1. Advance in the Research of Epidermal Growth Factor Receptor Inhibitors Related to Lung Cancer
Chinese Pharmaceutical Journal 2018;53(13):1037-1046
Epidermal growth factor receptor (EGFR), a member of the super family of protein tyrosine kinase receptors, plays a crucial role in proliferation, apoptosis, aggression and metastasis of tumor cells. The target-EGFR inhibitors have been a hotspot and tendency in the progress of anti-tumors. Currently, the target-EGFR inhibitors have made a steady progress and many valuable drugs in the clinical treatment have been developed. However, many patients will be resistance to the drugs due to the mutation of amino acid. Therefore, drugs which can be effective in the later treatment or long-term therapies will always be deficient. In this article, the research progress and mechanism of anti-tumor of small molecules EGFR inhibitors in detail are reviewed.
2.Nasopharyngeal adenoid cystic carcinoma: magnetic resonance imaging features in ten cases.
Xue-Wen LIU ; Chuan-Miao XIE ; Hui LI ; Rong ZHANG ; Zhi-Jun GENG ; Yun-Xian MO ; Jing ZHAO ; Mu-Yan CAI ; Yan-Chun LV ; Pei-Hong WU
Chinese Journal of Cancer 2012;31(1):19-28
Nasopharyngeal adenoid cystic carcinoma (NACC) is a rare malignancy with high local invasiveness. To date, there is no consensus on the imaging characteristics of NACC. To address this, we retrospectively reviewed 10 cases of NACC and summarized the magnetic resonance imaging (MRI) features. MR images of 10 patients with histologically validated NACC were reviewed by two experienced radiologists. The location, shape, margin, signal intensity, lesion texture, contrast enhancement patterns, local invasion, and cervical lymphadenopathy of all tumors were evaluated. Clinical and pathologic records were also reviewed. No patients were positive for antibodies against Epstein-Barr virus (EBV). The imaging patterns of primary tumors were classified into two types as determined by location, shape, and margin. Of all patients, 7 had tumors with a type 1 imaging pattern and 3 had tumors with a type 2 imaging pattern. The 4 tubular NACCs were all homogeneous tumors, whereas 3 (60%) of 5 cribriform NACCs and the sole solid NACC were heterogeneous tumors with separations or central necrosis on MR images. Five patients had perineural infiltration and intracranial involvement, and only 2 had cervical lymphadenopathy. Based on these results, we conclude that NACC is a local, aggressive neoplasm that is often negative for EBV infection and associated with a low incidence of cervical lymphadenopathy. Furthermore, MRI features of NACC vary in locations and histological subtypes.
Adult
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Aged
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Carcinoma, Adenoid Cystic
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diagnosis
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pathology
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surgery
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Female
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Humans
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Lymphatic Metastasis
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Magnetic Resonance Imaging
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methods
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Male
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Middle Aged
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Nasopharyngeal Neoplasms
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diagnosis
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pathology
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surgery
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Neoplasm Invasiveness
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Neoplasm Staging
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Retrospective Studies
3.Analysis of the therapeutic effect of esophagectomy with extended 2-field lymph node dissection for esophageal carcinoma.
Chang-rong WU ; Heng-chuan XUE ; Zong-hai ZHU ; Zhen-bin ZHANG ; Chang-you GENG ; Zhen-kai MA ; Yong GUO ; Jie GAO
Chinese Journal of Oncology 2009;31(8):630-633
OBJECTIVETo summarize the surgical effect and clinical application value of esophagectomy with extended 2-field lymph node dissection for patients with esophageal carcinoma.
METHODSFrom June 1987 to December 2008, 1690 patients with esophageal cancer underwent esophagectomy with extended 2-field (thoracic and abdominal) dissection of lymph nodes. Patients with the middle and lower thoracic esophageal cancer underwent Ivor-Lewis esophagectomy, and patients with upper thoracic esophageal cancer underwent Akiyama esophagectomy. 2-field (thoracic and abdominal) lymph node metastases information and the 1, 3, 5, 10-year survival rates were analyzed retrospectively.
RESULTSLymph node metastases were found in 713 patients. The lymph node metastases rate was 42.2% (713/1690).Thoracic lymph node metastasis rate was 39.3% (665/1690), among which in the right pleural apical para-tracheal triangle was 20.7% (349/1690), in the posterior upper mediastinum was 26.3% (444/1690), in the lower mediastinum was 18.2% (307/1690). Abdominal lymph node metastasis rate was 20.1% (339/1690). THE Postoperative complication rate was 16.4% (278/1690), among which the pulmonary complication rate ranking the first, was 43.6% (136/312). The operative mortality rate was 0.2%. The 1-year, 3-year, 5-year and 10-year survival rates were 88.2% (1388/1574), 63.5% (868/1367), 54.8% (705/1287) and 30.8% (232/754), respectively. The 5-year survival rate in patients without lymph node metastasis was 76.2% (448/588), but that in patients with lymph node metastases was 36.8% (257/669).
CONCLUSIONThe results of this study demonstrated that Ivor-Lewis and Akiyama esophagectomy with two-field lymph node dissection exposes the operation fields clearly and make radical lymphadenectomy thoroughly, especially the lymph nodes in the posterior upper mediastinum around the recurrent laryngeal nerve and in the right pleural apical para-tracheal triangle. It is essential that patients with esophageal carcinoma with lymph node metastases should undergo esophagectomy with extended 2-field dissection of lymph nodes. This can elevate the postoperative 5-year survival rate remarkably.
Adenocarcinoma ; mortality ; pathology ; surgery ; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Squamous Cell ; mortality ; pathology ; surgery ; Esophageal Neoplasms ; mortality ; pathology ; surgery ; Esophagectomy ; adverse effects ; methods ; Female ; Humans ; Lymph Node Excision ; adverse effects ; methods ; Lymphatic Metastasis ; Male ; Middle Aged ; Respiratory Insufficiency ; etiology ; Retrospective Studies ; Survival Rate
4.Enhanced recovery after preserving the left colonic artery during laparoscopic anterior resection for rectal cancer.
Yun-Geng LIU ; Lei ZHANG ; Ji-Ran HUANG ; Jin-Rong YI ; Chuan-Fa FANG ; Lai-Yang XIA ; Hong-Quan LIU ; Jian-Zhong YI
Journal of Southern Medical University 2017;37(9):1261-1264
OBJECTIVETo evaluate the postoperative outcomes of preserving the left colonic artery during laparoscopic anterior resection for rectal cancer.
METHODSThe clinicopathologic data of 91 rectal cancer patients (pathologic Stage II) undergoing laparoscopic anterior resection was retrospectively analyzed. During the surgeries, the left colonic artery was preserved in 40 patients (preserved group) and ligated in 51 patients (unpreserved group). The operating time, intraoperative blood loss, time to first flatus and defecation, duration of postoperative abdominal distension and pain, number of retrieved lymph nodes, ileum fistulation and anatomical leakage rate were compared between the two groups.
RESULTSThe surgeries were completed in all the 91 patients laparoscopically without conversion. There was no intraoperative complications including rectal perforation, injury to vessel or ureter in either group. The operating time, blood loss and number of retrieved lymph nodes were similar between the groups (P>0.05). Three patients in preserved group and 5 in ligation group received preventive ileum fistulation due to low rectal cancer. Anatomical leakage occurred in three patients of unpreserved group. The average duration of postoperative abdominal distension and pain was 2.14∓0.35 days in preserved group and 3.15∓0.42 days in ligation group. The time to first flatus and defecation was 37.15∓12.62 h and 3.16∓0.52 days in preserved group and 62.25∓11.75 h and 4.25∓0.75 days in ligation group. Postoperative hospital stay was 4.54∓0.42 days in preserved group and 6.23∓0.51 days in ligation group. Total hospitalization cost in the two groups was 34 525.32∓1206.36 Yuan and 41 215∓1051.32 Yuan, respectively. Significant differences were found the in duration of postoperative abdominal distension and pain, postoperative hospital stay, and total cost between the two groups (P<0.05).
CONCLUSIONDuring laparoscopic anterior resection for rectal cancer, preserving the left colonic artery effectively ensures the blood supply to the anastomosis and the remaining descending colon to promote the recovery of the patients after surgery.
5.Imaging features and clinicopathological manifestations of solitary fibrous tumors.
Jian-peng LI ; Chuan-miao XIE ; Rong ZHANG ; Hui LI ; Xue-wen LIU ; Yun ZHANG ; Shao-han YIN ; Yan-chun LÜ ; Zhi-jun GENG
Chinese Journal of Oncology 2010;32(5):363-367
OBJECTIVETo investigate the imaging features, clinical manifestations and pathological characteristics of solitary fibrous tumors (SFT).
METHODSThe clinicopathological manifestations and medical imaging findings were analyzed retrospectively in 27 patients with surgically confirmed SFT.
RESULTSThe SFTs originated from different parts of the body, including 18 in the chest, 4 in the abdomen, 1 in the lumboscral area, 3 in the pelvis, and 1 in the left shoulder. Twenty-three cases were found by CT scan, among which there were 16 benign diseases, presented with well-defined round or elliptic margins, with homogeneous attenuation and clearly surrounding; 6 malignant cases with unclear demarcations, invasive surrounding, heterogeneous attenuation due to calcification and/or irregular necrosis, and 1 junctional case with well-defined margins, which was enlarged during follow-up. There were 4 SFTs scanned by MRI with clear margin and homogeneous or heterogeneous signal intensity. All of the 4 cases were isointense or hyperintense to muscle on T1-weighted images, and were hyperintense on the T2-weighted images. All tumors showed heterogeneously intense enhancement with geographic pattern. Immunohistochemical staining showed that CD34-positive was 81.5%, vimentin (100.0%), CD99 (100.0%) and bcl-2 (96.3%), as well as negative CK (100.0%) and S-100 (96.3%).
CONCLUSIONThe location of SFT is varying. Though its clinical manifestations vary, the diagnosis is depended on pathology and immunohistochemistry. There are certain specific features related to SFTs on CT or MRI. These imaging techniques may serve to provide helpful information as to the location and vicinal anatomic structure of the tumor, which is of substantial importance for planning surgery.
12E7 Antigen ; Abdominal Neoplasms ; diagnosis ; metabolism ; pathology ; surgery ; Adult ; Aged ; Antigens, CD ; metabolism ; Antigens, CD34 ; metabolism ; Cell Adhesion Molecules ; metabolism ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Pelvic Neoplasms ; diagnosis ; metabolism ; pathology ; surgery ; Retrospective Studies ; Solitary Fibrous Tumor, Pleural ; diagnosis ; metabolism ; pathology ; surgery ; Solitary Fibrous Tumors ; diagnosis ; metabolism ; pathology ; surgery ; Tomography, Spiral Computed ; Vimentin ; metabolism ; Young Adult
6.Diagnostic value of ADC and rADC of diffusion weighted imaging in malignant breast lesions.
Chuan-miao XIE ; Shao-han YIN ; Hui LI ; Xue-wen LIU ; Yun ZHANG ; Yan-chun LÜ ; Rong ZHANG ; Jian-peng LI ; Zhi-jun GENG ; Pei-hong WU
Chinese Journal of Oncology 2010;32(3):217-220
OBJECTIVEThe aim of this study was to evaluate the value of diffusion weighted imaging (DWI) in the diagnosis of patients with breast diseases.
METHODSFifty-three consecutive patients were scanned with GE signa HDx 1.5 T magnetic resonance system equipped with 8-channel breast coil. DWI was scanned by SE-EPI sequence in b values of 500 s/mm(2) and 800 s/mm(2), respectively. The apparent diffusion coefficients (ADC) of these lesions were measured. The mean apparent diffusion coefficients (ADC) of these lesions were calculated in b values of 500 s/mm(2) and 800 s/mm(2), respectively. These lesions' ADC value (rADC) was counted respectively and the result of the rADC was equal to the lesion's ADC divided by the ADC of the ipsilateral normal breast tissue. Threshold of ADC and rADC for differential diagnosis was acquired by ROC (receiver operating characteristic curve) analysis. Different imaging technologies were evaluated emphasizing their sensitivity, specificity and accuracy.
RESULTSSixty-six lesions of 53 cases were confirmed by pathology, including 39 malignant lesions and 27 benign lesions. (1) b = 500 s/mm(2), the threshold of ADC value was 1.435 x 10(-3) mm(2)/s, with a sensitivity of 82.1% and a specificity of 81.5%. The threshold of rADC value was 0.62, with a sensitivity of 76.9% and a specificity of 100%. (2) b = 800 s/mm(2), the threshold of ADC value was 1.295 x 10(-3) mm(2)/s, with a sensitivity of 79.5% and a specificity of 81.5%. The threshold of rADC value was 0.71, with a sensitivity of 89.7% and specificity of 88.9%. (3) The area under the ROC curve was increased for the four diagnostic indicators (ADC(500), ADC(800), rADC(500), rADC(800)).
CONCLUSIONDWI spends short time, and it doesn't need contrast material. ADC value and rADC value have a high sensitivity and specificity as a diagnostic indicator. DWI is helpful in improving the specificity of MR and may become one of valuable conventional procedures for breast tumor diagnosis.
Adult ; Breast ; pathology ; Breast Neoplasms ; diagnosis ; pathology ; Carcinoma, Ductal, Breast ; diagnosis ; pathology ; Carcinoma, Intraductal, Noninfiltrating ; diagnosis ; pathology ; Diagnosis, Differential ; Diffusion Magnetic Resonance Imaging ; methods ; Female ; Fibroadenoma ; diagnosis ; pathology ; Fibrocystic Breast Disease ; diagnosis ; pathology ; Humans ; Middle Aged ; ROC Curve ; Sensitivity and Specificity
7.A modified method for locating parapharyngeal space neoplasms on magnetic resonance images: implications for differential diagnosis.
Xue-Wen LIU ; ; Ling WANG ; Hui LI ; Rong ZHANG ; Zhi-Jun GENG ; De-Ling WANG ; Chuan-Miao XIE
Chinese Journal of Cancer 2014;33(10):511-520
The parapharyngeal space (PPS) is an inverted pyramid-shaped deep space in the head and neck region, and a variety of tumors, such as salivary gland tumors, neurogenic tumors, nasopharyngeal carcinomas with parapharyngeal invasion, and lymphomas, can be found in this space. The differential diagnosis of PPS tumors remains challenging for radiologists. This study aimed to develop and test a modified method for locating PPS tumors on magnetic resonance (MR) images to improve preoperative differential diagnosis. The new protocol divided the PPS into three compartments: a prestyloid compartment, the carotid sheath, and the areas outside the carotid sheath. PPS tumors were located in these compartments according to the displacements of the tensor veli palatini muscle and the styloid process, with or without blood vessel separations and medial pterygoid invasion. This protocol, as well as a more conventional protocol that is based on displacements of the internal carotid artery (ICA), was used to assess MR images captured from a series of 58 PPS tumors. The consequent distributions of PPS tumor locations determined by both methods were compared. Of all 58 tumors, our new method determined that 57 could be assigned to precise PPS compartments. Nearly all (13/14; 93%) tumors that were located in the pre-styloid compartment were salivary gland tumors. All 15 tumors within the carotid sheath were neurogenic tumors. The vast majority (18/20; 90%) of trans-spatial lesions were malignancies. However, according to the ICA-based method, 28 tumors were located in the pre-styloid compartment, and 24 were located in the post-styloid compartment, leaving 6 tumors that were difficult to locate. Lesions located in both the pre-styloid and the post-styloid compartments comprised various types of tumors. Compared with the conventional ICA-based method, our new method can help radiologists to narrow the differential diagnosis of PPS tumors to specific compartments.
Carcinoma
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Diagnosis, Differential
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Humans
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Lymphoma
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diagnosis
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diagnostic imaging
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Magnetic Resonance Spectroscopy
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Nasopharyngeal Neoplasms
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diagnosis
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diagnostic imaging
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Neck
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diagnostic imaging
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Nervous System Neoplasms
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diagnosis
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diagnostic imaging
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Pharynx
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diagnostic imaging
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Radiography
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Salivary Gland Neoplasms
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diagnosis
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diagnostic imaging
8.First-line Xeloda (Capecitabine) treatment for advanced and recurrent colorectal cancer.
Zhong-zhen GUAN ; Dong-geng LIU ; Bao-ming YU ; Wei-qin WU ; De SHI ; Yu ZHAO ; Yu-quan WEI ; Li-qun ZOU ; Xiao-ding WU ; Wen ZHUANG ; Feng-yi FENG ; Pin ZHANG ; Shi-ying YU ; Hui-hua XIONG ; Qiang FU ; Shu ZHENG ; Jian-jin HUANG ; Gang WU ; Chuan-yong YANG ; Sheng-rong SUN ; Qing-lan RUAN
Chinese Journal of Oncology 2004;26(2):119-121
OBJECTIVETo evaluate the efficacy and safety of capecitabine as first-line therapy in patients with advanced and recurrent colorectal cancer.
METHODSFrom December 2000 to November 2001, sixty patients with advanced and recurrent colorectal cancer received first-line capecitabine treatment given at a dose of 1250 mg/m(2) twice daily, on days 1 - 14 every 21 days. At least 2 cycles were administered.
RESULTSThe overall response rate was 23.3% with 14 PR, 24 SD (40.0%) and 15 PD. The median survival time was 14.7 months. The survival rate was 63.9% at 12-months and 33.4% at 24-months. Grade III-IV adverse effects were diarrhea in 4 patients (6.6%), anemia in 2 (3.3%) and hand-foot syndrome (HFS) in 1 (1.7%); Grade I-II adverse effects were hyperpigmentation in 20 (33.3%), HFS in 18 (30.0%) and diarrhea in 10 (16.7%).
CONCLUSIONCapecitabine is an efficacious and better-tolerated alternative treatment for the patients with advanced and recurrent colorectal cancer.
Adult ; Aged ; Antimetabolites, Antineoplastic ; therapeutic use ; Capecitabine ; Colorectal Neoplasms ; drug therapy ; mortality ; Deoxycytidine ; adverse effects ; analogs & derivatives ; therapeutic use ; Female ; Fluorouracil ; analogs & derivatives ; Humans ; Male ; Middle Aged ; Survival Rate
9.Determination of six alkaloids in six types of Coptidis Rhizoma pieces by RP-HPLC and spectrum-effect relationships with anti-diabetes pharmacodynamics data.
Xian-Rong LAI ; Bang-Hua ZHOU ; Ming-Sheng DU ; Hai-Jie ZHENG ; Zhi-Peng GENG ; Jia-Chuan LI ; Xian-Li MENG ; Yi ZHANG ; Jing ZHANG
China Journal of Chinese Materia Medica 2016;41(24):4579-4586
To establish a method for determining the contents of six alkaloids (jatrorrhizine hydrochloride, columbamine hydrochloride, epiberberine hydrochloride, coptisine hydrochloride, palmatine hydrochloride, berberine hydrochloride) in six types of Coptidis Rhizoma pieces (crude pieces, ginger juice stir-fried pieces, vinegar stir-fried pieces, wine steamed pieces, wine stir-fried pieces, evodiae juice stir-fried pieces) by RP-HPLC, and explore the relationship with the curative effect of traditional Chinese medicine (TCM) and pharmacodynamics results. The chromatographic column was Welch XtimateTM C₁₈ (4.6 mm×250 mm, 5 μm), with 0.1% triethylamine solution (adjust pH at 10 with ammonium bicarbonate and ammonia) as mobile phase A and acetonitrile as mobile phase B for gradient elution (0-15 min, 10%-25%B; 15-25 min, 25%-30%B; 25-40 min, 30%-45%B) at a rate of 1.0 mL•min⁻¹. The column temperature was set at 30 ℃, and the wavelength was set at 270 nm. The six alkaloids showed a good linear relationship within the range of 0.85-16.96 mg•L⁻¹ (r=0.999 7), 1.25-24.96 mg•L⁻¹ (r=0.999 9), 2.05-40.96 mg•L⁻¹ (r=0.999 9), 3.65-72.96 mg•L⁻¹ (r=0.999 9), 2.88-57.60 mg•L⁻¹ (r=0.999 8), and 13.25-264.96 mg•L⁻¹ (r=0.999 6) respectively. The average recoveries (n=9) of the six alkaloids were 102.4% (RSD 1.2%), 101.8% (RSD 1.3%), 100.3% (RSD 1.8%), 100.7%(RSD 1.8%), 101.2% (RSD 1.5%) and 97.90% (RSD 2.0%) respectively, and their average contents were 3.55, 4.49, 9.12, 19.17, 15.69, 62.56 mg•g⁻¹, respectively. This determination method was accurate and repeatable, which could be used for the content determination in six types of Coptidis Rhizoma pieces. Data analysis on contents determination and preliminary pharmacodynamics results was conducted by using principal component analysis (PCA) and hierarchical clustering analysis (HCA). The analysis results showed that three types of Coptidis Rhizoma pieces (wine steamed pieces, wine stir-fried pieces, and evodiae juice stir-fried pieces) had significant differences with crude pieces, and the wine steamed Coptidis Rhizoma pieces showed most difference with crude pieces especially, mainly related to triglyceride (TG) and fasting blood glucose levels (FBG) in serum. In addition, columbamine hydrochloride was most affected among the six alkaloids. Those three types of Coptidis Rhizoma pieces (wine steamed pieces, wine stir-fried pieces, and evodiae juice stir-fried pieces), had more advantages for "anti-diabetes" in TCM clinical application, especially in the treatment of diabetic hyperlipidemia.
10.Electroacupuncture at Feishu (BL13) and Zusanli (ST36) down-regulates the expression of orexins and their receptors in rats with chronic obstructive pulmonary disease.
Xin-fang ZHANG ; Ji ZHU ; Wen-ye GENG ; Shu-jun ZHAO ; Chuan-wei JIANG ; Sheng-rong CAI ; Miao CHENG ; Chuan-yun ZHOU ; Zi-bing LIU ; E-mail: ZIBINGLIU@163.COM.
Journal of Integrative Medicine 2014;12(5):417-424
OBJECTIVEInflammation and lung function decline are the main pathophysiological features of chronic obstructive pulmonary disease (COPD). Acupuncture can improve lung function in patients with COPD, but the underlying mechanisms are not well understood. Orexins (OXs), which are found in peripheral plasma, are neuropeptides that regulate respiration and their levels are related to COPD. Therefore, we hypothesized that acupuncture might alter OXs, reduce lung inflammation and improve lung function in COPD.
METHODSCOPD was induced in rats by exposure to cigarette smoke for 8 weeks and injecting with lipopolysaccharide twice. Electroacupuncture (EA) was performed at Feishu (BL13) and Zusanli (ST36) for 30 min/d for 2 weeks. Rat lung function and morphology were assessed after EA. The levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in bronchoalveolar lavage fluid (BALF) and orexin A and B levels in the lung tissue were detected by enzyme-linked immunosorbent assay. OX receptor mRNA levels and immunopositive cells were assessed with real-time polymerase chain reaction and immunohistochemical methods, respectively. The relationships among lung function, cell factors, and OX levels were analyzed by Pearson correlation analyses.
RESULTSCompared with the control group, lung function was significantly decreased in the rats with COPD (P<0.05). There were increases in TNF-α and IL-1β levels in BALF (P<0.05 and P<0.01, respectively), orexin A level in lung tissue (P<0.01; but not orexin B) and mRNA expressions of OX (OXR1) and OX 2 (OXR2) in lung tissue (P<0.05 and P<0.01, respectively); the integrative optical densities (IODs) of both receptors were greater in the COPD group (P<0.05). For rats with COPD subjected to EA, lung function was improved (P<0.05). There were notable decreases in TNF-α and IL-1β levels (P<0.05 and <0.01, respectively) in BALF. Orexin A, but not orexinB, levels in lung tissue also decreased (P<0.01), as did mRNA expression of OX1R and OX2R in lung tissue (P<0.05 and P<0.01, respectively). Receptor IODs were also reduced after EA treatment (P<0.05). Furthermore, orexin A levels and ratio of forced expiratory volume in 0.3 s to forced vital capacity were strongly negatively correlated (P<0.01), and orexin A was positively correlated with TNF-α and IL-1β (P<0.001 and P<0.05, respectively).
CONCLUSIONEA at Zusanli and Feishu improved lung function of rats with COPD and had an anti-inflammatory effect, which may be related to down-regulation of OXA and its receptors.
Animals ; Down-Regulation ; Electroacupuncture ; Interleukin-1beta ; analysis ; Intracellular Signaling Peptides and Proteins ; analysis ; genetics ; Lung ; physiopathology ; Male ; Neuropeptides ; analysis ; genetics ; Orexin Receptors ; analysis ; genetics ; Orexins ; Pulmonary Disease, Chronic Obstructive ; physiopathology ; therapy ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha ; analysis