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1.
World J Gastroenterol ; 13(27): 3677-83, 2007 Jul 21.
Article in English | MEDLINE | ID: mdl-17659726

ABSTRACT

AIM: To investigate the relationship among the number of platelets and plasma levels of S-nitrosothiols (S-NO), nitrite, total non-protein SH (NPSH), glutathione (GSH), cysteine (CYS), malondialdehyde (MDA), 4-hydroxininenal (4HNE), tumor necrosis factor-alpha (TNFalpha) and interleukin (IL)-6 in patients with chronic hepatitis C (CH). METHODS: In vitro the aggregation of platelets derived from controls and CH patients was evaluated before and after the addition of adenosine diphosphate (ADP) and collagen, both in basal conditions and after incubation with nitrosoglutathione (GSNO). RESULTS: In vivo, S-NO plasma levels increased significantly in CH patients and they were significantly directly correlated with platelet numbers. Patients with platelet counts < 150000/microL, had a smaller increase in S-NO, lower levels of GSH, CYS, NPSH, TNFalpha, and IL-6, and higher levels of nitrite, MDA, and 4-HNE relative to those of patients with platelet counts > 150000/microL. In vitro, the ADP and collagen aggregation time was increased in platelets from patients and not from controls; in addition, platelets from CH patients but not from controls also showed a latency time after exposure to collagen. CONCLUSION: The incubation of platelets with GSNO improved the percentage aggregation and abolished the latency time.


Subject(s)
Blood Platelets/metabolism , Hepatitis C, Chronic/blood , Nitric Oxide/metabolism , Platelet Aggregation , S-Nitrosothiols/blood , Thrombocytopenia/virology , Adult , Aged , Aged, 80 and over , Aldehydes/blood , Biomarkers/blood , Case-Control Studies , Cysteine/blood , Female , Glutathione/blood , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/metabolism , Humans , Interleukin-6/blood , Male , Malondialdehyde/blood , Middle Aged , Nitrites/blood , Platelet Aggregation Inhibitors/metabolism , Platelet Count , Platelet Function Tests , S-Nitrosoglutathione/metabolism , S-Nitrosothiols/metabolism , Thrombocytopenia/blood , Thrombocytopenia/metabolism , Tumor Necrosis Factor-alpha/blood
2.
Am J Med Genet A ; 143A(1): 58-63, 2007 Jan 01.
Article in English | MEDLINE | ID: mdl-17152066

ABSTRACT

Aarskog-Scott syndrome (AAS) is a rare, clinically and genetically heterogeneous condition characterized by facial dysmorphic features, short stature, brachydactyly, and genital anomalies. The X-linked form is caused by mutations of the FGD1 gene. Although clinical manifestations and diagnostic criteria are well established, diagnosis is not simple, as the spectrum of phenotypical features may be extremely variable. Here, we report on the clinical and genetic characterization of a family in which molecular analyses revealed the inheritance of a novel truncating mutation of the FDG1 gene (c.945insC) in two affected brothers, with one of them displaying unusually severe craniofacial abnormalities. This previously unreported combination of anomalies might be due to the occurrence of two distinct disorders (AAS and hemifacial microsomia) or may represent an extension of the AAS phenotypic spectrum. Our findings highlight the phenotypic heterogeneity of AAS, supporting the opinion that the FGD1 mutations result in a broad spectrum of severity and, in some cases, may express a clinical appearance very different than typically described.


Subject(s)
Craniofacial Abnormalities/diagnosis , Craniofacial Abnormalities/genetics , Guanine Nucleotide Exchange Factors/genetics , Urogenital Abnormalities/diagnosis , Urogenital Abnormalities/genetics , Adolescent , Child , Humans , Magnetic Resonance Imaging , Male , Mutation , Pedigree , Siblings , Syndrome
3.
Br J Haematol ; 117(3): 693-8, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12028043

ABSTRACT

High tissue factor (TF), tissue factor pathway inhibitor (TFPI) levels and a hypercoagulability state have been documented in unstable angina patients. We evaluated whether short-term enoxaparin administration (100 IU/kg b.i.d. for 3 d) reduces the high TF levels and the hypercoagulability state, and whether it influences the fibrinolytic system in 20 unstable angina patients. On d 3, we observed a significant reduction in TF levels both 1 h and 4 h after the morning injection (-25.6% and -21.7%; P < 0.001 respectively) in comparison with the base-line levels. Both 1 and 4 h after the morning injection on the d 3, TFPI levels significantly (P < 0.001) increased (+96.4%, +96.9% respectively) with respect to the base-line values. After enoxaparin administration, at all observation times, thrombin-antithrombin complexes and prothrombin fragment F1 + 2 levels were significantly (P < 0.001) lower with respect to base-line levels. We observed a slight but significant increase in tissue plasminogen activator antigen levels in preinjection samples, as well as 1 h and 4 h after enoxaparin administration, in comparison with the base-line values. This study provides evidence that low-molecular-weight heparin (LMWH) administration, in addition to a reduction of hypercoagulability and a mild fibrinolytic activation, is associated with decreased TF levels, so indicating a novel mechanism of interference of LMWH with the haemostatic system.


Subject(s)
Angina, Unstable/drug therapy , Anticoagulants/therapeutic use , Enoxaparin/therapeutic use , Fibrinolytic Agents/therapeutic use , Lipoproteins/blood , Thromboplastin/metabolism , Adult , Aged , Angina, Unstable/blood , Antithrombin III/metabolism , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Peptide Fragments/metabolism , Peptide Hydrolases/metabolism , Protein Precursors/metabolism , Prothrombin/metabolism , Tissue Plasminogen Activator/blood
4.
J Cardiovasc Pharmacol ; 38(6): 922-9, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11707696

ABSTRACT

It has been documented that beta-adrenergic antagonists can influence platelet aggregation by a mechanism independent of their ability to antagonize beta-adrenoceptors. Nebivolol, a selective beta1-adrenergic receptor antagonist with additional hemodynamic effects, is able to vasodilate human forearm vasculature by acting on the L-arginine/nitric oxide pathway. Constitutive nitric oxide synthase is present also in human platelets, resulting in the formation of nitric oxide, an endogenous inhibitor of platelet aggregation. The aim of this study was to investigate the effects of nebivolol on platelet aggregation and in particular to determine the involvement of the platelet L-arginine/nitric oxide pathway. Propranolol, a nonselective beta-adrenergic antagonist, and carvedilol, a beta-blocker with vasodilating properties, were compared with nebivolol on platelet activity. Plasma from healthy male subjects was used. Platelet aggregation was achieved with adenosine diphosphate (ADP) (3 microM) and collagen (1 microg/ml), using the Born turbidimetric method to measure platelet aggregation. Our results showed that nebivolol, propranolol, and carvedilol all had an inhibitory effect on both ADP- and collagen-induced platelet aggregation. Nebivolol exhibited the greatest inhibition effect on platelet aggregation. The mechanism responsible for the inhibitory effect of nebivolol appeared to involve a nitric oxide-dependent pathway. Indeed, L-arginine augmented the inhibitory effects of nebivolol on platelet aggregation induced by collagen and ADP. Furthermore, the inhibitory effect of nebivolol on platelet aggregation was reduced in the presence of the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA). In conclusion, we have demonstrated in this study that nebivolol's mechanism of platelet aggregation inhibition differs from that of other beta-adrenergic antagonists by being partially dependent on nitric oxide production.


Subject(s)
Benzopyrans/pharmacology , Ethanolamines/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Adenosine Diphosphate/antagonists & inhibitors , Adrenergic beta-Agonists/pharmacology , Adrenergic beta-Antagonists/pharmacology , Adult , Arginine/pharmacology , Blood Platelets/drug effects , Blood Platelets/metabolism , Carbazoles/pharmacology , Carvedilol , Collagen/antagonists & inhibitors , Dose-Response Relationship, Drug , Drug Synergism , Enzyme Inhibitors/pharmacology , Humans , Male , Nebivolol , Nitric Oxide Synthase/antagonists & inhibitors , Propanolamines/pharmacology , Propranolol/pharmacology , Vasodilator Agents/pharmacology , omega-N-Methylarginine/pharmacology
5.
Br J Pharmacol ; 134(7): 1447-54, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11724750

ABSTRACT

1. In some asthmatics, muscarinic receptor antagonists are effective in limiting bronchoconstrictor response, suggesting an abnormal cholinergic drive in these subjects. There is a growing body of evidences indicating that cholinergic neurotransmission is also enhanced by endothelin-1 (ET-1) in rabbit bronchi, mouse trachea and in human isolated airway preparations. 2. We investigated the role of secondary mediators in ET-1 induced potentiation of cholinergic nerve-mediated contraction in human bronchi, in particular the possible role of neuropeptides in this phenomenon. 3. Bronchial tissues after endothelin treatment were exposed to a standard electrical field stimulation (EFS) (30% of EFS 30 Hz)-induced contraction. In addition, in some experiments, preparations were treated with a tachykinin NK(2) receptor antagonist and subsequently exposed to the same protocol. HPLC and RIA were performed on organ bath fluid samples. Moreover, the human bronchi were used for the beta-PPT (preprotachykinin) mRNA extraction and semiquantitative reverse transcription polymerase chain reaction (RT - PCR), prior to and 30-40 min following ET-1 challenge. 4. The selective tachykinin NK(2) receptor antagonist, SR48968, was effective to reduce ET-1 potentiation of EFS mediated contraction. HPLC or RIA showed significant increased quantities of NKA in organ bath effluents after EFS stimulation in bronchi pretreated with ET-1. Finally, beta-PPT mRNA level after stimulation of bronchi with ET-1 was increased about 2 fold respect to control untreated bronchi. 5. In conclusion, this study demonstrated that, at least in part, the ET-1 potentiation of cholinergic nerve-mediated contraction is mediated by tachykinin release, suggesting that in addition to nerves, several type of cells, such as airway smooth muscle cell, may participate to neuropeptide production.


Subject(s)
Bronchi/drug effects , Cholinergic Fibers/physiology , Endothelin-1/pharmacology , Muscle Contraction/drug effects , Tachykinins/drug effects , Acetylcholine/pharmacology , Aged , Benzamides/pharmacology , Bronchi/metabolism , Bronchi/physiology , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Electric Stimulation , Female , Humans , In Vitro Techniques , Male , Middle Aged , Neurokinin A/metabolism , Piperidines/pharmacology , Protein Precursors/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Radioimmunoassay , Receptors, Neurokinin-2/antagonists & inhibitors , Reverse Transcriptase Polymerase Chain Reaction , Substance P/metabolism , Tachykinins/biosynthesis , Tachykinins/genetics , Vasodilator Agents/pharmacology
6.
Semin Thromb Hemost ; 27(5): 543-9, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11668426

ABSTRACT

At present, unfractionated heparin (UFH) and low molecular weight heparins (LMWHs) are used extensively for the prophylaxis and treatment of venous thromboembolism (VTE) and in most cases represent the agents of choice for these indications. However, both UFH and LMWHs have biophysical limitations. Over the past years, the progress in molecular biology and biotechnology has stimulated growing interest in hirudin, the most potent known natural inhibitor of thrombin. The biological properties of hirudin combined with its ready availability as recombinant forms make this drug well-suited for use as an anticoagulant agent. Available studies indicate that hirudin is significantly more effective for prophylaxis of VTE after total hip replacement than is either UFH or enoxaparin. Only limited data are available on its efficacy in the treatment of deep vein thrombosis. Moreover, hirudin is effective in the management of patients with heparin-induced thrombocytopenia (HIT) who require further anticoagulation. In conclusion, hirudin is an antithrombotic drug of high quality and may represent an attractive alternative to UFH and LMWHs in the management of VTE, and it is among the agents of choice in patients with contraindications to heparin therapy (such as HIT patients).


Subject(s)
Hirudin Therapy , Thromboembolism/drug therapy , Thromboembolism/prevention & control , Venous Thrombosis/drug therapy , Venous Thrombosis/prevention & control , Animals , Hirudins/analogs & derivatives , Humans , Therapeutic Equivalency
7.
Life Sci ; 68(18): 2159-68, 2001 Mar 23.
Article in English | MEDLINE | ID: mdl-11324721

ABSTRACT

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.


Subject(s)
Adrenergic beta-Antagonists/pharmacology , Airway Resistance/drug effects , Benzopyrans/pharmacology , Ethanolamines/pharmacology , Lung Compliance/drug effects , Airway Resistance/physiology , Animals , Atenolol/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , Female , Histamine/pharmacology , Lung Compliance/physiology , Male , Nebivolol , Pindolol/pharmacology , Propranolol/pharmacology , Rabbits
8.
FEBS Lett ; 478(3): 216-20, 2000 Aug 04.
Article in English | MEDLINE | ID: mdl-10930571

ABSTRACT

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.


Subject(s)
Abnormalities, Multiple/genetics , Blood Proteins/chemistry , Mutation/genetics , Phosphoproteins/chemistry , Proteins/chemistry , Proteins/genetics , Amino Acid Sequence , Amino Acid Substitution/genetics , Binding Sites , Child, Preschool , Conserved Sequence/genetics , DNA Mutational Analysis , Exons/genetics , Female , Genetic Heterogeneity , Genetic Linkage/genetics , Guanine Nucleotide Exchange Factors , Humans , Italy , Male , Molecular Sequence Data , Pedigree , Phenotype , Polymorphism, Single-Stranded Conformational , Protein Structure, Tertiary , Proteins/metabolism , Sequence Alignment , Syndrome , X Chromosome/genetics
9.
Clin Orthop Relat Res ; (371): 169-77, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10693564

ABSTRACT

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.


Subject(s)
Arthroplasty, Replacement, Knee , Hemostasis, Surgical , Postoperative Complications/blood , Thrombophlebitis/blood , Tourniquets , Aged , Female , Fibrinolysis/physiology , Humans , Male , Middle Aged , Risk Factors , Thrombin/metabolism , Thrombophilia/blood
10.
Minerva Cardioangiol ; 48(12 Suppl 1): 27-35, 2000 Dec.
Article in Italian | MEDLINE | ID: mdl-11253337

ABSTRACT

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.


Subject(s)
Anticoagulants/therapeutic use , Evidence-Based Medicine , Fibrinolytic Agents/therapeutic use , Heparin/therapeutic use , Practice Guidelines as Topic , Thromboembolism/therapy , Venous Thrombosis/therapy , Administration, Oral , Adult , Aged , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Clinical Trials as Topic , Female , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/adverse effects , Heparin/administration & dosage , Heparin/adverse effects , Heparin, Low-Molecular-Weight/administration & dosage , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Infusions, Intravenous , Male , Postoperative Complications/prevention & control , Postoperative Complications/therapy , Pregnancy , Pregnancy Complications, Cardiovascular/prevention & control , Pregnancy Complications, Cardiovascular/therapy , Pulmonary Embolism/prevention & control , Pulmonary Embolism/therapy , Randomized Controlled Trials as Topic , Risk Factors , Streptokinase/administration & dosage , Streptokinase/therapeutic use , Thrombectomy , Thrombocytopenia/chemically induced , Thromboembolism/drug therapy , Thromboembolism/prevention & control , Thrombolytic Therapy , Time Factors , Urokinase-Type Plasminogen Activator/administration & dosage , Urokinase-Type Plasminogen Activator/therapeutic use , Vena Cava Filters , Venous Thrombosis/drug therapy
12.
Thromb Haemost ; 81(6): 874-8, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10404760

ABSTRACT

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.


Subject(s)
Blood Coagulation , Orthopedics , Surgical Procedures, Operative/adverse effects , Thrombophlebitis/blood , Thromboplastin/analysis , Aged , Female , Humans , Male , Middle Aged , Postoperative Complications/blood , Thrombophlebitis/etiology
13.
Thromb Haemost ; 81(4): 589-93, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10235445

ABSTRACT

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.


Subject(s)
Hemostatics/metabolism , Heparin/administration & dosage , Lipoproteins/metabolism , Thromboplastin/metabolism , Adult , Aged , Angina, Unstable/blood , Anticoagulants/blood , Anticoagulants/metabolism , Blood Coagulation Factors , Female , Hemostatics/blood , Humans , Leukocytes, Mononuclear/chemistry , Lipoproteins/blood , Male , Middle Aged , Monocytes/physiology , Oxidation-Reduction , Time Factors
14.
Eur J Pharmacol ; 364(2-3): 183-91, 1999 Jan 08.
Article in English | MEDLINE | ID: mdl-9932722

ABSTRACT

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.


Subject(s)
Capsaicin/pharmacology , Endothelin-1/pharmacology , Neuropeptides/drug effects , Vas Deferens/drug effects , Animals , Bronchodilator Agents/pharmacology , Calcitonin Gene-Related Peptide/pharmacology , Dose-Response Relationship, Drug , Electric Stimulation , Humans , In Vitro Techniques , Isoproterenol/pharmacology , Male , Muscle Contraction/drug effects , Neuropeptides/metabolism , Papaverine/pharmacology , Rats , Rats, Wistar , Tetrodotoxin/pharmacology , Vas Deferens/innervation , Vas Deferens/metabolism , Vasodilator Agents/pharmacology
15.
Naunyn Schmiedebergs Arch Pharmacol ; 360(6): 665-9, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10619183

ABSTRACT

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.


Subject(s)
Bronchi/drug effects , Bronchi/metabolism , Endothelin-1/administration & dosage , Endothelin-1/metabolism , Muscle, Smooth/metabolism , Receptors, Endothelin/metabolism , Respiratory Hypersensitivity/physiopathology , Administration, Inhalation , Airway Resistance/drug effects , Animals , Antihypertensive Agents/administration & dosage , Azepines/administration & dosage , Bosentan , Bronchoconstriction/drug effects , Bronchoconstriction/physiology , Endothelin Receptor Antagonists , Female , Histamine , Indoles/administration & dosage , Male , Muscle, Smooth/drug effects , Rabbits , Receptor, Endothelin A , Receptor, Endothelin B , Receptors, Endothelin/agonists , Respiratory Hypersensitivity/chemically induced , Respiratory Hypersensitivity/diagnosis , Sulfonamides/administration & dosage , Vasoconstrictor Agents/administration & dosage , Viper Venoms/administration & dosage
18.
Naunyn Schmiedebergs Arch Pharmacol ; 358(5): 561-6, 1998 Nov.
Article in English | MEDLINE | ID: mdl-9840425

ABSTRACT

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.


Subject(s)
Bronchial Hyperreactivity/physiopathology , Endothelin-1/pharmacology , Airway Resistance/drug effects , Animals , Bronchial Hyperreactivity/etiology , Bronchoalveolar Lavage , Bronchoalveolar Lavage Fluid/cytology , Capsaicin/pharmacology , Dose-Response Relationship, Drug , Endothelin-1/adverse effects , Eosinophils/cytology , Eosinophils/drug effects , Female , Histamine/pharmacology , Leukocyte Count/drug effects , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Lung/drug effects , Lung/physiology , Lung/physiopathology , Male , Neutrophils/cytology , Neutrophils/drug effects , Rabbits
19.
Ann Ital Med Int ; 13(2): 81-7, 1998.
Article in English | MEDLINE | ID: mdl-9734140

ABSTRACT

The aim of this paper is to review fibrinolysis laboratory tests of potential clinical usefulness. Since the activation of the fibrinolytic system may be responsible for several relevant pathological scenarios, it is crucial to know whether and to what extent fibrinolysis laboratory tests are useful for the diagnosis and therapy of individual patients. The plasma fibrinolytic system may be altered by deficiencies and/or abnormalities of some of its components. Few doubts remain concerning the possible role of fibrinolysis alterations in the pathophysiology of some hemorrhagic and thrombotic disorders. In hemorrhagic patients, laboratory tests may demonstrate the existence of increased plasmin activity and the presence of specific congenital defects leading to primary hyperfibrinolysis. Alterations of the fibrinolytic system should be looked for only in selected patients who have a history of venous thrombosis and negative results of initial screening tests.


Subject(s)
Fibrin/deficiency , Fibrinolysis , Hemorrhage/blood , Thrombosis/blood , Blood Coagulation Tests , Disseminated Intravascular Coagulation/diagnosis , Hemorrhage/etiology , Humans , Plasminogen Activator Inhibitor 1/blood , Plasminogen Activator Inhibitor 1/deficiency , Pulmonary Embolism/diagnosis , Thrombosis/diagnosis , Tissue Plasminogen Activator/blood
20.
Thromb Haemost ; 79(3): 495-9, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9531029

ABSTRACT

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.


Subject(s)
Lipoproteins/blood , Myocardial Ischemia/blood , Thromboplastin/metabolism , Adult , Angina, Unstable/blood , Blood Coagulation , Female , Humans , Male , Middle Aged , Myocardial Infarction/blood , Thrombin/metabolism
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