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1.
Arq. Asma, Alerg. Imunol ; 6(2): 170-196, abr.jun.2022. ilus
Artigo em Inglês, Português | LILACS | ID: biblio-1400199

RESUMO

O tratamento do angioedema hereditário tem início com a educação dos pacientes e familiares sobre a doença, pois é fundamental o conhecimento da imprevisibilidade das crises, assim como os seus fatores desencadeantes. O tratamento medicamentoso se divide em terapia das crises e profilaxia das manifestações clínicas. As crises devem ser tratadas o mais precocemente possível com o uso do antagonista do receptor de bradicinina, o icatibanto ou o concentrado de C1-inibidor. É necessário estabeler um plano de ação em caso de crises para todos os pacientes. A profilaxia de longo prazo dos sintomas deve ser realizada preferencialmente com medicamentos de primeira linha, como concentrado do C1-inibidor ou o anticorpo monoclonal anti-calicreína, lanadelumabe. Como segunda linha de tratamento temos os andrógenos atenuados. Na profilaxia de curto prazo, antes de procedimentos que podem desencadear crises, o uso do concentrado de C1-inibidor é preconizado. Existem algumas restrições para uso desses tratamentos em crianças e gestantes que devem ser consideradas. Novos medicamentos baseados nos avanços do conhecimento da fisiopatologia do angioedema hereditário estão em desenvolvimento, devendo melhorar a qualidade de vida dos pacientes. O uso de ferramentas padronizadas para monitorização da qualidade de vida, do controle e da atividade da doença são fundamentais no acompanhamento destes pacientes. A criação de associações de pacientes e familiares de pacientes com angioedema hereditário tem desempenhado um papel muito importante no cuidado destes pacientes no nosso país.


The treatment of hereditary angioedema begins with the education of patients and their families about the disease, as it is essential to know the unpredictability of attacks as well as their triggering factors. Drug treatment is divided into attack therapy and prophylaxis of clinical manifestations. Attacks should be treated as early as possible with the bradykinin receptor antagonist icatibant or C1-inhibitor concentrate. An action plan needs to be established for all patients with attacks. Long-term prophylaxis of symptoms should preferably be performed with first-line drugs such as C1-inhibitor concentrate or the anti-kallikrein monoclonal antibody lanadelumab. Attenuated androgens are the second line of treatment. In short-term prophylaxis, before procedures that can trigger attacks, the use of C1-inhibitor concentrate is recommended. There are some restrictions for the use of these treatments in children and pregnant women that should be considered. New drugs based on advances in knowledge of the pathophysiology of hereditary angioedema are under development and are expected to improve patient quality of life. The use of standardized tools for monitoring quality of life and controlling disease activity is essential in the follow-up of these patients. The creation of associations of patients and families of patients with hereditary angioedema has played a very important role in the care of these patients in Brazil.


Assuntos
Humanos , Tratamento Farmacológico , Angioedemas Hereditários , Anticorpos Monoclonais Humanizados , Antagonistas dos Receptores da Bradicinina , Pacientes , Qualidade de Vida , Terapêutica , Bradicinina , Preparações Farmacêuticas , Calicreínas , Medicamentos de Referência
2.
Cell Mol Neurobiol ; 41(1): 63-78, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32222846

RESUMO

Complex regional pain syndrome type-I (CRPS-I) is a chronic painful condition resulting from trauma. Bradykinin (BK) is an important inflammatory mediator required in acute and chronic pain response. The objective of this study was to evaluate the association between BK receptors (B1 and B2) and chronic post-ischaemia pain (CPIP) development in mice, a widely accepted CRPS-I model. We assessed mechanical and cold allodynia, and paw oedema in male and female Swiss mice exposed to the CPIP model. Upon induction, the animals were treated with BKR antagonists (HOE-140 and DALBK); BKR agonists (Tyr-BK and DABK); antisense oligonucleotides targeting B1 and B2 and captopril by different routes in the model (7, 14 and 21 days post-induction). Here, we demonstrated that treatment with BKR antagonists, by intraperitoneal (i.p.), intraplantar (i.pl.), and intrathecal (i.t.) routes, mitigated CPIP-induced mechanical allodynia and oedematogenic response, but not cold allodynia. On the other hand, i.pl. administration of BKR agonists exacerbated pain response. Moreover, a single treatment with captopril significantly reversed the anti-allodynic effect of BKR antagonists. In turn, the inhibition of BKRs gene expression in the spinal cord inhibited the nociceptive behaviour in the 14th post-induction. The results of the present study suggest the participation of BKRs in the development and maintenance of chronic pain associated with the CPIP model, possibly linking them to CRPS-I pathogenesis.


Assuntos
Dor Crônica/etiologia , Dor Crônica/metabolismo , Isquemia/complicações , Receptores da Bradicinina/metabolismo , Animais , Antagonistas dos Receptores da Bradicinina/farmacologia , Inibidores da Colinesterase/farmacologia , Dor Crônica/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Hiperalgesia/complicações , Masculino , Camundongos , Nociceptividade/efeitos dos fármacos , Receptores da Bradicinina/genética , Medula Espinal/patologia
3.
Eur J Pain ; 25(1): 189-198, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32965065

RESUMO

BACKGROUND: Paclitaxel (PCX) is the first-line choice for the treatment of several types of cancer, including breast, ovarian, and lung cancers. However, patients who receive even a single dose with PCX commonly develop mechanical and cold allodynia, a symptom known as PCX-associated acute pain syndrome (P-APS). Here, we assessed possible involvement of kinin-kallikrein and renin-angiotensin systems in P-APS in mice. METHODS: Male mice C57Bl/6 wild type (WT) and knockouts for bradykinin receptors, B1 (B1-/- ) and B2 (B2-/- ), were used. Mechanical and cold allodynia were evaluated by using von Frey filaments and acetone test, respectively. P-APS was induced by administration of PCX 4 mg/kg, i.v.. ACE inhibitors (captopril and enalapril), antagonists for angiotensin II type 1 (losartan) and type 2 ([AT2R]; PD123319 and EMA 401) receptors were administrated prior the treatment with PCX. RT-PCR was used to analyse the expression of mRNA for B1, B2 and AT2R receptors. RESULTS: Administration of PCX in B1-/- and B2-/- mice induced lower mechanical and cold allodynia compared to the WT. However, the pre-treatment with ACE inhibitors reduced the development of mechanical and cold allodynia in P-APS. Surprisingly, we found that mice pre-treatment with the PD123319 or EMA401, but not losartan, prevented the development of mechanical and cold allodynia induced by PCX. CONCLUSION: Our results demonstrated the involvement of bradykinin receptors B1 and B2 as well as AT2R in the induction of P-APS in mice, and suggest the use of AT2R antagonists as a potential therapy for the prevention of P-APS in humans. SIGNIFICANCE: Kinin-kallikrein and renin-angiotensin systems, through B1, B2 and AT2 receptors, potentiates paclitaxel-associated acute pain syndrome (P-APS) in mice. Antagonists for AT2R are potential alternatives to prevent P-APS.


Assuntos
Dor Aguda , Bloqueadores do Receptor Tipo 2 de Angiotensina II , Antagonistas dos Receptores da Bradicinina , Receptores da Bradicinina , Animais , Bradicinina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Paclitaxel/toxicidade , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina/genética
4.
Reprod Sci ; 27(8): 1648-1655, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32430711

RESUMO

INTRODUCTION: The pleiotropic kininogen-kallikrein-kinin system is upregulated in pregnancy and localizes in the uteroplacental unit. To identify the systemic and local participation of the bradykinin type 2 receptor (B2R), this was antagonized by Bradyzide (BDZ) during 2 periods: from days 20 to 34 and from days 20 to 60 in pregnant guinea pigs. METHODS: Pregnant guinea pigs received subcutaneous infusions of saline or BDZ from gestational day 20 until sacrifice on day 34 (Short B2R Antagonism [SH-B2RA]) or on day 60 (Prolonged B2R Antagonism [PR-B2RA]). In SH-BDZA, systolic blood pressure was determined on day 34, while in PR-BDZA it was measured preconceptionally, at days 40 and 60. On gestational day 60, plasma creatinine, uricemia, proteinuria, fetal, placental and maternal kidney weight, and the extent of trophoblast invasion were evaluated. RESULTS: The SH-B2RA increased systolic blood pressure on day 34 and reduced trophoblast myometrial invasion, spiral artery remodeling, and placental sufficiency. The PR-B2RA suppressed the normal blood pressure fall observed on days 40 and 60; vascular transformation, placental efficiency, urinary protein, serum creatinine, and uric acid did not differ between the groups. The proportion of all studied mothers with lost fetuses was greater under BDZ infusion than in controls. CONCLUSION: The increased systolic blood pressure and transient reduction in trophoblast invasion and fetal/placental weight in the SH-B2R blockade and the isolated impact on blood pressure in the PR-B2R blockade indicate that bradykinin independently modulates systemic hemodynamics and the uteroplacental unit through cognate vascular and local B2R receptors.


Assuntos
Pressão Sanguínea/fisiologia , Antagonistas dos Receptores da Bradicinina/farmacologia , Bradicinina/metabolismo , Receptor B2 da Bradicinina/metabolismo , Trofoblastos/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Bradicinina/antagonistas & inibidores , Feminino , Cobaias , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Pirrolidinas/farmacologia , Tiossemicarbazonas/farmacologia , Trofoblastos/efeitos dos fármacos
5.
Inflamm Res ; 67(4): 301-314, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29260240

RESUMO

OBJECTIVE: We investigated whether: (1) P2 × 7 receptor activation by its agonist (BzATP) induces articular hyperalgesia in the rat's knee joint via inflammatory mechanisms and (2) activation of P2 × 7 receptors by endogenous ATP contributes to the articular hyperalgesia induced by bradykinin, TNF-α, IL-1ß, CINC-1, PGE2, and dopamine. METHODS: The articular hyperalgesia was quantified using the rat knee joint incapacitation test. The knee joint inflammation, characterized by the concentration of pro-inflammatory cytokines and by neutrophil migration, was quantified in the synovial lavage fluid by ELISA and myeloperoxidase enzyme activity assay, respectively. RESULTS: BzATP induced a dose-dependent articular hyperalgesia in the rat's knee joint that was significantly reduced by the selective antagonists for P2 × 7, bradykinin B1 or B2 receptors, ß1 or ß2 adrenoceptors, and by pre-treatment with Indomethacin. BzATP induced a local increase of TNF-α, IL-1ß, IL-6, and CINC-1 concentration and neutrophil migration into the knee joint. The co-administration of the selective P2 × 7 receptor antagonist A-740003 significantly reduced the articular hyperalgesia induced by bradykinin and dopamine, but not by TNF-α, IL-1ß, CINC-1, and PGE2. CONCLUSIONS: P2 × 7 receptor activation induces articular hyperalgesia mediated by the previous inflammatory mediator release. P2 × 7 receptor-induced articular hyperalgesia is sustained by the involvement of this purinergic receptor in bradykinin and dopamine-induced hyperalgesia in the knee joint.


Assuntos
Hiperalgesia/etiologia , Articulação do Joelho/metabolismo , Receptores da Bradicinina/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Trifosfato de Adenosina/análogos & derivados , Antagonistas Adrenérgicos beta/farmacologia , Animais , Bradicinina , Antagonistas dos Receptores da Bradicinina/farmacologia , Citocinas/metabolismo , Dopamina , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Antagonistas de Prostaglandina/farmacologia , Antagonistas do Receptor Purinérgico P2/farmacologia , Agonistas do Receptor Purinérgico P2X/farmacologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Ratos Wistar
6.
Int Arch Allergy Immunol ; 174(1): 1-6, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28950264

RESUMO

Hereditary angioedema (HAE) with C1 inhibitor deficiency is a genetic disorder that clinically manifests with attacks of angioedema in the subcutaneous and submucosal tissues, mainly in the extremities, abdomen, and upper airway. During attacks, vascular permeability is increased due to increased bradykinin (BK). This means that special therapies are needed for attacks that do not respond to traditional antiallergic therapies involving antihistamines, corticosteroids, and epinephrine. The recurring attacks may disable patients and lead to frequent visits to emergency rooms where misdiagnoses are common. HAE attacks may be fatal when upper-airway edema occurs, if proper treatment with a C1 inhibitor concentrate or BK receptor antagonist is not administered or an emergency tracheostomy is not performed. We propose a mnemonic method for the warning signs of HAE for the use as a diagnostic tool, i.e., the so-called "ABC" of the warning signs of HAE. The letters represent the following: A = Angioedema, B = Bradykinin, C = C1 inhibitor, D = Distress factors, E = Epinephrine nonresponsive, F = Family history, and G = Glottis/Gastrointestinal edema. To avoid fatalities, medical staff and patients, including family members, must be aware of HAE. An alphabetical mnemonic method has been developed and we hope it may benefit patients.


Assuntos
Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/tratamento farmacológico , Antagonistas dos Receptores da Bradicinina/uso terapêutico , Bradicinina/análogos & derivados , Proteínas Inativadoras do Complemento 1/deficiência , Angioedemas Hereditários/patologia , Bradicinina/metabolismo , Bradicinina/uso terapêutico , Permeabilidade Capilar/genética , Permeabilidade Capilar/fisiologia , Proteínas Inativadoras do Complemento 1/genética , Proteína Inibidora do Complemento C1 , Predisposição Genética para Doença/genética , Humanos , Receptores da Bradicinina/metabolismo
7.
Clin Exp Immunol ; 177(2): 544-53, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24749847

RESUMO

Hereditary angioedema (HAE) is characterized by potentially life-threatening recurrent episodes of oedema. The open-label extension (OLE) phase of the For Angioedema Subcutaneous Treatment (FAST)-1 trial (NCT00097695) evaluated the efficacy and safety of repeated icatibant exposure in adults with multiple HAE attacks. Following completion of the randomized, controlled phase, patients could receive open-label icatibant (30 mg subcutaneously) for subsequent attacks. The primary end-point was time to onset of primary symptom relief, as assessed by visual analogue scale (VAS). Descriptive statistics were reported for cutaneous/abdominal attacks 1-10 treated in the OLE phase and individual laryngeal attacks. Post-hoc analyses were conducted in patients with ≥ 5 attacks across the controlled and OLE phases. Safety was evaluated throughout. During the OLE phase, 72 patients received icatibant for 340 attacks. For cutaneous/abdominal attacks 1-10, the median time to onset of primary symptom relief was 1·0-2·0 h. For laryngeal attacks 1-12, patient-assessed median time to initial symptom improvement was 0·3-1·2 h. Post-hoc analyses showed the time to onset of symptom relief based on composite VAS was consistent across repeated treatments with icatibant. One injection of icatibant was sufficient to treat 88·2% of attacks; rescue medication was required in 5·3% of attacks. No icatibant-related serious adverse events were reported. Icatibant provided consistent efficacy and was well tolerated for repeated treatment of HAE attacks.


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Bradicinina/análogos & derivados , Adulto , Angioedemas Hereditários/diagnóstico , Bradicinina/administração & dosagem , Bradicinina/efeitos adversos , Bradicinina/uso terapêutico , Antagonistas dos Receptores da Bradicinina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Retratamento , Resultado do Tratamento , Adulto Jovem
8.
Expert Opin Ther Targets ; 16(3): 299-312, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22339271

RESUMO

INTRODUCTION: Biological fluids of cancer patients contain increased levels of kinins. Activation of kinin B1 and B2 receptors expressed on cancer cells produce an increase in cell proliferation, migration of tumor cells and release of MMPs, which are cellular and molecular events of primary importance for tumor growth. The effects of kinins on tumor cells may be amplified by stimulation of kinin receptors expressed on other cells, within the tumor microenvironment, which may in turn increase tumor growth. AREAS COVERED: This review provides a comprehensive discourse on kinins and their receptors in human neoplasia. Concepts that view kinin receptors as targets for human cancer are explored, whilst the molecular basis by which the new dimerized kinin receptor antagonists produce arrest of cell proliferation and apoptosis of cancer cells is also examined. Finally, the role of kinin receptor antagonists as therapeutic tools against human neoplasia is analyzed. EXPERT OPINION: At the present time the available potent, dimerized kinin peptide antagonists, are either specific for B1 or B2 receptors, or are effective on both receptor types. The novel approach of using kinin receptor antagonists either alone or in combination therapy will play a definitive role in the treatment of cancer.


Assuntos
Neoplasias/metabolismo , Receptores da Bradicinina/metabolismo , Animais , Antineoplásicos/farmacologia , Antagonistas dos Receptores da Bradicinina , Humanos , Cininas/metabolismo , Neoplasias/tratamento farmacológico
9.
PLoS One ; 6(11): e27875, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22132157

RESUMO

BACKGROUND: Multiple sclerosis (MS) is a demyelinating and neuroinflammatory disease of the human central nervous system (CNS). The expression of kinins is increased in MS patients, but the underlying mechanisms by which the kinin receptor regulates MS development have not been elucidated. METHODOLOGY/PRINCIPAL FINDINGS: Experimental autoimmune encephalomyelitis (EAE) was induced in female C57BL/6 mice by immunization with MOG(35-55) peptide emulsified in complete Freund's adjuvant and injected with pertussis toxin on day 0 and day 2. Here, we report that blockade of the B(1)R in the induction phase of EAE markedly suppressed its progression by interfering with the onset of the immune response. Furthermore, B(1)R antagonist suppressed the production/expression of antigen-specific T(H)1 and T(H)17 cytokines and transcription factors, both in the periphery and in the CNS. In the chronic phase of EAE, the blockade of B(1)R consistently impaired the clinical progression of EAE. Conversely, administration of the B(1)R agonist in the acute phase of EAE suppressed disease progression and inhibited the increase in permeability of the blood-brain barrier (BBB) and any further CNS inflammation. Of note, blockade of the B(2)R only showed a moderate impact on all of the studied parameters of EAE progression. CONCLUSIONS/SIGNIFICANCE: Our results strongly suggest that kinin receptors, mainly the B(1)R subtype, play a dual role in EAE progression depending on the phase of treatment through the lymphocytes and glial cell-dependent pathways.


Assuntos
Encefalomielite Autoimune Experimental/complicações , Encefalomielite Autoimune Experimental/patologia , Inflamação/patologia , Inflamação/prevenção & controle , Receptores da Bradicinina/metabolismo , Medula Espinal/patologia , Animais , Antagonistas dos Receptores da Bradicinina , Linfócitos T CD4-Positivos/imunologia , Doença Crônica , Citocinas/biossíntese , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Feminino , Deleção de Genes , Humanos , Inflamação/complicações , Tecido Linfoide/imunologia , Tecido Linfoide/patologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Bainha de Mielina/metabolismo , Medula Espinal/metabolismo , Células Th1/imunologia , Células Th17/imunologia
10.
Br J Pharmacol ; 154(5): 1094-103, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18454165

RESUMO

BACKGROUND AND PURPOSE: We investigated the mechanisms underlying the pruritogenic response induced by trypsin in mice, to assess the relevance of neurogenic inflammation components in this response. EXPERIMENTAL APPROACH: Itching was induced by an intradermal injection of trypsin in the mouse neck. The animals were observed for 40 min and their scratching behaviour was quantified. KEY RESULTS: Trypsin-induced itching was blocked by the lima bean trypsin inhibitor, the selective proteinase-activated receptor-2 (PAR-2) antagonist FSLLRY and PAR-2 receptor desensitization. An important involvement of mast cells was observed, as chronic pretreatment with the mast cell degranulator compound 48/80 or the mast cell stabilizer disodium cromoglycate prevented scratching. Also, trypsin response was inhibited by the selective COX-2 inhibitor celecoxib and by the selective kinin B2 (FR173657) and B1 (SSR240612) receptor antagonists. Moreover, an essential role for the mediators of neurogenic inflammation was established, as the selective NK1 (FK888), NK3 (SR142801) and calcitonin gene-related peptide (CGRP(8-37) fragment) receptor antagonists inhibited trypsin-induced itching. Similarly, blockade of transient receptor potential vanilloid 1 (TRPV1) receptors by the selective TRPV1 receptor antagonist SB366791, or by genetic deletion of TRPV1 receptor reduced this behaviour in mice. C-fibre desensitization showed a very similar result. CONCLUSIONS AND IMPLICATIONS: Trypsin intradermal injection proved to be a reproducible model for the study of itching and the involvement of PAR-2 receptors. Also, trypsin-induced itching seems to be widely dependent on neurogenic inflammation, with a role for TRPV1 receptors. In addition, several other mediators located in the sensory nerves and skin also seem to contribute to this process.


Assuntos
Comportamento Animal , Inflamação Neurogênica/prevenção & controle , Prurido/prevenção & controle , Transdução de Sinais , Anilidas/farmacologia , Animais , Antipruriginosos/farmacologia , Comportamento Animal/efeitos dos fármacos , Antagonistas dos Receptores da Bradicinina , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Celecoxib , Degranulação Celular/efeitos dos fármacos , Cinamatos/farmacologia , Cromolina Sódica/farmacologia , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dioxóis/farmacologia , Modelos Animais de Doenças , Injeções Intradérmicas , Masculino , Mastócitos/efeitos dos fármacos , Camundongos , Camundongos Knockout , Fibras Nervosas Amielínicas/metabolismo , Inflamação Neurogênica/induzido quimicamente , Inflamação Neurogênica/metabolismo , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/farmacologia , Proteínas de Plantas/farmacologia , Prurido/induzido quimicamente , Prurido/metabolismo , Pirazóis/farmacologia , Quinolinas/farmacologia , Receptor PAR-2/antagonistas & inibidores , Receptor PAR-2/metabolismo , Receptores da Bradicinina/metabolismo , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Tripsina/administração & dosagem , p-Metoxi-N-metilfenetilamina/farmacologia
11.
Eur J Pharmacol ; 573(1-3): 221-9, 2007 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-17669394

RESUMO

Kinin receptors are involved in the genesis of inflammatory pain. However, there is controversy concerning the mechanism by which B(1) and B(2) kinin receptors mediate inflammatory hypernociception. In the present study, the role of these receptors on inflammatory hypernociception in mice was addressed. Mechanical hypernociception was detected with an electronic pressure meter paw test in mice and cytokines were measured by ELISA. It was observed that in naïve mice a B(2) (d-Arg-Hyp(3), d-Phe(7)-bradykinin) but not a B(1) kinin receptor antagonist (des-Arg(9)-[Leu(8)]-bradykinin, DALBK) inhibited bradykinin- and carrageenin-induced hypernociception. Bradykinin-induced hypernociception was inhibited by indomethacin (5 mg/kg) and guanethidine (30 mg/kg), while not affected by IL-1ra (10 mg/kg) or antibody against keratinocyte-derived chemokine (KC/CXCL-1, 500 ng/paw) or in TNFR1 knockout mice. By contrast, in previously lipopolysaccharide (LPS)-primed mouse paw, B(1) but not B(2) kinin receptor antagonist inhibited bradykinin hypernociception. Furthermore, B(1) kinin receptor agonist induced mechanical hypernociception in LPS-primed mice, which was inhibited by indomethacin, guanethidine, antiserum against TNF-alpha or IL-1ra. This was corroborated by the induction of TNF-alpha and IL-1beta release by B(1) kinin receptor agonist in LPS-primed mouse paws. Moreover, B(1) but not B(2) kinin receptor antagonist inhibited carrageenin-induced hypernociception, and TNF-alpha and IL-1beta release as well, in LPS-primed mice. These results suggest that in naïve mice the B(2) kinin receptor mediates inflammatory hypernociception dependent on prostanoids and sympathetic amines, through a cytokine-independent mechanism. On the other hand, in LPS-primed mice, the B(1) kinin receptor mediates hypernociception by a mechanism dependent on TNF-alpha and IL-1beta, which could stimulate prostanoid and sympathetic amine production.


Assuntos
Hiperalgesia/fisiopatologia , Inflamação/fisiopatologia , Interleucina-1beta/fisiologia , Receptores da Bradicinina/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Anticorpos/farmacologia , Bradicinina/administração & dosagem , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Antagonistas de Receptor B2 da Bradicinina , Antagonistas dos Receptores da Bradicinina , Carragenina/administração & dosagem , Carragenina/toxicidade , Relação Dose-Resposta a Droga , Guanetidina/farmacologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/prevenção & controle , Indometacina/farmacologia , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Interleucina-1beta/imunologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prostaglandinas/fisiologia , Receptor B1 da Bradicinina/agonistas , Receptor B1 da Bradicinina/fisiologia , Receptor B2 da Bradicinina/fisiologia , Receptores da Bradicinina/agonistas , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/fisiologia , Fator de Necrose Tumoral alfa/imunologia
12.
Neuropeptides ; 41(4): 263-70, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17400291

RESUMO

Bradykinin is one of the most potent endogenous algesic substances and its role in pain transmission has been intensively studied in the periphery. However, the action of this peptide in central structures involved in pain transmission remains unclear. Administration of bradykinin (0.25 nmol/site) into the right amygdala of adult male Wistar rats induced thermal hyperalgesia, evaluated in the paw-flick test. Bradykinin-induced hyperalgesia was abolished by co-administration with the B(2) receptor antagonist Hoe 140 (5 pmol/site), the NMDA antagonist MK-801 (5 nmol/site), the cyclooxygenase inhibitor indomethacin (10 nmol/site) and the glial metabolic inhibitor fluorocitrate (1 nmol/site). Since the intra-amygdala administration of bradykinin did not alter spontaneous locomotion in the open-field test, it is unlikely that the current described hyperalgesic effect of bradykinin is due to an unspecific action on motor activity. These findings provide evidence that bradykinin, through activation of amygdalar B(2) receptors induces hyperalgesia and that glutamatergic- and prostanoid-mediated mechanisms are involved in such effect.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Bradicinina/farmacologia , Hiperalgesia/induzido quimicamente , Tonsila do Cerebelo/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Bradicinina/administração & dosagem , Bradicinina/análogos & derivados , Bradicinina/metabolismo , Antagonistas dos Receptores da Bradicinina , Citratos/metabolismo , Inibidores de Ciclo-Oxigenase/metabolismo , Maleato de Dizocilpina/metabolismo , Antagonistas de Aminoácidos Excitatórios/metabolismo , Indometacina/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Neuroglia/metabolismo , Medição da Dor , Ratos , Ratos Wistar
13.
Peptides ; 26(8): 1339-45, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15908043

RESUMO

The influence of kinin and opioid receptor blockade in the paratrigeminal nucleus (Pa5) on the somatosensory reflex (SSR) to sciatic nerve stimulation (SNS) was assessed in anaesthetized-paralyzed rats. SNS (square 1 ms pulses at 0.6 mA and 20 Hz for 10s) increased mean arterial pressure from 87+/-3 to 106+/-3 mmHg. Pressor responses to SNS were reduced 40-60% by HOE-140 and LF 16-0687 (B2 receptor antagonists; 20 and 100 pmol respectively), CTOP or nor-binaltorphimine (mu and kappa opioid receptor antagonists, respectively; 1 microg) but potentiated by naltrindole (delta opioid receptor antagonist) receptor antagonist microinjections into the contralateral (but not ipsilateral) Pa5. The SSR to sciatic nerve stimulation was not changed by B1 kinin receptor or NK1, NK2 and NK3 tachykinin receptor antagonists administered to the Pa5. Capsaicin pretreatment (40 mg/kg/day, 3 days) abolished the effects of the opioid receptor antagonists, but did not change the effect of kinin B2 receptor blockade on the SSR. Thus, the activity of B2 and opioid receptor-operated mechanisms in the Pa5 contribute to the SSR in the rat, suggesting a role for these endogenous peptides in the cardiovascular responses to SNS.


Assuntos
Potenciais Somatossensoriais Evocados/fisiologia , Receptores da Bradicinina/fisiologia , Receptores Opioides/fisiologia , Reflexo Anormal/fisiologia , Nervo Isquiático/fisiologia , Núcleos do Trigêmeo/fisiologia , Animais , Artérias/efeitos dos fármacos , Artérias/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Antagonistas dos Receptores da Bradicinina , Estimulação Elétrica/métodos , Potenciais Somatossensoriais Evocados/efeitos dos fármacos , Masculino , Modelos Biológicos , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes , Quinolinas/farmacologia , Ratos , Ratos Wistar , Reflexo Anormal/efeitos dos fármacos , Nervo Isquiático/efeitos dos fármacos , Somatostatina/análogos & derivados , Somatostatina/farmacologia , Núcleos do Trigêmeo/efeitos dos fármacos
14.
Inflamm Res ; 53(2): 78-83, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15021973

RESUMO

OBJECTIVE: The effect of bradykinin (B(1) or B(2)) receptor antagonists was studied in allergic and immune-complex-induced lung inflammation. METHODS: Lungs of BALB/c mice were examined 24 h after induction of lung inflammation, either allergic (ovalbumin-sensitized submitted to two aerosol of antigen, one week apart) or immune-complex induced (intratracheal instillation of IgG antibodies followed by intravenous antigen). The bradykinin B(2) receptor antagonist, HOE-140 or bradykinin B(1) receptor antagonist, R-954 were given intraperitoneally (100 microg/kg), 30 min before induction. RESULTS: In allergic inflammation, pre-treatment with R-954 reduced eosinophil infiltration into the lungs, mucus secretion and the airway hyperreactivity to methacholine. Pre-treatment with HOE-140 increased eosinophil infiltration but did not affect the other parameters. In immune-complex inflammation, HOE-140 increased neutrophil infiltration but not their activation nor the hemorrhagic lesions. R-594 pre-treatment did not change the parameters examined. CONCLUSION: These results show important modulatory effects of bradykinin B(1) and B(2) receptor antagonists in both models of lung inflammation.


Assuntos
Antagonistas dos Receptores da Bradicinina , Bradicinina/análogos & derivados , Hipersensibilidade , Doenças do Complexo Imune , Pneumonia/imunologia , Pneumonia/prevenção & controle , Animais , Bradicinina/uso terapêutico , Antagonistas de Receptor B1 da Bradicinina , Antagonistas de Receptor B2 da Bradicinina , Broncoconstrição/efeitos dos fármacos , Eosinófilos/patologia , Masculino , Cloreto de Metacolina/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Muco/metabolismo , Ovalbumina/imunologia , Pneumonia/patologia
15.
Brain Res ; 969(1-2): 110-6, 2003 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-12676371

RESUMO

This study sought to establish whether sensory neuropeptides and the capsaicin-sensitive fibres are involved in the nociception and oedema formation caused by intraplantar (i.pl.) injection of glutamate into the mouse paw. The i.pl. co-injection of the selective neurokinin (NK) NK(2) (SR 48968, 0.05-0.5 nmol/paw), and to a lesser extent the selective NK(1) (FK 888, 0.25-1.0 nmol/paw) receptor antagonists, resulted in a significant inhibition of glutamate-induced nociception. The percentages of inhibition were 82 and 37%, respectively. In contrast, the selective NK(3) receptor antagonist (SR 142801, 0.25-1.0 nmol/paw) failed to significantly affect glutamate-induced nociception. SR 48968, but not FK 888 or SR 142801, significantly inhibited (36%) glutamate-induced paw oedema formation. The i.pl. injection of kinin B(1) receptor antagonist des-Arg(9)-[Leu(8)]-BK (0.2-0.8 nmol/paw), but not the B(2) receptor antagonist HOE 140 (1.0-4.0 nmol/paw), together with glutamate, also inhibited glutamate-induced nociception (53%) in a graded manner, without affecting glutamate-induced paw oedema. The i.pl. co-injection of the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP(8-37) (1 nmol/paw) failed to significantly inhibit glutamate-induced nociception or oedema. Finally, neonatal-capsaicin (50 mg/kg, s.c.) treatment inhibited glutamate-induced nociception by 69% and to a lesser extent glutamate-mediated oedema formation (30%). Collectively, the current results indicate that the nociception caused by i.pl. injection of glutamate in mice is clearly mediated by capsaicin-sensitive fibres and by release of neurokinins from sensory neurones that activate NK(2) receptors and to a lesser extent NK(1) receptors. Furthermore, kinins acting at B(1) (but not at B(2)) receptors also largely account for glutamate-mediated nociceptive behaviour response. In contrast, glutamate-induced paw oedema seems to be primarily mediated via activation of NK(2) receptors and stimulation of capsaicin-sensitive C-fibres. CGRP receptors do not seem to be involved in either of the glutamate responses.


Assuntos
Edema/fisiopatologia , Ácido Glutâmico/farmacologia , Fibras Nervosas/fisiologia , Nociceptores/fisiologia , Dor/fisiopatologia , Animais , Benzamidas/farmacologia , Antagonistas dos Receptores da Bradicinina , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Capsaicina/metabolismo , Capsaicina/farmacologia , Dipeptídeos/farmacologia , Edema/induzido quimicamente , Pé/fisiopatologia , Indóis/farmacologia , Masculino , Camundongos , Fibras Nervosas/efeitos dos fármacos , Antagonistas dos Receptores de Neurocinina-1 , Nociceptores/efeitos dos fármacos , Piperidinas/farmacologia , Receptor B1 da Bradicinina , Receptor B2 da Bradicinina , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Receptores da Neurocinina-1/efeitos dos fármacos , Receptores da Neurocinina-1/metabolismo , Receptores da Neurocinina-2/antagonistas & inibidores , Receptores da Neurocinina-2/efeitos dos fármacos , Receptores da Neurocinina-2/metabolismo
16.
Eur J Pharmacol ; 462(1-3): 185-92, 2003 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-12591112

RESUMO

The ability of allergens to induce hyperalgesia in immunoglobulin E (IgE)-sensitized rats was investigated. The left hind paws of Wistar rats were sensitized with intraplantar injections of IgE anti-dinitrophenylated bovine serum albumin monoclonal antibody, and challenged with dinitrophenylated bovine serum albumin 24 h later. Allergen challenge yielded rapid thermal hyperalgesia and oedema formation in the ipsilateral paws, both reaching a plateau from 15 min to 3 h, and both diminishing thereafter. Allergen-evoked hyperalgesia was inhibited by intraperitoneal treatment with meclizine or methysergide, histamine and 5-hydroxytryptamine receptor antagonists. There was also sensitivity to local treatment with either bradykinin B(1) or B(2) receptor antagonists, des-Arg(9)-[Leu(8)]-bradykinin or D-arginyl-[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin (Hoe 140). Anaphylactic hyperalgesia was mimicked by the combined administration of histamine, 5-hydroxytryptamine and bradykinin at doses which were ineffective when injected alone. This synergistic effect was abolished by treatment with either meclizine, methysergide, Hoe 140 or des-Arg(9)-[Leu(8)]-bradykinin. Our findings show that local thermal hyperalgesia is a feature of allergen-evoked inflammation, and that a synergistic interaction among bradykinin, 5-hydroxytryptamine and histamine plays a critical role in this phenomenon.


Assuntos
Bradicinina/análogos & derivados , Bradicinina/administração & dosagem , Histamina/administração & dosagem , Hiperalgesia/induzido quimicamente , Serotonina/administração & dosagem , Alérgenos/imunologia , Animais , Bradicinina/farmacologia , Antagonistas dos Receptores da Bradicinina , Ciproeptadina/farmacologia , Dinitrofenóis/metabolismo , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Edema/induzido quimicamente , Edema/prevenção & controle , Antagonistas dos Receptores Histamínicos H1/farmacologia , Hiperalgesia/imunologia , Hiperalgesia/prevenção & controle , Imunoglobulina E/imunologia , Masculino , Meclizina/farmacologia , Metisergida/farmacologia , Dor/induzido quimicamente , Dor/imunologia , Dor/prevenção & controle , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologia , Soroalbumina Bovina/administração & dosagem , Soroalbumina Bovina/metabolismo , Fatores de Tempo
17.
Eur J Pharmacol ; 460(1): 75-83, 2003 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-12535863

RESUMO

The effect of bradykinin receptor antagonists was studied in a mouse (C57Bl/6) model of allergic lung inflammation. Bradykinin B(2) receptor antagonist HOE-140 (D-Arg-[Hyp(3),Thi(5),Dtic(7)-Oic(8)]bradykinin) or bradykinin B(1) receptor antagonist R-954 (Ac-Orn[Oic(2),alphaMePhe(5),betaD-Nal(7)Ile(8)]des-Arg(9)-bradykinin) were given i.p. to ovalbumin sensitized mice 30 min before antigen challenge. After 24 h, bronchoalveolar lavage was performed for cell analysis and the lungs were removed for evaluation of airway hyperreactivity and histopathology. Treatment with HOE-140 caused a significant increase in bronchoalveolar lavage cell number: eosinophils (182%), neutrophils (98%), lymphocytes CD(4)(+) (192%), CD(8)(+) (236%), B220 (840%), Tgammadelta(+) (194%) and NK1.1(+) (246%). Hyperreactivity and mucus secretion were not significantly affected in this group. Treatment with R-954 significantly reduced eosinophil (79%) and neutrophil (83%) but has no effect on lymphocytes number in bronchoalveolar lavage fluid. Airway hyperreactivity and mucus secretion were reduced by this treatment (84% and 35%, respectively). These results show important modulatory effect of bradykinin B(1) and B(2) receptors on allergic lung inflammation.


Assuntos
Antagonistas dos Receptores da Bradicinina , Bradicinina/análogos & derivados , Pneumonia/tratamento farmacológico , Animais , Bradicinina/farmacologia , Bradicinina/uso terapêutico , Líquido da Lavagem Broncoalveolar/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/imunologia , Pneumonia/patologia , Receptor B1 da Bradicinina , Receptor B2 da Bradicinina , Receptores da Bradicinina/fisiologia
18.
Eur J Pharmacol ; 458(1-2): 175-81, 2003 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-12498923

RESUMO

This study was designed to investigate the mechanisms by which bradykinin induces contraction of the pig iris sphincter muscle in vitro. Addition of bradykinin, Lys-bradykinin and Met-Lys-bradykinin to the pig iris sphincter resulted in a graded contraction with a mean EC(50s) of 21, 11 and 5 nM, respectively. The bradykinin B(1) receptor agonist des-Arg(9)-bradykinin only caused a slight contraction, measured 6 h after the tissue was set up. The B(2) receptor antagonists FR 173657 ((E)-3-(6-acetamido-3-pyridyl)-N [N-2-4-dichloro-3-[(2-methyl-8-quinolinyl) oxymethyl] phenyl]-N-methylamino-carbonyl-ethyl] acrylamide) and Hoe 140 (D-Arg(0)-[Hyp(3), Thi(5), D-Tic(7), Oic(8)]-bradykinin produced a graded shift to the right associated with marked inhibition of the bradykinin-induced contraction. Atropine, guanethidine or tetrodotoxin significantly reduced the bradykinin-induced contraction. Dazoxiben, an inhibitor of thromboxane A(2), and MK-571 (3-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl ((3-dimethyl amino-3oxo-propyl) thio) methyl) propanoic acid, a leukotriene D(4) receptor-selective antagonist, also caused inhibition of the bradykinin-mediated contraction. Cyclooxygenase-1 and -2 inhibitors, indomethacin, ibuprofen, valeryl salicylate and NS 398 (N-[2-(cyclohexyloxy)-4-nitrophenyl]methanosulfonamide) all significantly inhibited the bradykinin-mediated contraction without affecting the carbachol-induced contraction of the pig iris sphincter. Taken together, these results indicate that the bradykinin-mediated contraction of the pig iris sphincter muscle seems to be mediated primarily by the activation of the B(2) receptor release of acetylcholine, noradrenaline and both cyclooxygenase-1 and -2 metabolites besides the release of leukotriene D(4) and tromboxane A(2) from the arachidonic acid pathway.


Assuntos
Bradicinina/análogos & derivados , Bradicinina/farmacologia , Iris/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Animais , Atropina/farmacologia , Antagonistas dos Receptores da Bradicinina , Inibidores de Ciclo-Oxigenase/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Guanetidina/farmacologia , Ibuprofeno/farmacologia , Imidazóis/farmacologia , Técnicas In Vitro , Indometacina/farmacologia , Iris/fisiologia , Calidina/farmacologia , Músculo Liso/fisiologia , Nitrobenzenos/farmacologia , Propionatos/farmacologia , Quinolinas/farmacologia , Salicilatos/farmacologia , Sulfonamidas/farmacologia , Suínos , Tetrodotoxina/farmacologia , Tromboxano-A Sintase/antagonistas & inibidores
19.
Neuropharmacology ; 43(7): 1188-97, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12504926

RESUMO

The mechanisms by which kinins induce hyperalgesia in the spinal cord were investigated by using B(1) or B(2) knockout mice in conjunction with kinin selective agonists and antagonists. The i.t. administration of the kinin B(2) receptor agonists, bradykinin (BK) or Tyr(8)-BK produced dose-related thermal hyperalgesia evaluated in the hot-plate test. BK-induced hyperalgesia was abolished by the B(2) receptor antagonist Hoe 140. The i.t. injection of the kinin B(1) receptor agonists, des-Arg(9)-bradykinin (DABK) or des-Arg(10)-kallidin (DAKD) also caused dose-related thermal hyperalgesia. Different from the B(2) agonists, the i.t. injection of DABK or DAKD caused a weak, but prolonged hyperalgesia, an effect that was blocked by the B(1) receptor antagonist des-Arg(9)-[Leu(8)]-bradykinin (DALBK). The i.t. injection of BK caused thermal hyperalgesia in wild-type mice (WT) and in the B(1) receptor knockout mice (B(1)R KO), but not in the B(2) receptor knockout mice (B(2)R KO). Similarly, the i.t. injection of DABK elicited thermal hyperalgesia in WT mice, but not in B(1)R KO mice. However, DABK-induced hyperalgesia was more pronounced in the B(2)R KO mice when compared with the WT mice. The i.t. injection of Hoe 140 or DALBK inhibited the second phase of formalin (F)-induced nociception. Furthermore, i.t. Hoe 140, but not DALBK, also inhibits the first phase of F response. Finally, the i.t. injection of DALBK, but not of Hoe 140, inhibits the long-term thermal hyperalgesia observed in the ipsilateral and in contralateral paws after intraplantar injection with complete Freund's adjuvant. These findings provide evidence that kinins acting at both B(1) and B(2) receptors at the spinal level exert a critical role in controlling the nociceptive processing mechanisms. Therefore, selective kinin antagonists against both receptors are of potential interest drugs to treat some pain states.


Assuntos
Cininas/farmacologia , Medição da Dor/efeitos dos fármacos , Receptores da Bradicinina/deficiência , Receptores da Bradicinina/genética , Medula Espinal/efeitos dos fármacos , Animais , Antagonistas dos Receptores da Bradicinina , Relação Dose-Resposta a Droga , Feminino , Hiperalgesia/induzido quimicamente , Masculino , Camundongos , Camundongos Knockout , Medição da Dor/métodos , Receptor B1 da Bradicinina , Receptor B2 da Bradicinina , Receptores da Bradicinina/agonistas , Medula Espinal/fisiologia
20.
Pharmacology ; 65(4): 182-6, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12174832

RESUMO

Quercetin, one of the most widely distributed flavonoids in the plant kingdom, inhibits various enzymes. This study examined its inhibitory effect on the angiotensin-converting enzyme activity through the cardiovascular response to bradykinin and angiotensin I. Quercetin pre-treatment (88.7 micromol/kg p.o., 45 min; 14.7 micromol/kg i.v., 5 min) significantly potentiated the hypotensive effect of bradykinin (10 nmol/kg i.v.). This association was significantly attenuated by an antagonist of the B2 receptor. In addition, the hypertensive response to angiotensin I (0.1 nmol/kg i.v.) was significantly reduced by quercetin pretreatment using the same parameters as before. These results suggest an inhibitory effect of quercetin on the angiotensin-converting enzyme activity, similar to that of captopril. Quercetin was equally effective when given orally or intravenously.


Assuntos
Angiotensina I/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Quercetina/farmacologia , Administração Oral , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Animais , Antagonistas dos Receptores da Bradicinina , Captopril/farmacologia , Injeções Intravenosas , Masculino , Quercetina/administração & dosagem , Ratos , Ratos Wistar
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