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Ruzicka T.,Ludwig Maximilians University of Munich | Hanifin J.M.,Oregon Health And Science University | Furue M.,Kyushu University | Pulka G.,Jagiellonian University | And 9 more authors.
New England Journal of Medicine | Year: 2017

BACKGROUND Interleukin-31 may play a role in the pathobiologic mechanism of atopic dermatitis and pruritus. We wanted to assess the efficacy and safety of nemolizumab (CIM331), a humanized antibody against interleukin-31 receptor A, in the treatment of atopic dermatitis. METHODS In this phase 2, randomized, double-blind, placebo-controlled, 12-week trial, we assigned adults with moderate-to-severe atopic dermatitis that was inadequately controlled by topical treatments to receive subcutaneous nemolizumab (at a dose of 0.1 mg, 0.5 mg, or 2.0 mg per kilogram of body weight) or placebo every 4 weeks or an exploratory dose of 2.0 mg of nemolizumab per kilogram every 8 weeks. The primary end point was the percentage improvement from baseline in the score on the pruritus visual-analogue scale (on which a negative change indicates improvement) at week 12. Secondary end points included changes in the score on the Eczema Area and Severity Index (EASI, on which a negative change indicates improvement), and body-surface area of atopic dermatitis. RESULTS Of 264 patients who underwent randomization, 216 (82%) completed the study. At week 12, among the patients who received nemolizumab every 4 weeks, changes on the pruritus visual-analogue scale were -43.7% in the 0.1-mg group, -59.8% in the 0.5-mg group, and -63.1% in the 2.0-mg group, versus -20.9% in the placebo group (P<0.01 for all comparisons). Changes on the EASI were -23.0%, -42.3%, and -40.9%, respectively, in the nemolizumab groups, versus -26.6% in the placebo group. Respective changes in body-surface area affected by atopic dermatitis were -7.5%, -20.0%, and -19.4% with nemolizumab, versus -15.7% with placebo. Among the patients receiving nemolizumab every 4 weeks, treatment discontinuations occurred in 9 of 53 patients (17%) in the 0.1-mg group, in 9 of 54 (17%) in the 0.5-mg group, and in 7 of 52 (13%) in the 2.0-mg group, versus in 9 of 53 (17%) in the placebo group. CONCLUSIONS In this phase 2 trial, nemolizumab at all monthly doses significantly improved pruritus in patients with moderate-to-severe atopic dermatitis, which showed the efficacy of targeting interleukin-31 receptor A. The limited size and length of the trial preclude conclusions regarding adverse events. Copyright © 2017 Massachusetts Medical Society.


Yoshida M.,Kumamoto Rosai Hospital | Kudoh J.,Kumamoto Rosai Hospital | Homma Y.,University of Tokyo | Kawabe K.,Tokyo Teishin Hospital
International Journal of Urology | Year: 2012

Lower urinary tract symptoms associated with benign prostatic hyperplasia are highly prevalent in older men. Pharmacological treatment is the first-line treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia. The first choice in the pharmacological treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia is the α 1-adrenoceptor antagonists. Many α 1-adrenoceptor antagonists are available in the world. Silodosin is an α 1-adrenoceptor antagonist developed by Kissei Pharmaceutical, and has a specific selectivity for the α 1A-adrenoceptor subtype. By antagonizing α 1A-adrenoceptor in the prostate and urethra, silodosin causes smooth muscle relaxation in the lower urinary tract. As a result of the high affinity for the α 1A-adrenoceptor than for the α 1B-adrenoceptor, silodosin minimizes the propensity for blood pressure-related adverse effects caused by blockade of α 1B-adrenoceptor. The efficacy and safety of silodosin for treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia was first reported by Japanese investigators in 2006. At present, silodosin is used in many countries. In the present review, we summarize the new clinical evidence for lower urinary tract symptoms associated with benign prostatic hyperplasia and introduce the data supporting the new clinical indications of silodosin. © 2012 The Japanese Urological Association.


Yoshida M.,Kumamoto Rosai Hospital | Kudoh J.,Kumamoto Rosai Hospital | Homma Y.,University of Tokyo | Kawabe K.,Tokyo Teishin Hospital
Clinical Interventions in Aging | Year: 2011

Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) are highly prevalent in older men. Medical therapy is the first-line treatment for LUTS associated with BPH. Mainstays in the treatment of male LUTS and clinical BPH are the α 1-adrenergic receptor antagonists. Silodosin is a new α 1-adrenergic receptor antagonist that is selective for the α 1A-adrenergic receptor. By antagonizing α 1A-adrenergic receptors in the prostate and urethra, silodosin causes smooth muscle relaxation in the lower urinary tract. Since silodosin has greater affinity for the α 1A-adrenergic receptor than for the α 1B-adrenergic receptor, it minimizes the propensity for blood pressure-related adverse effects caused by α 1B-adrenergic receptor blockade. In the clinical studies, patients receiving silodosin at a total daily dose of 8 mg exhibited significant improvements in the International Prostate Symptom Score and maximum urinary flow rate compared with those receiving placebo. Silodosin showed early onset of efficacy for both voiding and storage symptoms. Furthermore, long-term safety of silodosin was also demonstrated. Retrograde or abnormal ejaculation was the most commonly reported adverse effect. The incidence of orthostatic hypotension was low. In conclusion, silodosin, a novel selective α 1A-adrenergic receptor antagonist, was effective in general and without obtrusive side effects. This review provides clear evidence in support of the clinical usefulness of silodosin in the treatment of LUTS associated with BPH. © 2011 Yoshida et al, publisher and licensee Dove Medical Press Ltd.


Hirohata S.,Kitasato University | Shibuya H.,Tokyo Teishin Hospital | Tejima S.,Kitasato University
Clinical Immunology | Year: 2010

We examined the direct effects of IFN-α on the development of Th17 with a system using immobilized anti-CD3, which permits activation of CD4+ T cells in the complete absence of accessory cells. Highly purified CD4+ T cells obtained from healthy donors were stimulated with immobilized anti-CD3 with or without IFN-α. IFN-α suppressed the production of IL-17 of immobilized anti-CD3-stimulated CD4+ T cells in a dose-response manner. Accordingly, IFN-α inhibited IL-17 mRNA expression in immobilized anti-CD3-stimulated CD4+ T cells. IFN-α did not affect the production of TGF-β or IL-6, but inhibited RORC mRNA expression of anti-CD3-stimulated CD4+ T cells. These results indicate that IFN-α suppresses IL-17 expression and Th17 differentiation through down-regulation of RORC mRNA expression. It is therefore suggested that these effects might play a role in the mode of action of IFN-α in the treatment of various inflammatory diseases. © 2009 Elsevier Inc. All rights reserved.


Hayashi H.,Tokyo Medical University | Kawamura M.,Tokyo Teishin Hospital
Journal of Clinical Lipidology | Year: 2013

Ezetimibe, an inhibitor of intestinal cholesterol absorption, is effective in lowering serum low-density lipoprotein (LDL) cholesterol with or without coadministration of statin. Ezetimibe-plus-statin therapy enhances LDL receptor activity, but it is still unclear whether ezetimibe alone enhances LDL receptor activity, resulting in LDL cholesterol decrease. Objective We investigated whether ezetimibe lowers serum LDL cholesterol by raising LDL receptor activity in humans. Methods Patients with hypercholesterolemia (n = 28; age [mean ± SD], 61.6 ± 13.0 years; 57% men) were treated with ezetimibe (10 mg/d) for 4 months. Before and after the treatment, serum LDL cholesterol, apolipoprotein B (apo B), and apolipoprotein C-II (apo C-II) were measured. LDL receptor activities were estimated with the equation we reported previously as follows: LDL receptor activity (represented as a percentage of normocholesterolemic subjects) = 63.595 + apo C-II (in mg/dL) × 13.459-apo B (in mg/dL) × 0.366. Results By the treatment of ezetimibe, LDL cholesterol (176.8 ± 17.9 vs 138.0 ± 19.7 mg/dL) was lowered 21.9% significantly (P <.01). The estimated LDL receptor activities before and after the ezetimibe treatment were 86.8% ± 21.4% and 89.6% ± 19.7%, respectively, with no significant difference between them (P =.13). Conclusion Ezetimibe lowered LDL cholesterol significantly in patients with hypercholesterolemia without raising LDL receptor activity. The enhancement of LDL receptor activity is less involved in the pharmacologic action of ezetimibe. © 2013 National Lipid Association. All rights reserved.


Ikeda S.,Juntendo University | Takahashi H.,Asahikawa University | Suga Y.,Juntendo University | Eto H.,St Lukes International Hospital | And 8 more authors.
Journal of the American Academy of Dermatology | Year: 2013

Background: Generalized pustular psoriasis (GPP) is a chronic autoimmune disease characterized by fever, erythema, and neutrophilic pustules over large areas of the skin. GPP does not respond well to pharmacologic intervention. Objective: We sought to assess efficacy of selectively depleting the myeloid lineage leukocytes in patients with GPP. Methods: Fifteen patients with persistent moderate to severe GPP despite conventional therapy were included. Eligible patients had more than 10% of their skin area covered by pustules. Treatment with oral etretinate, cyclosporine, methotrexate, prednisolone, and topical prednisolone/vitamin D3 was continued if had been initiated well in advance of study entry. Five sessions of adsorptive granulocyte and monocyte apheresis (GMA) with the Adacolumn (JIMRO Co Ltd, Takasaki, Japan) were administered (1 session/wk over 5 weeks) to selectively deplete Fcγ receptor and complement receptor bearing leukocytes. Efficacy was assessed by measuring the skin areas covered by pustules at baseline and 2 weeks after the last GMA session. Results: One patient did not complete the first GMA session. Based on the GPP severity scores relative to entry, the overall scores improved (n = 14, P =.0027), and the area of erythroderma (P =.0042), pustules (P =.0031), and edema (P =.0014) decreased. Likewise, Dermatology Life Quality Index improved (P =.0016), reflecting better daily function and quality of life. Twelve patients were judged as responders (85.7%), and 10 patients maintained the clinical response for 10 weeks after the last GMA session without any change in medication. Limitations: This study was unblinded and without a placebo arm. Conclusion: GMA in this clinical setting was safe and effective, suggested a major role for granulocytes/monocytes in the immunopathogenesis of GPP. © 2012 by the American Academy of Dermatology, Inc.


Teramoto T.,Teikyo University | Kawamori R.,Juntendo University | Miyazaki S.,Tokyo Teishin Hospital | Teramukai S.,Kyoto University
Hypertension Research | Year: 2011

Dietary intake affects hypertension and metabolic syndrome (MS) and their management. In Japanese hypertensive patients, little evidence exists regarding the relation between diet and MS. A self-administered lifestyle questionnaire was completed by each patient at the baseline. Three dietary scores were calculated for each patient: sodium intake, potassium intake and soybean/fish intake. The relationships between dietary scores and systolic blood pressure (SBP) and diastolic blood pressure (DBP) were analyzed by multiple regression analysis. The relation between dietary intake of sodium, potassium and soybean/fish, and the presence of MS was evaluated by the Mantel-Haenszel test. A total of 9585 hypertensive patients (mean age, 64.9 years; women, 51.4%) were included in this sub-analysis. High sodium intake was significantly related to increased SBP (P0.0003) and DBP (P0.0130). Low potassium intake was significantly related to increased SBP (P0.0057) and DBP (P0.0005). Low soybean/fish intake was significantly related to increased SBP (P0.0133). A significantly higher prevalence of MS was found in men in the highest quartile of sodium intake compared with the lower quartiles (P0.0026) and in women in the lowest quartile of potassium intake compared with the higher quartiles (P0.0038). A clear relation between dietary habits and blood pressure was found in Japanese hypertensive patients using a patient-administered questionnaire. Sodium and potassium intake affect MS prevalence. Dietary changes are warranted within hypertension treatment strategies. © 2011 The Japanese Society of Hypertension All rights reserved.


A 58-year-old man was found to have an abnormal shadow on chest computed tomography (CT). The size and density of the nodule increased gradually over 7 years. Partial lung resection was performed by a thoracoscopic procedure. The pathological examination and gene analysis revealed that the tumor was primary pulmonary B-cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma). The CT findings showed that the level of substantial shadow with air bronchograms gradually increased in the center of the mass shadow, while a radial filamentous and ground glass shadow increased in the periphery. The pathological findings showed a cellular lymphocytic infiltrate that had expanded without destroying the existing blood vessels and bronchi in the center area of the tumor, while had expanded in the interstitial area along with vessel bundles in the border area. The CT findings were consistent with the pathological findings.


Mizutani E.,Tokyo Teishin Hospital
Kyobu geka. The Japanese journal of thoracic surgery | Year: 2012

Preoperative computed tomography( CT)-guided marking with a short hook wire for small sized lung tumors has become popular along with the spread of thoracoscopic surgery. Systemic arterial air embolism is a very rare but potentially fatal complication. The patient was a 79-year-old man who was found to have a mixed ground glass opacity shadow on chest CT. Almost immediately after marking, he lost consciousness and complete atrio-ventricular (AV) block was found on the electrocardiogram (ECG) monitor. Brain CT showed intravascular air bubbles in the right frontal lobe. Two hours later, his conscious level was recovered completely but remained left hemiplegia. Five hours later, he was transported to another hospital for hyperbaric oxygen therapy. After 3 episodes of the treatment, left hemiplegia recovered with slight sense disorder in the left little finger. When neurologic findings are remained after air embolism, hyperbaric oxygen therapy should be arranged immediately.


Asahina A.,Sagamihara National Hospital | Nakagawa H.,Jikei University School of Medicine | Etoh T.,Tokyo Teishin Hospital | Ohtsuki M.,Jichi Medical University
Journal of Dermatology | Year: 2010

Incidence of psoriasis vulgaris in Asians is estimated at 0.05-0.3%. Studies in North America and Europe demonstrated that adalimumab, a fully human, recombinant, immunoglobulin G1 monoclonal antibody, was efficacious and well-tolerated in patients with chronic plaque psoriasis. This 24-week, placebo-controlled study evaluated the efficacy and safety of three different dosing regimens of adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis (n = 169). Patients were randomized to receive adalimumab 40 mg every other week (eow), adalimumab 80-mg loading dose at week 0 followed by adalimumab 40 mg eow starting at week 2, adalimumab 80 mg eow, or placebo eow given as s.c. injections. The primary efficacy endpoint was the percentage of patients achieving a 75% or greater improvement in Psoriasis Area and Severity Index (PASI 75) score at week 16. At week 16, PASI 75 response rates were significantly greater for all three adalimumab groups (40 mg eow: 57.9%, P < 0.001; 40 mg eow plus loading dose: 62.8%, P < 0.001; 80 mg eow: 81.0%, P < 0.001) versus placebo (4.3%). As early as week 4, the 40-mg eow plus loading dose and 80-mg eow groups achieved significantly greater PASI 75 response rates compared with placebo. Injection-site reactions and hepatic events occurred in greater percentages of adalimumab-treated patients compared with placebo. Adalimumab therapy demonstrated efficacy and safety at all three dosage regimens. Rapid response rate in patients receiving 40 mg eow plus loading dose supports using an 80-mg loading dose in the treatment of psoriasis. © 2010 Japanese Dermatological Association.

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