以Ibuprofen及Indomethacin治療極低體重早產兒開放性動脈導管之療效與安全性之比較兼論先天性顏面發育異常新生兒之TCOF1基因之突變及多型性分析

Comparison of ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants Mutations and new polymorphic changes in the TCOF1 gene of patients with oculoauriculovertebral spectrum and Treacher Collins syndrome

蘇本華(Pen-Hua Su)

指導教授 ： 陳家玉

中山醫學大學/醫學院/醫學研究所/博士(2007年)

https://doi.org/10.6834/CSMU.2007.00112

摘要

Ⅰ：
背景
開放性動脈導管在極低體重早產兒中是一種極常見的疾病，而呼吸窘迫症的存在，則會更加重開放性動脈導管的嚴重度，因此如何治療早產兒之開放性動脈導管是新生兒科相當重要的課題。自從西元1976年，從靜脈給予indomethacin的方式已被使用在治療與預防早產兒之開放性動脈導管，但是使用indomethacin的安全性—特別是對於早產兒腎臟、腸胃道及腦血流之影響，令人擔憂；而使用靜脈給予ibuprofen，則也在近年來開始被使用在治療及預防早產兒開放性動脈導管，這個方法被發現對早產兒之腦血流、腸胃道及腎臟影響較小。因此本研究之目的在比較極低體重早產兒早期使用靜脈給予indomethacin及ibuprofen的療效及安全性。
方法
收集63位患有呼吸窘迫症之早產兒，他們的體重均小於或等於1500公克且妊娠周數均小於或等於32週，所有的病人均為使用持續性經鼻正壓呼吸器，或是使用機械式呼吸器，供應氧氣濃度大於30%。病人的血小板計數均大於10萬/μL，血清中Creatinine濃度均小於1.5mg/dL，腦部均無嚴重腦室內出血，且均於出生2到7天內接受彩色心臟超音波發現，有顯著的開放性動脈導管。病人經隨機分派為二組，A組使用靜脈給予ibuprofen三劑，(負荷劑量10mg/kg，之後隔24小時及48小時給5 mg/kg)，B組使用靜脈給予indomethacin三劑，(每隔12小時給0.2mg/kg)。
結果
1. A組(ibuprofen group)有27位(84.4%)關閉開放性動脈導管，B組(indomethacin group)有25位(80.6%)關閉開放性動脈導管。
2. 各組均有三位患者發生關閉之動脈導管重新開放，其中A組(ibuprofen group)有一位需接受ligation手術，B組(indomethacin group)有二位需接受ligation手術。
3. Ibuprofen組較indomethacin組血清中之Creatinine和BUN較低，有顯著差異。
4. Ibuprofen組較indomethacin組之尿液輸出量及Creatinine廓清率較高，有顯著差異。
結論
1. Ibuprofen的療效與indomethacin 一致。
2. 以ibuprofen治療之早產兒有較高的尿液輸出量及Creatinine廓清率和較低的血清中Creatinine和BUN。

Ⅱ：
我們在臨床上，常接觸到一些顱顏異常的新生兒，有單獨的顏面異常，我們則傾向以單一異常表現來命名，例如hemifacial microsomia、microtia等等；亦有另外比較複雜的病例，他們的臨床症狀有部分相同，也有部分相異，因此傳統上，我們傾向接受以臨床症狀來分析並歸類其為何種症候群，例如Treacher Collins 症候群、Oculo-auriculo-vertebral spectrumu眼、耳、脊椎症候群等等。Treacher Collins症候群在臨床表現上有明顯的雙側顱顏畸型；眼耳脊椎症候群，則是有單側顱顏構造異常合併脊椎發育異常，其發生之原因及機制目前尚未明瞭。本研究認為，臨床表現不同而被命名為不同的症候群，其基因層次有可能是相同基因的不同突變造成蛋白破壞嚴重度的差別，而使得表現型有極大的差異。因此我們利用Treacher Collins 症候群(TCS)的相關基因—TCOF1，來進行顱顏異常病人與其家屬及51個正常人的基因分析，結果發現完全型OAVS患者在exon 9處發生一個錯意突變，在exon 10及23處各發生一個靜默突變。而三個不完全型OAVS患者，則未發現突變點。一個TCS患者在exon 14處發現一個無意義突變，而另一個TCS患者在exon 22處發現一段架構移改。且共有4個未被報告之多型性變異，分別被發現在exon 9、17及22的地方。我們認為TCS是因為TCOF1基因產生突變造成終止密碼(stop codons)，而使轉譯提早停止。結果造成基因劑量不足或是負顯性效果而產生TCS之臨床表現。而OAVS可能是TCOF1基因之突變造成蛋白質的改變未如TCS那麼嚴重，因此臨床表現較輕微[Hedera 2002]。這樣的觀念可提供眼耳脊椎症候群的基因層次探討及臨床判斷的準則。

關鍵字

開放性動脈導管 ； Ibuprofen ； Indomethacin ； 鰓弓發育 ； 眼耳脊椎症候群 ； Treacher-Collins 症候群 ； TCOF1 基因

並列摘要

PartⅠ：
Background
Patent ductus arteriosus (PDA) is commonly found in very low-birthweight (VLBW) infants. The presence of respiratory distress syndrome (RDS) is also associated with increased frequency of significant PDA. Intravenous indomethacin has been used to treat and to prevent PDA in premature infants since 1976. However, concern remains regarding the safety of indomethacin, which affects renal, gastrointestinal and cerebral perfusion. Intravenous ibuprofen has recently been used to treat and to prevent PDA premature infants with PDA without reducing cerebral blood flow or affecting intestinal or renal hemodynamics. The aim of the present study is to compare intravenous ibuprofen and indomethacin with regard to efficacy and safety for the early treatment of PDA in preterm infants.
Methods
A total of 63 preterm infants with RDS who had a birthweight of ≦
1500 g and gestational age of ≦ 32 weeks, were enrolled in the present study. All patients were treated with nasal continuous positive airway pressure with additional oxygen supply in inspired air ≧30%, or with mechanical ventilation. The patients’
serum platelet counts were ≧100 000/uL, and serum creatinine values were ≦1.5 mg/dL. There were no grade 3-4 intraventricular hemorrhages before randomization, and all patients were aged 2-7 days and had echocardiographic evidence of significant PDA. Patients were randomized into two groups: the first group of neonates (group A, n = 32) received intravenous ibuprofen lysine 10 mg/kg, followed by 5 mg/kg after 24 and 48 h; the second group (group B, n = 31) received intravenous indomethacin 0.2 mg/kg every 12 h for three doses.
Results
Patent ductus arteriosus closed in 27 patients from the ibuprofen group (84.4%) and in 25 patients from the indomethacin group (80.6%). PDA reopened in three patients from the ibuprofen group (9.4%) and in three patients from the indomethacin group (9.7%). One patient in the ibuprofen group and two patients in the indomethacin group required ductal ligation. Serum creatinine and blood urea nitrogen (BUN) concentrations were lower in the ibuprofen group than in the indomethacin group. Urine output and creatinine clearance values were higher in the ibuprofen group than in the indomethacin group.
Conclusions
Ibuprofen therapy is as efficacious as indomethacin for the treatment of PDA in preterm infants. Infants treated with ibuprofen have higher creatinine clearance learance and urine output and lower serum creatinine and BUN values than infants treated with indomethacin.

PartⅡ：
Oculo-auriculo-vertebral spectrum (OAVS), the exact genetic predisposition of which has not yet been resolved, is characterized by varying degrees of the prevalently unilateral underdevelopment of craniofacial structures and spinal anomalies. Here, we analyzed four cases exhibiting multiple features of OAVS and two case with Treacher-Collins syndrome (TCS). The cranium was analyzed using three-dimensional computed tomography (3DCT), which reliably identifies craniofacial malformations. We detected one typical OAVS subject who had a missense mutation in exon 9 of the TCOF1 gene complex and two silent mutations in exons 10 and 23, three partial OAVS subjects who had no detectable mutations in the TCOF1 gene complex, and one TCS subject who had a nonsense mutation in exon 14, another TCS subject had a frameshift mutation in exon 22. All six subjects had eight previously reported polymorphic changes in the TCOF1 exons 10, 11, 12, 16, 21, 22, and 23, and four unreported polymorphisms in exons 9, 17, and 22 that were also detected in 51 Taiwanese control subjects. These observations strongly suggest that the TCOF1 genetic changes observed in the six subjects studied herein might be related to OAVS symptoms.

並列關鍵字

patent ductus arteriosus ； ibuprofen ； indomethacin ； branchial-arch development ； TCOF1 gene

參考文獻

Perez CA, Bustorf-Silva JM, Villasenor E, Fonkalsrud EW, Atkinson JB. Surgical ligation of patent ductus arteriosus in very low birth weight infants：Is it safe？Am Surg 1998；64：1007-9.

Anonymous. An international classification of retinopathy of prematurity. Pediatrics 1984；74：127-33.

Bell EF, Warburton D, Stonestreet BS, Oh W. Effect of fluid administration on the development of symptomatic patent ductus arteriosus and congestive heart failure in premature infants, N Engl J Med 1978；302：598-655.

Carolis MPD, Romagnoli C, Polimeni V, Piersigilli F, Zecca E, Papacci P, et al. Prophylactic ibuprofen therapy of patent ductus arteriosus in preterm infants. Eur J Pediatr 2000；159：364-8.

Chemtob S, Beharry K, Rex J, Varma DR, Aranda JV. Prostanoids determine the range of cerebral blood flow autoregulation of newborn piglets. Stroke 1990；21：777-84.