耳后注射糖皮质激素治疗内耳疾病的实验研究

发布时间：2018-07-08 16:59

本文选题：内耳 + 给药方式　；参考：《山东大学》2016年博士论文

【摘要】：第一部分经耳后注射地塞米松靶向内耳给药作用途径的初步研究目的耳后给药是一种简单易行、效果可靠的治疗内耳疾病的给药方式。耳后注射糖皮质激素在治疗低频感音神经性聋、突发性耳聋等方面取得良好的临床效果。动物实验也证实耳后给药在内耳的药物浓度较肌肉注射高,而且维持时间长。然而,耳后注射药物进入内耳的途径尚不清楚。本研究就耳后注射地塞米松后药物在局部的分布进行观察,对药物进入内耳的可能途径进行初步探讨。方法1.用磺酸基-Cy5羧酸标记地塞米松。2.豚鼠随机分为两组：耳后注射组和肌肉注射组。3.Cy5-地塞米松0.5ml进行右耳后和右臀大肌注射,用动物体内可见光成像连续观察120h,评估药物局部代谢的动态变化。4.Cy5-地塞米松0.5ml进行右耳后和右臀大肌注射,在注射后8h断头处死动物,用动物体内可见光成像观察荧光标记的药物在头颅、颞骨、脏器的分布。5.Cy5-地塞米松0.5ml进行右耳后和右臀大肌注射,每天一次,连续三天,在第四天断头处死动物,将鼓膜、中耳粘膜、内淋巴囊、耳蜗基底膜等组织铺片,用共聚焦显微镜观察荧光标记的药物在组织的精确分布。结果1.药物局部代谢：耳后注射和肌肉注射后药物在局部浓集,而后向四周扩散。耳后注射和肌肉注射分别在注射后12h和8h药物在局部达到峰值,且肌肉注射药物峰值更高,而后药物荧光逐渐下降。相比肌肉注射,耳后注射药物荧光下降缓慢,注射后96h,耳后注射仍然有较强荧光,而肌肉注射已经检测不到药物荧光。耳后注射药物代谢曲线下面积大于肌肉注射,差异具有统计学意义(P0.05)。2.药物在头颅、脏器的分布：耳后注射组头皮、顶骨、颞骨的荧光强度均高于肌肉注射组,差异具有显著统计学意义(均P0.01)。耳后注射组心脏、膀胱的荧光强度均低于肌肉注射组,差异具有显著统计学意义(P0.01)。3.药物在中耳粘膜、鼓膜、内淋巴囊、耳蜗基底膜的分布：耳后注射组鼓膜、中耳粘膜、内淋巴囊、耳蜗基底膜的荧光强度均高于肌肉注射组,差异具有统计学意义(均P0.05)。耳后注射在同侧耳蜗基底膜的药物分布以底转荧光最强,中转次之,顶转只能检测到微弱的荧光。结论耳后注射有明显的缓释效应,在局部保持高药物浓度的同时,减少了药物在全身脏器的分布。与肌肉注射相比,耳后注射药物在内耳的浓度更高。耳后注射后药物可能经内淋巴囊途径、局部扩散渗透途径、体循环途径和茎乳动脉途径进入内耳。第二部分糖皮质激素耳后注射与全身用药在低频突发性聋中的疗效目的分析低频下降型突发性聋的临床特点,探讨甲泼尼龙琥珀酸钠耳后注射与地塞米松全身用药,在低频下降型突发性聋中的疗效。方法1.对低频下降型突发性聋的临床资料进行统计分析,对其临床特点进行观察。2.将低频下降型突发性聋患者随机分为2组,全身治疗组和耳后注射组。除常规治疗(金纳多、巴曲梅、甲钴胺)外,全身激素治疗组：地塞米松10mg静推,1次/d×3d,续5mg静推,1次/d×4d；耳后注射治疗组：甲泼尼龙琥珀酸钠40mg耳后注射,1次/2d,至听力恢复正常或15天。治疗前,治疗后4d(治疗当天为治疗后Id)、7d、10d、14d、30d、60d行纯音测听检查,分析听阈的变化情况。3.应用SPSS18.0软件进行统计分析,总有效率包括痊愈率、显效率和有效率。各组间总有效率和痊愈率的比较均采用x2检验,P0.05为差异具有统计学意义。结果1.临床资料低频下降型突发性聋患者102例,其中男43例,女59例,男女比例1：1.37。平均年龄(42±21.38)；病程(9.23±6.05)；首发症状依次为耳鸣93例(91.18%)、耳闷89例(87.25%)、听力下降77例(75.49%)、眩晕14例(13.73%)。2.纯音听阈疗效对比全身激素治疗：48例采用全身激素治疗的患者,痊愈19例(39.6%),显效11例(23.0%),有效7例(14.6%),无效11例(13.0%),总有效率为77.1%(37/48)。耳后注射治疗：54例采用耳后注射激素治疗的患者,痊愈33例(61.1%),显效7例(13.0%),有效5例(9.3%),无效9例(16.7%),总有效率为83.3%(45/54)。对两组患者的不同疗效结果进行两两比较,痊愈率的组间差异具有统计学意义(x 2=4.71,P0.05),余各疗效组间差异无显著性意义(均P0.05)。3.血压、血糖变化102例患者中伴原发性高血压病19例(18.6%),全身激素治疗组8例,耳后注射治疗组11例,治疗期间全身激素治疗组血压均有不同程度的升高,而耳后注射治疗组血压升高不明显,只有1例血压升高至100/150mmHg。本研究中伴有2型糖尿病者13例(12.8%),全身激素治疗组4例,耳后注射治疗组9例,治疗期间全身激素治疗组血糖升高1.5～5mmoL/L,9例耳后注射治疗者血糖升高1.0～2.0mmoL/L。4.听力随访随访期内13例患者出现复发,其中耳后给药治疗组复发5例,全身给药治疗组复发8例,总复发率12.74%,平均听阈提高15-35dB。复发者中所有患者都有耳闷症状,6例伴有眩晕。6例伴有眩晕患者中有2例出现听力下降、眩晕反复发作,最终确诊为梅尼埃病。复发患者全部采用耳后注射激素治疗,痊愈4例、显效1例、有效3例、无效5例,再次耳后给药的总有效率为61.5%。结论低频下降型突发性聋发病以年轻女性多见,临床表现为耳鸣、听力下降、耳闷、眩晕等,在临床工作中应与咽鼓管疾病相鉴别。低频下降型突发性聋临床治愈率高,但复发率亦高,伴有眩晕的患者有发展为梅尼埃病的可能。耳后注射甲泼尼龙琥珀酸钠治疗低频下降型突发性聋痊愈率较全身用药高,操作简单,建议将其作为低频下降型突发性聋的初始治疗。耳后注射甲泼尼龙琥珀酸钠对全身血压、血糖等情况影响小,特别适用于高血压、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.
【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R764.3

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