We investigated tyrosine phosphorylation of proteins in primary human acute myelogenous leukemia (AML) cells stimulated by cytokines (G-CSF, GM-CSF, TNF, M-CSF, IL-3 and SCF) .These cytokines induced protein tyrosine phosphorylation in 14-17 cases out of total 18 cases tested, except that M-CSF induced this response only in 9 cases. In the present study, we observed cytokine-specific pattern of tyrosine phosphorylation of proteins in all cases. GM-CSF and IL-3 induced tyrosine phosphorylation of p92, p80, p70 and p42. In addition to these proteins, p95 was specifically tyrosine-phosphorylated by G-CSF in most of G-CSF-responsive cases. SCF induced tyrosine phosphorylation of p140-200, p110, p95, p60, p55 and p42, and M-CSF induced tyrosine phosphorylation of p140-200, p110 and p42. On the other hand, TNF exclusively induced tyrosine phosphorylation p42. p92 was identified as c-fes product in some cases, but was found to be STAT 5 in the other cases. p95 was identified as vav product in all cases tested. p42 and p140-200 (in M-CSF stimulation) was identified as microtubule-associated protein kinase and c-fms product, respectively.
Respiratory burst activity of abnormal neutrophils in patients with myeloproliferative disorders such as chronic myelogenous leukemia was also investigated. In these patients, superoxide-producing capacity of neutrophils was markedly increased as compared with normal neutrophils. This phenomenon was observed only when neutrophils were stimulated with receptor-mediated agonists to release superoxide, and superoxide release induced by phorbol ester was normal in patients. In addition, in vitro responsiveness of patient neutrophils to cytokines was decreased. These findings suggest in vivo priming and activation of neutrophils by cytokines or via related mechanism in patients with myeloproliferative disorders.

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In a last decade, new types of skin manifestations have been recognized in atopic dermatitis, especially in Japan. These include persistent erythema of the face (atopic red face), reticular poikilodermic pigmentation on the neck (dirty neck) and acute onset of generalized swelling of the skin with occasional superficial bacterial infection (rubor of the skin) . The number of the patients with these clinical features and refractory dermatitis have been increasing and being serious clinical and social problems in Japan. Triggering factors for induction and progression of refractory atopic dermatitis have been studied extensively and impaired skin barrier function has been recognized as an important factor for the development of skin lesions in atopic dermatitis in addition to Th2 type predominant immune response to environmental allergens. At present, refractory dermatitis is thought to be induced by various kinds of skin irritants including bacterial superantigen, environmental allergen, sweat, UV light or hair care products in atopic dermatitis patients with impaired skin barrier function. IgE antibody might initiate or facilitate these skin inflammation in conjunction with various cytokines and skin resident cells such as mast cells, vascular endothelial cells or epidermal cells.

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Objectives: In order to detect the early stage of cartilage destruction of rheumatoid arthritis, we histopathologically examined the knee joints of MRL/Mp-lpr/lpr (MRL/l) mice.
Materials and methods: The serum levels of anti-type II collagen antibodies and rheumatoid factors in female MRL/l mice (3-36 weeks old) were detected by enzymelinked immunosorbent assay (ELISA) . Knee joints were obtained from female MRL/l mice (3-22weeks old) and examined by hematoxylin-eosin staining, tartrate resistant acid phosphatase (TRAP) staining and immunohistochemical method. Anti-cathepsin-L antibody was used in this study to detect the relation between inflammatory cells and matrix degradation.
Results: The anti-type II collagen antibodies in sera were found from 4 weeks old preceding the increase of rheumatoid factors. Inflammatory cells were appeared from 4 weeks old. They were remarkably accumulated in the ossification groove of Ravier (R-zone) in the posterior part of the femur. The osteoclasts were confirmed by TRAP staining and their number was increased in the course of the age as well as the serum level of anti type II collagen antibodies. Some inflammatory cells in R-zone strongly expressed cathepsin-L, which indicated that these cells participated in the carilage destruction.
Conclusion: These results suggest that the direct cartilage destruction occurs with few or no evidences of synovitis.

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Ninty nine cases with severe infection were evaluated their endotoxin levels with two different methods during endotoxin adsobing therapy (Toraymyxin^®) .
84 patients out of 99 had multiple organ failure. Survival rate at 2 weeks after direct hemoperfusion (DHP) with Toraymyxin was 63%. The endotoxin was measured in 45 cases by PCA method, and in 52 cases by Toxikolor method.
The endotoxin levels measured by PCA showed 27% decrease after DHP in survived group but no changes in died group. But measured values by Toxikolor showed a decrease in both groups.
The result of two methods showed the similar tendency that the plasma endotoxin changes by DHP correlated with the changes of blood pressure (BP) and PaO₂/FiO₂ (P/F) ratio. The cases with BP under 100 mmHg showed a significant increase over 100 mmHg after DHP in the group whose endotoxin level decreased with DHP. The same tendency was shown in P/F ratio. But in the group whose endotoxin levels did not decreased with DHP, both BP and P/F ratio could not improved significantly by DHP.

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To evaluate the efficacy of cyclosporin A (CsA) therapy for interstitial pneumonitis (IP) associated with PM/DM, 49 patients were retrospectively analysed. Thirty seven (76%) patients had IP and 7 died of respiratory failure. The patients were subgrouped by treatment for IP; 6 patients were treated with CsA (CsA-group), 5 with azathioprin (AZ) (AZ-group) and 26 with oral steroid alone (PSL-group) . After 1 month's treatment, both PaO₂ and AaDO₂ of the CsA-group patients significantly improved in comparison with the other 2 groups. Muscle strength of 6 among 7 expired DM patients with IP was normal or mild. These patients have been reported as amyopathic DM. CsA was considered to be effective in one amyopathic DM patient (M. H.), suggesting that CsA could be effective for IP in such a poor prognostic patient. There were no serious side effects during the observation period (2-37 months) . Serum soluble IL-2 receptor (sIL2R) levels were measured in 4 CsA-group patients. Those of 3 improved patients were high before CsA therapy and retured to the normal value. However the other patient who died had low sIL2R level before CsA therapy.
[Conclusion] CsA was effective for IP in some patients with PM/DM, and could also be effective for even a poor prognostic IP associated with amyopathic DM. High serum level of sIL2R could be a marker to predict the effectiveness for CsA treatment of IP in patients with PM/DM.

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Aiming at investigating the dose-response of UHAC62 (Generic Name: Meloxicam), a novel non-steroidal anti-inflammatory drug of the oxycam group, in the treatment of 75 patients with rheumatoid arthritis, a double-blind group comparative study was conducted at 20 medical centers disseminated nationwide.
Regarding the method of the study, the protocol which was far stricter than usual study protocols on the NSAIDs that were employed. This involved selecting only those patients who had shown a high rheumatic activities and who had never received any DMARDs or immunomodulators; further, any NSAIDs which had been administered were completely washed-out before the study. The doses administered were 1 mg/day (Group L) and 10 mg/day (Group H) ; and, the treatments were carried out principally for 4 weeks.
1) The rate of the patients who showed better than “Moderate Improvement” in the Final Global Improvement Rating was 41.4 % and 7.7 % in GroupH and Group L, respectively; and there was a significant difference between the groups.
2) The overall safety ratings of both groups were not significantly different from each other. Neither was there any significant difference in the incidence of adverse drug reactions between both groups, which was 10.8 % and 2.9 % in Group H and Group L, respectively.
3) The ratio of the patients on whom the usefulness ratings were made better than “Useful” was 36.4 % and 6.9 % in Group H and Group L, respectively; and thus the rating in Group H was significantly higher than that of Group L.
According to these results, it was clarified that the high dose of UHAC62, 10 mg/day, showed a significantly higher clinical effect than that of the low dose, 1 mg/day; and the efficacy of UHAC62 in the treatment of rheumatoid arthritis was clearly verified.

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A double-blind comparative study among 9 medical centers was conducted in order to investigate the optimal daily administration schedule of UHAC62 (Generic name: Meloxicam), a kind of non-steroidal anti-inflammatory oxycam agent. The daily 10 mg of UHAC62, which had been considered as an optimal dose, was administered either once daily, immediately after supper (Group O), or given twice a day divided into 5 mg immediately after breakfast and supper (Group T), both for weeks to patients with rheumatoid arthritis.
Out of the total 52 patients, 1 patient was excluded from the analyses; and 41 patients (Group O: 23 cases, Group T: 18 cases), 51 patients (Group O: 27 cases, Group T: 24 cases) and 44 patients (Group O: 24 cases, Group T: 20 cases) were subjected to the ratings of Final Global Improvement, Overall Safety, and Usefulness, respectively. The results showed the following:
(1) The ratio of the patients who showed a better than “Moderate Improvement” in the Final Global Improvement Rating was 30.4 % and 27.8 % in the Group O and Group T, respectively.
(2) The ratio of the patients on whom the test drug was shown to be “Completely Safe” in the Overall Safety Rating was 88.9% and 91.7% in the Group O and Group T, respectively. All of the adverse drug reactions which were seen in the patients of Group O and the 2 patients of the Group T were assessed as “mild”.
(3) The ratio of the patients on whom the test drug was rated as better than “Useful” was 29.2% and 25.0 % in the Group O and Group T, respectively.
There was no significant difference in the overall evaluations and the improvement rating of the symptoms between the groups.
According to these results, it was considered that the once daily administration of UHAC62 might be more promising for materializing a higher compliance in the patients who need long-term administration, although both regimens, the once and the twice daily administrations are applicable.

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We compared TS-110 with a control drug, diclofenac, by means of the doubleblind method for objective assessment of the clinical usefulness of TS-110 against osteoarthritis.
Study drugs were administered to a total of 225 subjects, and 94 and 95 subjects in TS-110 and diclofenac sodium groups, respectively, were included in efficacy analysis, 107 and 108 subjects, respectively, in safety analysis, and 98 and 100 subjects, respectively, in analysis of usefulness. The following results were obtained:
1. As to the final global improvement rating, the percentage of subjects with “improvement” or better grades was 72.3% (68/94 subjects) in the TS-110 group and 65.3% (62/95 subjects) in diclofenac sodium group and no significant differences were observed. The relative 90% confidence interval in Group T was-4.0 to 18.1% in comparison to the improvement rate in Group D, and was in the range in which equivalence could be verified.
2. The incidences of adverse reactions were 25.2% (27/107 subjects) and 25.9% (28/108 subjects) in TS-110 and diclofenac sodium groups, respectively. Gastrointestinal symptoms such as abdominal pain and discomfort in the abdominal region were common in both groups, but no serious adverse reactions were observed.
3. Concerning the overall safety rating, the percentage of subjects in whom the drug was “safe” was 74.8% (80/107 subjects) in the TS-110 group and 73.1% (79/108 subjects) in the diclofenac sodium group, and no significant differences were observed.
4. As to the utility rating, the percentage of subjects in whom the drug was “useful” or better was 59.2% (58/98 subjects) in the TS-110 group and 53.0% (53/100 subjects) in diclofenac sodium group, and no significant differences were noted.
Thus, TS-110 was judged to be a clinically useful drug for osteoarthritis.

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