Phospholipase A₂ (PLA₂) plays a crucial role in diverse cellular responses including phospholipid digestion and metabolism, host defene, and signal transduc-tion. PLA₂ provides precursors for eicosanoid generation when the cleaved fatty acid is arachidonate. Mammalian tissues and cells generally contain more than one PLA₂ enzyme. Recent advances in molecular and cellular biology enabled us to understand the molecular nature, possible function and regulation of each PLA₂ isozymes. Cytosolic PLA₂ (cPLA₂) and secretory PLA₂ (sPLA₂) are the most well characterized PLA₂s amongst a still expanding large family of mammalian PLA₂s. cPLA₂ exists in the cytosol of various types of cells almost ubiquitously. It exhibits arachidonate-preference and the activity is regulated by protein phosphorylation. sPLA₂ is also widely distributed in mammalin tissues and cells. In particular, sPLA₂ in detected extracellularly in inflamed sites of experimental animals and human. Participation of sPLA₂ in arachidonate metabolism is also demonstrated. Here, I focus on recent studies of involvement of cPLA₂ and sPLA₂ in eicosanoid generation.

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The role of adhesion molecules in cultured human osteoblasts (OB) and osteoclasts (OC) in bone destruction was studied. OB and OC were obtained from human periosteum and human bone marrow. Adhesion molecules were quantified by cell ELISA using monoclonal antibodies (mab) . Ca release was estimated by ⁴⁵Ca release assay.
In OC, both ICAM-1 and VCAM-1 were expressed and strongly enhanced by IL-1β, TNF-α and mildly by IL-6. LFA-1, Mac -1 and VLA-4 were also expressed and enhanced by IL-1β and TNF-α. In OB, both ICAM-1 and VCAM-1 were highly expressed. OC strongly adhered to IL-1β-stimulated OB, and released Ca from OB. ICAM-1 mab did not abolish the adhesion and Ca release. The results obtained suggest that OB-OC cell interaction and OC-matrix interaction play important roles in OC-mediated bone resorption and that not only ICAM-1/LFA-1 (Mac -1) adhesion pathway but also other adhesion pathways mediate cell-cell or cell-matrix interaction in bone.

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Le^y antigen expression is assumed to be a predisposing marker for apoptosis. In this study we semi-quantitatively examined apoptosis of cells in joint tissues, such as synovia, cartilage and bone in rheumatoid arthritis (RA) by means of an immuno-histochemical technique with anti-Le^y antigen antibodies.
In synovia of patients with trauma or osteoarthritis (OA), only a few inflammatory cells were positive for Le^y, while in RA, inflammatory cells, mainly neutrophils, were strongly Le^y positive. Furthermore capillary endothelial cells were also Le^y positive.
In RA the number of Le^y positive inflammatory cells increased with the progression of inflammation, and decreased with the progression of fibrosis. The number of capillaries with Le^y positive endothelial cells, revealed same tendency. We concluded therefore that apoptosis is related to the degree of inflammation in RA.
In bone and cartilage of patients with RA, some chondrocytes neighboring granulations were Le^y positive, but there were no positive cells in patients with OA. For this reason we propose that apoptosis of chondrocytes may be triggering to cartilagenous destruction as well as production of proteinases in RA.

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When a cyst is infected, the cyst wall is damaged. The treatment procedure using the irrigation method is as follows : before the operation, the cyst fluids in cyst cavities are replaced with a solution of Solcoseryl^® or 20% glucose, containing antibiotics ; the infection of the cyst cavity disappears and osmotic pressure decreases, so the formation of free radicals ( O^-/⋅₂, HO⋅) and lipoperoxides (TBARs, PC-OOH) in the cyst wall is suppressed, as is the function of 12-HETE, LTB₄ and 6-keto-PGF₁α generated in the cyst walls. The blood circulation in the capillary vessels of the connective tissues in the cyst walls improves, and the cyst gradually diminishes in size until bone remodelling takes place. Recovery occurs soon after the operation.

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SIL-6R levels in serum and synovial fluid were in thousand folds excess of IL-6 levels. Both of them showed no significant correlation to any clinical or laboratory data. From histopathological analysis, IL-6R contributed to synovial inflammation.

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According to the previous concepts of antiallergic drugs, it was difficult to select the essential antiallergic drugs which was necessary for treatment of patients with allergy. We, therefore, attempted to discover that antiallergic drugs have the any pharmacologic actions on the process of allergic response. We divided into three stages on the process of allergic response in this animal experiment. Antiallergic drugs used in this study were azelastine hydrochloride, ketotifen fumarate, tranilast and oxatomide. First, we observed the suppression of IgE production in rats on the administration of azelastine hydrochloride. Secondly, we observed that azelastine hydrochloride and ketotifen fumarate inhibited the interaction between anti-DNP-As and DNP-As on ELISA. Thirdly, we observed that tranilast and azelastine hydrochloride reduced, more effectively than any other antiallergic drug, the release of histamine from rabbit washed platelets by PAF.
In addition, it was observed that azelastine hydrochloride and ketotifen inhibited dose-dependently the increase of permeability induced by PAF or histamine in rats. From these results, we could propose the new concepts that some of antiallergic drug inhibited the IgE production.

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Using subacute arthritis induced by inoculation of Freund's complete adjuvant into the knee-joint of beagles, the anti-inflammatory effect of indometacin farnesil (IMF) was observed and compared with that of indometacin (IND) . The side effects of both drugs were studied as well. The therapeutic efficacy of the two drugs was clarified through comparison of the efficacy rates against arthritis and those for side effects.
Freund's complete adjuvant was injected into the knee-joints of the beagles 5 min before the initial administration of the test drugs. Thereafter, the test drugs were administered at 2 dose levels egivalent to clinical rates, once a day for 8 days. Local inflammatory symptoms such as pain, hyperthermia and swelling in the inflammatory lesions were monitored and the rectal temperature was measured during the experiment. Three hours after the final administration, PGE₂, IND and IMF concentrations in the synovial fluid, and PGE₂⋅I₂ and IND concentrations were measured in the pyloro-duodenum. The pyloroduodenum was also investi-gated histologically. Both IMF (30mg/kg) and IND (1.7mg/kg) reduced pain dose-dependently and were almost equipotent in analgesic activity on the 3rd day.
Only IMF (30mg/kg) showed a significant ability to reduce the higher temperature in the inflamed joints (p<0.05) . IMF (30mg/kg) and IND (5.0mg/kg) were almost equipotent in anti-pyretic activity on both the 1st and 3rd days. A significant amount of IND, which might have come from the blood stream and/or result from the hydrolysis of IMF in the synovial fluid, and levels of PGE₂ lower than those of the control detected in the synovial fluids in both the IMF and IND groups, seem to indicate that the anti-inflammatory and analgesic effects are due to the tissue levels of IND, which inhibited the action of cyclooxygenase in the fluid.
The side effects in the IND groups were very severe with bloody stool in one out of six and four out of six animals in the 1.7mg/kg and 5.0mg/kg groups, respectively, while no severe side effects were seen in either the IMF or control groups, except for mild anolexia and ref lexible vomiting. Ulcers and erosions with hemorrhage were seen in the pyloroduodenum and severe ulcers were observed in the IND 1.7mg/kg and 5.0mg/kg. These abnormalities were also confirmed in the histological examination. Similar reductions of PGE₂⋅I₂ when compared with the control group were detected in the pyloroduodenum in both the IMF and IND groups but there was a significant difference in mucosal damage between them. It is therefore most likely that the inhibition of PGs syntheses by IND is not solely responsible for the mucosal damage and some other factors may be involved. In terms of anti-inflammatory effect, although IMF at 30mg/kg was weaker than IND at 5.0mg/kg, IMF had a similar effect or was a little stronger than IND at 1.7mg/kg. Even at the same effective dose, the frequency of side effects for IMF was much less for IND. These results indicate that IMF, a prodrug of IND, has a different action from IND, and is prefered since IMF would expect to cause lesser side effects associated with IND.

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On 15 patients with rheumatoid arthritis (RA) who were treated with mizoribine, a novel immunosuppressive drug, we measured concentrations of mizoribine in the plasma and synovial fluid over time. The plasma and synovial fluid levels were reached to the maximum of 0.84 of the concentration ratio (synovial fluid/plasma) . Mizoribine transfer into the plasma and synovial fluid was delayed in RA patients with renal dysfunction. Also, drug absorption may be disturbed in cases having stomach disorders. As a whole, mizoribine can easily be transfered from plasma to synovial fluid.

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Effect of azelastine, an anti-allergic compound, on granulocyte-endothelial cell adhesive reactions induced by PAF was investigated using human granulocytes and human umbilical vein endothelial cells. Azelastine inhibited surface expression of CD18 on granulocytes induced by PAF. In addition, azelastine reduced CD18-dependent granulocyte adherence to endothelial cells elicited by PAF.
These results indicate that azelastine has an anti-inflammatory action through inhibiting granulocyte-endothelial cell interactions at inflammatory site.

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25 mg powder of NaCl or asprin mixed 25 mg of lactose was administered to the target on gastric mucosa by air flow carrying system through endoscope. NaCl or aspirin produced gastric ulcer, but, the mixture of lactose produced redness and/or erosions on target sites after 24 hour. The direct gastric mucosal injury of drug can be reduced the mixing of lactose.
When powder of sucralfate mixed with NaCl or asprin was administered to gastric mucosa, redness and/or erosions lesions observed after 24 hour at target sites. Similarly, benexate hydrochloride β-cyclodextrin clathrate mixing NaCl or aspirin, produced redness and/or erosions lesions in canine stomach. The direct gastric mucosal injury can be reduced the mixing of sucralfate and/or benexate hydrochloride β-cyclodextrin clathrate which have direct effect to gastric lesions.

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The clinical usefulness of cilostazol, a platelet aggregation inhibitor, in the treatment of skin ulcer was evaluated in 31 patients with collagen diseases, including 16 patients with systemic sclerosis, 7 with SLE, 2 with MCTD and 6 with other subtypes of the disease. This evaluation followed administration of the drug at a daily dose of 100mg (50mg×2) for 8 successive weeks.
Twenty-four patients, excluding 7 patients with protocol violations, were included in the efficacy evaluation. The size of skin ulcer significantly decreased from 6.6±6.7mm (mean ± SD) to 3.8 ± 3.2mm at 2 weeks of treatment and to 2.2 ± 2.9mm at 8 weeks of treatment. The appearance of granuloma, and redness, swelling, spontaneous pain and haphalgesia were significantly improved at 2 weeks of treatment and thereafter. The final global improvement rating revealed an assessment of“moderately improved”or better in 87.5% (21/24) of the 24 patients. Adverse reactions were experienced by 48.4% (15/31 patients) : headache in 29%, palpitation or tachycardia in 9.7%, dull headache in 6.5% and tinnitus in 3.2%. Treatment was discontinued due to adverse reactions in 19.4% (6 patients) of the 31 patients.
Overall usefluness, which was assessed based on the final global improvement rating and overall safety, revealed an assessment of“useful”or better in 83.3% (20/24 patients), indicating that cilostazol is useful in the treatment of skin ulcer accompanying collagen diseases.

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Long-term (over 12 months) study of nabumetone was conducted in patient with RA in a PMS drug evaluation effort. Only a small number of patients dropped out or discontinued nabumetone therapy at an early stage, with the treatment period being less than 3 months in 12 of 162 patients (7.4%), 3-6 months in 14 patients (8.6%) and 6-9 months in 9 patients (5.6%) . Treatment was continued for more than 12 months in 121 patients (74.7%), suggesting that the drug is well-tolerated by most of the patients.
Grip strength, erythrocyte sedimentation rate, number of painful joints, number of swollen joints, duration of morning stiffness and Lansbury's index showed statistically significant improvement from the pre-treatment base line at every evaluation time point.
The global improvement rate (“markedly improved”+“moderately improved”+“slightly improved”) was 56.6%, 64.1%, 63.6% and 64.9% respectively at 3, 6, 9, and 12 months. The improvement rate thus increased till 6 months after starting the treatment. Adverse events occurred in only 12 of 159 patients (7.5%), with GI symptoms, which are major adverse events of non-steroidal anti-inflammatory agents, in only 9 patients (5.6%; 11 episodes) .
Severity of adverse events was rated“mild”or“moderate”and no severe adverse event was reported. Abnormal laboratory findings observed were 4 patients (4 episodes), but all of them cleared after the discontinuation of nabumetone.

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