本文選題：內(nèi)耳 + 給藥方式　； 參考：《山東大學》2016年博士論文

【摘要】：第一部分經(jīng)耳后注射地塞米松靶向內(nèi)耳給藥作用途徑的初步研究目的耳后給藥是一種簡單易行、效果可靠的治療內(nèi)耳疾病的給藥方式。耳后注射糖皮質(zhì)激素在治療低頻感音神經(jīng)性聾、突發(fā)性耳聾等方面取得良好的臨床效果。動物實驗也證實耳后給藥在內(nèi)耳的藥物濃度較肌肉注射高,而且維持時間長。然而,耳后注射藥物進入內(nèi)耳的途徑尚不清楚。本研究就耳后注射地塞米松后藥物在局部的分布進行觀察,對藥物進入內(nèi)耳的可能途徑進行初步探討。方法1.用磺酸基-Cy5羧酸標記地塞米松。2.豚鼠隨機分為兩組：耳后注射組和肌肉注射組。3.Cy5-地塞米松0.5ml進行右耳后和右臀大肌注射,用動物體內(nèi)可見光成像連續(xù)觀察120h,評估藥物局部代謝的動態(tài)變化。4.Cy5-地塞米松0.5ml進行右耳后和右臀大肌注射,在注射后8h斷頭處死動物,用動物體內(nèi)可見光成像觀察熒光標記的藥物在頭顱、顳骨、臟器的分布。5.Cy5-地塞米松0.5ml進行右耳后和右臀大肌注射,每天一次,連續(xù)三天,在第四天斷頭處死動物,將鼓膜、中耳粘膜、內(nèi)淋巴囊、耳蝸基底膜等組織鋪片,用共聚焦顯微鏡觀察熒光標記的藥物在組織的精確分布。結果1.藥物局部代謝：耳后注射和肌肉注射后藥物在局部濃集,而后向四周擴散。耳后注射和肌肉注射分別在注射后12h和8h藥物在局部達到峰值,且肌肉注射藥物峰值更高,而后藥物熒光逐漸下降。相比肌肉注射,耳后注射藥物熒光下降緩慢,注射后96h,耳后注射仍然有較強熒光,而肌肉注射已經(jīng)檢測不到藥物熒光。耳后注射藥物代謝曲線下面積大于肌肉注射,差異具有統(tǒng)計學意義(P0.05)。2.藥物在頭顱、臟器的分布：耳后注射組頭皮、頂骨、顳骨的熒光強度均高于肌肉注射組,差異具有顯著統(tǒng)計學意義(均P0.01)。耳后注射組心臟、膀胱的熒光強度均低于肌肉注射組,差異具有顯著統(tǒng)計學意義(P0.01)。3.藥物在中耳粘膜、鼓膜、內(nèi)淋巴囊、耳蝸基底膜的分布：耳后注射組鼓膜、中耳粘膜、內(nèi)淋巴囊、耳蝸基底膜的熒光強度均高于肌肉注射組,差異具有統(tǒng)計學意義(均P0.05)。耳后注射在同側耳蝸基底膜的藥物分布以底轉熒光最強,中轉次之,頂轉只能檢測到微弱的熒光。結論耳后注射有明顯的緩釋效應,在局部保持高藥物濃度的同時,減少了藥物在全身臟器的分布。與肌肉注射相比,耳后注射藥物在內(nèi)耳的濃度更高。耳后注射后藥物可能經(jīng)內(nèi)淋巴囊途徑、局部擴散滲透途徑、體循環(huán)途徑和莖乳動脈途徑進入內(nèi)耳。第二部分糖皮質(zhì)激素耳后注射與全身用藥在低頻突發(fā)性聾中的療效目的分析低頻下降型突發(fā)性聾的臨床特點,探討甲潑尼龍琥珀酸鈉耳后注射與地塞米松全身用藥,在低頻下降型突發(fā)性聾中的療效。方法1.對低頻下降型突發(fā)性聾的臨床資料進行統(tǒng)計分析,對其臨床特點進行觀察。2.將低頻下降型突發(fā)性聾患者隨機分為2組,全身治療組和耳后注射組。除常規(guī)治療(金納多、巴曲梅、甲鈷胺)外,全身激素治療組：地塞米松10mg靜推,1次/d×3d,續(xù)5mg靜推,1次/d×4d；耳后注射治療組：甲潑尼龍琥珀酸鈉40mg耳后注射,1次/2d,至聽力恢復正�；�15天。治療前,治療后4d(治療當天為治療后Id)、7d、10d、14d、30d、60d行純音測聽檢查,分析聽閾的變化情況。3.應用SPSS18.0軟件進行統(tǒng)計分析,總有效率包括痊愈率、顯效率和有效率。各組間總有效率和痊愈率的比較均采用x2檢驗,P0.05為差異具有統(tǒng)計學意義。結果1.臨床資料低頻下降型突發(fā)性聾患者102例,其中男43例,女59例,男女比例1：1.37。平均年齡(42±21.38)；病程(9.23±6.05)；首發(fā)癥狀依次為耳鳴93例(91.18%)、耳悶89例(87.25%)、聽力下降77例(75.49%)、眩暈14例(13.73%)。2.純音聽閾療效對比全身激素治療：48例采用全身激素治療的患者,痊愈19例(39.6%),顯效11例(23.0%),有效7例(14.6%),無效11例(13.0%),總有效率為77.1%(37/48)。耳后注射治療：54例采用耳后注射激素治療的患者,痊愈33例(61.1%),顯效7例(13.0%),有效5例(9.3%),無效9例(16.7%),總有效率為83.3%(45/54)。對兩組患者的不同療效結果進行兩兩比較,痊愈率的組間差異具有統(tǒng)計學意義(x 2=4.71,P0.05),余各療效組間差異無顯著性意義(均P0.05)。3.血壓、血糖變化102例患者中伴原發(fā)性高血壓病19例(18.6%),全身激素治療組8例,耳后注射治療組11例,治療期間全身激素治療組血壓均有不同程度的升高,而耳后注射治療組血壓升高不明顯,只有1例血壓升高至100/150mmHg。本研究中伴有2型糖尿病者13例(12.8%),全身激素治療組4例,耳后注射治療組9例,治療期間全身激素治療組血糖升高1.5～5mmoL/L,9例耳后注射治療者血糖升高1.0～2.0mmoL/L。4.聽力隨訪隨訪期內(nèi)13例患者出現(xiàn)復發(fā),其中耳后給藥治療組復發(fā)5例,全身給藥治療組復發(fā)8例,總復發(fā)率12.74%,平均聽閾提高15-35dB。復發(fā)者中所有患者都有耳悶癥狀,6例伴有眩暈。6例伴有眩暈患者中有2例出現(xiàn)聽力下降、眩暈反復發(fā)作,最終確診為梅尼埃病。復發(fā)患者全部采用耳后注射激素治療,痊愈4例、顯效1例、有效3例、無效5例,再次耳后給藥的總有效率為61.5%。結論低頻下降型突發(fā)性聾發(fā)病以年輕女性多見,臨床表現(xiàn)為耳鳴、聽力下降、耳悶、眩暈等,在臨床工作中應與咽鼓管疾病相鑒別。低頻下降型突發(fā)性聾臨床治愈率高,但復發(fā)率亦高,伴有眩暈的患者有發(fā)展為梅尼埃病的可能。耳后注射甲潑尼龍琥珀酸鈉治療低頻下降型突發(fā)性聾痊愈率較全身用藥高,操作簡單,建議將其作為低頻下降型突發(fā)性聾的初始治療。耳后注射甲潑尼龍琥珀酸鈉對全身血壓、血糖等情況影響小,特別適用于高血壓、糖尿病患者。
[Abstract]:The first part of the first part of the ear injection of dexamethasone to the inner ear of the inner ear: a simple, reliable and effective way to treat the inner ear diseases. The post ear injection of glucocorticoid in the treatment of low frequency sensorineural deafness and sudden deafness has achieved good clinical effects. It is also confirmed that the drug concentration in the inner ear is higher than that of the intramuscular injection and maintains a long time. However, the way to enter the inner ear after the ear injection is not clear. In this study, the local distribution of the drugs after the post ear injection of dexamethasone was observed and the possible way to enter the inner ear was preliminarily discussed. Method 1. using sulfonic -Cy 5 carboxylic acid labelled dexamethasone.2. guinea pigs were randomly divided into two groups: Post ear injection group and intramuscular injection group.3.Cy5- dexamethasone 0.5ml was injected into right ear and right gluteal muscle. 120h was observed continuously with visible light imaging in animal body, and the dynamic changes of local metabolism of.4.Cy5- were evaluated by.4.Cy5- dexamethasone 0.5ml after right ear and right gluteal muscle injection. The animals were killed after the injection of 8h, and the visible light imaging of the animals was used to observe the fluorescence labeled drugs in the head, the temporal bone and the organs of.5.Cy5- 0.5ml, after the right ear and right gluteal muscle injection, once a day for three days, the animals were sacrificed on the fourth day, the tympanic membrane, the middle ear mucosa, the endolymphatic sac, the cochlear basement membrane and other tissues. With a confocal microscope, a confocal microscope was used to observe the accurate distribution of the fluorescent drug in the tissue. Results 1. local metabolism of drugs: after the ear injection and after the intramuscular injection, the drug was partially concentrated and then spread around. After the injection and the intramuscular injection, the 12h and 8h drugs reached the peak at the local level, and the peak value of the intramuscular injection drugs was higher. The fluorescence of the drug decreased gradually. Compared with the intramuscular injection, the drug fluorescence decreased slowly after the ear injection. After the injection, 96h, the post ear injection still had a strong fluorescence, but the muscle injection had not been detected. The area of the post ear injection drug metabolism curve was larger than the intramuscular injection, the difference was statistically significant (P0.05).2. drugs in the skull and viscera. The fluorescence intensity of the scalp, parietal bone and temporal bone in the post ear injection group was higher than that in the intramuscular injection group. The difference had significant statistical significance (all P0.01). The fluorescence intensity of the posterior injection group was lower than that of the intramuscular injection group. The difference had significant statistical significance (P0.01) in the middle ear mucosa, the tympanic membrane, the endolymphatic sac and the cochlear basement membrane (P0.01). The fluorescence intensity of the tympanic membrane, the middle ear mucosa, the endolymphatic sac and the basilar membrane of the cochlea were higher than that in the intramuscular injection group, and the difference was statistically significant (P0.05). The distribution of the drugs in the basilar membrane of the cochlea was the strongest in the same side of the cochlear basement membrane. Compared with the intramuscular injection, the concentration of the drug in the inner ear is higher than that of the intramuscular injection. After the ear injection, the drug may pass through the endolymphatic sac pathway, the local diffusion permeation pathway, the body circulation pathway and the stem mammary artery pathway into the inner ear. Second The clinical characteristics of low frequency descending sudden deafness by posterior injection of glucocorticoid and general medication in low frequency sudden deafness, the clinical characteristics of low frequency descending sudden deafness were analyzed. The therapeutic effect of methylprednisolone sodium succinate injection and dexamethasone in the low frequency descending sudden deafness was discussed. The clinical data of Fang method 1. for low frequency descending sudden deafness The clinical characteristics of.2. were randomly divided into 2 groups, the whole body treatment group and the post ear injection group. Except for the routine treatment (Ginaton, batroxobin, Mecobalamin), the whole body hormone treatment group: Dexamethasone 10mg static push, 1 /d * 3D, 1 /d * 4D, and 1 /d x 4D; Methylprednisolone sodium succinate 40mg after ear injection, 1 /2d, to normal hearing or 15 days. Before treatment, after treatment, 4D (after treatment Id after treatment), 7d, 10d, 14d, 30d, 60d pure tone audiometry, analysis of hearing threshold changes of.3. application SPSS18.0 software for statistical analysis, the total effective rate including recovery, significant efficiency and efficiency. The total efficiency and recovery rate were compared by x2 test, and the difference of P0.05 was statistically significant. Results there were 102 cases of low frequency descending sudden deafness in 1. clinical data, including 43 males and 59 females, and the average age of 1:1.37. (42 + 21.38) in male and female ratio (42 + 21.38); the first symptoms were tinnitus 93 (91.18%) and 89 (87.25%) in the first symptom. 77 cases (75.49%) of hearing loss, 14 cases of vertigo (13.73%).2. pure tone hearing threshold effect compared with the whole body hormone therapy: 48 cases with total body hormone treatment, 19 cases (39.6%), 11 cases (23%), 7 cases (14.6%), invalid 11 cases (13%), total effective rate (37/48). After ear injection therapy: patients who were treated with post ear injection of hormone therapy There were 33 cases (61.1%), 7 cases (13%), 5 cases (9.3%), 9 cases (16.7%), and the total effective rate was 83.3% (45/54). The difference of recovery rate between groups of two groups was statistically significant (x 2=4.71, P0.05). There was no significant difference between the other groups (P0.05).3. blood pressure and blood glucose change 102. There were 19 cases of primary hypertension (18.6%), 8 cases in the whole body hormone treatment group and 11 cases in the post ear injection group. The blood pressure in the whole body hormone treatment group was elevated in different degrees during the treatment, but the blood pressure in the post ear injection group was not significantly elevated. Only 1 cases of blood pressure increased to 100/150mmHg. in 13 cases with type 2 diabetes mellitus (12.8%). There were 4 cases in the whole body hormone treatment group and 9 cases in the post ear injection group. The blood sugar increased by 1.5 ~ 5mmoL/L in the whole body hormone treatment group during the treatment. 13 cases had recurrence during the follow-up period of 1 ~ 2.0mmoL/L.4. hearing follow up period of 9 cases of ear injection treatment. Among them, 5 cases were relapsed in the post ear administration group and 8 cases relapsed in the whole body treatment group, the total recurrence rate was 12.. 74%, all of the patients with 15-35dB. recurrence had ear symptoms. 6 cases with vertigo were accompanied by vertigo, 2 had hearing loss, vertigo occurred repeatedly, and the final diagnosis was Meniere's disease. All the recurrent patients were treated with post ear injection of hormone, 4 cases were cured, 1 cases were markedly effective, 3 cases were effective, 5 cases were invalid, and the drug after the second ear was given again. The total effective rate is 61.5%. conclusion the incidence of low frequency descending sudden deafness is more common in young women. The clinical manifestation is tinnitus, hearing loss, ear boredom and vertigo. In clinical work, it should be identified with eustachian tube disease. The clinical cure rate of low frequency descending sudden deafness is high, but the recurrence rate is high, and the patients with vertigo are developed to Meniere's disease. It is possible that the recovery rate of posterior injection of methylprednisolone in the treatment of low frequency descending sudden deafness is higher than that of the whole body, and it is simple to use as the initial treatment of low frequency descending sudden deafness. The posterior injection of methylprednisolone sodium succinate to the whole body blood pressure, blood sugar and so on is small, especially suitable for hypertension and diabetic patients.
【學位授予單位】：山東大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R764.3

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