RESUMO
The aim of this study has been to investigate the antiplatelet activity of a new series of thienylacylhydrazone derivatives analogous to the lead compound LASSBio-294 ((2-thienylidene) 3,4-methylenedioxybenzoylhydrazine). The antiplatelet effect was investigated in rabbit and human platelet rich plasma stimulated by arachidonic acid, collagen, ADP and in washed platelet stimulated by thrombin. The effects on the production of cyclic nucleotides and thromboxane A(2) (TXA(2)) in human platelets were also investigated. Compounds LASSBio-785 (N-Methyl (2-thienylidene) 3,4-methylenedioxybenzoylhydrazine), LASSBio-786 (N-Benzyl (2-thienylidene) 3,4-methylenedioxybenzoylhydrazine), LASSBio-787 ((5-Methyl-2-thienylidene) 3,4-methylenedioxybenzoylhydrazine), LASSBio-788 (N-Allyl (2-thienylidene) 3,4-methylenedioxybenzoylhydrazine) and LASSBio-789 ((5-Bromo-2-thienylidene) 3,4-methylenedioxybezoylhydrazine) inhibited platelet aggregation induced by arachidonic acid, collagen and ADP. LASSBio-785, LASSBio-788 and LASSBio-789 presented the higher potency in platelet aggregation induced by arachidonic acid (IC(50) values of 0.3, 0.2 and 3.1 microM, respectively) and collagen (IC(50) values of 0.9, 1.5 and 3.4 microM, respectively), with a 20 to 70-fold increase in potency compared to LASSBio-294. They inhibited the ATP release reaction by 95%, the whole blood aggregation by 35-45% and the TXB(2) production was totally abolished. In addition, they presented a significant effect on bleeding time. Qualitative studies in thrombin-induced washed platelet aggregation in the presence of sodium nitroprusside (SNP) suggested a phosphodiesterase-2 (PDE2) like effect for LASSBio-785, LASSBio-788 and LASSBio-789. They were able to increase the cGMP levels in non-stimulated platelets, in SNP-stimulated platelets and in the presence of 1-H- [1, 2, 4] oxadiazolo [4, 3- a] quinoxalin- 1- one (ODQ). The antiplatelet aggregation activity exerted by thienylacylhydrazone derivatives seems to be related to cyclic nucleotides regulation and TXA(2) synthesis inhibition. The structural modification of compound LASSBio-294 led to the optimization of its pharmacological properties and to the discovery of new potent antiplatelet prototypes with an antithrombotic potential.
Assuntos
Hidrazonas/farmacologia , Nucleotídeos Cíclicos/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Tiofenos/farmacologia , Tromboxano A2/antagonistas & inibidores , Animais , Ácido Araquidônico/antagonistas & inibidores , Ácido Araquidônico/farmacologia , Tempo de Sangramento , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Colágeno/antagonistas & inibidores , Colágeno/farmacologia , Feminino , Humanos , Masculino , Camundongos , Estrutura Molecular , Nucleotídeos Cíclicos/antagonistas & inibidores , Nucleotídeos Cíclicos/farmacologia , Diester Fosfórico Hidrolases/efeitos dos fármacos , Coelhos , Relação Estrutura-Atividade , Trombina/antagonistas & inibidores , Trombina/farmacologia , Tromboxano A2/biossínteseRESUMO
Acute rejection of a transplanted organ is characterized by intense inflammation within the graft. Yet, for many years transplant researchers have overlooked the role of classic mediators of inflammation such as prostaglandins and thromboxane (prostanoids) in alloimmune responses. It has been demonstrated that local production of prostanoids within the allograft is increased during an episode of acute rejection and that these molecules are able to interfere with graft function by modulating vascular tone, capillary permeability, and platelet aggregation. Experimental data also suggest that prostanoids may participate in alloimmune responses by directly modulating T lymphocyte and antigen-presenting cell function. In the present paper, we provide a brief overview of the alloimmune response, of prostanoid biology, and discuss the available evidence for the role of prostaglandin E2 and thromboxane A2 in graft rejection.
Assuntos
Dinoprostona/fisiologia , Rejeição de Enxerto/imunologia , Inflamação/imunologia , Prostaglandinas/imunologia , Tromboxano A2/fisiologia , Doença Aguda , Dinoprostona/antagonistas & inibidores , Dinoprostona/imunologia , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/fisiologia , Tromboxano A2/antagonistas & inibidores , Tromboxano A2/imunologiaRESUMO
Lobenzarit disodium (LBZ) is an immunomodulator and antioxidative drug developed and used successfully in Japan for the treatment of rheumatoid arthritis (RA). Studies in animals and humans have shown striking differences between the pharmacological profile of LBZ and nonsteroidal antiinflammatory drugs commonly used in the treatment of RA. LBZ does not inhibit the biosynthesis of prostaglandins and leukotrienes and is ineffective on acute inflammatory reactions induced in animals. Therefore, its usefulness in RA is ascribed to immunopharmacological properties of the drug. Currently, evidence is available that B- and T-lymphocytes are targets of LBZ's actions which regulates the functions of these cells. LBZ reduces IgE titers in serum of sensitized mice by activating suppressor T-lymphocytes and inhibiting anaphylactic shock induced by ovalbumin. These results provide evidence in favor of the potential use of LBZ in the treatment of allergic diseases, which must be elucidated in controlled double-blind clinical trials. The suppressive effects of LBZ on the function of activated B cells as well as in the production of anti-DNA antibody have been reported. These findings suggest that LBZ may be effective in the treatment of other autoimmune diseases such as lupus erythematosus that are also characterized by the production of autoantibodies from activated B cells. Recently, an open clinical trial in patients with systemic lupus erythematosus supports this point of view. Other potential therapeutic uses of LBZ are in autoimmune-related diabetes and in autoimmune liver disease which are documented in this review. LBZ also selectively antagonizes the contractile responses of isolated rabbit aorta strips induced by thromboxane A2-mimetic U-46619. This result provides evidence in favor of an antagonist of LBZ at the level of TxA2 receptors and supports the potential usefulness of LBZ in some cardiovascular disorders such as cardiopulmonary diseases and thrombosis. LBZ is a scavenger of oxygen-free radicals such as hydroxyl radicals, superoxide, peroxyl and singlet oxygen. This property contributes substantially to its pharmacological and therapeutic profile as well as its mechanism of action.
Assuntos
Adjuvantes Imunológicos/farmacologia , ortoaminobenzoatos/farmacologia , Adjuvantes Imunológicos/química , Animais , Humanos , Fígado/efeitos dos fármacos , Camundongos , Estrutura Molecular , Coelhos , Tromboxano A2/antagonistas & inibidores , ortoaminobenzoatos/químicaRESUMO
The production of 14CO2 from labelled glucose by isolated uterine strips from ovariectomized-diabetic rats has been studied. U46619, an analogue of TXA2 did not affect basal glucose metabolism; however, insulin-induced increment in CO2 production was completely blocked, both in ovariectomized (OVD) or ovariectomized-estrogenized (OVED) diabetic uterus. OKY064 as well as UK38485, both inhibitors of TXA2 synthesis, stimulated glucose metabolism (p < 0.05) similar to that of insulin in uterine tissue from OVD and OVED rats. Inhibition in the synthesis and release of TXB2 was detected (p < 0.01) by uterine radioconversion of 14C-arachidonic acid when adding OKY38485 to the incubation medium, and the production of other prostanoids such as 6-keto-PGF1 alpha, PGF2 alpha and PGE2 was enhanced. In summary, TXA2 inhibited insulin-induced glucose metabolism in diabetic animals.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Glucose/metabolismo , Insulina/farmacologia , Endoperóxidos Sintéticos de Prostaglandinas/farmacologia , Tromboxano A2/análogos & derivados , Tromboxano A2/antagonistas & inibidores , Útero/efeitos dos fármacos , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Animais , Radioisótopos de Carbono , Estrogênios/metabolismo , Feminino , Imidazóis/farmacologia , Técnicas In Vitro , Ovariectomia , Prostaglandinas/biossíntese , Ratos , Ratos Wistar , Tromboxano A2/biossíntese , Tromboxano A2/farmacologia , Tromboxano-A Sintase/antagonistas & inibidores , Útero/metabolismoRESUMO
Arthritis induced in hyperimmune rabbits by the intra-articular injection of the specific antigen was associated with a fall in circulating platelet number that lasted up to 60 days. Pretreatment of the animals with indomethacin and econazol at doses that significantly decreased thromboxane levels in the synovial fluids reduced the arthritis-related thrombocytopenia in the acute phase of arthritis. A similar inhibition was seen when L-655,240, a specific Thromboxane A2 antagonist, and BN 52021, a Platelet Activating Factor antagonist were used. The results suggest that both thromboxane and PAF are involved in the mechanisms leading to thrombocytopenia in this experimental model of arthritis.
Assuntos
Artrite Experimental/complicações , Diterpenos , Trombocitopenia/etiologia , Animais , Econazol/uso terapêutico , Feminino , Ginkgolídeos , Indóis/uso terapêutico , Indometacina/uso terapêutico , Lactonas/uso terapêutico , Masculino , Fator de Ativação de Plaquetas/antagonistas & inibidores , Fator de Ativação de Plaquetas/fisiologia , Coelhos , Líquido Sinovial/metabolismo , Trombocitopenia/prevenção & controle , Tromboxano A2/antagonistas & inibidores , Tromboxano A2/fisiologia , Tromboxano B2/fisiologiaRESUMO
This study evaluated the efficacy of a prostacyclin analog, iloprost, and a thromboxane A2 receptor antagonist, daltroban, as inhibitors of experimental intimal hyperplasia. The vascular injury model used is based on an endothelial injury induced by a brief infusion of air into an isolated segment of the common carotid artery in the rat. Iloprost and daltroban were administered by continuous IV infusion for two weeks. The infusion rates were 0.1 micrograms/kg/min for iloprost and 0.1 mg/kg/hr for daltroban; these dosing rates are associated with significant alterations in eicosanoid-related pharmacologic effects. The animals were sacrificed at two weeks and the carotid arteries fixed in situ for light microscopy. The myointimal thickening was measured as the intima to media area (I/M) ratio. The control animals developed marked intimal thickening, with an I/M ratio of 0.76 +/- 0.12 (mean +/- SEM; N = 7). There was no inhibition of intimal hyperplasia (P greater than 0.05) after either iloprost (I/M ratio: 1.04 +/- 0.13; N = 8) or daltroban (I/M ratio: 0.70 +/- 0.04; N = 6). It is concluded that neither of these two modulators of eicosanoid activity, iloprost and daltroban, inhibit intimal hyperplasia following experimental endothelial injury.
Assuntos
Endotélio Vascular/lesões , Iloprosta/farmacologia , Fenilacetatos/farmacologia , Sulfonamidas/farmacologia , Tromboxano A2/antagonistas & inibidores , Animais , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/patologia , Lesões das Artérias Carótidas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Hiperplasia , Iloprosta/administração & dosagem , Técnicas In Vitro , Infusões Intravenosas , Masculino , Fenilacetatos/administração & dosagem , Ratos , Ratos Endogâmicos , Receptores de Prostaglandina/efeitos dos fármacos , Receptores de Prostaglandina/fisiologia , Receptores de Tromboxanos , Sulfonamidas/administração & dosagemRESUMO
Splanchnic artery occlusion (SAO) followed by release of the occlusive clamps produces circulatory shock characterized by an abrupt hypotension, cardiac depression and high lethality. We studied the effects of the thromboxane receptor antagonist, BM-13505, in rats during SAO shock. Anesthetized rats subjected to total occlusion of the celiac and superior mesenteric arteries for 40 minutes developed a severe shock state following reperfusion, usually resulting in death within 90-120 minutes of release of the occlusion. BM-13505 was started at reperfusion for 10 minutes. SAO shock rats treated with BM-13505 (1 mg/kg) maintained post-reperfusion mean arterial blood pressure (MABP) at significantly higher values compared to those receiving only the vehicle (0.9% NaCl). Treatment with BM-13505 attenuated the plasma activity of the lysosomal protease cathepsin D (p less than 0.05 from vehicle) and the plasma accumulation of free amino-nitrogen compounds (p less than 0.01 from vehicle). Furthermore, the plasma activity of a myocardial depressant factor was significantly lower in BM-13505 treated rats than in non-treated rats (p less than 0.01 from vehicle). SAO shock rats treated with BM-13505 also exhibited a higher survival rate than the vehicle group (75% vs. 20%). These results suggest an important role of thromboxane A2 in the pathophysiology of SAO shock.
Assuntos
Oclusão Vascular Mesentérica/fisiopatologia , Fenilacetatos/farmacologia , Choque/fisiopatologia , Sulfonamidas/farmacologia , Tromboxano A2/antagonistas & inibidores , Animais , Pressão Sanguínea/efeitos dos fármacos , Catepsina D/sangue , Modelos Animais de Doenças , Hematócrito , Masculino , Fator Depressor Miocárdico/sangue , Nitrogênio/sangue , Ratos , Ratos Endogâmicos , Circulação EsplâncnicaRESUMO
Thromboxane A2 (TxA2) production increases significantly during acute myocardial ischemia. Since TxA2 induces platelet aggregation, coronary vasoconstriction and has a direct cytolytic effect, thromboxane receptor antagonists would be expected to be beneficial in acute myocardial ischemia. A new thromboxane A2 receptor antagonist, AH-23,848, was studied in a cat model of acute myocardial ischemia. Myocardial ischemia was induced by ligation of the left anterior descending (LAD) coronary artery. Thirty minutes later, AH-23,848 or vehicle was given as a bolus (1 mg.kg-1) followed by a continuous infusion (1 mg.kg-1.h-1). AH-23,848 effectively reduced the S-T segment elevation while vehicle treated cats showed an increase. From direct myocardial biopsies, it was also seen that AH-23,848 prevented the loss of creatine kinase (CK) activity from the ischemic myocardium. Furthermore, the loss of amino-nitrogen compounds was also significantly reduced (p less than 0.05) by treatment with the receptor antagonist. This protective effect was not due to an indirect reduction of myocardial oxygen demand since blood pressure, heart rate or their product was unaltered by AH-23,848 administration. Moreover, the specificity of AH-23,848 to thromboxane receptors was confirmed in isolated cat coronary arteries and in cat platelets. These experiments demonstrate that blockade of the thromboxane receptor by AH-23,848 is an effective means of preventing acute myocardial ischemic damage in the cat, and thus thromboxane A2 plays a role in propagating the extension of ischemic damage during acute myocardial ischemia.