Hiroyuki Ohbayashi

Neutrophil elastase inhibitors as treatment for COPD

Chronic obstructive pulmonary disease, characterised by a slowly progressive, irreversible airways limitation, is a major worldwide cause of chronic morbidity and mortality. The imbalance between human neutrophil elastase and endogenous antiproteases may cause excess human neutrophil elastase in pulmonary tissues, which may be considered a major pathogenic factor in chronic obstructive pulmonary disease. Great effort has been devoted to finding a method to restore the balance, resulting in the discovery of potent two-typed small-molecular-weight human neutrophil elastase inhibitors. In the application of chronic obstructive pulmonary disease therapy, the human neutrophil elastase inhibitors mainly focused upon include ONO-5046, MR-889, L-694,458, CE-1037, GW-311616 and TEI-8362 as the acyl-enzyme inhibitors; and ONO-6818, AE-3763, FK-706, ICI-200,880, ZD-0892 and ZD-8321 as the transition-state inhibitors. In this review, various problems that remain to be solved in the clinical use of human neutrophil elastase inhibitors are discussed.

Current synthetic inhibitors of human neutrophil elastase in 2005

The human neutrophil elastase (HNE)-related diseases, such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), are a serious problem worldwide. To prevent excessive production of HNE, which is a major pathogenic factor of these disorders, and to restore the appropriate balance between HNE and its inhibitors, research and development of potent synthetic HNE inhibitors has been conducted for > 30 years worldwide. At present, the following four agents can be described as the most successful: the acyl-enzyme inhibitors, ONO-5046 and MR-889, and the transition-state inhibitors, ONO-6818 and AE-3763. Additionally, protein inhibitors such as DX-890 (EPI-hNE-4), recombinant α1-antitrypsin, elafin and secretory leukocyte protease inhibitor (SLPI) are also being developed and actively researched in 2005. This review focuses upon the major synthetic HNE inhibitors, including those patented in 2004.

Current synthetic inhibitors of human neutrophil elastase

The imbalance between human neutrophil elastase (HNE, EC 3.4.21.37) and endogenous antiproteinases is considered to cause various HNE-mediated inflammatory disorders, such as adult respiratory distress syndrome, cystic fibrosis, pulmonary emphysema and rheumatoid arthritis. To realise the optimum therapeutic approach and investigate accurate pathogenic mechanism of these diseases, new synthetic HNE inhibitors have been under development. Through the long-time intensive research by many pharmaceutical industries and institutes, the most promising strategies at present may result in the application of two-types of small-molecular-weight HNE inhibitors: acyl-enzyme inhibitors (ONO-5046, L-694458 and MR-889) or transition-state inhibitors (ONO-6818, AE-3763 and FK-706). This review mainly focuses on the experimental and clinical evaluation of recent synthetic HNE inhibitors, including 14 current patent reports claimed since 1998.

Both inhalant and intravenous uroguanylin inhibit leukotriene C4-induced airway changes.

Uroguanylin, a well-known ligand of guanylyl cyclase C receptor in the gastrointestinal tissue, has recently been reported to have pulmonary effects. We investigated the inhibitory effects of uroguanylin against leukotriene C4-induced bronchoconstriction and airway microvascular leakage. Anesthetized guinea pigs, ventilated via a tracheal cannula in a plethysmograph box, were measured by pulmonary mechanics for 10 min after i.v. administering 2 microg/kg leukotriene C4. Airway microvascular leakage was assessed by extravasation of Evans blue dye into airway tissues. Both inhalant and i.v. pretreatment of uroguanylin significantly inhibited leukotriene C4-induced pulmonary changes in a dose-dependent manner, suggesting its effectiveness against an asthmatic condition.

NEUTRAL ENDOPEPTIDASE 3.4.24.11 INHIBITION POTENTIATES THE INHIBITORY EFFECTS OF TYPE-C NATRIURETIC PEPTIDE ON LEUKOTRIENE D4-INDUCED AIRWAY CHANGES

1. Microvascular leakage, a primary feature of inflammation, is well known for worsening the asthmatic condition. Gene expression of and a specific receptor for type‐C natriuretic peptide (CNP), initially considered a neuropeptide, have been detected in the human vascular wall and secretion of CNP from vascular endothelial cells has recently been demonstrated. These facts suggest the presence of a vascular natriuretic peptide system and led us to expect that CNP may act beneficially on airway microvascular leakage in asthma. In the present study, we investigated the effects of CNP against leukotriene (LT) D4 ‐induced airway microvascular leakage and bronchocon‐striction and how these effects were potentiated by thiorphan, a potent neutral endopeptidase 3.4.24.11 (NEP) inhibitor.

The Results of a Survey of Smoking in the Students of JA Gifu Kouseiren Nurses' School.

JA岐阜厚生連看護専門学校の全校生徒101名を対象に, 無記名アンケート形式の喫煙状況調査を行った。平成13年 (2001) 7月時点の同校学生の喫煙率は17.8%(18名) である。喫煙学生のほとんどはニコチン量0.9mg/本以下のタバコ15本以内/日の喫煙量であり, Fagerstrom Tolerance Questionnaire (FTQ) 指数は1.94±1.51とニコチン依存度はそれ程高くなく, 喫煙学生の約8割が禁煙を希望・意識している実態が把握された。又, 非喫煙学生の約8割が周りの喫煙に不快感を抱く一方, 約2割の学生は機会により, 容易に喫煙を開始し得る可能性が示された。同校学生に対し, 今後十分な啓蒙が必要であり, カリキュラムの一貫としての禁煙教育の必要性が示唆された。