本文選題：早產(chǎn)兒 + 動脈導(dǎo)管未閉�。� 參考：《山東大學(xué)》2014年博士論文

【摘要】：研究背景 1、動脈導(dǎo)管未閉的的發(fā)病率及發(fā)生機(jī)制 動脈導(dǎo)管未閉(PDA)是早產(chǎn)兒生后早期重要的并發(fā)癥之一。胎齡越小、出生體重越低越易發(fā)生。生后第4天,胎齡30周以上的早產(chǎn)兒有10%動脈導(dǎo)管仍持續(xù)開放,而胎齡小于30周的早產(chǎn)兒則可達(dá)65%。另有報道,胎齡低于28周的早產(chǎn)兒需藥物或手術(shù)治療PDA者約占60-70%。出生體重低于1500g的極低出生體重(VLBW)兒中,30%動脈導(dǎo)管持續(xù)開放。而出生體重低于1000g的超低出生體重(ELBW)兒和胎齡小于27周的極早產(chǎn)兒絕大多數(shù)在整個新生兒期動脈導(dǎo)管均持續(xù)開放,其中60%發(fā)生有癥狀性PDA,需藥物或手術(shù)治療。 動物實驗和臨床研究均表明PDA可增加早產(chǎn)兒的死亡率和嚴(yán)重并發(fā)癥的發(fā)生率。因此,對于早產(chǎn)兒,特別是VLBW兒和ELBW兒,絕大部分新生兒專家認(rèn)為,應(yīng)積極干預(yù)PDA以降低并發(fā)癥的發(fā)生率及嬰幼兒死亡率。 胎兒期動脈導(dǎo)管持續(xù)開放,聯(lián)結(jié)肺動脈與降主動脈。胎兒期動脈導(dǎo)管主要是由低氧和高前列腺素水平來維持開放的,前列腺素主要包括前列腺素E2(PGE2)和前列環(huán)素(PGl2)。足月兒生后氧分壓明顯上升,PGE2、PGI2水平明顯下降,導(dǎo)致動脈導(dǎo)管平滑肌細(xì)胞收縮,功能性關(guān)閉。而高氧誘發(fā)動脈導(dǎo)管關(guān)閉的重要通路之一即為內(nèi)皮素通路。高氧可導(dǎo)致由動脈導(dǎo)管產(chǎn)生的血管收縮物質(zhì)—內(nèi)皮素1(ET-1)釋放。但目前ET-1在動脈導(dǎo)管關(guān)閉中的具體作用尚有爭議。 2、動脈導(dǎo)管未閉的藥物治療 早產(chǎn)兒對高氧介導(dǎo)的動脈導(dǎo)管關(guān)閉通路不敏感。相對而言,早產(chǎn)兒對于PGE2、NO通路更為敏感。因此,早于1976年就有學(xué)者提出應(yīng)用非選擇性環(huán)氧化酶抑制劑,抑制前列腺素的產(chǎn)生,來提高早產(chǎn)兒PDA的關(guān)閉率。目前,靜脈用吲哚美辛已被公認(rèn)為藥物治療早產(chǎn)兒PDA的經(jīng)典方案。 吲哚美辛可顯著降低早產(chǎn)兒腎、腸系膜灌注及腦血流,可導(dǎo)致腎功損傷、少尿等不良反應(yīng)。近年來,布洛芬作為另一非選擇性環(huán)氧化酶抑制劑受到越來越多的重視。研究表明,靜脈用布洛芬治療早產(chǎn)兒PDA同樣有效,而且少尿、腎功損傷等不良反應(yīng)較吲哚美辛減少。但對于用藥的時間尚存在較大爭議。有學(xué)者認(rèn)為ELBW兒預(yù)防性應(yīng)用布洛芬PDA關(guān)閉率較高,且副作用無明顯增加。另外一些研究則顯示預(yù)防性應(yīng)用布洛芬可致腸穿孔等近期并發(fā)癥增加,且增加了不必要的藥物暴露。因此是否應(yīng)采用預(yù)防性應(yīng)用布洛芬需進(jìn)一步研究。 另外布洛芬靜脈制劑價格較貴,且目前國內(nèi)尚無布洛芬靜脈制劑,因此口服布洛芬成為一種可能的替代選擇。近年來陸續(xù)有關(guān)于口服布洛芬治療早產(chǎn)兒PDA的研究報道,但多數(shù)研究局限性較大,存在如樣本量較小,非雙盲研究,未作到隨機(jī)化等缺陷,所以目前大多數(shù)新生兒專家仍對口服布洛芬持否定態(tài)度。目前需要更多的研究來進(jìn)一步證實口服布洛芬的是否有效、是否安全。 3、動脈導(dǎo)管未閉的監(jiān)測 研究表明早產(chǎn)兒動脈導(dǎo)管有較高的自發(fā)性關(guān)閉率,因此有學(xué)者提出過度的干預(yù)可能增加不必要的藥物暴露率,主張僅給予限制液體等基礎(chǔ)治療,而不給予藥物干預(yù)。但是鑒于早產(chǎn)兒生后早期合并PDA可明確增加死亡率,因此,我們認(rèn)為,嚴(yán)格篩選病例,積極尋找預(yù)測PDA發(fā)生和發(fā)展的有效指標(biāo),顯然是更為穩(wěn)妥的方法。 心臟超聲作為PDA診斷的金標(biāo)準(zhǔn),具有不可替代的優(yōu)勢。多數(shù)研究認(rèn)為左室(LV)徑、左房主動脈根部直徑比(LA/AO)和動脈導(dǎo)管(DA)直徑可作為預(yù)測PDA是否需干預(yù)的指標(biāo)。不過,超聲診斷自身存在很大的局限性。因心臟超聲設(shè)備昂貴,且需專門技術(shù)人員操作,在國內(nèi)基層醫(yī)院很難做到對早產(chǎn)兒PDA的床頭超聲追蹤篩查。因此,將心臟超聲作為唯一預(yù)測和監(jiān)測治療反應(yīng)的指標(biāo),難度較大。臨床上迫切需要尋找一些相對簡便,且經(jīng)濟(jì)安全的指標(biāo)來作為替代。 近年來,有學(xué)者致力于研究能夠預(yù)測動脈導(dǎo)管發(fā)生及轉(zhuǎn)歸的生物學(xué)指標(biāo),其中較受關(guān)注的有B型鈉尿肽(BNP)、氨基末端B型鈉尿肽(NT-proBNP)、心房利鈉肽(ANP)等,但相應(yīng)的研究不多,且尚無明確的結(jié)論。 研究目的 1、探討預(yù)防性口服布洛芬治療早產(chǎn)兒PDA的有效性,及其療效是否優(yōu)于常規(guī)治療性口服。 2、監(jiān)測口服布洛芬后早產(chǎn)兒外周血中NT-proBNP、ET-1. PGE2的變化,尋找可用于預(yù)測PDA發(fā)生及監(jiān)測治療反應(yīng)的生物學(xué)指標(biāo)。 研究方法 設(shè)計前瞻性雙盲隨機(jī)對照試驗。2011年7月至12月,山東省立醫(yī)院新生兒科收治的胎齡小于36周的早產(chǎn)兒,共103人。隨機(jī)分為三組,預(yù)防性治療組于生后24小時內(nèi)口服第一劑布洛芬(10mg/kg),各間隔24小時后口服第二、三劑布洛芬(5mg/kg)。常規(guī)治療組于生后第3天行超聲檢查,證實存在PDA的患兒給予相同劑量的布洛芬口服。安慰劑組自生后24小時始口服等量的5%葡萄糖,間隔時間、療程與預(yù)防性治療組相同。生后24小時內(nèi)、第3天,第7天分別行心臟超聲檢查,并抽外周血查NT-proBNP、ET-1、PGE2水平及腎功、血常規(guī)、C反應(yīng)蛋白,并監(jiān)測有無不良反應(yīng)。 結(jié)果 1、三組患兒基本資料無顯著性差異(P0.05),生后24小時內(nèi)的超聲檢查指標(biāo)無顯著性差異(P0.05)； 2、預(yù)防性治療組較安慰劑組生后第7天動脈導(dǎo)管關(guān)閉率明顯增加,有顯著性差異(97.14%對78.38%,P0.05)。但與常規(guī)治療組相比,差異不顯著(97.14%與87.10%,P0.05)。而常規(guī)治療組與安慰劑組間相比關(guān)閉率亦明顯上升,但統(tǒng)計學(xué)上無顯著性差異(87.10%對78.38%,P0.05)。 3、三組間不良反應(yīng)統(tǒng)計學(xué)上無差異(P0.05)。 4、動脈導(dǎo)管自發(fā)性閉合的早產(chǎn)兒生后24小時內(nèi)的導(dǎo)管直徑明顯小于未自發(fā)性閉合者,兩者間差異明顯(0.11±0.06對0.19±0.06,P0.05)。 5、早產(chǎn)兒外周血NT-proBNP水平隨日齡增加而下降。生后第3天、第7天預(yù)防性治療組較安慰劑組明顯下降,有統(tǒng)計學(xué)差異(13.27±8.29對19.41±10.69,9.98±4.14對13.85±7.19,均P0.05)。 6、三組早產(chǎn)兒生后7天內(nèi)ET-1水平無明顯變化,三組間無差異。 7、動脈導(dǎo)管自發(fā)性閉合的早產(chǎn)兒生后24小時內(nèi)的ET-1水平低于未能自發(fā)性閉合者,兩者間差異明顯(16.74±6.50對20.65±4.61,P0.05)。 8、早產(chǎn)兒外周血中PGE2水平隨日齡增加而下降,但三組間無差異(P0.05)。 結(jié)論 1、預(yù)防性口服布洛芬可提高早產(chǎn)兒PDA的關(guān)閉率,且不良反應(yīng)未增加。 2、預(yù)防性口服布洛芬與常規(guī)治療性口服布洛芬相比,無明顯優(yōu)勢。 3、生后24小時內(nèi)的動脈導(dǎo)管直徑可作為預(yù)測早產(chǎn)兒PDA發(fā)生的指標(biāo)之一。 4、預(yù)防性口服布洛芬治療后NT-proBNP水平明顯下降,提示可作為觀察早產(chǎn)兒PDA治療后反應(yīng)的生物學(xué)指標(biāo),此為國內(nèi)外首次報道。 5、早產(chǎn)兒生后24小時內(nèi)的血漿ET-1水平,可作為有前途的預(yù)測PDA發(fā)生的生物學(xué)指標(biāo)之一。此為國內(nèi)外首次報道,需進(jìn)一步研究證實。
[Abstract]:Research background
1, the incidence and mechanism of patent ductus arteriosus
Patent ductus arteriosus (PDA) is one of the important early complications after birth in preterm infants. The smaller the gestational age and the lower the birth weight, the more likely it will occur. Fourth days after birth, 10% arterial ducts are still open in preterm infants over 30 weeks of gestational age, while preterm infants less than 30 weeks of gestational age can reach another report. Preterm infants whose gestational age is less than 28 weeks need drugs or surgery. In the treatment of PDA, the 30% arterial ductus arteriosus continued to open in the very low birth weight (VLBW) of the 60-70%. birth weight less than 1500g, while the majority of the ultra low birth weight (ELBW) and the gestational age of less than 27 weeks of gestational age were continuously open in the whole neonatal period, and 60% of them had symptomatic PDA. A physical or surgical treatment.
Both animal experiments and clinical studies have shown that PDA can increase the mortality of premature infants and the incidence of severe complications. Therefore, for preterm infants, especially VLBW and ELBW infants, the overwhelming majority of newborns believe that PDA should be actively intervened to reduce the incidence of complications and the death and death rate of infants.
The ductus arteriosus is open and connected with the pulmonary artery and the descending aorta. The fetal ductus arteriosus is maintained open mainly by hypoxia and high prostaglandin levels. Prostaglandins mainly include prostaglandin E2 (PGE2) and prostacyclin (PGl2). The oxygen partial pressure rises obviously after birth, and the level of PGE2 and PGI2 decreases significantly, leading to the catheterization of the ductus arteriosus. Smooth muscle cells constriction and functional closure. One of the important pathways that induces the closure of the ductus arteriosus by hyperoxia is the endothelin pathway. Hyperoxia can lead to the release of endothelin 1 (ET-1), a vasoconstrictor produced by the ductus arteriosus, but the specific role of ET-1 in the closure of the ductus arteriosus is still controversial.
2, drug treatment of patent ductus arteriosus
Premature infants are not sensitive to hyperoxic ductus arteriosus pathway. Relatively speaking, preterm infants are more sensitive to PGE2, NO pathway. Therefore, some scholars have proposed the application of non selective cyclooxygenase inhibitors in 1976 to inhibit the production of prostaglandins to improve the closure rate of PDA in premature infants. The classic drug for the treatment of PDA in premature infants.
Indomethacin can significantly reduce the renal, mesenteric perfusion and cerebral blood flow in preterm infants, which can lead to renal injury and oliguria. In recent years, ibuprofen has been paid more and more attention as another non selective cyclooxygenase inhibitor. The study shows that intravenous ibuprofen is also effective in the treatment of PDA in premature infants, and no urine, renal dysfunction, and so on. Good reaction is less than indomethacin, but there is still a lot of controversy over the time of drug use. Some scholars believe that the preventive use of ELBW PDA is high and side effects have not increased significantly. In other studies, some recent studies have shown that the prophylactic use of ELBW can cause an increase in recent complications such as intestinal perforation, and increases unnecessary drug exposure. Therefore, the preventive use of ibuprofen should be further studied.
In addition, ibuprofen intravenous preparation is more expensive and there are no ibuprofen intravenous preparations at present. Therefore, oral ibuprofen has become a possible alternative. In recent years, there has been a research report on the treatment of PDA in premature infants with oral ibuprofen, but most of the studies are limited, such as small sample size, non double blind study, and not random. So far, most newborn experts still have a negative attitude to oral ibuprofen. More research is needed to confirm whether oral ibuprofen is effective and safe.
3, the monitoring of patent ductus arteriosus
Studies have shown a high spontaneous closure rate for the ductus arteriosus in premature infants. Therefore, some scholars suggest that excessive intervention may increase the exposure rate of unnecessary drugs, advocating only limiting liquid and other basic treatments without drug intervention. However, we believe that the early postnatal birth with PDA can increase the mortality rate clearly, so we think, strict It is obviously a safer way to screen cases and actively seek effective indicators to predict the occurrence and development of PDA.
Cardiac ultrasound has an irreplaceable advantage as the gold standard for PDA diagnosis. Most studies suggest that the diameter of the left ventricle (LV), the diameter ratio of the left atrial aorta (LA/AO) and the diameter of the patent ductus arteriosus (DA) can be used as an indicator of whether the PDA should be intervened. However, the ultrasonic diagnosis itself is very limited. It is difficult to perform the bedside ultrasound tracking screening for preterm PDA in the domestic primary hospitals. Therefore, it is difficult to use the heart ultrasound as the only indicator to predict and monitor the response of the treatment. It is urgent to find some relatively simple and economic safety indicators as a substitute.
In recent years, some scholars have been devoted to the study of biological indicators that can predict the occurrence and prognosis of ductus arteriosus, including B type natriuretic peptide (BNP), amino terminal B natriuretic peptide (NT-proBNP), and atrial natriuretic peptide (ANP), but there is not much research and no clear conclusion.
research objective
1, to investigate the efficacy of prophylactic oral ibuprofen in the treatment of PDA in preterm infants and whether the efficacy is better than that of conventional oral therapy.
2, monitor the changes of NT-proBNP and ET-1. PGE2 in peripheral blood of preterm infants after oral ibuprofen, and find out biological indicators that can be used to predict PDA occurrence and monitor therapeutic response.
research method
We designed a prospective double blind randomized controlled trial from July to December.2011 to December. A total of 103 children were admitted to the Department of Pediatrics of Shangdong Province-owned Hospital for a total of less than 36 weeks. They were randomly divided into three groups. The preventive treatment group took the first dose of Bloven (10mg/kg) within 24 hours after birth, and second, third doses of oral administration 24 hours after each interval. The group was examined by ultrasound at third days after birth. The same dose of ibuprofen was given to the children with the same dose of PDA. The placebo group was given an equal amount of 5% glucose at 24 hours after birth. The interval was the same as that of the preventive treatment group. The cardiac ultrasound examination was performed within 24 hours, third days, seventh days after birth, and the peripheral blood was examined for NT-proBNP, ET-1, and PGE. 2 level and renal function, blood routine, C reactive protein, and monitor whether there was any adverse reaction.
Result
1, there was no significant difference in the basic data between the three groups (P0.05), and there was no significant difference in ultrasonic examination within 24 hours after birth (P0.05).
2, there was a significant increase in the closure rate of the arterial ductus arteriosus in the prophylactic group seventh days after the birth of the placebo group (97.14% to 78.38%, P0.05). However, the difference was not significant (97.14% and 87.10%, P0.05) compared with the conventional treatment group, but the rate of closure was also significantly higher in the routine treatment group than in the placebo group, but there was no significant difference in Statistics (87.10%) For 78.38%, P0.05).
3, there was no statistically significant difference in adverse reactions between the three groups (P0.05).
4, the diameter of the catheter within 24 hours after the spontaneous closure of the patent ductus arteriosus was significantly smaller than that of the non spontaneous closure (0.11 + 0.06 to 0.19 + 0.06, P0.05).
5, the level of NT-proBNP in the peripheral blood of preterm infants decreased with the increase of age. The third day after birth and the seventh day prophylactic treatment group were significantly lower than those in the placebo group (13.27 + 8.29 pairs of 19.41 + 10.69,9.98 + 4.14 pairs 13.85 + 7.19, all P0.05).
6, there was no significant change in the level of ET-1 in the three groups of premature infants within 7 days after birth, and there was no difference between the three groups.
7, the level of ET-1 in the spontaneous closure of the patent ductus arteriosus was lower within 24 hours after the birth of the patent ductus arteriosus than those in the non spontaneous closure (16.74 + 6.50 to 20.65 + 4.61, P0.05).
8, the level of PGE2 in the peripheral blood of preterm infants decreased with the increase of age, but there was no difference between the three groups (P0.05).
conclusion
1, prophylactic oral ibuprofen can improve the closure rate of PDA in premature infants, and the side effects are not increased.
2, prophylactic oral ibuprofen has no obvious advantage compared with conventional oral ibuprofen.
3, ductus arteriosus diameter within 24 hours after birth can be used as a predictor of PDA in preterm infants.
4, the level of NT-proBNP in the prophylactic oral ibuprofen treatment was significantly decreased, suggesting that it could be used as a biological index to observe the response of preterm infants after PDA treatment. This is the first report at home and abroad.
5, the level of plasma ET-1 within 24 hours after birth is one of the promising biological indicators for predicting the occurrence of PDA. This is the first report at home and abroad and needs further research.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R722.6

【共引文獻(xiàn)】

中國期刊全文數(shù)據(jù)庫 前10條

1 張慎榮;張園海;徐強(qiáng);仇慧仙;陳其;;腦鈉肽和氨基末端腦鈉肽在小兒先天性心臟病心功能評估中的價值[J];中國當(dāng)代兒科雜志;2009年06期

2 Maria Emília Guimar嗾es Areias;Catarina I.Pinto;Patrícia F.Vieira;Flávio Teixeira;Rosália Coelho;Isabela Freitas;Samantha Matos;Marta Castro;Sofia Sarmento;Victor Viana;Jorge Quintas;José C.Areias;;青少年和年輕成人先天性心臟病的心理社會遠(yuǎn)期轉(zhuǎn)歸[J];中國當(dāng)代兒科雜志;2013年10期

3 徐君;林怡翔;顧若漪;王慧君;馬曉靜;馬端;黃國英;;法洛四聯(lián)癥患兒組蛋白乙�；捌涿傅谋磉_(dá)[J];中國當(dāng)代兒科雜志;2013年10期

4 穆世茵;張宏艷;;胰島因子1基因2個SNP位點(diǎn)與兒童先天性心臟病的相關(guān)性研究[J];中國當(dāng)代兒科雜志;2013年10期

5 錢鷺葵;呂國榮;陳文龍;;實時三維時空關(guān)聯(lián)成像技術(shù)對20孕周前胎兒心臟畸形的診斷價值[J];臨床醫(yī)學(xué);2013年09期

6 黎新艷;田曉先;林蓮恩;李雪芹;周旋;黃歡;劉萍萍;;四維時空關(guān)聯(lián)成像技術(shù)在中晚孕胎兒心臟篩查中的應(yīng)用[J];廣西醫(yī)學(xué);2013年12期

7 朱沈華;吳柱中;莊洪濤;;海寧市0～12月活產(chǎn)嬰兒先天性心臟病患病調(diào)查分析[J];中國兒童保健雜志;2014年02期

8 韓莉;肖憲杰;旅朝霞;郭然;;動脈導(dǎo)管未閉封堵術(shù)后即刻血壓變化研究[J];大連醫(yī)科大學(xué)學(xué)報;2014年02期

9 麥瑞芝;房曉yN;;小兒動脈導(dǎo)管未閉的藥物治療進(jìn)展[J];發(fā)育醫(yī)學(xué)電子雜志;2013年04期

10 張樂;孫美平;高衛(wèi)線;洪世欣;張亞黎;;縣、鄉(xiāng)級超聲醫(yī)生開展胎兒期復(fù)雜先天性心臟病超聲篩查的可行性研究[J];北京大學(xué)學(xué)報(醫(yī)學(xué)版);2014年03期

中國博士學(xué)位論文全文數(shù)據(jù)庫 前10條

1 王恩世;第二生心區(qū)發(fā)育相關(guān)基因變異在右心發(fā)育不良綜合征發(fā)生中的作用[D];北京協(xié)和醫(yī)學(xué)院;2013年

2 龔立;肺動脈閉鎖遺傳學(xué)初步研究[D];華中科技大學(xué);2013年

3 李倩;蘋果寡糖的制備、結(jié)構(gòu)鑒定與抗腫瘤活性研究[D];第四軍醫(yī)大學(xué);2013年

4 丁金立;心血管手術(shù)規(guī)劃的血流動力學(xué)數(shù)值研究[D];北京工業(yè)大學(xué);2013年

5 羅成;先天性心臟病伴肢體畸形相關(guān)基因突變分析和拷貝數(shù)變異研究[D];中南大學(xué);2012年

6 易偉;大鼠AOC3基因在重癥失血性休克及復(fù)蘇中的表達(dá)與功能[D];第二軍醫(yī)大學(xué);2013年

7 駱志玲;胰島素信號轉(zhuǎn)導(dǎo)異常與先天性心臟病的相關(guān)性研究[D];昆明醫(yī)科大學(xué);2014年

8 周新剛;心臟缺陷少見于攜帶包括GATA4在內(nèi)的8p23.1基因組重復(fù)的患者[D];哈爾濱醫(yī)科大學(xué);2012年

9 趙趣鳴;中國新生兒先天性心臟病篩查體系的建立與應(yīng)用研究[D];復(fù)旦大學(xué);2013年

10 陳偉呈;合并內(nèi)臟異位的先心病患者術(shù)后死亡率和呼吸道并發(fā)癥及其與呼吸道纖毛功能障礙關(guān)系的研究[D];復(fù)旦大學(xué);2013年

中國碩士學(xué)位論文全文數(shù)據(jù)庫 前10條

1 王珍珍;血清NTpro-BNP、cTNI及IMA對急性百草枯中毒心肌損傷的診斷價值及預(yù)后評估[D];鄭州大學(xué);2011年

2 惠迎春;腦鈉肽及氮端腦鈉肽對新生兒敗血癥心肌損傷的診斷價值[D];蘭州大學(xué);2009年

3 楊璐;先天性心臟病患兒圍術(shù)期血漿氮末端腦鈉肽前體濃度的變化及意義[D];重慶醫(yī)科大學(xué);2009年

4 張茜;N-末端腦利鈉肽與內(nèi)皮素在左、右心功能不全患者中水平的比較[D];中南大學(xué);2009年

5 陳會強(qiáng);人抗鼠抗體（HAMAs）干擾導(dǎo)致BNP假陽性一例[D];浙江大學(xué);2010年

6 李彥曉;AHA推薦的實驗室指標(biāo)在診斷不完全川崎病中的臨床意義[D];鄭州大學(xué);2012年

7 李敏;嚴(yán)重膿毒癥患兒各臟器功能評估及NT-Pro BNP對其早期心血管功能評估的價值[D];山東大學(xué);2012年

8 黨丹;對乙酰氨基酚與布洛芬治療早產(chǎn)兒PDA的隨機(jī)對照試驗[D];吉林大學(xué);2013年

9 王忠德;淄博市2000～2011年5歲以下兒童死亡狀況研究[D];山東大學(xué);2013年

10 匙瑩;辛伐他汀對人牙髓細(xì)胞增殖及堿性磷酸酶活性的影響[D];河北醫(yī)科大學(xué);2013年

，

本文編號：1971413