發(fā)布時間：2018-04-23 08:48

  本文選題：利福平 + 異煙肼　； 參考：《南方醫(yī)科大學》2012年碩士論文

【摘要】：背景和目的 結核性胸膜炎(Tuberculous pleuritis)是最常見的肺外結核(IEPTB)之一,近年來由于艾滋病的流行和結核分枝桿菌合并感染增加,使其發(fā)病率呈上升趨勢,全球有將近三分之一的人感染結核,大約3-25%的結核病人會發(fā)生結核性胸膜炎,據(jù)報道統(tǒng)計,呼吸科住院病人中10%伴有胸腔積液,其中結核性胸腔積液占46.7%。結核性胸腔積液是結核性滲出性胸膜炎的表現(xiàn),是干性胸膜炎的進一步發(fā)展形成,由近胸膜的原發(fā)病灶直接侵入胸膜腔,或經淋巴管血行播散至胸膜而引起的滲出性炎癥。多急性發(fā)病且好發(fā)于青年人,臨床上表現(xiàn)為單側胸腔少至中等量的積液,常見的癥狀是胸痛、干咳、乏力等,大部分病人會發(fā)熱,但是其中也有15%沒有發(fā)熱癥狀,如果積液量大,病人會呼吸困難。若得不到早期科學合理治療,容易引起胸膜肥厚、粘連,形成包裹性積液,甚至膿胸,從而嚴重影響肺的呼吸功能。高達50%的病人會出現(xiàn)胸膜增厚,胸膜增厚導致肺限制性通氣功能障礙,并可產生后遺癥如繼發(fā)性支氣管擴張、不可逆性壓縮性肺不張等使病情加重。 胸膜腔位于肺和胸壁之間的一個的潛在腔,作為肺和胸壁之間的連接系統(tǒng)而成為呼吸系統(tǒng)結構的重要部分。過去認為,結核性胸腔積液的發(fā)病機制是宿主對結核菌或其代謝產物發(fā)生了遲發(fā)變態(tài)反應(DTH),結核桿菌不直接侵犯胸膜和胸腔。主要依據(jù)是大部分結核性胸膜炎病例胸腔積液結核菌培養(yǎng)陰性。目前臨床實踐發(fā)現(xiàn)胸膜活檢有50%-80%的病例胸膜上有典型結核結節(jié)形成,故認為胸膜的病理損傷是結核性胸膜炎乃至結核性胸腔積液發(fā)生的主要機制,DTH在其中起一定作用。這說明在胸腔積液中或者胸膜上存在有結核菌。因此,能否有效殺死病灶部位的致病菌是治療的一個根本措施。 抗菌藥物是治療胸膜炎的主要藥物,通常認為抗生素在胸腔積液中的濃度和血清中相似,所以,目前臨床結核性胸膜炎的藥物治療方法一直沿用肺結核的化療方案為主：短療程異煙肼(INH)、利福平(RFP)、吡嗪酰胺(PZA)和鹽酸乙胺丁醇(EMB)治療2個月,再INH和RFP口服4個月,根據(jù)病情可延長療程達12個月。但是,缺乏相關的實際數(shù)據(jù)支持這種經驗用藥方案,由于胸膜腔密閉結構的特殊性以及藥物透過胸膜的差異性,導致胸膜腔內各種抗結核藥物濃度透過程度和藥動學過程不同。國內外的少量研究數(shù)據(jù)表明：在結核性膿腫中,INH濃度可能會降低,但高于最低抑菌濃度或殺菌濃度,RFP在病灶中濃度可能會低于最低抑菌或殺菌濃度。但是抗結核治療只有各個抗結核藥物分別達到各自的有效治療濃度才會發(fā)揮協(xié)同作用,從而降低耐藥的發(fā)生率。因此,這就需要增加對病灶部位抗結核藥物的藥動學和抗菌作用的認識,從而設計更好的治療方案,改善治療效果。文獻檢索結果表明,目前國內外尚無對抗結核藥物在胸腔積液中完整的藥代動力學及療效分析的報道,因此,研究單次和多次給藥后藥物在胸腔積液中的動態(tài)過程以及藥物的胸膜滲透是有較高的學術價值和重要的臨床指導意義。 本課題研究初治的結核性胸膜炎患者服藥第1、2、3天后藥物在結核性胸腔積液中的藥代動力學,對各抗結核藥物濃度進行檢測,更直接地評價臨床療效,為臨床藥物治療方案的調整提供重要的理論依據(jù),尤其是對于治療失敗的病例,可以推斷是否藥物滲透受影響或藥物耐藥的情況發(fā)生,從而根據(jù)檢測結果及時改變給藥方案和用藥劑量,以改善療效,縮短療程,減少耐藥性的產生。 內容和結果 選取南方醫(yī)院呼吸內科2010年6月-2012年4月23例結核性胸膜炎患者,納入標準是：1.中等量或者大量滲出性胸腔積液患者；2.符合滲出性結核性胸膜炎的診斷標準：①結核中毒癥狀：發(fā)熱,畏寒,胸痛,氣短,出汗,乏力。②體征：局部叩診濁音,呼吸音減弱。③經過細菌學、組織學或者超聲波和CT胸片檢查確診。 排除標準：復治結核,惡性胸腔積液患者,合并心血管、肝、腎或者造血系統(tǒng)等嚴重原發(fā)性疾病患者,精神病患者,具有慢性疾病或者其他器質性疾病患者,需同時應用影響抗結核藥物藥動學的患者,近期參加其他臨床試驗的患者。 采樣分為兩部分：1.引流13名患者胸腔置管后初次服藥的第1、2、3天每天空腹晨服藥藥后2、4、6、8、12、24h的胸腔積液,同時采集其中5名患者第3天服藥前和服藥后2、4、8、24h的血樣；2.收集20名患者胸腔置管后初次服藥后2h的胸腔積液,以及第3天服藥后2h的胸腔積液和血樣。所有樣品經過前處理提取后,采用高效液相色譜方法檢測樣品中INH和RFP的濃度,EMB的濃度采用液相質譜聯(lián)用儀測量。 RFP的色譜條件：KromasiL C18色譜柱(150mm×4.60mm,5micron);流動相：甲醇-10mmol/l磷酸二氫鉀緩沖鹽(磷酸調節(jié)pH4.5)(v/v62:38)；波長：340nm；流速：1.0ml/min；柱溫：30℃,進樣量：20μl。RFP在胸腔積液和血漿的線性范圍分別是0.046875～6.0μg/ml和0.09375～12.0μg/ml,線性良好；回歸方程分別是：C=2.627e-5*A-3.443e-2(R2=0.994), C=2.021e-5*A+3.784e-2(R2=0.999)；在此條件下,胸腔積液中RFP的最低檢測限為0.02μg/ml,樣品取樣回收率大于80%,提取后室溫下放置24h及反復凍融3次穩(wěn)定性良好。 INH的色譜條件：流動相甲醇-20mM磷酸二氫鉀(70%高氯酸,20%三乙胺,調節(jié)pH3.2)(v/v:30-70),色譜柱：NucLeosiL CN-RP(250mm,4.61/mm×5μm),流速：1.0ml/min,波長：340nm,溫度：30℃,時間：20min,進樣量：20μl。INH在血漿和胸液中的線性范圍分別是0.01～10.0μg/ml,0.01～5.0μg/ml,線性良好；回歸方程分別是C=4.35×10-6A+2.05×l0-2(R2=0.9999), C=4.44×10-6A+3.84×10-3(R2=0.9999),檢測限均為0.01μg/ml;提取回收率理想,日內和日間精密度小于10%,樣品處理后放置12h及反復凍融3次穩(wěn)定性良好。 EMB的色譜條件：Agilent ZORBAX SB-C18柱(2.1x150mm,3.5mm);流動相：甲醇-0.1%甲酸水溶液(v/v=15：85)；流速：0.2ml/min;柱溫為25℃；進樣量：2μ1。質譜條件：電噴霧離子源(ESI)正模式,以多重反應離子監(jiān)測(MRM)進行檢測,檢測離子為m/z205.1→m/z116.0(EMB), m/z130.1→m/z60.2(二甲雙胍,內標)。EMB胸腔積液中的最低定量限為31.25ng/ml,胸腔積液和血漿線性范圍分別是為31.25-4000ng/ml和31.25-8000ng/ml,回歸方程分別是Y=0.211X-0.094(R2=0.991), Y=0.332X+0.386(R2=0.998),回收率高于80%,日內及日間RSD均小于10%。 根據(jù)檢測結果計算滲透率和胸腔積液中抗結核藥物的藥代動力學參數(shù)Tmax， Cmax, AUC及滲透率,結果如下： 第3天給藥后2h胸腔積液和血漿藥物濃度之比為： RFP：16.051±8.345； INH：65.701±39.682； EMB：71.621±71.503。 第3天藥物在胸腔積液中的Tmax(h)、Cmax(μg/ml)、AUC0-24(mg/l·h)分別是： RFP：6.67±2.449,2.368±0.848,33.374±8.147； INH：3.78±1.563,2.759+1.013,26.258±13.580； EMB:5.11+1.054,1.673+0.696,17.843±4.657。 第3天藥物在血漿中Tmax(h)、Cmax(μg/ml)、AUC0-24(mg/l·h)分別是： RFP：3.60±0.894,7.820±1.034,72.878±16.306； INH：2.400±0.894,4.614+1.213,29.283±13.125; EMB：2.40±0.894,1.943±0.780,12.216±4.048。 第3天藥物在血漿和胸腔積液中AUC0-24(mg/1·h)的比值分別是： RFP：37.338+11.005,49.683+9.731; INH：79.194+24.098,111.792±7.341; EMB：131.164±108.840,180.997+123.952。 血漿和胸腔積液RFP的AUC/MIC125,對胸腔積液和血漿中RFP的濃度和AUC做相關性分析,結果表明均無相關性(r=0.411,P=0.072；r=0.613,P=0.271)。血漿和胸腔積液INH的AUC/MIC125,對胸腔積液和血漿中INH的濃度和AUC做相關性分析,結果表明均呈正相關(r=0.702,P=0.001；r=0.995,P=0.000)。血漿和胸腔積液EMB的AUC/MIC125,對胸腔積液和血漿中EMB的濃度和AUC分別做相關性分析,結果表明均無相關(r=0.411,P=0.072；r=-0.248,P=0.687)。 結論與討論 試驗結果表明：RFP血漿和胸腔積液濃度均超過了最低殺菌濃度,RFP從血漿進入胸膜腔的滲透率較低,其在胸腔積液中的AUC較高,可能與RFP蛋白結合率高,使其在胸膜腔中呈一定蓄積作用,隨著給藥次數(shù)的增加,胸腔積液中Tmax減小,Cmax接近血漿穩(wěn)態(tài)濃度。對于治療非耐藥結核性胸膜炎有效并且能抑制結核桿菌耐藥。 INH的胸腔積液濃度較高,達峰時間較血漿稍晚,胸腔積液濃度隨血漿濃度增加而升高,說明INH透過胸膜的速度快,吸收程度高。第3天胸腔積液AUC和血漿AUC相當,隨著給藥次數(shù)增加,推測第3天血漿和胸腔積液可達到穩(wěn)態(tài)濃度,對沒有包裹性胸腔積液的患者不需要胸腔注射給藥INH即可達到有效的治療濃度。因此,INH治療結核性胸膜炎有效并能抑制細菌耐藥。 大部分患者EMB胸腔積液和血漿濃度較低于最小抑菌濃度,胸腔積液中Tmax明顯延后,AUC/MIC125,治療作用很小,應根據(jù)EMB監(jiān)測濃度進行劑量調整,在達到有效治療的同時,盡量避免其毒副作用的發(fā)生。 因此,RFP和INH連續(xù)每天給藥1次,胸腔積液中能達到有效治療濃度,INH不需要胸腔注射給藥,長期用藥時需要監(jiān)測RFP濃度,防止肝藥酶誘導作用使其濃度降低,建議EMB根據(jù)監(jiān)測濃度調整劑量。 RFP、INH、EMB均為濃度依賴型抗菌藥物,比較三種藥物在胸腔積液中的滲透率,可推測RFP與INH、EMB經胸膜進入胸腔積液中的滲透方式可能不同,這可能與藥物的極性、蛋白結合率或者胸膜的間皮屏障作用有關,從而使不同藥物胸膜滲透率具有顯著差異,這些機制還有待進一步的研究。
[Abstract]:Background and purpose
Tuberculous pleurisy (Tuberculous pleuritis) is one of the most common extrapulmonary tuberculosis (IEPTB). In recent years, due to the prevalence of AIDS and the increase of Mycobacterium tuberculosis combined infection, the incidence of tuberculosis is on the rise. There are nearly 1/3 people around the world infected with tuberculosis, about 3-25% of tuberculosis patients will have tuberculous pleuritis, according to reports. In the Department of respiration, 10% of the patients in the Department of respiration were accompanied by pleural effusion, in which tuberculous pleural effusion accounted for 46.7%. tuberculous pleural effusion, the manifestation of tuberculous exudative pleuritis, and the further development of dry pleuritis, which was directly intruded into the pleural cavity, or disseminated to the pleura through the lymphatic vessel blood, and the exudative inflammation caused by the lymphatic vessels. Multiple acute onset and good hair in young people, clinical manifestations of the unilateral pleural less to moderate amount of fluid, the common symptoms are chest pain, dry cough, fatigue and so on, most patients will fever, but 15% of them have no fever, if the amount of fluid is large, the patient will breathe difficult. If no early scientific and reasonable treatment, it is easy to cause the pleura. Hypertrophy, adhesion, forming Encapsulated Effusion, even empyema, seriously affects the respiratory function of the lung. Up to 50% of the patients will have pleural thickening, pleura thickening and pulmonary restrictive ventilation dysfunction, and can produce sequelae such as secondary bronchiectasis, irreversible compressible pulmonary atelectasis.
The pleural cavity is a potential cavity between the lung and the chest wall, which is an important part of the respiratory system as a connection between the lung and the chest wall. In the past, the pathogenesis of tuberculous pleural effusion was the late onset metamorphosis (DTH) of the host to the Mycobacterium tuberculosis or its metabolites, and the Mycobacterium tuberculosis did not directly infringe the pleura and chest. The main basis is that the tubercle bacillus culture of pleural effusion is negative in most cases of tuberculous pleurisy. At present, clinical practice has found typical tuberculosis nodules on the pleura of 50%-80% cases with pleural biopsy, so the pathological injury of the pleura is the main mechanism of tuberculous pleurisy and even tuberculous pleural effusion. DTH plays a certain role in it. This indicates that there are tuberculous bacteria in pleural effusion or pleura. Therefore, it is a fundamental measure to effectively kill pathogenic bacteria in the lesions.
Antibacterials are the main drugs for the treatment of pleurisy. It is generally believed that the concentration of antibiotics in the pleural effusion is similar to that in the serum. Therefore, the current drug therapy for tuberculous pleurisy always follows the chemotherapy regimen of pulmonary tuberculosis: short course isoniazid (INH), Fu Ping (RFP), PZA, and ethambutol hydrochloric acid (EMB) After 2 months of treatment, INH and RFP were taken orally for 4 months, and the duration of the treatment could be prolonged for 12 months. However, the lack of relevant practical data supported the experience of the drug regimen. The specificity of the pleural cavity and the difference in the pleura through the pleura resulted in the permeability of various antituberculous drugs in the pleural cavity and the pharmacokinetic process. A small number of research data at home and abroad show that the concentration of INH may be reduced in tuberculous abscess, but higher than the minimum or bactericidal concentration, the concentration of RFP in the focus may be lower than the minimum bacteriostasis or bactericidal concentration. The same effect, thus reducing the incidence of drug resistance, therefore, it is necessary to increase the understanding of the pharmacokinetics and antiseptic effect of anti tuberculosis drugs on the focus, so as to design a better treatment plan and improve the therapeutic effect. The results of literature retrieval show that there is no complete pharmacokinetics and treatment of anti tuberculosis drugs in the pleural effusion at home and abroad. Therefore, it is of high academic value and important clinical significance to study the dynamic process of the drug in the pleural effusion and the pleura permeation after a single and multiple drug delivery.
This topic is to study the pharmacokinetics of drug in tuberculous pleural effusion after 1,2,3 days after the first treatment of tuberculous pleurisy, to detect the drug concentration of various anti tuberculosis drugs, to evaluate the clinical efficacy more directly, and to provide an important theoretical basis for the adjustment of the clinical drug treatment scheme, especially for the cases of treatment failure. It is inferred whether drug penetration is affected or drug resistance occurs, thus changing the dosage regimen and dosage in time to improve the efficacy, shorten the course of treatment and reduce the production of drug resistance according to the results of the test.
Content and results
23 cases of tuberculous pleurisy in the Department of respiratory medicine of the southern hospital in June 2010 -2012 April were included in the standard: 1. of the patients with equal or massive exudative pleural effusion; 2. conformed to the diagnostic criteria for exudative tuberculous pleurisy: (1) symptoms of tuberculosis poisoning: fever, cold, chest pain, shortness of breath, sweat, fatigue. Voiced sounds and respiratory sounds were weakened. (3) confirmed by bacteriology, histology or ultrasound and CT chest radiography.
Exclusion criteria: retreated tuberculosis, patients with malignant pleural effusion, patients with severe primary diseases such as cardiovascular, liver, kidney or hematopoietic systems, patients with psychosis, chronic diseases or other organic diseases, should be used in patients with antituberculous pharmacokinetics and in other clinical trials in the near future.
The samples were divided into two parts: 1. drainage 13 patients after the first medicine after the thoracic cavity for the first 1,2,3 day after the first dose of 2,4,6,8,12,24h in the pleural effusion, and 5 patients before and after third days of medication and after the drug 2,4,8,24h blood samples; 20 patients after the first medicine after the chest catheterization of the 2H pleural effusion, and third days The pleural effusion and blood samples of 2h after taking the medicine were obtained. All samples were extracted by preprocessing, and the concentration of INH and RFP in the samples was detected by high performance liquid chromatography. The concentration of EMB was measured by liquid phase mass spectrometry.
The chromatographic conditions of RFP: KromasiL C18 column (150mm x 4.60mm, 5micron); mobile phase: methanol -10mmol/l potassium dihydrogen phosphate buffer salt (phosphoric acid regulated pH4.5) (v/v62:38); wavelength: 340nm; flow rate: 1.0ml/min; column temperature: 30 degrees C, sampling quantity: 20 mu l.RFP in pleural and plasma linear range of 0.046875 to 6 micron and 0.093 75 to 12 mu g/ml, linear good, regression equation: C=2.627e-5*A-3.443e-2 (R2=0.994), C=2.021e-5*A+3.784e-2 (R2=0.999). Under this condition, the minimum detection limit of RFP in pleural effusion is 0.02 mu g/ml, sample recovery rate is more than 80%, and 24h and repeated freezing and thawing at room temperature are good for 3 times.
INH chromatographic conditions: mobile phase methanol -20mM potassium dihydrogen phosphate (70% perchloric acid, 20% three ethylamine, regulating pH3.2) (v/v:30-70), chromatographic column: NucLeosiL CN-RP (250mm, 4.61/mm * 5 micron), flow rate: 1.0ml/min, wavelength: 340nm, temperature: 30 degrees, time: 20min, the linear range of 20 Mu in plasma and thoracic fluid is 0.01 to 10 um, respectively. G/ml, 0.01 ~ 5 mu g/ml, good linearity; the regression equation is C=4.35 x 10-6A+2.05 x l0-2 (R2=0.9999), C=4.44 x 10-6A+3.84 x 10-3 (R2=0.9999), and the detection limit is 0.01 mu g/ml; the recovery rate is ideal, the intra day and day precision is less than 10%, and the stability of 12h and repeated freezing and thawing after the sample treatment is good.
The chromatographic conditions of EMB: Agilent ZORBAX SB-C18 column (2.1x150mm, 3.5mm); mobile phase: methanol -0.1% formic acid water solution (v/v=15:85); flow rate: 0.2ml/min; the column temperature is 25 C; the sample volume: 2 mu 1. mass spectrometry conditions: electrospray ion source (ESI) positive mode, detection by multiple reactivity monitoring (MRM) MB), the minimum quantitative limit of m/z130.1 to m/z60.2 (metformin, internal standard).EMB pleural effusion is 31.25ng/ml, and the linear range of pleural effusion and plasma is 31.25-4000ng/ml and 31.25-8000ng/ml respectively. The regression equation is Y=0.211X-0.094 (R2=0.991), Y=0.332X+0.386 (R2=0.998), and the recovery rate is higher than 80%, both within and between day and day RSD are less than those
The pharmacokinetic parameters Tmax, Cmax, AUC and permeability of anti tuberculosis drugs in pleural effusion were calculated according to the test results. The results are as follows:
After third days of administration, the ratio of 2H pleural effusion and plasma drug concentration was:
RFP:16.051 + 8.345;
INH:65.701 + 39.682;
EMB:71.621 + 71.503.
The Tmax (H), Cmax (g/ml) and AUC0-24 (mg/l. H) of third day drugs in pleural effusion were:
RFP:6.67 + 2.449,2.368 + 0.848,33.374 + 8.147;
INH:3.78 + 1.563,2.759+1.013,26.258 + 13.580;
EMB:5.11+1.054,1.673+0.696,17.843 + 4.657.
Third days in the plasma, Tmax (H), Cmax (g/ml), AUC0-24 (mg/l. H) were:
RFP:3.60 + 0.894,7.820 + 1.034,72.878 + 16.306;
INH:2.400 + 0.894,4.614+1.213,29.283 + 13.125;
EMB:2.40 + 0.894,1.943 + 0.780,12.216 + 4.048.
The ratio of AUC0-24 (mg/1? H) in plasma and pleural effusion on the third day was:
RFP:37.338+11.005,49.683+9.731;
INH:79.194+24.098111.792 + 7.341;
EMB:131.164 + 108.840180.997+123.952.
The AUC/MIC125 of RFP in plasma and pleural effusion was correlated with the concentration of RFP in pleural effusion and plasma and AUC. The results showed no correlation (r=0.411, P=0.072; r=0.613, P=0.271). The AUC/MIC125 of INH in plasma and pleural effusion was correlated with INH concentration in pleural effusion and plasma and correlation analysis of AUC. 702, P=0.001; r=0.995, P=0.000). AUC/MIC125 of EMB in plasma and pleural effusion. The correlation of EMB concentration and AUC in pleural effusion and plasma was analyzed, and the results showed no correlation (r=0.411, P=0.072; r=-0.248, P=0.687).
Conclusion and discussion
The results showed that the concentration of plasma and pleural effusion in RFP was higher than the lowest bactericidal concentration. The permeability of RFP from plasma into the pleural cavity was low, and the AUC in the pleural effusion was higher. It might have a high binding rate with the RFP protein and made it accumulate in the pleural cavity. With the increase of the number of drug delivery, the Tmax decreased in the pleural effusion and Cmax connection. Near plasma steady state concentration is effective in treating non drug resistant tuberculous pleurisy and can inhibit the drug resistance of Mycobacterium tuberculosis.
The concentration of INH pleural effusion was higher than that of plasma, and the concentration of pleural effusion increased with the increase of plasma concentration, indicating that INH was faster and more absorbed by the pleura. The third day pleural effusion was equivalent to AUC and plasma AUC. With the increase of the number of drug delivery, it was speculated that the plasma and pleural effusion could reach steady state concentration, and there was no inclusion in the pleural effusion. Patients with pleural effusion do not need intrapleural administration of INH to achieve an effective therapeutic concentration. Therefore, INH is effective in treating tuberculous pleurisy and can inhibit bacterial resistance.
In most patients, the concentration of EMB pleural effusion and plasma is lower than the minimum inhibitory concentration, and the Tmax in the pleural effusion is obviously delayed, and the effect of AUC/MIC125 is very small. The dosage should be adjusted according to the monitoring concentration of EMB. While the effective treatment is achieved, the occurrence of its toxic and side effects is avoided as much as possible.
Therefore, RFP and INH are administered 1 times a day. The effective treatment concentration in the pleural effusion is achieved. INH does not need to be injected into the thoracic cavity. The concentration of RFP needs to be monitored in the long term, and the concentration of the liver is prevented from reducing the concentration of the liver drug enzyme induction. It is suggested that EMB adjust the dose according to the monitoring concentration.
RFP, INH and EMB are all concentration dependent antimicrobial agents. Comparing the permeability of three drugs in the pleural effusion, it is possible to speculate that the infiltration of RFP and INH in the pleural effusion may be different, which may be related to the polarity of the drug, the binding rate of protein, or the mesothelial barrier effect of the pleura, so that the permeability of the pleura of different drugs can be obtained. These mechanisms still need further study.

【學位授予單位】：南方醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2012
【分類號】：R521.7

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