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1.
Clin Exp Immunol ; 163(2): 235-41, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21091669

ABSTRACT

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrotic changes in skin and other organs involving excessive collagen deposition. Here we investigated the effect of intravenous immunoglobulin (IVIG) on fibrosis in a murine model of bleomycin (BLM)-induced scleroderma. Scleroderma was induced in C3H/He J mice by subcutaneous BLM injections daily for 35 days. The collagen content in skin samples from the BLM-injected group (6·30 ± 0·11 mg/g tissue) was significantly higher than the PBS group (5·80 ± 0·10 mg/g tissue), and corresponded with dermal thickening at the injection site. In contrast, mice treated with IVIG for 5 consecutive days after initiating BLM injection showed lesser collagen content significantly (IVIG group, 5·61 ± 0·09 mg/g tissue; BLM vs. IVIG). In order to investigate the cellular and protein characteristics in the early stage of the model, the skin samples were obtained 7 days after the onset of experiment. Macrophage infiltration to the dermis, monocyte chemoattractant protein (MCP-1)-positive cells, and increased TGF-ß1 mRNA expression were also observed in the BLM group. IVIG inhibited these early fibrogenic changes; MCP-1 expression was significantly lesser for the IVIG group (1·52 ± 0·19 pg/mg tissue) than for the BLM group (2·49 ± 0·26 pg/mg tissue). In contrast, TGF-ß1 mRNA expression was significantly inhibited by IVIG. These results suggest that IVIG treatment may inhibit macrophage recruitment to fibrotic sites by down regulating MCP-1 and TGF-ß production, and thus could be a potential drug for managing fibrotic disorders such as SSc.


Subject(s)
Collagen/metabolism , Immunoglobulins, Intravenous/therapeutic use , Scleroderma, Systemic/drug therapy , Scleroderma, Systemic/metabolism , Skin/drug effects , Skin/metabolism , Animals , Bleomycin/toxicity , Chemokine CCL2/analysis , Collagen/analysis , Down-Regulation , Female , Humans , Macrophages/immunology , Mice , Mice, Inbred C3H , Scleroderma, Systemic/chemically induced , Skin/pathology , Transforming Growth Factor beta1/analysis
2.
J Med Chem ; 41(16): 2985-93, 1998 Jul 30.
Article in English | MEDLINE | ID: mdl-9685237

ABSTRACT

In continuation of our previous work on eosinophilia inhibitors, we synthesized an additional series of inhibitors, which consisted of 5-amino-1-[(methylamino)thiocarbonyl]-1H-1,2,4-triazole derivatives and a newly developed series of 1,2,4-triazolo[1,5-a]-1,3,5-triazine derivatives. We evaluated their inhibitory activity on the airway eosinophilia model, which was induced by the intravenous (iv) injection of Sephadex particles. In the 1,2,4-triazole series with various substituents at the 3 position of the triazole ring such as 2-furyl, pyridyl, and phenoxy, none of derivatives had comparable activity to the previously reported compound GCC-AP0341, 5-amino-3-(4-chlorophenyl)-1-[(methylamino)thiocarbonyl]-1H-1,2, 4-triazole. In the triazolo[1,5-a]triazine series, 2-(4-chlorophenyl)-6-methyl-1,2,4-triazolo[1,5-a]-1,3, 5-triazine-7(6H)-thione (3h) was highly potent, and when given orally it had an ID50 value of 0.3 mg/kg, which is comparable to that of GCC-AP0341. The fact that the structure-activity relationship of these two series was quite similar suggests that a common substructure, such as the 1,2,4-triazole ring with a substituted phenyl ring at the 3 position and a thiocarbonyl moiety at the 1 position, could contribute to the activity. Our selected compound 3h was less active than GCC-AP0341 in the antigen-induced hyper-responsiveness model in guinea pigs; however, we plan to carry out further studies on eosinophil functions, especially on their activation, using our two compounds, 3h and GCC-AP0341.


Subject(s)
Anti-Asthmatic Agents , Pulmonary Eosinophilia/prevention & control , Triazines , Triazoles , Animals , Anti-Asthmatic Agents/chemical synthesis , Anti-Asthmatic Agents/chemistry , Anti-Asthmatic Agents/pharmacology , Antigens, Helminth/immunology , Ascaris/immunology , Asthma/drug therapy , Asthma/immunology , Cell Count/drug effects , Dextrans/toxicity , Drug Evaluation, Preclinical , Eosinophils/cytology , Eosinophils/drug effects , Guinea Pigs , Humans , In Vitro Techniques , Male , Pulmonary Eosinophilia/chemically induced , Pulmonary Eosinophilia/immunology , Respiratory Hypersensitivity/drug therapy , Respiratory Hypersensitivity/immunology , Structure-Activity Relationship , Triazines/chemical synthesis , Triazines/chemistry , Triazines/pharmacology , Triazoles/chemical synthesis , Triazoles/chemistry , Triazoles/pharmacology
3.
J Med Chem ; 39(15): 3019-29, 1996 Jul 19.
Article in English | MEDLINE | ID: mdl-8709136

ABSTRACT

In order to develop novel antiasthmatic agents based on a new mechanism of action, a series of 3-substituted 5-amino-1-[(methylamino)(thiocarbonyl)]-1H-1,2,4-triazole derivatives were synthesized and evaluated in a model in which eosinophilia was induced in the airway through intravenous (iv) injection of Sephadex particles on days 0, 2, and 5. After screening of several hundred derivatives, we finally identified the highly potent eosinophilia inhibitor 5-amino-3-(4-chlorophenyl)-1-[(methylamino)(thiocarbonyl)]-1H-tria zole (23c, GCC-AP0341), which had ID50 values of 0.3 and 0.07 mg/kg when administered orally (os) and intraperitoneally (ip), respectively. This compound showed complete inhibition of the hypersensitivity induced by ascaris inhalation at an ip dose of 1 mg/kg as well as low toxicity, with an LD50 value of > 2.0 g/kg in mice. Extensive study of its mechanism of action revealed that 23c inhibited eosinophil survival induced by interleukin-5 (IL-5), but had little or no effect on leukotriene D4 (LTD4) or platelet-activating factor (PAF)-induced responses. Taken together, these results suggest 23c as a novel candidate for the treatment of chronic asthma. Further studies are now underway.


Subject(s)
Anti-Asthmatic Agents/chemical synthesis , Eosinophilia/drug therapy , Triazoles/chemical synthesis , Animals , Anti-Asthmatic Agents/pharmacology , Anti-Asthmatic Agents/therapeutic use , Antigens, Helminth/immunology , Ascaris/immunology , Cell Survival/drug effects , Dexamethasone/pharmacology , Dextrans , Eosinophils/drug effects , Guinea Pigs , Humans , Interleukin-5/pharmacology , Male , Molecular Structure , Pulmonary Eosinophilia/chemically induced , Pulmonary Eosinophilia/drug therapy , Rats , Rats, Wistar , Recombinant Proteins/pharmacology , Respiratory Hypersensitivity/drug therapy , Respiratory Hypersensitivity/immunology , Structure-Activity Relationship , Triazoles/pharmacology , Triazoles/therapeutic use
4.
Acta Paediatr Jpn ; 38(2): 137-42, 1996 Apr.
Article in English | MEDLINE | ID: mdl-8677790

ABSTRACT

Owing to improved technology and care for patients who need mechanical ventilation, the quality of life as well as the prognosis for long-term ventilator-assisted patients has improved significantly in recent years. However, the increased number of these patients has raised economic, ethical and medical problems. In order to assess the magnitude of these problems, we conducted the first nationwide survey on the status of long-term ventilator-assisted children in Japan. Questionnaires were mailed to 2524 pediatric departments at hospitals in Japan with more than 100 beds. At the time of the survey, 282 hospitals had 567 patients who had been ventilated for more than a month. Among these patients, 434 were younger than 20 years and had been ventilated for more than 3 months. The most common basic disorders were: various myopathies (n = 65), hypoxic-ischemic encephalopathy (n = 60), spinal muscular atrophy type 1 (Werdnig-Hoffmann disease, n = 55), chronic lung disorders of prematurity (n = 21), Ondine's curse (n = 22), drowning (n = 17) and congenital heart diseases (n = 16). Of these 434 patients, only 61 were ventilated at home. Although home care was considered suitable for chronic ventilator patients by many pediatricians who responded to the survey, its realization has been hampered by the lack of a system and regulations to support it. The fact that many pediatricians in Japan have actively prolonged the life of Werdnig-Hoffmann patients, from whom aggressive life saving measures have been withheld in most Western countries, has raised ethical as well as medical issues.


Subject(s)
Respiration, Artificial/statistics & numerical data , Adolescent , Adult , Child , Child, Preschool , Humans , Infant , Japan/epidemiology , Surveys and Questionnaires , Time Factors
5.
J Med Chem ; 37(13): 1977-82, 1994 Jun 24.
Article in English | MEDLINE | ID: mdl-7913134

ABSTRACT

In order to develop novel compounds for topical use possessing antiallergic as well as antiinflammatory activities, a series of o-aminophenol derivatives bearing H1-antihistaminic structures were synthesized and their effects were investigated on lipid peroxidation in rat brain homogenates, antiinflammatory effection arachidonic acid- and 12-O-tetradecanoylphorbol-13- acetate-induced mouse ear edema and antiallergic effect on 48-h homologous passive cutaneous anaphylaxis in rats. Furthermore, the effects of these compounds on delayed-type hypersensitivity reaction in mice were examined. Several N-monosubstituted amino-4-methylphenols were found to exert potent inhibitory activities in all of these assays. Of these compounds, 4m was chosen for further development as AD0261.


Subject(s)
Aminophenols/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Histamine H1 Antagonists/pharmacology , Hypersensitivity, Delayed/drug therapy , Lipid Peroxidation/drug effects , Passive Cutaneous Anaphylaxis/drug effects , Administration, Topical , Aminophenols/administration & dosage , Aminophenols/chemical synthesis , Aminophenols/chemistry , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antioxidants/chemical synthesis , Antioxidants/chemistry , Antioxidants/pharmacology , Arachidonic Acid/pharmacology , Brain/drug effects , Ear , Edema/drug therapy , Guinea Pigs , Histamine H1 Antagonists/administration & dosage , Histamine H1 Antagonists/chemical synthesis , Male , Mice , Mice, Inbred ICR , Rats , Rats, Sprague-Dawley , Skin Tests , Tetradecanoylphorbol Acetate/pharmacology
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