發(fā)布時間：2018-05-26 16:56

  本文選題：氨苯砜綜合征 + 藥物超敏反應　； 參考：《青島大學》2017年博士論文

【摘要】：研究背景:氨苯砜(dapsone,DDS)具有抗菌、抗炎雙重效應,是治療麻風病的基本藥物并被廣泛應用于瘧疾、HIV感染所致的卡氏肺囊蟲肺炎及多種慢性炎癥性疾病的治療。氨苯砜化學名稱為4,4’-對位氨基雙苯砜,其分子量為248.31。氨苯砜口服吸收后在肝臟進行代謝,經(jīng)細胞色素P450酶的作用,發(fā)生羥基化和乙�；瘍蓚�過程,代謝產(chǎn)物為羥胺氨苯砜和乙酰氨苯砜。羥胺氨苯砜在藥物的藥理作用及不良反應的產(chǎn)生方面起關(guān)鍵作用。其代謝產(chǎn)物在皮膚、心臟、肝臟和腎臟等全身多器官廣泛分布。氨苯砜經(jīng)口服后通過小腸吸收,口服2-8小時后達到血漿峰濃度。單次劑量50-300mg氨苯砜可到達血藥濃度為0.63-4.82mg/L。在100mg/d的常規(guī)用量下,血漿峰濃度可達3.26 mg/L。約有20%的代謝產(chǎn)物直接經(jīng)尿液排出,70-85%的代謝產(chǎn)物與葡萄糖醛酸共價結(jié)合后經(jīng)尿液排出,此外,氨苯砜也可經(jīng)膽汁排出體外。氨苯砜最大的副作用在于部分患者服藥后會發(fā)生一種嚴重的藥物超敏反應,臨床上表現(xiàn)為突然發(fā)生的丘疹或剝脫性皮疹,伴發(fā)熱、淋巴結(jié)腫大、單核細胞增多及肝臟或造血系統(tǒng)功能受損,通常在服用氨苯砜4-6周后發(fā)生(故又稱為“5周皮炎”),發(fā)生率為0.5%~3.6%,死亡率9.9%。該藥物不良反應在1951年被正式命名為氨苯砜綜合征。當前對于該綜合征的診斷主要依據(jù)Richardus和Smith于1989年提出的診斷標準,即患者在服用氨苯砜后出現(xiàn)皮疹、發(fā)熱、肝功能異常及淋巴結(jié)腫大中的2條或以上即可診斷。但上述診斷由于無有效的實驗室診斷指標的支持,缺乏特異性,往往很難與疾病本身伴隨的感染、炎癥反應相鑒別,且對于疾病的治療,患者往往會在同一時間段服用多種藥物,這也導致致敏藥物難以判定及準確停用,以致臨床漏診、誤診現(xiàn)象嚴重。氨苯砜綜合征是由T淋巴細胞介導的一種藥物超敏反應,在機體首次接觸致敏藥物后,體內(nèi)T淋巴細胞被激活致敏。當機體再次接觸該藥物后,致敏的T淋巴細胞活化增殖,釋放細胞因子IFN-γ等,吸引和激活巨噬細胞,在局部產(chǎn)生以T細胞和巨噬細胞浸潤為主的炎癥反應。斑貼試驗作為測定機體變態(tài)反應的一種輔助診斷方法即是基于以上原理產(chǎn)生,迄今在皮膚科的應用已有120多年的歷史。目前國際上診斷臨床常見的28種致敏藥物(卡馬西平、布洛芬、阿莫西林、雙氯芬酸鈉等)已研發(fā)了具有獨立知識產(chǎn)權(quán)的斑貼試劑盒,已獲得美國FDA、中國c FDA以及歐盟認證,在臨床上廣泛應用,為藥物所致不良反應的診斷及鑒別診斷提供了有效的工具,獲得了良好的社會經(jīng)濟效益。研究目的:本研究旨在研發(fā)氨苯砜斑貼試劑,建立氨苯砜綜合征免疫確證方法,為疾病的診斷提供有效技術(shù)手段,以推動該技術(shù)在臨床上的應用。研究對象:1、氨苯砜綜合征病例組:臨床擬診氨苯砜綜合征并攜帶HLA-B*1301位點的麻風病患者24例。2、氨苯砜綜合征對照組:服用過氨苯砜并攜帶HLA-B*1301位點但未出現(xiàn)氨苯砜綜合征的麻風病患者25例。健康志愿者50例。納入標準:病例組:1、2008.01-2016.12新發(fā)的麻風病患者且服用過氨苯砜進行治療;2、患者服用氨苯砜治療過程中出現(xiàn)發(fā)熱、皮疹、肝功能異常、淋巴結(jié)腫大等疑似氨苯砜綜合癥,符合Richardus和Smith提出的該病診斷標準;3、攜帶HLA-B*1301等位基因;4、同意參與本研究并簽署書面知情同意書。對照組1、2008.01-2016.12全國新發(fā)的麻風病患者且服用氨苯砜進行治療,服藥時間至少1個月;2、患者服用氨苯砜治療過程中未發(fā)現(xiàn)發(fā)熱、皮疹、肝功能異常、淋巴結(jié)腫大等臨床癥狀;3、攜帶HLA-B*1301等位基因;4、同意參與本研究并簽署書面知情同意書。排除標準:1.對磺胺類、呋塞米類、噻嗪類、磺酰脲類以及碳酸酐酶抑制藥過敏的患者;2.無法提供正確信息的患者,如精神障礙等;3.并發(fā)嚴重疾病的患者,如心衰、惡性腫瘤等;研究內(nèi)容:本研究分為三部分:研究I:研發(fā)可供臨床應用的氨苯砜綜合征斑貼試劑,探索穩(wěn)定的試劑基質(zhì)及濃度范圍并明確其穩(wěn)定性情況:以臨床診斷和激發(fā)試驗陽性的1例疑似氨苯砜綜合征患者為實驗對象,探索氨苯砜斑貼試劑合適的基質(zhì)及濃度范圍;研究II:對配置的斑貼試劑進行含量測定,明確試劑的穩(wěn)定性情況;研究III:明確氨苯砜斑貼試劑臨床應用的敏感度及特異度:對臨床擬診且攜帶HLA-B*1301位點的23例疑似氨苯砜綜合征患者及25例服用氨苯砜且攜帶HLA-B*1301位點但未出現(xiàn)疑似氨苯砜綜合征癥狀的25例麻風病患者采用建立的斑貼試劑進行檢測。選擇50例健康志愿者用于排除斑貼試劑本身所致的皮膚刺激反應。使用卡方檢驗用于確定各組間差異的統(tǒng)計學意義,確定研發(fā)的斑貼試劑臨床應用的敏感度及特異度情況。研究方法:研究I:采用溶解法觀察凡士林基質(zhì)、聚乙二醇200基質(zhì)、聚乙二醇200基質(zhì)+二甲基亞砜、聚乙二醇基質(zhì)+油酸、聚乙二醇基質(zhì)+氮酮在氨苯砜中的溶解程度,并根據(jù)斑貼試驗結(jié)果調(diào)整斑貼試劑的濃度;研究II:采用高效液相色譜儀對配制的凡士林基質(zhì)、聚乙二醇200基質(zhì)的斑貼試劑進行含量測定,同時對其初步的穩(wěn)定性情況進行考察;研究III:對研究對象進行氨苯砜斑貼試驗,方法如下:1.將氨苯砜斑貼試劑按0.1%、0.5%、1%、5%、10%、15%、20%、25%的濃度擺放好,把對照放好。2.將斑試器從帶有三角撕口的一側(cè)撕開,然后將氨苯砜斑貼試劑及空白對照按順序加在斑試器上。注意記錄斑貼試劑的濃度順序。3.讓患者充分暴露背部皮膚,選擇無皮疹、無色素沉著的正常皮膚進行試驗。4.用酒精棉球?qū)ζつw進行充分消毒,然后將斑試器貼在患者后背皮膚上,輕壓排凈空氣,將斑試器貼牢。5.用記號筆在斑試器的四角做好標記。并在實驗記錄紙上做好記錄,特別注意記錄斑貼試劑不同的濃度的位置。6.囑咐患者在48小時后撕掉斑試器,試驗期間不宜洗澡、不宜干農(nóng)活、不宜劇烈運動、不宜飲酒等。試驗期間若發(fā)生強烈反應需撕掉斑試器。7.72小時后,也就是撕掉斑試器24小時后觀察實驗結(jié)果。用酒精棉球擦拭清潔受試部位,再次用記號筆對斑試器的四個角進行標注,仔細觀察受試部位有無紅斑、丘疹、水泡出現(xiàn)(部分患者實驗效果不明顯,需仔細觀察)。根據(jù)國際接觸性皮炎研究組ICDRG(International Contact Dermatitis Research Group)指南判讀結(jié)果。斑貼試驗結(jié)果均由同一技術(shù)人員判定。統(tǒng)計學方法:研究結(jié)果分析在意向性分析(intention to treat,ITT)人群進行,ITT人群是指所有進入研究并至少有過一次用藥措施的受試者。數(shù)據(jù)統(tǒng)計應用SPSS 16.0版軟件,根據(jù)研究目的和資料的性質(zhì)選用卡方檢驗,得出試驗組與對照組的各項指標差異是否有統(tǒng)計學意義。所有統(tǒng)計檢驗均采用雙側(cè)檢驗,檢驗水準定義為α=0.05,P值小于0.05將被認為所檢驗的差別有統(tǒng)計學意義。研究結(jié)果:研究I:經(jīng)過氨苯砜凡士林基質(zhì)、聚乙二醇200基質(zhì)、聚乙二醇200基質(zhì)+二甲基亞砜、聚乙二醇基質(zhì)+油酸、聚乙二醇基質(zhì)+氮酮5種基質(zhì)的比較,最終選擇聚乙二醇200基質(zhì)+二甲基亞砜做為最佳制劑。研究II:采用聚乙二醇200作為基質(zhì)的斑貼,常溫狀態(tài)以及4℃低溫放置6個月樣品含量無明顯下降趨勢,且低溫保存與常溫保存對樣品穩(wěn)定性無差異,采用此基質(zhì)可保證樣品在一定時間內(nèi)穩(wěn)定,無需現(xiàn)用現(xiàn)配。研究III:在全國范圍內(nèi)對23例氨苯砜綜合征患者做斑貼試驗,其中10例斑貼試驗陽性,13例斑貼試驗陰性。服用過氨苯砜且未出現(xiàn)氨苯砜綜合征的麻風病患者25例氨苯砜斑貼試驗均陰性,健康志愿者50例氨苯砜斑貼試驗均陰性。結(jié)論:本研究建立了基于斑貼實驗的氨苯砜綜合癥免疫確證方法,為該病的精準診斷提供了有效的實驗室技術(shù)手段,也將為其他藥物所致藥物超敏反應綜合征的免疫確證方法的建立提供思路與借鑒,對于在臨床實踐中判定患者的致敏藥物、明確疾病診斷具有重要意義。
[Abstract]:Background: dapsone (DDS) is a basic drug for the treatment of leprosy, and is widely used in the treatment of Pneumocystis carinii pneumonia and a variety of chronic inflammatory diseases caused by HIV infection. The chemical name of sulfoxide is 4,4 '- para Diphenyl Sulfoxide, its molecular weight is 248.31. amamyl sulfoxide After absorption, it is metabolized in the liver. Through the action of cytochrome P450 enzyme, there are two processes of hydroxylation and acetylation. The metabolites are hydroxyaminophen sulfoxide and acetaminophen sulfoxide. Hydroxylaminyl sulfoxide plays a key role in the pharmacological action and adverse reactions of the drug. Its metabolic products are in the skin, heart, liver and kidney. It is widely distributed. After oral administration of sulfoxide, it is absorbed through the small intestine and reaches the plasma peak concentration after 2-8 hours of oral administration. A single dose of 50-300mg sulfoxide can reach the concentration of 0.63-4.82mg/L. at 100mg/d, and the plasma peak concentration is up to 3.26 mg/L., about 20% of the metabolites are directly connected to the urine, and the metabolites of 70-85% and grapes Aldonic acid is covalently combined and excreted in urine. In addition, sulfoxide can also be discharged through bile. The biggest side effect of sulfoxide is that some patients take a serious drug hypersensitivity after taking medicine, which are clinically manifested by sudden papules or exfoliative rashes, fever, lymph node enlargement, mononuclear cells and liver or formation. The function of the blood system is impaired, usually after taking 4-6 weeks after the use of sulfoxide (which is also called "5 weeks of dermatitis") with a rate of 0.5%~3.6% and the death rate of 9.9%., which was formally named the sulfoxide syndrome in 1951. The current diagnosis of the syndrome is based on the diagnostic criteria proposed by Richardus and Smith in 1989, that is, the patient. The diagnosis of rash, fever, abnormal liver function and 2 or more of Zhong Dazhong's lymph nodes can be diagnosed after taking Diphenyl Sulfoxide, but the above diagnosis is often difficult to identify with the infection of the disease itself, the inflammatory reaction and the treatment of the disease. Taking a variety of drugs for a period of time, this also causes the allergy drugs to be difficult to determine and disable, so that the clinical misdiagnosis and misdiagnosis are serious. The sulfoxide syndrome is a drug hypersensitivity reaction mediated by T lymphocytes. After the body is first exposed to the sensitized drug, the T lymphatic cells are activated and sensitized. When the body is again exposed to the drug, The sensitized T lymphocytes activate and proliferate, release cytokine IFN- gamma, etc., attract and activate macrophages, and produce an inflammatory reaction dominated by T cells and macrophages. Patch test as an auxiliary diagnostic method for the determination of the body's allergy is based on the above origin. So far, more than 120 applications in the Department of dermatology have been used. At present, 28 common clinical sensitizing drugs (C Masi Bing, ibuprofen, amoxicillin, diclofenac sodium, etc.) have been developed and have developed a patch kit with independent intellectual property rights. It has obtained FDA, C FDA and EU certification in the United States. It is widely used in clinical practice to diagnose and identify adverse drug reactions caused by drugs. The purpose of this study is to develop a good social and economic benefit. The purpose of this study is to develop the reagents for the DDF patch and establish an immune confirmatory method for the sulfoxide syndrome to provide an effective technique for the diagnosis of the disease and to promote the clinical application of this technique. 1 24 cases of leprosy with HLA-B*1301 site.2, 24 cases of leprosy syndrome, and 25 cases of leprosy with HLA-B*1301 site but without sulfoxide syndrome. Healthy volunteers were included in the standard: case group: 12008.01-2016.12 new leprosy patients and taking ammonia 2, in the treatment of sulfoxide, patients were treated with fever, rash, liver dysfunction, lymph node enlargement and other suspected sssone syndrome, conforming to Richardus and Smith's diagnostic criteria for the disease; 3, carrying HLA-B*1301 alleles; 4, agreed to participate in the study and signed a written informed consent. 12008.01-2016.12 in the control group. The national new leprosy patients were treated with Diphenyl Sulfoxide for at least 1 months. 2, patients did not find fever, rash, liver dysfunction, lymph node enlargement and other clinical symptoms during the treatment of Daba; 3, carrying HLA-B*1301 allele; 4, agreed to participate in the study and signed written informed consent. 1. pairs of exclusion criteria: 1. Patients with sulfonamides, furasamides, thiazides, sulfonylureas, and carbonic anhydrase inhibitors; 2. patients who could not provide correct information, such as mental disorders, and 3. patients with severe disease, such as heart failure, malignant tumor, etc.; study: This study was divided into three points: the study of I: development for clinical application of the SF patch test To explore the stability of the reagent matrix and concentration range and to clarify its stability: 1 patients with suspected ssone syndrome with positive clinical diagnosis and excitation test were used as experimental subjects to explore the appropriate matrix and concentration range of the reagents for the reagents. The content of patch reagents was determined by II: and the stability of the reagents was determined. A study of the sensitivity and specificity of the clinical application of III: specific Diphenyl Sulfoxide patch reagents: 23 patients with suspected clinical diagnosis and carrying HLA-B*1301 loci and 25 cases of leprosy with HLA-B*1301 loci but no symptoms of dsone syndrome with 25 cases of dsone syndrome Test. Select 50 healthy volunteers to remove the skin irritation reaction caused by patch reagent itself. Use the chi square test to determine the statistical significance of the differences between each group, determine the sensitivity and specificity of the clinical application of the patch reagent. Research methods: I: the use of dissolving method to observe Vaseline matrix, poly (two) Alcohol 200 matrix, polyethylene glycol 200 matrix + two methyl sulfoxide, polyethylene glycol matrix + oleic acid, polyethylene glycol matrix + azone in sulfoxide, and adjust the concentration of patch reagents according to the patch test results; study II: using high performance liquid chromatograph for the preparation of Vaseline matrix, polyethylene glycol 200 matrix patch reagents containing Measurement and Study on the initial stability of the study. The study of III: on the research object was carried out by the patch test of sulfoxide. The methods were as follows: 1. the concentration of the reagents was put in the concentration of 0.1%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, and the control was ripped from one side with the triangular tearing, and then the sulfoxide spot was tested. The concentration sequence of the agent and the blank control was added in the spot test device. Note the concentration sequence of the patch reagents,.3. let the patient fully expose the back skin, choose no rash, the normal skin without the pigmentation, the.4. use the alcohol cotton ball to sterilize the skin fully, and then paste the spot test device on the back of the patient's back skin, gently press the net air and spot the spot. The test device is fastened to.5. with the mark pen in the four corner of the spot test device. And the record is made on the experiment paper. Special attention is paid to the location of the different concentration of the patch reagents..6. tells the patient to tear out the spot test device after 48 hours. After 24 hours of ripping off the spot test device, the test result was observed after 24 hours of ripping out the spot test device. Cleaning the tested parts with the alcohol cotton ball and marking the four corners of the spot test device again with the marker pen, and carefully observing whether there were erythema, papules, and bubble out of the subjects. The results were judged according to the ICDRG (International Contact Dermatitis Research Group) guide of the international contact dermatitis research group. The results of the patch test were determined by the same technician. Statistical method: the results of the study were analyzed in the intention analysis (intention to treat, ITT) population, and the ITT population was at least one in the study and at least one The subjects of the secondary drug use. Data statistics application of SPSS 16 software, according to the purpose of the study and the nature of the data of the selection of chi square test, the test group and the control group of the indicators of the difference is statistically significant. All statistical tests are both tested by bilateral test, water calibration sense is alpha =0.05, P value less than 0.05 will be considered to be tested The difference has statistical significance. The results of the study were to study the comparison of I: through the Vaseline matrix, polyethylene glycol 200 matrix, polyethylene glycol 200 matrix + two methyl sulfoxide, polyethylene glycol matrix + oleic acid, polyethylene glycol matrix + azone 5 substrates, and finally selected polyethylene glycol 200 base + two methyl sulfoxide as the best preparation. The content of ethylene glycol 200 as the matrix patch, the normal temperature state and the low temperature of 4 centigrade for 6 months did not decrease obviously, and there was no difference in the stability of the sample at low temperature and storage at normal temperature. The use of this matrix could guarantee the stability of the sample for a certain time and no need for present use. In the study of III:, 23 cases of sulfoxide syndrome were studied throughout the country. The spot patch test was used in 10 cases of plaque test positive and 13 cases of patch test negative. 25 cases of leprosy patients taking ddsone and 25 cases of leprosy patch test were negative and 50 cases of healthy volunteers were negative. Conclusion: This study established the immunization of sssone syndrome based on patch test. The method of proof provides an effective laboratory technique for the accurate diagnosis of the disease. It will also provide some ideas and reference for the establishment of the immune confirmation method of the drug hypersensitivity syndrome caused by other drugs. It is of great significance to determine the sensitizing drugs of the patients in clinical practice and to clear the diagnosis of the disease.
【學位授予單位】：青島大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R595.3

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