-1 was thought to potentiate the capsaicin-evoked release of neuropeptides from sensory neurones of the rat. We have investigated the neuromodulatory effects of endothelin-1 on capsaicin-induced release of neurotransmitters from rat vas deferens. Capsaicin and human alpha calcitonin gene-related peptide (human alphaCGRP) reduced the rat vas deferens twitch responses induced by electrical field stimulation. Human beta calcitonin gene-related peptide-(8-37) [human betaCGRP-(8-37)] (1 microM), a selective alphaCGRP receptor antagonist, antagonized the inhibitory effects of both drugs. Endothelin-1 concentration dependently evoked an increase in basal tone of the musculature and potentiated the amplitude of the electrically stimulated responses, blocking inhibitory effects of capsaicin but not of human alphaCGRP. Moreover, endothelin-1 did not markedly change the inhibitory effects of papaverine (0.1-100 microM) or isoprenaline (1 nM-100 microM) on responses to electrical field stimulation. FR 139317 [(N,N-hexamethylene) carbamoyl-Leu-D-Trp(N-Me)-D-2-Pya], a selective endothelin ET(A) receptor antagonist, administered 30 min before endothelin-1 restored the capsaicin effects whereas BQ 788 [Dmpc-gamma-MeLeu-D-Trp-(1-methoxycarbonyl)-D-Nle], a selective endothelin ET(B) receptor antagonist, was completely ineffective. The endothelin-1-induced block of the capsaicin effect was resistant to tetrodotoxin (1 microM) and 30-min pre-treatment with MEN 10.627 (cyclo[(Met-Asp-Trp-Phe-Dap-Leu) cyclo (2beta-5beta)]), a selective tachykinin NK2 receptor antagonist, did not abolish the endothelin-1 effect on the inhibitory response to capsaicin. These results suggest that endothelin-1 selectively inhibits the capsaicin-induced release of neurotransmitters from rat vas deferens and these effects are mediated via endothelin ET(A) receptors but not by tachykinin release.

Animals↗
PubMed1999

Endothelin-1 induced bronchial hyperresponsiveness in the rabbit: an ET(A) receptor-mediated phenomenon.

Endothelin-1 (ET-1) is a potent and efficacious spasmogen of airway smooth muscle. Recent observations suggest that an increased intrapulmonary production of ET-1 may occur in asthma. Our previous study showed that endothelin-1 induced bronchial hyperresponsiveness to inhaled histamine in the rabbit. The aim of this study was to investigate whether the ET(A) and ET(B) receptors mediate the bronchial hyperresponsiveness induced by endothelin-1 in the rabbit. Our data showed that bronchial hyperresponsiveness induced by ET-1 was significantly inhibited (P<0.01) by the ET(A) receptor-selective antagonist, FR 139317 (from 2.5 to 10 mg kg(-1)). Moreover, bosentan (from 2.5 mg kg(-1) to 10 mg kg(-1)), an ET(A)/ET(B) receptor antagonist, also inhibited the bronchial hyperresponsiveness achieved 24 h following endothelin-1 challenge (P<0.01), but with no difference from FR 139317. The ET(B) receptor agonist, sarafotoxin S6c (from 25 microg to 2.5 mg kg(-1)) did not modify airway responsiveness to inhaled histamine in the rabbit. These results indicate that bronchial hyperresponsiveness induced by ET-1 may be mediated by ET(A) receptor activation.

Administration, Inhalation↗
PubMed1999

Tissue factor reduction and tissue factor pathway inhibitor release after heparin administration.

Elevated plasma levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) and large amounts of monocyte procoagulant activity (PCA) have been documented in unstable angina (UA) patients. In in vitro experiments heparin is able to blunt monocyte TF production by inhibiting TF and cytokine gene expression by stimulated cells and after in vivo administration it reduces adverse ischemic outcomes in UA patients. TF and TFPI plasma levels and monocyte PCA have been investigated in 28 refractory UA patients before and during anticoagulant subcutaneous heparin administration (thrice daily weight- and PTT-adjusted for 3 days) followed by 5000 IU X 3 for 5 days. After 2-day treatment, immediately prior to the heparin injection, TF and TFPI plasma levels [(median and range): 239 pg/ml, 130-385 pg/ ml and 120 ng/ml, 80-287 ng/ml] were lower in comparison to baseline samples (254.5 pg/ml, 134.6-380 pg/ml and 135.5 ng/ml, 74-306 ng/ml). Four h after the heparin injection TF furtherly decreased (176.5 pg/ml, 87.5-321 pg/ml; -32.5%. p<0.001) and TFPI increased (240.5 ng/ml, 140-450 ng/ml; +67%, p<0.0001). After 7-day treatment, before the injection of heparin, TF and TFPI plasma levels (200 pg/ml, 128-325 pg/ml and 115 ng/ml, 70-252 ng/ml) significantly decreased (p<0.05) in comparison to the pre-treatment values. On the morning of the 8th day, 4 h after the injection of heparin TF plasma levels and monocytes PCA significantly decreased (156.5 pg/ml, 74-259 pg/ml and from 180 U/105 monocytes, 109-582 U/10(5) monocytes to 86.1 U/10(5) monocytes, 28-320 U/10(5) monocytes; - 38% and -55% respectively) and TFPI increased (235.6 ng/ml, 152-423 ng/ ml; +70%, p<0.001). In conclusion, heparin treatment is associated with a decrease of high TF plasma levels and monocyte procoagulant activity in UA patients. These actions of heparin may play a role in determining the antithrombotic and antiinflammatory properties of this drug.

Adult↗
PubMed1999

Procedure-dependence and tissue factor-independence of hypercoagulability during orthopaedic surgery.

The increased risk for deep vein thrombosis (DVT) after orthopaedic surgery has been well documented as well as hypercoagulable state during both total hip arthroplasty (THA) and total knee replacement (TKR). To investigate the influence of the surgical procedure [posterolateral (PL) or lateral (L) approach for THA, use of tourniquet (TQ) or not use of TQ for TKR] on the hypercoagulability and the role of extrinsic pathway activation and endothelial stimulation during orthopaedic surgery we have examined 40 patients (20 patients undergoing primary THA--10 with PL approach and 10 with L approach--and 20 patients undergoing TKR--10 with TQ application and 10 without TQ). Thrombin-antithrombin complexes (TAT), tissue factor (TF), tissue factor pathway inhibitor (TFPI), thrombomodulin (TM) and von Willebrand factor antigen (vWF:Ag) were analyzed before and during the orthopaedic surgery. During THA, TAT plasma levels increased more markedly in patients assigned to the L than PL approach (p <0.05); during TKR an elevation of TAT of higher degree (p <0.05) was observed when TQ was not applicated. Blood clotting activation was significantly (p <0.001) more relevant during THA than TKR. No changes in TF and vWF:Ag plasma levels were observed in all patients undergoing THA and TKR. TFPI plasma levels significantly (p <0.05) decreased 1 h after the end of the THA in group PL and group L, whereas they remained unaffected in the two groups of patients undergoing TKR. Similarly TM plasma levels significantly decreased during THA, but not during TKR. In conclusion, these results show that: 1) the site of surgical procedures and the type of approach affect the degree of hypercoagulability, 2) the blood clotting activation takes place in the early phases of orthopaedic surgery, without signs of extrinsic pathway and endothelial activation.

Aged↗
PubMed1998

Neuronorm is a potent and water soluble neurokinin A receptor antagonist.

We report here the synthesis and preliminary pharmacological characterization of a novel water soluble Neurokinin A receptor antagonist named Neuronorm. The synthesis was achieved in high yield by a combination of classical peptide synthesis methodologies, in both solution and solid phase. The pharmacological properties as neurokinin A receptor antagonist were assessed in in vitro experiments on rat vas deferens and guinea pig trachea, and were compared to those of MEN10627.

Animals↗
PubMed1998

A novel super-potent neurokinin A receptor antagonist containing dehydroalanine.

We report here the synthesis and preliminary pharmacological characterization of a novel Neurokinin A receptor antagonist. This molecule contains a dehydroalanine residue. It displays a high conformational rigidity and possesses very high activity. Its pharmacological properties as a neurokinin A receptor antagonist were assessed in in vitro experiments on rat vas deferens and were compared to those of Neuronorm and MEN10627.

Alanine↗
PubMed1998

Endothelin-1 and bronchial hyperresponsiveness in the rabbit.

Endothelins (ETs) are a family of peptide mediators that have a number of biological properties, including the ability to act as potent bronchoconstrictors of isolated human airways. Moreover, elevated concentrations of ET-1 in the bronchoalveolar lavage fluid from patients with symptomatic asthma have also been detected. We investigated the possible contribution of ET-1 in the development of bronchial hyperresponsiveness and the role of inflammatory cell accumulation in rabbit lungs. Our data show that ET-1 challenge to rabbits does not modify basal lung function but results in an increased airway responsiveness to inhaled histamine. Endothelin-treated rabbits were 3-fold (P<0.01) more responsive to inhaled histamine when compared with vehicle-treated rabbits. This hyperresponsiveness was not associated with an alteration in either total or differential inflammatory cell numbers as assessed by bronchoalveolar lavage (BAL). Pre-treatment with capsaicin (80 mg/kg s.c.) did not alter basal lung function or basal responsiveness to inhaled histamine. While capsaicin had no significant effect on the acute bronchoconstriction induced by endothelin-1, this dose was sufficient to significantly inhibit the increase in airway responsiveness to inhaled histamine, achieved 24 h following endothelin-1 challenge. These results indicate that ET-1 may play a role in the development of bronchial hyperresponsiveness to inhaled histamine and that the maintenance of this state is unrelated to a detectable alteration in cellular infiltration within the airway lumen, but probably via the involvement of capsaicin-sensitive nerves.

Airway Resistance↗
PubMed1998

Elevated tissue factor and tissue factor pathway inhibitor circulating levels in ischaemic heart disease patients.

Several studies have shown that thrombosis and inflammation play an important role in the pathogenesis of Ischaemic Heart Disease (IHD). In particular, Tissue Factor (TF) is responsible for the thrombogenicity of the atherosclerotic plaque and plays a key role in triggering thrombin generation. The aim of this study was to evaluate the TF/Tissue Factor Pathway Inhibitor (TFPI) system in patients with IHD. We have studied 55 patients with IHD and not on heparin [18 with unstable angina (UA), 24 with effort angina (EA) and 13 with previous myocardial infarction (MI)] and 48 sex- and age-matched healthy volunteers, by measuring plasma levels of TF, TFPI, Prothrombin Fragment 1-2 (F1+2), and Thrombin Antithrombin Complexes (TAT). TF plasma levels in IHD patients (median 215.4 pg/ml; range 72.6 to 834.3 pg/ml) were significantly (p<0.001) higher than those found in control subjects (median 142.5 pg/ml; range 28.0-255.3 pg/ml). Similarly, TFPI plasma levels in IHD patients were significantly higher (median 129.0 ng/ml; range 30.3-316.8 ng/ml; p<0.001) than those found in control subjects (median 60.4 ng/ml; range 20.8-151.3 ng/ml). UA patients showed higher amounts of TF and TFPI plasma levels (TF median 255.6 pg/ml; range 148.8-834.3 pg/ml; TFPI median 137.7 ng/ml; range 38.3-316.8 ng/ml) than patients with EA (TF median 182.0 pg/ml; range 72.6-380.0 pg/ml; TFPI median 115.2 ng/ml; range 47.0-196.8 ng/ml) and MI (TF median 213.9 pg/ml; range 125.0 to 341.9 pg/ml; TFPI median 130.5 ng/ml; range 94.0-207.8 ng/ml). Similar levels of TF and TFPI were found in patients with mono- or bivasal coronary lesions. A positive correlation was observed between TF and TFPI plasma levels (r = 0.57, p<0.001). Excess thrombin formation in patients with IHD was documented by TAT (median 5.2 microg/l; range 1.7-21.0 microg/l) and F1+2 levels (median 1.4 nmol/l; range 0.6 to 6.2 nmol/l) both significantly higher (p<0.001) than those found in control subjects (TAT median 2.3 microg/l; range 1.4-4.2 microg/l; F1+2 median 0.7 nmol/l; range 0.3-1.3 nmol/l). As in other conditions associated with cell-mediated clotting activation (cancer and DIC), also in IHD high levels of circulating TF are present. Endothelial cells and monocytes are the possible common source of TF and TFPI. The blood clotting activation observed in these patients may be related to elevated TF circulating levels not sufficiently inhibited by the elevated TFPI plasma levels present.

Adult↗
PubMed1997

Transglutaminase-synthesized spermine derivative of substance P recognizes rat portal vein neurokinin-3 receptors.

The effects of the transglutaminase-synthesized polyamine derivatives of Substance P (SP) have been further characterized by their ability to contract in vitro the rat portal vein strip (RPV), a pharmacological preparation particularly rich in NK-3 receptors. The effects of selective agonists of NK-1, NK-2 and NK-3 receptors [Sar9,Met(O(2))11]SP, beta-Ala8 NKA(4-10), and senktide respectively, were also evaluated by measuring RPV concentration-response curves. Peptide [GR-82334 (NK-1) and MEN-10,376 (NK-2)] and nonpeptide [WIN 51,708 (NK-1) and SR 142801 (NK-3)] NK receptor antagonists were used to confirm the participation of the different NK receptors to contractile response. Our results demonstrated that the spermine derivative of SP (Spm-SP), previously shown to be unable to recognize NK-1 and NK-2 receptors in some bioassays, contracts RPV (EC50 = 588 nM) better than the native neuropeptide (EC50 = 1120 nM). A pretreatment with thiorphan, an inhibitor of neutral endopeptidases, significantly reduced such a difference. While this inhibitor shifts the SP concentration-response curves to the left (EC50 = 720 nM) the action of Spm-SP and [Sar9,Met(O(2))11]SP were completely thiorphan-resistant. In the absence of thiorphan we found the following rank order of potency: senktide > > beta-Ala8 NKA(4-10) > [Sar9,Met(O(2))11]SP = Spm-SP > SP. Among the mentioned NK receptor antagonists, only the selective NK-3 receptor antagonist, SR 142801, shifted to the right Spm-SP and [Sar9,Met(O(2))11]SP concentration-response curve, showing pKB values of 5.84 and 5.88, respectively. Therefore, the reported results suggest that the introduction of a Spm moiety into the SP alters the parent peptide molecule by increasing its affinity for NK-3 receptors and/or by preventing its degradation by some proteolytic enzymes.

Androstanes↗
PubMed1997

Identification of candidates for prevention of venous thromboembolism.

The rationale for prophylaxis of venous thromboembolism (VTE) is based on the frequently clinically silent nature of the disease. A number of risk factors for VTE have been known for a long time, even if some of them are still controversial. Many studies have been performed in the surgical field, and have established different risk classes for VTE. Such risk stratification is especially determined by type of surgery and to some extent by personal characteristics of patients, and it defines operations at high, intermediate, and low risk for VTE. According to this classification, prophylaxis of VTE is mandatory in some cases, less useful in others. Less information is available on medical diseases, in which the clinical conditions and the intrinsic characteristics of patients determine the class of risk for VTE. Different strategies for identifying patients who should undergo prophylaxis have been proposed based on risk factor evaluation in the individual patient. However, even if such an approach may be of help for the physician, its validity is still impaired by the difficulty of taking into account all of the variables possibly involved in VTE occurrence.

Humans↗
PubMed1997

Role of nitric oxide in a nonseptic shock model induced by zymosan in the rat.

Nitric oxide (NO) is a short-lived mediator, the synthesis of which is induced by various cytokines during inflammatory processes. Recently, it has been proposed that zymosan, a nonbacterial agent, causes inflammation by inducing the production of various cytokines and proinflammatory mediators. In the present study we investigated the role of NO in a nonseptic shock model induced by zymosan administration in the rat. Administration of zymosan (500 mg/kg, intraperitoneally) in the rat induced acute peritonitis, as assessed by a marked increase in the leukocytes count in the exudate, as well as by an increase in the exudate nitrate/nitrite concentration. Zymosan-treated rats developed a severe hypotension and showed signs of systemic illness, significant loss of body weight, and a high mortality rate (53% of animals died within 72 h). Elevated plasma levels of nitrite and nitrate were also observed in zymosan-treated rats compared with control rats (67 +/- 4 microM and 23 +/- 2 microM, respectively; p < .01). In ex vivo experiments, vascular reactivity was studied in thoracic aorta rings of zymosan-treated rats. The contractile responses to norepinephrine (100 nM) and endothelin-1 (5 nM) were significantly reduced. An impairment of the endothelial-dependent relaxation in response to acetylcholine was also observed. Pretreatment of zymosan-shocked rats with NG-nitro-L-arginine methyl ester (L-NAME) or NG-monomethyl-L-arginine (L-NMA), (10 mg/kg, subcutaneously, 15 min before zymosan) decreased mortality, prevented the development of peritonitis, improved ex vivo vascular reactivity, and significantly reduced hypotension. Our data suggest that overproduction of NO plays a role in the zymosan-induced peritonitis and cardiovascular derangements in the rats.

Acute Disease↗