Tadalafil analgesia in experimental arthritis involves suppression of intra-articular TNF release

BACKGROUND AND PURPOSE We investigated the effect of the phosphodiesterase-5 inhibitor, tadalafil, on the acute hypernociception in rat models of arthritis. EXPERIMENTAL APPROACH Rats were treated with either an intra-articular injection of zymosan (1 mg) or surgical transection of the anterior cruciate ligament (as an osteoarthritis model). Controls received saline intra-articular or sham operation respectively. Joint pain was evaluated using the articular incapacitation test measured over 6 h following zymosan or between 4 and 7 days after anterior cruciate ligament transection. Cell counts, tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and the chemokine, cytokine-induced neutrophil chemoattractant-1 (CINC-1) were measured in joint exudates 6 h after zymosan. Groups received tadalafil (0.02-0.5 mg.kg(-1) per os) or saline 2 h after intra-articular zymosan. Other groups received the mu-opioid receptor antagonist naloxone or the cGMP inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ) before tadalafil. KEY RESULTS Tadalafil dose-dependently inhibited hypernociception in zymosan and osteoarthritis models. In zymosan-induced arthritis, tadalafil significantly decreased cell influx and TNF-alpha release but did not alter IL-1 or CINC-1 levels. Pretreatment with ODQ but not with naloxone prevented the anti-inflammatory effects of tadalafil. CONCLUSIONS AND IMPLICATIONS Therapeutic oral administration of tadalafil provided analgesia mediated by guanylyl cyclase and was independent of the release of endogenous opioids. This effect of tadalafil was associated with a decrease in neutrophil influx and TNF-alpha release in inflamed joints.

Combined glucosamine and chondroitin sulfate provides functional and structural benefit in the anterior cruciate ligament transection model

Evidence that combined glucosamine sulfate and chondroitin sulfate (Gluchon) or isolated glucosamine (Glu) modifies joint damage in osteoarthritis (OA) is still lacking. We studied joint pain and cartilage damage using the anterior cruciate ligament transection (ACLT) model. Wistar rats were subjected to ACLT of the right knee ( OA) or sham operation. Groups received either Glu (500 mg/kg), Gluchon (500 mg/kg glucosamine +400 mg/kg chondroitin) or vehicle (non-treated-NT) per os starting 7 days prior to ACLT until sacrifice at 70 days. Joint pain was evaluated daily using the rat-knee joint articular incapacitation test. Structural joint damage was assessed using histology and biochemistry as the chondroitin sulfate ( CS) content of cartilage by densitometry (microgram per milligram dried cartilage), comparing to standard CS. The molar weight (Mw) of the CS samples, used as a qualitative biochemical parameter, was obtained by comparing their relative mobility on a polyacrylamide gel electrophoresis to standard CS. Gluchon, but not Glu, significantly reduced joint pain (P<0.05) compared to NT. There was an increase in CS content in the OA group (77.7 +/- 8.3 mu g/mg) compared to sham (53.5 +/- 11.2 mu g/mg) (P<0.05). The CS from OA samples had higher Mw (4:62 +/- 0:24 x 10(4) g/mol) compared to sham (4:18 +/- 0:19 x 10(4) g/mol) (P<0.05). Gluchon administration significantly reversed both the increases in CS content (54.4 +/- 12.1 mu g/mg) and Mw (4:18 +/- 0:2 x 104 g/mol) as compared to NT. Isolated Glu decreased CS content though not reaching statistical significance. Cartilage histology alterations were also significantly prevented by Gluchon administration. Gluchon provides clinical (analgesia) and structural benefits in the ACLT model. This is the first demonstration that biochemical alterations occurring in parallel to histological damage in OA are prevented by Gluchon administration.

Characterization and pharmacological evaluation of febrile response on zymosan-induced arthritis in rats

Kanashiro A, Pessini AC, Machado RR, Malvar DC, Aguiar FA, Soares DM, Vale ML, Souza GEP. Characterization and pharmacological evaluation of febrile response on zymosan-induced arthritis in rats. Am J Physiol Regul Integr Comp Physiol 296: R1631-R1640, 2009. First published February 25, 2009; doi:10.1152/ajpregu.90527.2008.-The present study investigated the febrile response in zymosan-induced arthritis, as well as the increase in PGE(2) concentration in the cerebrospinal fluid (CSF), along with the effects of antipyretic drugs on these responses in rats. Zymosan intra-articularly injected at the dose of 0.5 mg did not affect the body core temperature (Tc) compared with saline (control), whereas at doses of 1 and 2 mg, zymosan promoted a flattened increase in Tc and declined thereafter. The dose of 4 mg of zymosan was selected for further experiments because it elicited a marked and long-lasting Tc elevation starting at 3 1/2 h, peaking at 5 1/2 h, and remaining until 10 h. This temperature increase was preceded by a decrease in the tail skin temperature, as well as hyperalgesia and edema in the knee joint. No febrile response was observed in the following days. In addition, zymosan-induced fever was not modified by the sciatic nerve excision. Zymosan increased PGE2 concentration in the CSF but not in the plasma. Oral pretreatment with ibuprofen (5-20 mg/kg), celecoxib (1-10 mg/kg), dipyrone (60-240 mg/kg), and paracetamol (100-200 mg/kg) or subcutaneous injection of dexamethasone (0.25-1.0 mg/kg) dose-dependently reduced or prevented the fever during the zymosan-induced arthritis. Celecoxib (5 mg/kg), paracetamol (150 mg/kg), and dipyrone (120 mg/kg) decreased CSF PGE2 concentration and fever during zymosan-induced arthritis, suggesting the involvement of PGE2 in this response.

Protective effect of an extract from Ascaris suum in experimental arthritis models

We investigated the effect of an extract from a helminth (Ascaris suum) in zymosan-induced arthritis (ZYA) or collagen-induced arthritis (CIA). Rats and mice, respectively, received 1 mg and 0.1 mg zymosan intra-articularly (i.a.). Test groups received an A. suum extract either per os (p.o.) or intraperitoneally (i.p.) 30 min prior to i.a. zymosan. Controls received saline. Hypernociception was measured using the articular incapacitation test. Cell influx, nitrite, and cytokine levels were assessed in joint exudates. The synovia and distal femoral extremities were used for histopathology. Cartilage damage was assessed through determining glycosaminoglycan (GAG) content. DBA/1J mice were subjected to CIA. The test group received A. suum extract i.p. 1 day after CIA became clinically detectable. Clinical severity and hypernociception were assessed daily. Neutrophil influx was determined using myeloperoxidase activity. The A. suum extract, either i.p. or p.o., significantly and dose-dependently inhibited cell influx and hypernociception in ZYA in addition to reducing GAG loss and ameliorating synovitis. The A. suum extract reduced i.a. levels of NO, interleukin-1 beta (IL-1 beta), and IL-10 but not tumor necrosis factor alpha (TNF-alpha) in rats subjected to ZYA while reducing i.a. IL-10, but not IL-1 beta or TNIT-alpha, levels in mice. Clinically, mice subjected to CIA treated with the A. suum extract had less severe arthritis. Hypernociception, myeloperoxidase activity, and synovitis severity were significantly reduced. These data show that a helminth extract given p.o. protects from arthritis severity in two classical arthritis models. This A. suum effect is species independent and functions orally and parenterally. The results show clinical and structural benefits when A. suum extract is given either prophylactically or therapeutically.

Involvement of LTB4 in zymosan-induced joint nociception in mice: participation of neutrophils and PGE(2)

Leukotriene B-4 (LTB4) mediates different inflammatory events such as neutrophil migration and pain. The present study addressed the mechanisms of LTB4-mediated joint inflammation-induced hypernociception. It was observed that zymosan-induced articular hypernociception and neutrophil migration were reduced dose-dependently by the pretreatment with MK886 (1-9 mg/kg; LT synthesis inhibitor) as well as in 5-lypoxygenase-deficient mice (5LO(-/-)) or by the selective antagonist of the LTB4 receptor (CP105696; 3 mg/kg). Histological analysis showed reduced zymosan-induced articular inflammatory damage in 5LO(-/-) mice. The hypernociceptive role of LTB4 was confirmed further by the demonstration that joint injection of LTB4 induces a dose (8.3, 25, and 75 ng)-dependent articular hypernociception. Furthermore, zymosan induced an increase in joint LTB4 production. Investigating the mechanism underlying LTB4 mediation of zymosan-induced hypernociception, LTB4-induced hypernociception was reduced by indomethacin (5 mg/kg), MK886 (3 mg/kg), celecoxib (10 mg/kg), antineutrophil antibody (100 mu g, two doses), and fucoidan (20 mg/kg) treatments as well as in 5LO(-/-) mice. The production of LTB4 induced by zymosan in the joint was reduced by the pretreatment with fucoidan or antineutrophil antibody as well as the production of PGE(2) induced by LTB4. Therefore, besides reinforcing the role of endogenous LTB4 as an important mediator of inflamed joint hypernociception, these results also suggested that the mechanism of LTB4-induced articular hypernociception depends on prostanoid and neutrophil recruitment. Furthermore, the results also demonstrated clearly that LTB4-induced hypernociception depends on the additional release of endogenous LTs. Concluding, targeting LTB4 synthesis/action might constitute useful therapeutic approaches to inhibit articular inflammatory hypernociception.

Torque articular e ativação dos musculos biceps femoral e semi-tendineo durante movimentos isocineticos de flexão do joelho em atletas de futebol

Universidade Estadual de Campinas . Faculdade de Educação Física

Influência da hipermobilidade articular na performance e incidência de lesões no atleta de natação = : Influence of articular hypermobility in the performance and incidence of injuries in the athlete swimming

Universidade Estadual de Campinas . Faculdade de Educação Física

IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice

IL-33, a new member of the IL-1 family, signals through its receptor ST2 and induces T helper 2 (Th2) cytokine synthesis and mediates inflammatory response. We have investigated the role of IL-33 in antigen-induced hypernociception. Recombinant IL-33 induced cutaneous and articular mechanical hype rn ociception in a time- and dose-dependent manner. The hypernociception was inhibited by soluble (s) ST2 (a decoy receptor of IL-33), IL-1 receptor antagonist (IL-1ra), bosentan [a dual endothelin (ET)(A)/ETB receptor antagonist], clazosentan (an ETA receptor antagonist), or indomethacin (a cyclooxygenase inhibitor). IL-33 induced hypernociception in IL-18(-/-) mice but not in TNFR1(-/-) or IFN gamma(-/-) mice. The IL-33-induced hypernociception was not affected by blocking IL-15 or sympathetic amines (guanethidine). Furthermore, methylated BSA (mBSA)-induced cutaneous and articular mechanical hypernociception depended on TNFR1 and IFN gamma and was blocked by sST2, IL-1ra, bosentan, clazosentan, and indomethacin. mBSA also induced significant IL-33 and ST2 mRNA expression. Importantly, we showed that mBSA induced hypernociception via the IL-33 -> TNF alpha -> IL-1 beta -> IFN gamma -> ET-1 -> PGE(2) signaling cascade. These results therefore demonstrate that IL-33 is a key mediator of immune inflammatory hype rn ociception normally associated with a Th1 type of response, revealing a hitherto unrecognized function of IL-33 in a key immune pharmacological pathway that may be amenable to therapeutic intervention.

IL-17 mediates articular hypernociception in antigen-induced arthritis in mice

IL-17 is an important cytokine in the physiopathology of rheumatoid arthritis (RA). However, its participation in the genesis of nociception during RA remains undetermined. In this study, we evaluated the role of IL-17 in the genesis of articular nociception in a model of antigen (mBSA)-induced arthritis. We found that mBSA challenge in the femur-tibial joint of immunized mice induced a dose-and time-dependent mechanical hypernociception. The local IL-17 concentration within the mBSA-injected joints increased significantly over time. Moreover, co-treatment of mBSA challenged mice with an antibody against IL-17 inhibited hypernociception and neutrophil recruitment. In agreement, intraarticular injection of IL-17 induced hypernociception and neutrophil migration, which were reduced by the pre-treatment with fucoidin, a leukocyte adhesion inhibitor. The hypernociceptive effect of IL-17 was also reduced in TNFR1(-/-) mice and by pre-treatment with infliximab (anti-TNF antibody), a CXCR1/2 antagonist or by an IL-1 receptor antagonist. Consistent with these findings, we found that IL-17 injection into joints increased the production of TNF-alpha, IL-1 beta and CXCL1/KC. Treatment with doxycycline (non-specific MMPs inhibitor), bosentan (ET(A)/ET(B) antagonist), indomethacin (COX inhibitor) or guanethidine (sympathetic blocker) inhibited IL-17-induced hypernociception. IL-17 injection also increased PGE(2) production, MMP-9 activity and COX-2, MMP-9 and PPET-1 mRNA expression in synovial membrane. These results suggest that IL-17 is a novel pro-nociceptive cytokine in mBSA-induced arthritis, whose effect depends on both neutrophil migration and various pro-inflammatory mediators, as TNF-alpha, IL-1 beta, CXCR1/2 chemokines ligands, MMPs, endothelins, prostaglandins and sympathetic amines. Therefore, it is reasonable to propose IL-17 targeting therapies to control this important RA symptom. (C) 2009 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved.

Articular Cartilage in the Knee: Current MR Imaging Techniques and Applications in Clinical Practice and Research

Magnetic resonance (MR) imaging is the most important imaging modality for the evaluation of traumatic or degenerative cartilaginous lesions in the knee. It is a powerful noninvasive tool for detecting such lesions and monitoring the effects of pharmacologic and surgical therapy. The specific MR imaging techniques used for these purposes can be divided into two broad categories according to their usefulness for morphologic or compositional evaluation. To assess the structure of knee cartilage, standard spin-echo (SE) and gradient-recalled echo (GRE) sequences, fast SE sequences, and three-dimensional SE and GRE sequences are available. These techniques allow the detection of morphologic defects in the articular cartilage of the knee and are commonly used in research for semiquantitative and quantitative assessments of cartilage. To evaluate the collagen network and proteoglycan content in the knee cartilage matrix, compositional assessment techniques such as T2 mapping, delayed gadolinium-enhanced MR imaging of cartilage (or dGEMRIC), T1 rho imaging, sodium imaging, and diffusion-weighted imaging are available. These techniques may be used in various combinations and at various magnetic field strengths in clinical and research settings to improve the characterization of changes in cartilage. (C)RSNA, 2011 , radiographics.rsna.org

Estudo comparativo da eminectomia e do uso de miniplaca na eminência articular para tratamento da luxação recidivante da articulação temporomandibular

AA luxação da articulação temporomandibular ocorre quando o côndilo mandibular move-se para fora da cavidade glenóide e permanece travado anteriormente à eminência articular, sendo sua ocorrência repetitiva (luxação recidivante) geralmente associada a hipermobilidade mandibular e a inclinação da eminência articular. OBJETIVO: Neste estudo avaliou-se, clínica e radiograficamente, a técnica de eminectomia e do uso de miniplaca na eminência articular para tratamento da luxação recidivante da articulação temporomandibular de pacientes operados no Hospital Universitário Osvaldo Cruz (HUOC/UPE), no período de janeiro de 2001 a setembro de 2003. FORMA DE ESTUDO: Retrospectivo. MATERIAL E MÉTODO: A amostra foi composta por 11 pacientes. A cirurgia de eminectomia foi realizada em nove articulações de cinco pacientes, enquanto a cirurgia para colocação de miniplaca na eminência articular em 11 articulações de seis pacientes. A obtenção dos dados foi efetuada através da análise de prontuários e de nova consulta pós-operatória. RESULTADOS: Os resultados mostraram não haver maiores complicações pós-operatórias para as duas técnicas. A abertura bucal máxima foi maior nos pacientes operados pela técnica de eminectomia e nenhum dos pacientes apresentou recorrência da luxação. CONCLUSÃO: Concluiu-se que as duas técnicas mostraram-se eficientes para o tratamento da luxação recidivante da articulação temporomandibular.

Técnica de pontas : análise do trabalho muscular, articular e postural, no 3ºano do Ensino Vocacional de Dança, na Academia de Música de Vilar do Paraíso

Relatório Final de Estágio apresentado à Escola Superior de Dança com vista à obtenção do Grau de Mestre em Ensino de Dança.

A efectividade de um programa de exercícios terapêuticos na doença osteo-articular no idoso

RESUMO: O presente estudo teve como objectivo avaliar a efectividade de um programa de intervenção de fisioterapia comparativamente ao tratamento conservador (calor húmido, ultra-som e massagem), relativamente à dor e capacidade funcional, no utente idoso com doença osteoarticular do joelho. A amostra foi aleatória, tendo sido seleccionados 20 utentes que respeitaram os critérios de inclusão, e que foram distribuídos aleatoriamente pelos dois grupos de tratamento, 9 no grupo A (experimental) e 11 no grupo B (controle). Todos os utentes deram o seu consentimento informado. Trata-se de um estudo experimental, controlado aleatorizado (RCT). A intervenção em estudo consistiu em 15 sessões de tratamento individuais, efectuadas 3 vezes por semana. O programa terapêutico efectuado pelo grupo A incluiu o tratamento conservador (20 minutos calor húmido, 5 minutos ultra-som (contínuo; 1,5W/cm2) e aproximadamente 10 minutos de massagem local) e o protocolo de exercícios terapêuticos em estudo. Este protocolo de exercícios foi progredindo semanalmente em termos da sua intensidade. Os utentes do Grupo B efectuaram apenas o tratamento conservador (tal como no grupo A). Para avaliar a dor e a capacidade funcional foi utilizado o Questionário knee Injury and Osteoarthritis Outcome Score. A análise dos resultados foi realizada através dos testes Mann-Whitney e Kruskal-Wallis para a comparação entre grupos. Os resultados sugerem não haver diferenças estatisticamente significativos entre os grupos, embora o grupo de controle tenha obtido melhores resultados. O grupo B apresentou uma diminuição da dor de 17,33, comparativamente aos valores de -3,00 no grupo A (p=0,101), e melhoria da capacidade funcional de 13,00, mantendo-se a capacidade funcional igual, no grupo A (0,00) p=0,080). Estes resultados parecem sugerir que não há diferenças significativas entre as duas modalidades de intervenção, realçando a necessidade de continuar a investigar este protocolo de exercícios e a sua efectividade.-----------------ABSTRACT: The aims of this study was to evaluate the effectiveness of a treatment program compared with conventional treatment (post hoots, ultrasound and massage), for the outcomes pain and functional ability in elderly with knee osteoarthritis. The sample was non-probability, and 20 patients have been selected that fulfilled the criteria for inclusion and who were randomly assigned to the two treatment groups, in group A and 11 in group B. All of the patients gave their informed consent. This is an experimental, randomized controlled trial (RCT) with blinded assessment, of comparative design. This study protocol program was carry out in 15 individual treatment sessions, 3x per week. The therapeutic program made by group A consisted of the performance of conservative treatment: 20 minutes of hot packs, 5 minutes of ultrasound (continuous, 1.5 W/cm2) and 10 minutes of massage plus the exercise protocol therapy consisted of: isometric exercises of quadriceps contractions, muscle strengthening for knee and aerobic training. This exercise protocol was progressing every week in terms of its intensity. The users in Group B, only made the conservative treatment (such as in group A). In this study there were evaluated the pain and functional capacity, assessed by questionnaire knee Injury Osteoarthritis Outcome Score. For comparison between groups were used Mann-Whitney and Kruskal-Wallis tests. The results revealed that in group B was that it obtained better results, although they are not statistical significance. The group B show a decrease in pain of 17.33 compared to -3.00 in group A (p = 0.101), and improved capacity functional of 13.00, keeping in group A (0.00) (p = 0.080). However, the differences are not statistically significant. These results show that there are not statistically significant in both treatments, but more studies are needed.

Efeito da compressão isquémica no ponto gatilho latente do trapézio superior, na magnitude de atividade muscular do complexo articular do ombro

Introdução: A síndrome dolorosa miofascial é um dos principais problemas encontrados na prática clínica, tendo como principais características os pontos gatilho (PG), ativos ou latentes. Os PG latentes têm uma elevada prevalência na musculatura da cintura escapular, nomeadamente ao nível do trapézio superior (TS), influenciando o controlo motor do ombro. A compressão isquémica aplicada no PG do TS poderá influenciar o comportamento muscular dos sinergistas durante o movimento de abdução no plano da omoplata. Objetivos: Este estudo visa estudar a influência da compressão isquémica aplicada no PG do TS na magnitude de ativação dos músculos TS, trapézio inferior (TI), grande dentado (GD), infra-espinhoso (IE) e deltóide médio (DM), assim como a relação muscular através da razão entre o TS e os restantes músculos em análise, durante o movimento de abdução no plano da omoplata. Métodos: O presente estudo é experimental, aleatório e controlado. Foram criados dois grupos, grupo controlo (GC) (n=14) e grupo experimental (GE) (n=15), a partir de uma amostra de 67 indivíduos. No GC foi aplicado um procedimento placebo e no GE foi aplicada no PG latente do TS a técnica de compressão isquémica. Antes e após a intervenção foi recolhida a atividade eletromiográfica dos músculos em análise, assim como os dados cinemáticos, durante o movimento de elevação do ombro no plano da omoplata. Para a análise registou-se a amplitude máxima de abdução e foi analisada a atividade muscular individual dos músculos em estudo assim como a razão entre o TS e os restantes músculos. Esta análise foi realizada em intervalos de 30° até ao final do movimento. Resultados: Não se verificaram diferenças na amplitude máxima de abdução, nem entre grupos (1º momento p=0,608, t=0,816; 2º momento p=0,119; t=1,252) nem entre os dois momentos em cada grupo (GC, t=-1,119; p=0,256; GE, t=-1,604, p=0,135). Na magnitude de ativação individual de cada músculo também não se verificaram diferenças significativas com a aplicação da técnica, tendo-se verificado no DM uma tendência para o aumento da ativação aquando da intervenção, ao longo de todo o arco de movimento, em comparação com a pré-intervenção, já no GC de controlo não se verificaram alterações entre momentos. Também na análise da razão entre músculos não se verificaram diferenças entre grupos. Conclusão: A intervenção realizada não influenciou nenhum dos parâmetros em análise do complexo articular do ombro nem a amplitude de movimento de abdução.

Instabilidade Multidirecional do Complexo Articular do Ombro: Estudo de Caso

Introdução: A articulação do ombro é a maior e mais complexa do corpo humano, possui características como cavidade glenóide rasa e pouca coaptação com a cabeça do úmero, o que a possibilita alcançar amplitudes que nenhuma outra articulação é capaz de alcançar, uma amplitude de movimento de 180º na flexão e abdução. Essa grande amplitude gera uma alta instabilidade na articulação do ombro tornando propenso a subluxação e luxação. O fisioterapeuta deverá realizar uma correta avaliação e interpretação dos sintomas e das alterações posturais e biomecânicas do paciente com instabilidade multidirecional do ombro. Objetivo: Realização de uma breve revisão atualizada desta temática, visando a sua avaliação e reabilitação, bem como a aplicação prática dos métodos de avaliação e tratamento num caso concreto, à luz destes conceitos. Métodos: Após a avaliação inicial, foi estabelecido um plano de tratamento com a duração de quatro semanas. A intervenção visou a diminuição da dor, normalização das alterações articulares, reforço da musculatura enfraquecida, promoção da estabilidade do complexo articular do ombro. Como instrumentos de avaliação foram utilizados a END (escala numérica de dor), goniometria, teste muscular, diversos testes adicionais de avaliação. Resultados: Ao final de quatro semanas de tratamento, houve uma melhoria significativa nos ganhos de amplitude articular, força muscular e correto posicionamento da articulação. A dor e instabilidade articular foram controladas, até que deixaram de existir. Conclusão: Uma das patologias mais frequentes em traumatologia é a instabilidade do complexo articular do ombro. Essa instabilidade é explicada pela função integral anormal dos estabilizadores estáticos e dinâmicos. Com um programa de fisioterapia adequado, englobando exercícios de correção postural, mobilização com movimento, reforço muscular, e exercícios de reeducação propriocetiva, a recuperação é possível e eficaz em casos de lesão no ombro por instabilidade multidirecional.