Practical development of re-usable terminologies: GALEN-IN-USE and the GALEN Organisation

Excessive nitric oxide (NO) synthesis, by inducible NO synthase (iNOS), has been implicated in the pathogenesis of inflammatory diseases such as rheumatoid arthritis. We investigated the pathophysiological role of NO using an adjuvant-induced arthritis model. Kinetics of iNOS mRNA expression in paw and spleen showed that it was induced from an early stage of the disease. To further characterize the pathophysiological relevance of iNOS induction in spleen, the mitogenic response of spleen cells was examined. ConA-induced proliferation of spleen cells from arthritic rats was completely suppressed in comparison to normal rats. Elevation of nitrite, which could be converted from NO, was also observed in the culture supernatants. Addition of three NOS inhibitors, S-(2-aminoethyl) isothiouronium bromide (ITU), aminoguanidine (AG) and LNG-nitroarginine methyl ester (L-NAME) all reduced the nitrite level and restored the proliferative response dose-dependently. These NOS inhibitors also showed anti-arthritic effects. Daily subcutaneous administration of either ITU at 50 mg/kg or AG at 200 mg/kg suppressed the paw swelling by 50% in arthritic rats on day 18. Oral administration of L-NAME at 30 mg/kg showed a tendency to suppress the development of arthritis from day 11 to day 15. However, drug-induced hypertension was observed with L-NAME due to poor selectivity for iNOS isozyme. These results suggest that augmented NO synthesis, via iNOS induction, may be partly involved in the pathogenesis of adjuvant-induced arthritis by causing defects in lymphocyte function. Thus, selective inhibition of iNOS might be beneficial for the treatment of immunological abnormalities associated with inflammatory diseases.     

Modification of a rheumatoid model disease using a benzopyron preparation

The influence of a benzopyrone-preparation on the process of an experimental erysipelas in the rat, an animal model for the human rheumatoid arthritis, was studied. By plethysomometric determination of the paw volume it was shown that the swelling of the paw was significantly smaller in the benzopyrone-group than in the control-group. Furthermore it was observed that the administration of benzopyrones significantly reduced cornea-oedemas, a characteristic of the erysipelas model. The reduction of body weight, occurring during erysipelas disease, is not significantly improved by benzopyrone administration. The mortality, which is much smaller in the benzopyrone-group (30%) than in the matened control group (60%), demonstrates the good tolerance of the drug. The revealed results are described and the influence of benzopyrones on this rheumatoid disease is discussed.     

Human monoclonal rheumatoid factors augment arthritis in mice by the activation of T cells

In order to investigate the in vivo role of rheumatoid factor (RF), the effects of the administration of human monoclonal (m) IgM-RF and IgG-RF on the development of arthritis in mice were examined. The administration of human mRFs into mice immunized with type II collagen (CII) markedly enhanced the clinical score and paw swelling. The severity of arthritic joint disease with a marked infiltration of lymphoid cells, proliferation of synovial membrane, pannus formation and destruction of articular cartilage was significantly enhanced in both groups receiving RF (RF-enhanced arthritis). Skin ulcers were also observed in some of these RF-enhanced arthritis mice, whereas no such signs were observed in CII-immunized mice without mRFs. Both IgM-RF and IgG-RF increased CII-specific IgG antibodies in circulation, and the severity of arthritis correlated with the production of high titres of anti-CII antibodies. In vivo treatment of RF-enhanced arthritis mice with an anti-CD4 MoAb or an anti-CD8 MoAb inhibited the induction and progression of arthritis in these mice. Administration of RF to severe combined immunodeficient (SCID) mice with arthritis developed by the transfer of spleen cells from CII-immunized mice, prolonged the arthritis and enhanced the severity. This murine model of RF-enhanced arthritis may provide a useful tool for analysing the pathogenesis of rheumatoid arthritis in RF-positive patients.     

The lipids of buffalo spermatozoa and seminal plasma

An allometric method for estimating the volume change in inflamed paw of rats is described. The technique is effective and advantageous for long term observation of adjuvant arthritis which lacks a suitable reference criterion due to the simultaneous swelling of the control paw. In the present method, the inflammatory intensity (IF) of paw edema is estimated by means of the formula; IF(%)=(2Vr/cXd(I+Wt/aXb)-I) X 100 where Vt is the paw volume, Wt is the body weight weight and X is the tail length of the inflamed rat. The constants a, b, c, and d are obtained from tthe normal rats using the relative growth law, W=aXb and V=cXd (where W is the body weight, V is the paw volume and X is the tail length).     

Abuse, threat, and irritable bowel syndrome: what is the connection?

OBJECTIVE AND DESIGN: The effects of two hydroxamate inhibitors of metalloproteinase and tumor necrosis factor alpha (TNF alpha) processing on endotoxin-induced plasma TNF alpha and arthritic lesions in adjuvant-induced arthritic (AA) rats were determined. MATERIAL AND TREATMENT: BB-1101 and BB-1433 were administered orally twice daily to AA Lewis rats with an established disease (days 13 to 22). AA rats (day 16) or normal rats were injected with bacterial endotoxin and plasma levels of TNF alpha were also determined. METHODS: Hindpaw swelling was measured plethysmographically. Bone degradation was determined by radiography and bone mineral densitometry. TNF alpha was quantified using a sandwich ELISA. RESULTS: The hydroxamic-acid pseudopeptides inhibited plasma. TNF alpha levels in vivo and significantly reduced swelling and bone degradation of the tibiotarsal joints of AA rats in the range of 10-50 mg/kg given orally (p < 0.01 by Student's t-test). CONCLUSIONS: Thus, these novel compounds offer a new disease modifying therapy for arthritis and the results also suggest that inhibition of TNF alpha production may contribute, at least in part, to their anti-arthritic activity.     

Epoxyquinomicins A, B, C and D, new antibiotics from Amycolatopsis. II. Effect on type II collagen-induced arthritis in mice

The anti-arthritic effects of epoxyquinomicins on type II collagen-induced arthritis in DBA/1J mice were examined. Prophylactic treatment with epoxyquinomicins A, B, C and D (1-4 mg/kg) had potent inhibitory effects on type II collagen-induced arthritis. In contrast to nonsteroidal anti-inflammatory drugs (NSAIDs), epoxyquinomicin C (1-30 mg/kg) had neither an anti-inflammatory effect on carrageenan-induced paw edema in rats nor an analgesic effect on acetic acid-induced writhing in mice. These results suggest that the mode of action of epoxyquinomicins is different from that of NSAIDs and that epoxyquinomicins may become useful drugs for the treatment of rheumatoid arthritis.     

Adjuvant arthritis: influence of the adjuvant volume and composition on the non-specific inflammation

Adjuvant-induced arthritis is an animal model of chronic inflammatory disease widely used in anti-inflammatory and immunosuppressive drugs testing. When the development and the inhibition of the induced arthritis are measured by the injected paw oedema, it is difficult to delineate the immunological contribution from the persistent non-specific primary section. To study the influence of volume and composition of the injected adjuvant upon the primary non-specific inflammation, we devised a 3X4 factorial experiment on a strain of inbred rats with a low susceptibility to adjuvant-induced arthritis. The injection of mineral oil alone produces a persistent oedema. The injection of mycobacteriae in suspension in saline induces a rapid inflammatory response followed by a fast decrease of the oedema. When complete adjuvant is used, there is always a very strong interaction between the effects of the two components of the adjuvant, i.e. the measured oedemas are much greater than the calculated values, For a given injected volume, the inflammation is maximum when the concentration of mycobacteriae is 2.5 mg/ml. All the rats injected with complete adjuvant present a transient oedema of the non-injected hind paw. This oedema is very small and proportional to the amount of mycobacteria injected.     

Intraarterial calcium stimulation test for detection of insulinomas

The choice of drugs to reduce pain and excessive inflammatory reactions after surgery or accidental trauma is reviewed and discussed, with particular reference to a series of Norwegian studies based on bilateral oral surgery. In this model, paracetamol has proved capable of reducing post-operative swelling by about 30%, while acetylsalicylic acid (in common analgesic doses) failed to reduce or even tended to increase swelling. Paracetamol is a recommendable alternative for reducing acute post-traumatic pain and swelling, while acetylsalicylic acid should be avoided. Non-steroidal anti-inflammatory drugs which efficiently reduce rheumatoid swelling may provide good pain relief, but the effect on an acute post-operative swelling is less impressive. In the oral surgical model, glucocorticoids reduced post-traumatic swelling by about 50% and provided better or at least as good pain relief as any tested non-steroidal anti-inflammatory drug, including paracetamol. Single dose or short-term administration of a glucocorticoid is recommended as an efficient and valuable means of reducing both pain and excessive inflammation in surgery and traumatology. Of practical implication in traumatology is the finding that, for both paracetamol and glucocorticoids, almost the same reductions were recorded in swelling and pain whether the drug was administered prior to surgery or 2-3 hours afterwards.     

Pyrroles and other heterocycles as inhibitors of p38 kinase

Investigation of furans, pyrroles and pyrazolones identified 3-pyridyl-2,5-diaryl-pyrroles as potent, orally bioavailable inhibitors of p38 kinase. 3-(4-pyridyl-2-(4-fluoro-phenyl)-5-(4-methylsulfinylphenyl)-pyrrol e (L-167307) reduces secondary paw swelling in the rat adjuvant arthritis model: ID50 = 7.4 mg/kg/b.i.d.     

Involvement of endogenous kinins in the pathogenesis of peptidoglycan-induced arthritis in the Lewis rat

OBJECTIVE: To investigate the pathophysiologic roles of endogenous bradykinin (BK) and des-Arg9-BK on local and systemic inflammatory responses in a rat model of acute arthritis induced by peptidoglycan-polysaccharide (PG-APS). METHODS: Female Lewis rats were injected intraperitoneally with PG-APS. Selective antagonists of B1 (Lys-[Leu8]-des-Arg9-BK) and B2 (Hoe 140) receptors were infused at 500 microg/kg and 5 mg/kg per day for 6 days, starting 3 days before induction of inflammation, with subcutaneous micro-osmotic pumps. The local inflammatory response was assessed by paw edema, joint swelling, and tissue content of BK and des-Arg9-BK. These peptides were measured by highly sensitive and specific chemiluminescent enzyme immunoassays. Systemic inflammatory reaction was evaluated by the hepatic concentration of the type 2 acute-phase protein T-kininogen. RESULTS: PG-APS induced significant paw edema and joint swelling 24-72 hours after intraperitoneal injection. The maximal responses to PG-APS observed at 72 hours were significantly reduced (31-38%) by the combination of both B1 and B2 receptor antagonists at 5 mg/kg per day. PG-APS induced a significant increase of BK (up to 5.3-fold) and des-Arg9-BK (up to 4.1-fold) 72 hours after challenge. Liver T-kininogen content was increased by 5.3-, 7.7-, and 5.8-fold at 24, 48, and 72 hours, respectively, after PG-APS injection. At 24 hours, Hoe 140 and Lys-[Leu8]-des-Arg9-BK increased liver T-kininogen content by 43% and 45%, respectively, but they had no effect at 72 hours. CONCLUSION: The results indicate that endogenous kinins are involved in local and systemic acute inflammatory responses, through both B1 and B2 kinin receptors, in the model of PG-APS-induced arthritis.     

Effects of cytogenin, a novel anti-arthritic agent, on type II collagen-induced arthritis in DBA/1J mice and adjuvant arthritis in Lewis rats

The anti-arthritic effects of cytogenin (8-hydroxy-3-hydroxymethyl-6- methoxyisocoumarin) on type II collagen-induced arthritis in DBA/1J mice and adjuvant arthritis in Lewis rats were examined. Prophylactic treatment with cytogenin (30, 100 mg/kg) had a potent inhibitory effect on type II collagen-induced arthritis. Prophylactic or therapeutic treatment with cytogenin (10, 30 and 100 mg/kg) also had a potent inhibitory effect on adjuvant arthritis. In contrast to nonsteroidal anti-inflammatory drugs (NSAIDs), cytogenin (10, 30 and 100 mg/kg) had neither an anti-inflammatory effect on carrageenan-induced paw oedema in rats nor an analgesic effect on acetic acid-induced writhing in mice. These results suggest that the mode of the anti-arthritic action of cytogenin is different from that of NSAIDs and that cytogenin may become a useful drug for the treatment of rheumatoid arthritis.     

Structure and chromosomal mapping of the mouse P2X3 gene

Since arthritis induced by Mycobacterium products (adjuvant) in rats is considered to be immunologically driven, the objective of the present study was to determine if the immunosuppressor drug cyclosporin could affect hindpaw edema and joint hyperalgesia simultaneously. Female Holtzman rats (140-170 g) presented hyperalgesia and edema on the 8th and 12th day following adjuvant injection. Daily systemic (oral or intramuscular) administration of cyclosporin (0.5-5.0 mg kg (-1) day (-1)) or dexamethasone (0.01-0.1 mg kg (-1) day (-1)) for 15 days starting on day zero dose-dependently inhibited the hindpaw edema and hyperalgesia in arthritic rats. However, hyperalgesia but not edema could be detected two days after cyclosporin withdrawal. We concluded that a) the continuous presence of cyclosporin is essential to reduce the development of joint hyperalgesia and that b) different mechanisms underlie the appearance of hyperalgesia and edema in this model. The intracerebroventricular (i.c.v.) administration of 5-50-fold smaller doses of cyclosporin (1.5-150 micrograms/day) or dexamethasone (15 micrograms/day) also reduced the arthritic hindpaw edema and hyperalgesia. Peripheral blood from animals injected with effective systemic cyclosporin doses showed detectable levels of the drug, whereas peripheral blood from those injected with i.c.v. cyclosporin did not, as measured by specific RIA. Our results indicate that cyclosporin administered by the central route is as effective as by the systemic route to reduce joint hyperalgesia and hindpaw edema in arthritic rats. The antiarthritic effect induced by low doses of cyclosporin in the central nervous system (CNS) could be explored to avoid it often associated systemic side effects during chronic therapy. However, the mechanism(s) involved in the antiarthritic response to cyclosporin in the CNS remain to be elucidated.     

Effects of interleukin-1 receptor antagonist in a slow-release hylan vehicle on rat type II collagen arthritis

PURPOSE: To determine the effect of hylan fluid (HA), a model slow release vehicle on the pharmacokinetic profile and efficacy of interleukin-1 receptor antagonist (IL-1ra) in rats with established type II collagen arthritis. METHODS: Female Lewis rats with type II collagen arthritis were treated daily, every other day or every third day with single subcutaneous (sc) injections of IL-1ra formulated in HA and the effects on arthritis determined. Results were compared to those obtained with IL-1ra in citrate buffered saline with EDTA and polysorbate (CSEP). Sequential blood levels were determined in rats injected sc with IL-1ra in CSEP or HA. RESULTS: Incorporation into HA led to slower release of IL-1ra into the bloodstream and maintained therapeutic blood levels of IL-1ra for a longer time compared to the IL-1ra/CSEP formulation. Single daily sc doses of 100 mg/kg IL-1ra in CSEP were ineffective in type II collagen arthritis. By contrast, once per day dosing of 100 mg/kg IL-1ra in HA provided 78% inhibition of paw swelling. Every other day dosing with 100 mg/kg IL-1ra in HA resulted in 62% inhibition. IL-1ra (100 mg/ kg in HA) given every third day provided 19% inhibition of arthritis. Improved efficacy correlated with improved pharmacokinetics. CONCLUSIONS: Administration of IL-1ra in the slow release vehicle HA improves pharmacokinetics and efficacy in rat type II collagen arthritis.     

Acetylsalicylic acid potentiates the antinociceptive effect of morphine in the rat: involvement of the central serotonergic system

Acetylsalicylic acid and morphine are the most widely distributed and most frequently used drugs in the relief of pain, but their analgesic activity has adverse side-effects. Mixtures containing these two drugs are frequently used to relieve mild to moderate pain despite the paucity of relevant experimental evidence so far published. We set out to study the possible antinociceptive effect of a combination of subactive doses of the two drugs in rats. A combination of low doses of acetylsalicylic acid (50 mg/kg i.p.) and morphine (3 mg/kg s.c.) was administered and the pain threshold was evaluated in the hot-plate and formalin tests, and 5-HT2 receptor binding capacity, 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels were measured in the cortex and pontine areas of the brain. The combination of acetylsalicylic acid and morphine had an analgesic effect in both tests that was associated with an increase in 5-HT levels and a decrease in 5-HT2 receptors in the cortex. These effects were either completely abolished or partially prevented by i.p. pretreatment with naloxone (1 mg/kg i.p.). Our results demonstrate that subactive doses of acetylsalicylic acid and morphine can exert analgesic and biochemical effects when given in combination in the rat and suggest an involvement of serotonergic and opiatergic systems.     

Effect of mu-opioids morphine and buprenorphine on the development of adjuvant arthritis in rats

OBJECTIVE AND DESIGN: On the basis that endogenous opioids play a role in the physiological response to inflammation, this study tests the anti-arthritic effects of a mu-opioid agonist, morphine and the partial mu-agonist, buprenorphine. MATERIAL: Male Lewis rats were used. TREATMENT: Rats were inoculated subcutaneously with 0.05 ml of Freund's complete adjuvant (5 mg/ml) into the right hind paw to produce adjuvant arthritis. Morphine (either 10 to 60 mg/kg/day s.c. bolus or 60 mg/kg/day s.c. infusion) and buprenorphine (0.65 +/- 0.06 mg/kg/day, orally), respectively, were administered for 3 days during the primary inflammatory phase of adjuvant arthritis. METHODS: The progression of adjuvant arthritis was monitored every three days by body weight change and hind limb oedema (ipsilateral and contralateral). On day 21 the animals were sacrificed and histology and radiography of the contralateral limb were performed. In rats receiving Freund's adjuvant and no drug treatment, the incidence of arthritis was 89%. Effect was expressed as the pooled severity index (PSI) derived from the arithmetic average of the volume, histology and radiography scores in the contralateral hind limb. RESULTS: Buprenorphine had no effect on experimental arthritis (PSI control vs treated: 242 +/- 28 vs 253 +/- 28%). In contrast, morphine by subcutaneous injection twice daily (10 to 60 mg/kg/day) but not by subcutaneous infusion (60 mg/kg/day) was found to attenuate the progression of adjuvant arthritis in a dose-dependent manner. This indicates that the anti-arthritic effects of morphine are opioid receptor mediated (ED50, 58 +/- 9 mg/kg) and suggests that the local concentration reached effective levels only after subcutaneous injection. It is also possible that the high doses of morphine were anti-inflammatory through effects at the kappa receptor. However, these high doses of morphine produced death in one third of the rats, the calculated lethal dose (LD50, 63 +/- 2 mg/kg) being close to the effective dose. CONCLUSION: Anti-arthritic effects of morphine are opioid receptor mediated but morphine use for this indication is restricted by its adverse effects.     

Prognosis value of the expression of Ki-67 for squamous cell carcinoma of the oral cavity

A single dose of either cyclosporin-A (CsA) or lobenzarit (CCA) given with an arthrogenic adjuvant completely prevented expression of experimental adjuvant arthritis in rats. The aim of this study was to understand how these drugs prevented the arthritis expression by studying the popliteal lymph nodes draining the arthritic joints at various times after adjuvant injection. Neither drug affected the proliferation in popliteal lymph nodes at the time arthritis was normally expressed, however, there was a marked change in the types of cells present. Immunofluorescence assays showed a reduction in the proportion of CD4+ cells, while the proportion of B-lymphocytes was almost doubled. This coincided with a marked elevation in the ability of these cells to produce interleukin (IL)-6. At the same time production of other cytokines (IL-2, tumour necrosis factor (TNF) and interferon (IFN)-gamma) was not greatly affected. However, one day after adjuvant injection IL-2 and IFN-gamma production was reduced. In vitro experiments showed that IL-6 production by lymphoid cells was relatively unaffected by CsA and CCA but IL-2, TNF and IFN-gamma were suppressed by CsA. The results indicate that CsA and CCA may modify the response to the arthritic adjuvant by specifically inhibiting IL-2, TNF and IFN-gamma production at the time of adjuvant injection. The lack of inhibition of IL-6 by these drugs reveals it may not play a key role in the initiation of this model of chronic inflammation.     

Incidence of acral nodulosis with long-term methotrexate therapy in patients with inflammatory rheumatic diseases

The significance of acral nodulosis under methotrexate therapy is still controversial. Among patients with rheumatoid arthritis and methotrexate therapy this manifestation could be observed in 8/163 (5%). All cases were seropositive and already treated with other LAAD. Patients with other inflammatory rheumatic diseases under methotrexate therapy (n = 83) did not develop this nodulosis. The acral nodulosis is interpreted as a typical side-effect of methotrexate only in patients with rheumatoid arthritis. Histopathologically, these nodules do not differ from the typical rheumatoid nodule.     

Antisense targeting of the urokinase receptor blocks urokinase-dependent proliferation, chemoinvasion, and chemotaxis of human synovial cells and chondrocytes in vitro

Proliferation and invasion of synovial pannus in rheumatoid arthritis and cartilage remodeling in osteoarthritis are key events in development of disability of arthritic joints. The mechanisms that trigger these events are still poorly understood. The production of urokinase-type plasminogen activator (u-PA) by synovial cells and chondrocytes and the subsequent interaction of u-PA with its membrane receptor (u-PAR) is under the control of a variety of growth factors and cytokines released within the inflamed joints. Here we show that u-PA, on interaction with the specific receptor, regulates movement and invasion as well as proliferation of human synovial cells and chondrocytes. Targeting the urokinase receptor with an antisense oligonucleotide blocks the u-PA-dependent synoviocyte and chondrocyte proliferation and chemoinvasion, suggesting a possible use for this new class of drugs in the progression of the disease in rheumatoid arthritis and osteoarthritis.     

Reoperations on the spine--outcome studies

Rheumatoid arthritis is described by Swanson (1995) as 'the greatest crippler from the standpoint of severity and prolonged disability' (p. 1307). One key factor in keeping persons with rheumatoid arthritis independent in their activities of daily living is maintaining functional use of their hands. In rural areas, where a move to assisted accommodation may require a person to leave the locality, this splint may help older citizens to remain functional and at home. The deformity and instability caused in rheumatoid arthritic hands by radial deviation of the wrist and subsequent ulnar deviation of the metacarpophalangeal (MCP) joints can greatly affect functional use of the hands. In this article, design and fabrication instructions for a lycra working splint which is suitable for the rheumatoid arthritic hand with MCP ulnar deviation are presented. Health professionals working in rural areas will find this splint inexpensive and easy to design, either alone or, ideally, with the assistance of regional occupational therapists.     

Pavlovian conditioning of immunosuppression modifies adjuvant arthritis in rats.

Dosed 36 female Wistar rats, in 3 groups, with cyclophosphamide (CY), an immunosuppressive drug, 10 days before induction of adjuvant arthritis (by injection of complete Freund's adjuvant into each S's hind paw). A saccharin/vanilla solution (SV) was presented either 2 days before CY treatment (Group NC) or immediately before (Groups C and C2). Three further SV presentations started either 30 min after antigenic stimulation (Groups C and NC) or 2 days afterward (Group C2). The groups did not differ with respect to the degree of swelling in the injected paws. In contrast, Group C showed no external signs of a proliferation of inflammation in the uninjected hind paws, whereas approximately half of the Ss in Groups NC and C2 developed small lesions. Exp II, similar to Exp I, with 48 Ss, yielded the same results. The results essentially confirm previous findings on conditioned immunosuppression and extend them to an inflammatory joint disease. (21 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)