No adverse effects on periarticular tissue by intra-articular vitamin D analogue calcipotriol in a reduced-dose zymosan-induced arthritis model in rats.

Calcipotriol, a vitamin D analogue, is an antiproliferative and anti-inflammatory drug currently used in psoriasis. Here, our aim was to analyse the safety of calcipotriol for cartilage and bone in alleviated-dose (0.1 mg instead of usual ≥1mg dose) zymosan-induced arthritis in rats. Theoretically, high doses of vitamin D or analogues could have detrimental effects on bone or cartilage. The rats were divided into four groups: vehicle (n = 9), dexamethasone 0.1 mg/kg (n = 9), calcipotriol 0.1 mg/kg (n = 8) and negative control (n = 10) with no injections. Arthritic rats were given phosphate-buffered saline (PBS) injections to left knees as a control. After euthanasia on day 8, all knees were imaged with micro-computed tomography for surface lesions and decalcified for histological analyses. Contrary to our expectations, no significant changes could be observed in the tomography data and histological scores among the three treatment groups or between the vehicle-treated and non-arthritic group. Calcipotriol did not cause adverse effects on cartilage or subchondral bone within a week, suggesting that it could be safely used in local treatment of arthritis. The alleviated model caused synovitis with local and systemic inflammatory response without cartilage erosions, which might be useful in studying self-limiting synovitis where cartilage or bone effects are not of primary interest.

A single intra-articular dose of vitamin D analog calcipotriol alleviates synovitis without adverse effects in rats.

1,25-dihydroxyvitamin-D3 and its derivatives have shown anti-arthritic and chondroprotective effects in experimental animal models with prophylactic dosing. The purpose of this preliminary study was to test the efficacy and safety of calcipotriol, vitamin D analog, as a treatment for a fully-developed knee arthritis in Zymosan-induced arthritis (ZIA) model. Forty 5-month-old male Sprague-Dawley rats were randomized into three arthritis groups and a non-arthritic control group with no injections (10 rats/group). A day after Zymosan (0.1 mg) had been administrated into the right knee joints, the same knees were injected with calcipotriol (0.1 mg/kg), dexamethasone (0.1 mg/kg) or vehicle in a 100 µl volume. The left control knees were injected with saline (PBS) on two consecutive days. All injections, blood sampling and measurements were performed under general anesthesia on days 0, 1, 3 and 8. Internal organs and knees were harvested on day 8 and the histology of the whole knees was assessed blinded. Joints treated with calcipotriol showed a milder histological synovitis than those treated with vehicle (p = 0.041), but there was no statistically significant difference between the dexamethasone and vehicle groups. The clinical severity of arthritis did not differ between the arthritis groups measured by body temperature, swelling of the knee, thermal imaging, clinical scoring or cytokine levels on days 1, 3 and 8. Weight loss was bigger in rats treated with dexamethasone, propably due to loss of appetite,compared to other arthritis groups on days 2-3 (p<0.05). Study drugs did not influence serum calcium ion and glucose levels. Taken together, this preliminary study shows that a single intra-articular injection of calcipotriol reduces histological grade of synovitis a week after the local injection, but dexamethasone did not differ from the vehicle. Calcipotriol may have an early disease-modifying effect in the rat ZIA model without obvious side effects.

Chrysin Attenuates the NLRP3 Inflammasome Cascade to Reduce Synovitis and Pain in KOA Rats.

PURPOSE: Our recent reports have revealed that inhibiting NLRP3 activation reduces synovial inflammation and fibrosis in knee osteoarthritis (KOA). Synovial inflammation is involved the entire process of KOA and promotes the progression of KOA. Natural flavonoid Chrysin from Scutellariae Radix, a traditional Chinese medicine, exhibits multifarious biological activities and potentially has protective activity against osteoarthritis. However, the mechanism of Chrysin in the treatment of synovial inflammation remains elusive. The purpose of our research was to explore the anti-inflammatory effects of Chrysin on KOA, which was induced by monoiodoacetic acid (MIA) in rats by targeting the NLRP3 inflammasome in the hopes of identifying an effective drug to treat KOA. METHODS: The MIA-induced KOA model was used to evaluate the cold pain threshold and paw withdrawal threshold (PWT) of joints after MIA (40 mg/mL) injection into the knee joints. Microscopically, we used LPS (5 ug/mL) and ATP (4 mmol/L) to stimulate fibroblast-like synovial cells (FLSs) to explore the underlying mechanisms and effects of Chrysin. Two staining methods, H&E and Sirius Red, were applied to assess histopathological changes in synovial membranes. Cellular signal transduction was determined by qRT-PCR and WB. Cytokine expression (inflammatory cytokines and pain-related cytokines) was detected by ELISA. The degree of chronic inflammatory pain was evaluated by c-Fos immunofluorescence. RESULTS: The results showed that Chrysin not only attenuated synovial inflammation but also reduced the secretion of pain-related factors and increased the PWT and cold pain threshold in rats. Chrysin also inhibited NLRP3 inflammasome activation and increased IL-1ß levels to alleviate the synovitis. CONCLUSION: Chrysin can relieve knee synovial inflammation and improve pain behavior in KOA rats, which may be related to the ability of Chrysin to inhibit NLRP3 inflammasome activation. Therefore, Chrysin may be developed as a new drug for the treatment of KOA.

Influence of an n-3 long-chain polyunsaturated fatty acid-enriched diet on experimentally induced synovitis in horses.

Dietary n-3 long-chain polyunsaturated fatty acid (LCPUFA) supplementation has previously been shown to modify joint-related inflammation in several species, although information in the horse is lacking. We investigated whether dietary supplementation with n-3 LCPUFA would modify experimentally induced synovitis in horses. Twelve, skeletally mature, non-pregnant mares were randomly assigned to either a control diet (CONT) or an n-3 long-chain fatty acid-enriched treatment diet (N3FA) containing 40 g/day of n-3 LCPUFA for 91 days. Blood samples taken on days 0, 30, 60 and 90, and synovial fluid collected on days 0 and 90 were processed for lipid composition. On day 91, joint inflammation was stimulated using an intra-articular (IA) injection of 100 ng of recombinant equine IL-1beta (reIL-1ß). Synovial fluid samples taken at post-injection hours (PIH) 0, 4, 8 and 24 were analysed for prostaglandin E2 (PGE2 ), matrix metalloproteinase (MMP) activity and routine cytology. Synovium and articular cartilage samples collected at PIH 8 were analysed for gene expression of MMP 1 and MMP 13, interleukin-1beta (IL-1ß), cyclooxygenase 2 (COX-2), tumour necrosis factor-alpha and the aggrecanases, a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5. A 90-day feeding period of n-3 LCPUFA increased serum phospholipid and synovial fluid lipid compositions of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) compared to CONT horses. The reIL-1ß injection caused an inflammatory response; however, there was no effect of dietary treatment on synovial fluid PGE2 content and MMP activity. Synovial tissue collected from N3FA horses exhibited lower expression of ADAMTS-4 compared to CONT horses. Despite the presence of EPA and DHA in the synovial fluid of N3FA horses, dietary n-3 LCPUFA supplementation did not modify synovial fluid biomarkers compared to CONT horses; however, the lower ADAMTS-4 mRNA expression in N3FA synovium warrants further investigation of n-3 LCPUFA as a joint therapy.

Effect of anesthetizing individual compartments of the stifle joint in horses with experimentally induced stifle joint lameness.

OBJECTIVE: To evaluate the effects of sequential anesthesia of the individual compartments of the equine stifle joint on lameness induced by intra-articular deposition of interleukin (IL)-1ß. ANIMALS: 6 horses. PROCEDURES: For each horse, baseline hind limb lameness was first evaluated. A randomly selected compartment of 1 stifle joint was then injected with IL-1ß to induce synovitis and lameness; subsequently, the same compartment was anesthetized with 2% mepivacaine hydrochloride, and lameness was reevaluated. Two weeks later, baseline lameness was evaluated, and lameness was similarly induced; thereafter, the 2 synovial compartments of the stifle joint not injected with IL-1ß were anesthetized sequentially in random order (ie, first and second blocks); lameness was evaluated after each block. Finally, the IL-1ß-treated compartment was anesthetized (third block); lameness was again evaluated. This second experiment was repeated for the contralateral stifle joint 2 weeks later. Throughout the study, lameness was quantified objectively by assessing vertical pelvic movement asymmetry with a wireless, inertial sensor-based system. RESULTS: Intra-articular deposition of IL-1ß induced lameness in all injected limbs. In the first experiment, anesthesia of the compartment injected with IL-1ß resulted in a significant decrease in lameness, with vertical pelvic movement asymmetry approaching baseline. In the second experiment, lameness improved significantly after the second and third blocks and was almost completely abolished after all 3 synovial compartments were anesthetized. CONCLUSIONS AND CLINICAL RELEVANCE: In horses, lameness caused by a lesion in 1 compartment of a stifle joint can be improved more by instillation of local anesthetic solution into that compartment than by anesthesia of the other compartments.

Periarticular bone loss in antigen-induced arthritis.

OBJECTIVE: Bone loss in arthritis is a complex process characterized by bone erosions and periarticular and generalized bone loss. The antigen-induced arthritis (AIA) model is mainly used to study synovitis and joint destruction, including bone erosions; however, periarticular bone loss has been less extensively investigated. The objectives of this study were to characterize and establish AIA as a model for periarticular bone loss, and to determine the importance of NADPH oxidase 2 (NOX-2)-derived reactive oxygen species (ROS) in periarticular bone loss. METHODS: Arthritis was induced in mice by local injection of antigen in one knee; the other knee was used as a nonarthritis control. At study termination, the knees were collected for histologic assessment. Periarticular bone mineral density (BMD) was investigated by peripheral quantitative computed tomography. Flow cytometric analyses were performed using synovial and bone marrow cells. RESULTS: AIA resulted in decreased periarticular trabecular BMD and increased frequencies of preosteoclasts, neutrophils, and monocytes in the arthritic synovial tissue. Arthritis induction resulted in an increased capability to produce ROS. However, induction of arthritis in Ncf1 / mice, which lack NOX-2-derived ROS, and control mice resulted in similar reductions in periarticular trabecular BMD. CONCLUSION: The initiation of AIA resulted in periarticular bone loss associated with local effects on inflammatory cells and osteoclasts. Furthermore, based on our observations using this model, we conclude that NOX-2-derived ROS production is not essential for inflammation-mediated periarticular bone loss. Thus, AIA can be used as a model to investigate the pathogenesis of local inflammation-mediated bone loss.

Beneficial effects of Anadenanthera colubrina (Vell.) Brenan extract on the inflammatory and nociceptive responses in rodent models.

ETHNOPHARMACOLOGICAL RELEVANCE: Anadenanthera colubrina (Vell.) Brenan, popularly known as "angico", is a plant that has been widely used in folk medicine due to its anti-inflammatory property. To evaluate the pharmacological activities of this plant, studies were performed on its antinociceptive and anti-inflammatory properties. MATERIALS AND METHODS: The AE of Anadenanthera colubrina, made from the bark, was used in rodents via oral route (p.o.), at 100, 200, and 400mg/kg in classical models of nociception (acetic acid-induced writhing and hot-plate test) and inflammation evoked by carrageenan (e.g., paw edema, peritonitis, and synovitis). RESULTS: The acetic acid-induced abdominal writhes in mice were significantly reduced (P<0.001) by oral treatment with the extract (100, 200, and 400mg/kg), but the extract did not significantly increase the latency in the nociceptive hot-plate test. Anadenanthera colubrina aqueous extract reduced significantly the edema and, besides, diminished the mieloperoxidase activity (200 and 400mg/kg, P<0.01). The carrageenan-induced peritonitis was significantly reduced (P<0.05) by the aqueous extract at 100, 200, and 400mg/kg. The aqueous extract (200mg/kg) reduces the synovial leukocyte infiltration on carrageenan-induced synovitis in rats (P<0.01), but failed to significantly affect joint swelling and impaired mobility. CONCLUSIONS: We show for the first time that the anti-inflammatory and peripheral antinociceptive activities of Anadenanthera colubrina are consistent, at least in part, with the use of this plant in popular medicine practices.

Efficacy of ABT-116, an antagonist of transient receptor potential vanilloid type 1, in providing analgesia for dogs with chemically induced synovitis.

OBJECTIVE: To investigate the ability of ABT-116 (a proprietary antagonist of transient receptor potential vanilloid type 1) administered at 2 doses to attenuate lameness in dogs with experimentally induced urate synovitis. ANIMALS: 8 purpose-bred mixed-breed dogs. PROCEDURES: In a 4-way crossover study, dogs orally received each of low-dose ABT-116 treatment (LDA; 10 mg/kg), high-dose ABT-116 treatment (HDA; 30 mg/kg), firocoxib (5 mg/kg), and no treatment (nontreatment) once a day for 2 days, in a randomly assigned order. Synovitis was induced on the second day of each treatment period by intra-articular injection of either stifle joint with sodium urate, alternating between joints for each treatment period, beginning with the left stifle joint. Ground reaction forces, clinical lameness scores, and rectal temperature were assessed before the injection (baseline) and at various points afterward. RESULTS: Lameness scores at the 2-, 6-, and 12-hour assessment points were higher than baseline scores for HDA and nontreatment, whereas scores at the 2- and 6-hour points were higher than baseline scores for LDA. For firocoxib, there was no difference from baseline scores in lameness scores at any point. Compared with baseline values, peak vertical force and vertical impulse were lower at 2 and 6 hours for HDA and nontreatment and at 2 hours for LDA. No changes in these values were evident for firocoxib. The HDA or LDA resulted in higher rectal temperatures than did treatment with firocoxib or nothing, but those temperatures did not differ among treatments. CONCLUSIONS AND CLINICAL RELEVANCE: HDA had no apparent effect on sodium urate-induced lameness; LDA did attenuate the lameness but not as completely as firocoxib treatment. High rectal temperature is an adverse effect of oral ABT-116 administration that may be of clinical concern.

Differing effects of exogenous and endogenous hydrogen sulphide in carrageenan-induced knee joint synovitis in the rat.

BACKGROUND AND PURPOSE: Recent findings suggest that the noxious gas H(2)S is produced endogenously, and that physiological concentrations of H(2)S are able to modulate pain and inflammation in rodents. This study was undertaken to evaluate the ability of endogenous and exogenous H(2)S to modulate carrageenan-induced synovitis in the rat knee. EXPERIMENTAL APPROACH: Synovitis was induced in Wistar rats by intra-articular injection of carrageenan into the knee joint. Sixty minutes prior to carrageenan injection, the rats were pretreated with indomethacin, an inhibitor of H(2)S formation (DL-propargylglycine) or an H(2)S donor [Lawesson's reagent (LR)]. KEY RESULTS: Injection of carrageenan evoked knee inflammation, pain as characterized by impaired gait, secondary tactile allodynia of the ipsilateral hindpaw, joint swelling, histological changes, inflammatory cell infiltration, increased synovial myeloperoxidase, protein nitrotyrosine residues, inducible NOS (iNOS) activity and NO production. Pretreatment with LR or indomethacin significantly attenuated the pain responses, and all the inflammatory and biochemical changes, except for the increased iNOS activity, NO production and 3-NT. Propargylglycine pretreatment potentiated synovial iNOS activity (and NO production), and enhanced macrophage infiltration, but had no effect on other inflammatory parameters. CONCLUSIONS AND IMPLICATIONS: Whereas exogenous H(2)S delivered to the knee joint can produce a significant anti-inflammatory and anti-nociceptive effect, locally produced H(2)S exerts little immunomodulatory effect. These data further support the development and use of H(2)S donors as potential alternatives (or complementary therapies) to the available anti-inflammatory compounds used for treatment of joint inflammation or relief of its symptoms.

All-trans retinoic acid-induced focal myositis, synovitis, and mononeuritis.

All-trans retinoic acid has revolutionized the treatment of acute promyelocytic leukemia, but this therapy is often complicated by the all-trans retinoic acid syndrome. Here we report a patient with newly diagnosed acute promyelocytic leukemia who developed acute focal myositis, synovitis, and possible vasculitis, after receiving all-trans retinoic acid therapy. We review the existing literature on this rare clinical entity, all-trans retinoic acid-induced myositis. This condition can manifest as fever, myalgia, arthralgia, and Sweet syndrome, accompanied by distinct magnetic resonance findings involving the lower extremity musculature. Treatment consists of discontinuation of the offending drug and often high dose corticosteroids.

Aplicação do laser 808nm na dor articular crônica de ratos Wistar / Aplication of 808nm laser in chronic joint pain in Wistar rats

Durante o processo inflamatório, alguns tipos de células predominam e estão envolvidos com a produção de dor. O laser de baixa potência mostra-se útil no controle de mediadores inflamatórios, mas a ampla divergência nos parâmetros dosimétricos, conduz a variações nos resultados positivos. O objetivo deste estudo foi analisar o uso do laser 808nm, na dor articular crônica e edema de ratos Wistar submetidos a sinovite. Foram utilizados 10 ratos Wistar, divididos em dois grupos: GC - indução de sinovite em joelho direito e tratamento placebo; GT - indução de sinovite e irradiado com laser 10J/cm². Para a produção de sinovite foram injetados 100µl de formalina a 5 por cento, no espaço articular tibiofemoral direito. A avaliação da dor ocorreu pelo tempo de elevação da pata (TEP). No 10º dia após a indução de sinovite, iniciou-se o tratamento com laser sobre a face articular medial do joelho, procedimento mantido no decorrer de 10 dias. Os resultados mostraram que o laser apresentou efeitos analgésicos, visto que, para o grupo tratado, houve redução significativa nos valores de TEP, indicando redução da dor, quando comparados os valores pós-tratamento com os pré-tratamento, o que não ocorreu para o grupo que recebeu tratamento placebo; para o edema, o laser também mostrou redução significativa do mesmo. Concluiu-se que o laser 808nm, com 10J/cm², é eficaz na redução da dor articular crônica e edema, em animais submetidos a sinovite experimental.

During the inflammatory process some kinds of cells are predominant and are involved with pain production. Low power laser seems to be useful in the control of inflammatory mediators, but wide divergence in the dosemetric parameters leads to variations in its positive results. The aim of this study was to assess the use of the 808nm laser in the chronic joint pain and edema of Wistar rats submitted to synovitis. Sample was composed of 10 Wistar rats divided in two groups: CG - synovitis induction on right knee and placebo treatment; TG - synovitis induction and irradiated with 10J/cm² laser. 100µl of 5 percent phormaline were injected in the right tibiofemoral joint space. Pain assessment occurred by the time of paw elevation (TPE). On the 10th day after synovitis induction, laser treatment began on the knee medial joint surface and this procedure was kept for 10 days. The outcomes showed that laser presented analgesic effects, since significant reduction of the TPE values was observed for the treated group, hence indicating pain reduction when compared with the pre-treatment values; the same situation did not occur to the group which received the placebo treatment. Concerning edema, laser has also shown significant reduction. It can be concluded that laser 808nm with 10J/cm² is efficient in reduction of chronic joint pain and edema in animals submitted to experimental synovitis.

[Study of therapeutic effect and mechanism of Sihuang powder treating acute synovitis in experimental rabbit induced by papain injection].

OBJECTIVE: To prove the therapeutic effects of Sihuang powder (composed by four traditional Chinese herbs: root of baikal skullcap, bark of amur corktree, root of sorrel rhubarb, fruit of cape jasmine, which were mixed with wild Chrysanthemum flower solution)in treating acute synovitis in experimental rabbit knee osteoarthritic models induced by papain injection and to explore its mechanism. METHODS: Thirty-two New-Zealand white rabbits were divided into 6 groups: blank group, model group, Sihuang powder with high dosage group (2 g/kg), Sihuang powder with low dosage group (1 g/kg), Yingtaiqing group and wild Chrysanthemum flower group. The latter four groups were treated respectively with low and high dose Sihuang powder synovium and cartilage were tested concentrations of nitrogen monoxide (NO) and IL-1 level and then were prepared for pathologic and histologic observation 10 days later. Cartilage pathologic changes were record and synovium pathologic changes were valued by means of Mankin's value system. RESULTS: The NO concentration of synovium in Sihuang powder with high dosage group was lower than that of model group, and there was significantly differences between the two groups (P < 0.01). The IL-1 level of synovium was failed after treated with Sihuang powder with high dosage (P < 0.05). Sihuang powder with low dosage and Yingtaiqing also could restrain IL-1's release (P < 0.05). In Mankin's value system, Sihuang powder with high dosage almost eliminated inflammatory cells infiltrating in synovium, which was seldom found in other groups. The value of Sihuang powder with high dosage group was the lowest in treatment groups (P < 0.005). Sihuang powder with low dosage group and wild Chrysanthemum flower group also decreased the degree of inflammatory in synovium (P < 0.05). CONCLUSION: Sihuang powder can reduce the concentration of NO and IL-1 and improve inflammatory cell infiltrate in lining cells of synovium. Moreover, it can alleviate swelling and pain of joint, improve joint movement and postpone degeneration of the cartilage.

Reactive nitrogen species scavenging, rather than nitric oxide inhibition, protects from articular cartilage damage in rat zymosan-induced arthritis.

1. The contribution of nitric oxide (NO) and peroxynitrite (PN) to inflammation in a zymosan-induced (1 mg, intra-articular, i.art.) rat model of arthritis was assessed by histopathology and by measuring the glycosaminoglycan (GAG) content of the articular cartilage. 2. Progression of the chronic synovitis in zymosan-induced arthritis (ZYA) was associated with increased nitrite and nitrotyrosine (3-NT) levels in the joint exudates that paralleled a progressive loss of the GAG content. An increase in 3-NT was also observed after i.art. PN. 3. The nonselective nitric oxide synthase (NOS) inhibitor l-N(G)-nitroarginine methyl ester (25-75 mg x kg(-1)day(-1)) or the selective inducible NOS inhibitor aminoguanidine (50-100 mg x kg(-1)day(-1)) given 1 h before (prophylactic) or 3 days after (therapeutic) injection of the zymosan ameliorated the synovitis, but worsened the GAG loss, as measured at the end of the experiment (day 7). 4. The PN scavenger uric acid (100-250 mg x kg(-1) i.p. four times daily) given prophylactically until the end of the experiment (day 14), in a dose compatible with its PN scavenging activity, significantly decreased both the synovitis and the GAG loss. 5. In conclusion, PN formation is associated with cartilage damage in addition to proinflammatory activity in ZYA. NOS inhibitors and a PN scavenger were able to reduce the cellular infiltration, while displaying opposite effects on cartilage homeostasis either by enhancing or ameliorating the damage, respectively.

Deficiency of NADPH oxidase components p47phox and gp91phox caused granulomatous synovitis and increased connective tissue destruction in experimental arthritis models.

Recent studies indicated that the nicotinamide dinucleotide phosphate oxidase (NADPH) oxidase-derived oxygen radicals plays a deleterious role in arthritis. To study this in more detail, gonarthritis was induced in NADPH oxidase-deficient mice. Mice received an intraarticular injection of either zymosan, to elicit an irritant-induced inflammation, or poly-L-lysine coupled lysozyme, to evoke an immune-complex mediated inflammation in passively immunized mice. In contrast to wild-type mice, arthritis elicited in both p47phox(-/-) and gp91(-/-) mice showed more severe joint inflammation, which developed into a granulomatous synovitis. Treatment with either Zileuton or cobra venom factor showed that the chemokines LTB4 and complement C3 were not the driving force behind the aggravated inflammation in these mice. Arthritic NADPH oxidase-deficient mice showed irreversible cartilage damage as judged by the enhanced aggrecan VDIPEN expression, and chondrocyte death. Furthermore, only in the absence of NADPH oxidase-derived oxygen radicals, the arthritic joints showed osteoclast-like cells, tartrate-resistant acid phosphatase (TRAP)-positive/multinucleated cells, extensive bone erosion, and osteolysis. The enhanced synovial gene expression of tumor necrosis factor-alpha, interleukin-1alpha, matrix metalloproteinase (MMP)-3, MMP-9 and receptor activator of NF-kappaB ligand (RANKL) might contribute to the aggravated arthritis in the NADPH oxidase-deficient mice. This showed that the involvement of NADPH oxidase in arthritis is probably far more complex and that oxygen radicals might also be important in controlling disease severity, and reducing joint inflammation and connective tissue damage.

Effect of deracoxib, a new COX-2 inhibitor, on the prevention of lameness induced by chemical synovitis in dogs.

Twenty-four healthy, mixed-breed hound-type dogs were evenly and randomly assigned to a placebo control group, one of four dosages of deracoxib (0.3, 1, 3, or 10 mg/kg), or carprofen (2.2 mg/kg). Oral dosing of placebo, carprofen, or deracoxib was done 30 minutes before intraarticular injection of urate crystal suspension for induction of synovitis. Ground reaction forces, subjective clinical lameness scores, pain, joint effusion, and quantitative pain threshold responses were measured in a blinded fashion before induction of synovitis and 2, 4, 6, 8, 12, and 24 hours after injection. The medium and high dosages of deracoxib were effective in preventing lameness and pain associated with synovitis. Carprofen was also somewhat effective in attenuating the severity of urate-induced synovitis but to a lesser degree than the medium dose of deracoxib. Preemptive deracoxib treatment at dosages as low as 1 mg/kg reduced lameness and pain of synovitis associated with intraarticular administration of urate crystals.

Low frequency TENS is less effective than high frequency TENS at reducing inflammation-induced hyperalgesia in morphine-tolerant rats.

Both transcutaneous electrical nerve stimulation (TENS) and morphine are commonly used for relief of pain. Extensive research has been done on the effectiveness of each of these two methods for pain relief when given independently. However, very little literature exists examining the effectiveness of their combined use. Systemically administered morphine activates mu opioid receptors and when administered for prolonged periods results in analgesic tolerance. Low (4 Hz) and high (100 Hz) frequency TENS activate mu- and delta-opioid receptors, respectively, It is thus possible that TENS would be less effective in morphine-tolerant subjects. The current study investigated the effectiveness of high- and low-frequency TENS in the reversal of hyperalgesia in inflamed rats that were morphine-tolerant. Morphine tolerance was induced by subcutaneous implantation of morphine pellets over 10 days. Knee joint inflammation was induced by injection of kaolin and carrageenan into the knee joint cavity. Secondary heat hyperalgesia was tested by measuring the paw withdrawal latency to radiant heat (1) before pellet implantation (either morphine or placebo), (2) after pellet implantation and before inflammation, (3) after inflammation and (4) after TENS. Both high (100 Hz) and low (4 Hz) frequency TENS caused nearly 100% inhibition of secondary hyperalgesia in animals receiving placebo pellets. In contrast, the hyperalgesia in morphine-tolerant animals with knee joint inflammation was unaffected by low frequency TENS but fully reversed by high frequency TENS. These results suggest that patients who are tolerant to morphine may respond better to high frequency TENS than to low frequency TENS.

Effects of the NSAIDs meloxicam and indomethacin on cartilage proteoglycan synthesis and joint responses to calcium pyrophosphate crystals in dogs.

NSAIDs are a major cause for concern for their propensity to cause joint deterioration in canine, as in human, patients receiving these drugs for treatment of pain in osteoarthritis and other acute and chronic painful conditions. To determine the potential effects of the new NSAID meloxicam on cartilage integrity, the effects of this drug on proteoglycan biosynthesis in vitro and ex vivo were compared with those of indomethacin, a known inhibitor of sulphated proteoglycans that accelerates joint injury in human osteoarthritis. In vitro cartilage proteoglycan synthesis from a radiosulphate precursor was unaffected by 0.5-10.0 micromol/L meloxicam but was significantly inhibited by 50 micromol/L indomethacin after 6 or 24 h incubation of femoral or tibial cartilage explants in organ culture. This is in accord with previous observations in human or porcine articular cartilage under the same culture conditions. Studies were performed in vivo to establish the effects of the NSAIDs on joint integrity. This involved determining cartilage proteoglycan synthesis ex vivo, leukocyte, fluid and protein accumulation, as well as pain relief. Thus, meloxicam (0.2 mg/kg i.v. x 3 doses) or indomethacin (0.5 mg/kg i.v. x 3 doses) was given for 26 h and the effects were compared with a control (1.0 ml saline i.v. x 3 doses) in dogs in which acute inflammation had been induced by intra-articular (i.a.) injection of calcium pyrophosphate dihydrate (CPPD) crystals into the right stifle joint, an equivalent volume of saline being injected into the left stifle joint as a control. No effects were observed of the treatment with the NSAIDs on ex vivo sulphated proteoglycan synthesis. The lack of the expected inhibitory effects of indomethacin may be related to the relatively low plasma concentrations of this drug obtained during the 26 h period of treatment. The pain response, which was elicited up to 6 h following i.a. injection of CPPD crystals, was totally prevented by the treatment with meloxicam and to a lesser extent with indomethacin. There were no effects from the drug treatment on synovial inflammatory reactions (fluid and cell accumulation), although the protein concentration of the exudate was reduced by meloxicam. This indicates that, at the doses given, it was possible to discriminate the analgesic action from the anti-inflammatory action of the two NSAIDs, this being achieved at relatively low plasma concentrations of these drugs. In conclusion, while relatively high therapeutic concentrations of indomethacin inhibit cartilage proteoglycan synthesis, this is not an effect seen even at high concentrations of meloxicam. Furthermore, the lack of effects on proteoglycan synthesis was evident when these two drugs were given in vivo to dogs. However, the signs of pain, but not the inflammation in the joint, were relieved by low plasma concentrations of the drugs. Meloxicam may thus be safely employed for acute analgesia without the potential risks of joint cartilage damage that occurs with indomethacin given at antiinflammatory doses for long periods of time.

The effect of hyperthermia (42.5 degrees C) on zymosan-induced synovitis of the knee.

Though heat has been used for many years for the treatment of painful joints such therapy rarely increases the intra-articular temperature significantly. This pilot study investigated the effect of intra-articular hyperthermia induced by microwaves from a combined heating/cooling instrument on zymosan-induced synovitis in the rabbit. There was histological evidence not only of a reduction in the intensity of the inflammatory response but also in its type with the absence of giant cell formation. However, hyperthermia was not totally without effect on the synovium of control joints and further studies are required to investigate the relevance of this effect.

Assessment of a human recombinant manganese superoxide dismutase in models of inflammation.

We evaluated a novel human recombinant preparation of manganese superoxide dismutase (MnSOD) for anti-inflammatory and anti-oxidant activity compared with a copper zinc (CuZn) SOD preparation. The results showed that administration of MnSOD (50, 100 and 200 micrograms kg-1) in the Freund's Complete Adjuvant (FCA) mediated paw oedema model suppressed the inflammation at 4 hours by 43, 25 and 43% (P < 0.001, P < 0.01 and P < 0.001 at respective doses). However, 24 hours post-challenge, MnSOD (50 and 100 micrograms kg-1), suppressed the inflammation by 19% (P < 0.001). In contrast, Mn SOD at higher doses (400-800 micrograms kg-1; 2 mgkg-1) exacerbated the inflammatory response at 4 hours. This pro-inflammatory response declined progressively by 24 hours. Furthermore, CuZn SOD produced no significant effects on the inflammatory response. In the carrageenan-induced synovitis model, Mn SOD (25 and 50 micrograms; intra-articular administration) exacerbated the inflammation at 48 hours. In contrast, Mn SOD at 5 micrograms produced a significant suppression (44%, P < 0.05) in knee joint swelling at 24 hours. The CuZn SOD preparation produced marked pro-inflammatory effects in the joints whilst it lacked activity in the FCA-mediated paw oedema model. These findings support a therapeutic potential of MnSOD in inflammatory disorders, however the compound has a complex pharmaco-dynamic profile.

Effect of intravenous iron-dextran (Imferon) infusion on antigen induced monarticular arthritis in rabbits.

The effect of intravenously infused iron-dextran (Imferon) on the progression of antigen induced monarticular arthritis in rabbits was studied. A rapid deposition of iron and apoferritin in the synovia of arthritis joints occurred after infusion of iron-dextran during either the acute or chronic phases of the disease. This coincided with the appearance of catalytic (bleomycin reactive) iron in the synovial fluid. There was no evidence, however, for an exacerbation of the antigen induced arthritis as a result of the iron-dextran, and synovial and bleomycin reactive iron concentrations decreased with time after administration, indicating a redistribution of the synovial iron load. Thus although intravenously infused iron-dextran appears to 'prime' the rabbit arthritic joint transiently with the potential for iron stimulated oxygen free radical damage, other factors may determine its occurrence.