Improvement of the Synthesis Technology of Sorafenib Tosylate / 中国药房

OBJECTIVE:To improve the synthesis technology of sorafenib tosylate (Ⅰ). METHODS:The intermediate N-methyl-(4-chlorpyridin-2-yl)carboxamide(Ⅳ)was obtained by chlorination and amidation with 2-picolinic acid as the starting com-pound. Meanwhile,N-[4-chloro-3-(triflouromethyl)phenyl]-N′-(4-hydroxyphenyl)urea (Ⅶ) was prepared from aminophenol and 4-chloro-3-trifluoromethyl phenyl isocyanate,which was obtained from 4-chloro-3-(trifluoromethyl)aniline(Ⅴ)by reaction with initiator triethylamine. Sorafenib tosylate was synthesized from Ⅳ and Ⅶ with potassium tert-butoxide by condensation and salt for-mation. The target compound was characterized by 1H-NMR. RESULTS:The target compound was confirmed as Ⅰ,with the over-all yield of 74% [based on 4-chloro-3-(trifluoromethylanilin)]. The purification of chromatogram was 94%. Optimized technology improves yield and simplifies multi-step intermediate decompression,distillation and purification process;the application of initia-tor shortens the duration of reaction. CONCLUSIONS:Ⅰ is prepared successfully,and raw material can be obtained easily and is easy to operate with high yield.

Role of vitamin D-binding protein in isocyanate-induced occupational asthma

The development of a serological marker for early diagnosis of isocyanate-induced occupational asthma (isocyanate-OA) may improve clinical outcome. Our previous proteomic study found that expression of vitamin D-binding protein (VDBP) was upregulated in the patients with isocyanate-OA. In the present study, we evaluated the clinical relevance of VDBP as a serological marker in screening for isocyanate-OA among exposed workers and its role in the pathogenesis of isocyanate-OA. Three study groups including 61 patients with isocyanate-OA (group I), 180 asymptomatic exposed controls (AECs, group II), 58 unexposed healthy controls (NCs, group III) were enrolled in this study. The baseline serum VDBP level was significantly higher in group I compared with groups II and III. The sensitivity and specificity for predicting the phenotype of isocyanate-OA with VDBP were 69% and 81%, respectively. The group I subjects with high VDBP (> or = 311 microg/ml) had significantly lower PC20 methacholine levels than did subjects with low VDBP. The in vitro studies showed that TDI suppressed the uptake of VDBP into RLE-6TN cells, which was mediated by the downregulation of megalin, an endocytic receptor of the 25-hydroxycholecalciferol-VDBP complex. Furthermore, toluene diisocyanate (TDI) increased VEGF production and secretion from this epithelial cells by suppression of 1,25-dihydroxycholecalciferol [1,25(OH)2D3] production. The findings of this study suggest that the serum VDBP level may be used as a serological marker for the detection of isocyanate-OA among workers exposed to isocyanate. The TDI-induced VEGF production/secretion was reversed by 1,25(OH)2D3 treatment, which may provide a potential therapeutic strategy for patients with isocyanate-OA.

Occupational Asthma in Korea

Occupational asthma (OA) is the leading occupational respiratory disease. Cases compensated as OA by the Korea Workers' Compensation and Welfare Service (COMWEL) (218 cases), cases reported by a surveillance system (286 cases), case reports by related scientific journals and cases confirmed by the Occupational Safety and Health Research Institute (OSHRI) over 15 yr from 1992 to 2006 were analyzed. Annual mean incidence rate was 1.6 by compensation and 3.5 by surveillance system, respectively. The trend appeared to increase according to the surveillance system. Incidence was very low compared with other countries. The most frequently reported causative agent was isocyanate followed by reactive dye in dyeing factories. Other chemicals, metals and dust were also found as causative agents. OA was underreported according to compensation and surveillance system data. In conclusion, a more effective surveillance system is needed to evaluate OA causes and distribution, and to effectively prevent newly developing OA.

Exposure to Toluene Diisocyanate (TDI) Induces IL-8 Production from Bronchial Epithelial Cells: Effect of Pro-inflammatory Cytokines

This investigation was designed to confirm IL-8 production from human bronchial epithelial cells with toluene diisocyanate (TDI) exposure and to examine the effects of pro-inflammatory cytokine and dexamethasone. We cultured Beas-2B, a bronchial epithelial cell line with TDI-HSA conjugate and compared with those without conjugate. IL-8 in the supernatant was measured by ELISA. To evaluate the effect of proinflammatory cytokines, peripheral blood mononuclear cells (PBMC) were collected from TDI- and non-TDI asthma patients, and were added to the epithelial cell culture. Dexamethasone or antibodies to TNF-alpha and IL-1beta were pre-incubated with PBMC supernatant. There was a significant production of IL-8 from bronchial epithelial cells with addition of TDI-HSA conjugate in a dose-dependent manner, which was significantly augmented with addition of PBMC supernatant. Higher production of IL-8 was noted with addition of PBMC supernatant from TDI-asthma patients than in those from non-TDI asthma patients. IL-1beta and IL-1beta/TFNalpha antibodies were able to suppress the IL-8 productions. Pre-treatment of dexamethasone induced dose-dependent inhibition of the IL-8 production. These results suggest that the IL-8 production from bronchial epithelial cells contribute to neutrophil recruitment occurring in TDIinduced airway inflammation. IL-1beta released from PBMC of TDI-induced asthma patients may be one of the pro-inflammatory cytokines to enhance IL-8 production.

Diagnosis and prevention of diseases induced by isocyanate

Isocyanates are among the most frequent causes of occupational asthma in industrialized countries. Early diagnosis of diisocyanate asthma followed by prompt termination of chemical exposure can prevent chronic morbidity due to persistent asthma. Chronic exposure to isocyanates also induces hypersensitivity pneumonitis (HP). The accurate diagnosis of diisocynate asthma requires a systematic approach that combines information obtained from the occupational history, immunologic tests and physiologic studies. The prevention of health problems from toluene diisocyanate (TDI), 4,4'-methylenediphenyl diisocyanate (MDI) and 1,6'-hexamethylene diisocyanate (HDI) is essential for all those handling the chemicals. Regulatory exposure limits should be observed. However, wheezing, coughing or even asthmatic attacks may occur after exposure much below the regulatory exposure limits especially in sensitive individuals. Preventing or minimizing exposure is of prime importance and should be supported by the installation of engineering controls, by education of the workforce, by regular monitoring of the workplace exposure and by medical surveillance. To prevent such asthma it is suggested that workers should be tested airway sensitivity and should avoid working in areas that have dust containing specific-IgE. Such tests must be periodically performed after working. Symptoms induced by isocyanate need earlier discover and early isolation of the associated individuals.

Diagnosis and Prevention of Diseases Induced by Isocyanate

Isocyanates are among the most frequent causes of occupational asthma in industrialized countries. Early diagnosis of diisocyanate asthma followed by prompt termination of chemical exposure can prevent chronic morbidity due to persistent asthma. Chronic exposure to isocyanates also induces hypersensitivity pneumonitis (HP). The accurate diagnosis of diisocynate asthma requires a systematic approach that combines information obtained from the occupational history, immunologic tests and physiologic studies. The prevention of health problems from toluene diisocyanate (TDI), 4,4’-methylenediphenyl diisocyanate (MDI) and 1,6’-hexamethylene diisocyanate (HDI) is essential for all those handling the chemicals. Regulatory exposure limits should be observed. However, wheezing, coughing or even asthmatic attacks may occur after exposure much below the regulatory exposure limits especially in sensitive individuals. Preventing or minimizing exposure is of prime importance and should be supported by the installation of engineering controls, by education of the workforce, by regular monitoring of the workplace exposure and by medical surveillance. To prevent such asthma it is suggested that workers should be tested airway sensitivity and should avoid working in areas that have dust containing specific-IgE. Such tests must be periodically performed after working. Symptoms induced by isocyanate need earlier discover and early isolation of the associated individuals.

Prognostic factors in patients with reactive dye or isocyanate-induced occupational asthma after avoidance of causative agents / 천식및알레르기

BACKGROUND: Although occupational asthma is defined as a reversible airway obstruction causally related to exposure in the working environment, many occupational asthmatics complain of asthmatic symptoms despite avoidance of the causative agent. Subjects and methods. Twenty-nine patients with occupational asthma who had been confirmed by specific bronchial challenge with reactive dye or isocyanates and had avoided the causative agent for at least 6 months were included in this study. A questionnaire about asthmatic symptoms and medication requirements, a lung functiontest, and a methacholine bronchial provocation test were performed. RESULTS: Asthmatic symptoms at follow-up were remitted in seven (41.2%) isocyanate-induced asthmatics, but none with reactive dye-induced asthma were remitted. At follow-up, the symptom-medication score and FEV1 were significantly improved in isocyanate-induced asthmatics than in those with reactive dye-induced asthma, but the geometric mean of PC20-methacholine was not different between the two groups. Among 17 isocyanate-induced asthmatics, a duration from symptom onset to avoidance was significantly shorter in the remission group than in the nonremission group, although the symptom-medication scores, FEV1 (% predictive value) and logPC20-methacholine at an initial diagnosis, and follow-up period defined as duration from avoidance to follow-up, showed no difference between the two groups. CONCLUSION: The outcome of occupational asthma may be determined by the causative agents and the duration from onset of asthmatic symptoms to avoidance.