治疗慢性湿疹新药消炎止痒凝胶的开发研究
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摘要
消炎止痒霜是全国名老中医、广东省中医院皮肤科学科带头人禤国维教授禤教授40余年临床经验方的基础上研制而成,在广东省中医院作为作为院内制剂应用于临床10余年,临床用于湿疹、皮肤瘙痒症等疾病,临床疗效确切。目前,国内对于湿疹的外用药物多为激素类软膏,激素类药物虽然消炎、止痒及减少渗出的作用比较快,但停药后很快复发,长期使用易引起许多不良反应,如皮肤粗糙、毛孔增大和色素沉着。中医药治疗方法虽多,但外用药物较少,又存在着剂型落后、使用不方便、透皮吸收差、生物利用度低、易脱落、影响美观等不足。因此,研究高效、使用方便的中药外用制剂是临床医疗的迫切需要。为此,我们从以下几个方面进行了研究:
一、文献研究
湿疹是各种内外因素引起的一种急性或慢性皮肤炎症。在急性期以红斑丘疹、丘疱疹为主的多形性损害,有渗出倾向,在慢性期以皮肤肥厚和苔藓样变为主,常反复发作,多年不愈,瘙痒剧烈,其发病原因复杂,外在因素如日光,紫外线、寒冷、炎热、干燥、搔抓及各种动物皮毛、植物、化学物质的刺激均可使湿疹加重。内在因素如慢性消化道系统疾病,胃肠道障碍、精神紧张、失眠、过劳、病灶感染、内分泌功能失调等也可加重病情。关于其发病机理,国外内都有相关的研究,主要在遗传、过敏源、感染、免疫、神经精神等方面的研究,但一般认为:本病的发病机理主要是复杂的内外因素引起的一种迟发型变态反应。
治疗上,目前主要是对症治疗,予以抗过敏,抗炎,止痒等治疗,但在使用的过程中也存在一些问题如:(1)抗组胺药一般对急性期作用显著,而慢性期疗效随时间延长而下降;长期应用抗组胺药可出现对药物的依赖性和精神影响,突然撤药可出现明显不良反应;该药的抗中枢抑制作用明显,副作用较大。(2)激素类药物虽然能迅速控制症状,但停药易复发甚至加重,一般不主张内服。(3)免疫调节剂如环孢素长期使用或剂量过大可导致肾中毒,硫唑嘌呤可有严重的骨髓抑制,导致粒细胞减少,甚至发生再障及中毒性肝炎等严重不良反应。
祖国医学对湿疹的认识由来已久,本病属于中医“浸淫疮”、“湿疮”、“绣球风”、“旋耳疮”等范畴,其中慢性湿疹相当于中医所称的“顽癣”范畴。中医认为湿疹的发生是由于禀赋不耐,风、湿、热阻于肌肤而致,或因饮食失节,过食辛辣荤腥之品而致脾胃损伤,健运失司,湿热内生,内外相搏,风湿热邪浸淫肌肤所致本病。在湿疹的治疗上,明清之前的文献记载主要以外治法为主。到了明清,医家们逐渐认识到单靠外用药治疗湿疹不能解决根本问题,开始重视针对内因的辨证论治,并用针灸及物理疗法以解郁毒,治疗方法逐渐丰富;现在中医在治疗本病方面做了大量的临床及实验研究,内容涉及多个方面,目前临床研究主要集中在单纯辨证分型、专方专药研究、单纯外治疗法研究及内服和外治结合治疗本病的研究,疗效各有差别,从收集的病例总结来看,有效率一般在80%以上,有的甚至达到100%,展示了中医药治疗湿疹的美好前景。但由于不同医家在总结各自临床经验的基础上进行各种各样的研究,因地区的差异及个人的主观因素的影响,现代医家对湿疹的认识各有差异,很难做出统一的客观的评价,把这些研究成果用于指导临床时遇到了很大的困难。
二、动物试验研究
药效学研究:
共进行了以下六个动物试验:(1)在豚鼠右耳廓内侧外涂二硝基氯苯(DNCB)以致敏与激发、制备湿疹模型,同时耳廓局部给药,观察药物对耳廓肿胀值和病理改变的影响。(2)DNCB局部皮肤致敏与耳廓激发制备迟发型超敏反应模型,腹部皮肤局部给药,观察药物对小鼠耳廓肿胀度和免疫器官脾脏、胸腺的影响。(3)组氨(HA)法制备豚鼠瘙痒模型,局部给药,观察药物对豚鼠HA致痒阈的影响。(4)用角叉菜胶致大鼠足跖致炎,局部给药,观察药物对足跖肿胀率的影响。(5)二甲苯耳廓致炎,观察药物对取NIH小鼠耳廓肿胀值的影响。(6)伊文思蓝法测毛细血管通透性,皮肤局部给药,观察药物对动物皮肤伊文思蓝渗出量的影响。
动物试验研究表明:
(1)消炎止痒凝胶剂能明显降低豚鼠湿疹模型耳廓肿胀值和真皮浸润炎性细胞数,耳廓表皮增厚、真皮内炎性细胞浸润明显减少,血管内皮细胞肿胀明显减轻;
(2)消炎止痒凝胶剂能抑制小鼠DNCB引起的迟发型超敏反应;表明消炎止痒凝胶剂对湿疹有治疗作用。
(3)消炎止痒凝胶剂能明显提高豚鼠磷酸组织胺致痒阈,表明有止痒作用;
(4)能明显降低角又菜胶所致大鼠足跖肿胀率和二甲苯所致小鼠耳廓肿胀值,表明有抗炎作用;
(5)能降低大鼠用药局部皮片浸泡液中伊文思蓝浓度,表明有降低毛细血管通透性的作用。
结论:通过动物实验,证实消炎止痒凝胶具有抗炎、抗过敏、止痒等作用。
药物毒理研究:
共进行了以下四个试验:(1)用8%硫化钠将兔背部脊柱两侧脱毛,面积约相当于体表面积的10%。进行完整皮肤和破损皮肤急性毒性试验。(2)消炎止痒凝胶剂相当生药量0.91g/g和3.64g/g2种浓度,按0.91g/kg和3.64g/kg给兔完整皮肤和破损皮肤局部用药,涂药厚度约为0.1mm,每天给药1次,维持6小时,共给药3个月,停药观察2周。(3)豚鼠背部两侧剪毛,面积每侧3×3cm~2,进行皮肤过敏性试验,观察局部用药时对皮肤的过敏反应。(4)兔脊柱两侧背部脱毛,面积约相当于体表面积的10%,进行完整皮肤和破损皮肤刺激性试验。
药物毒理研究结果:
(1)消炎止痒凝胶剂兔完整皮肤和破损皮肤局部给药,未观察到药物对皮肤局部和动物全身的急性毒性反应;
(2)消炎止痒凝胶剂对动物行为、活动、毛色、大小便、饮食、饮水和眼、鼻、口腔无明显影响;给药1周后破损皮肤局部结痂,2周后脱落;对动物体重、脏器系数、组织病理学无明显影响;对外周血细胞、血液生化和肝、肾功能指标无明显影响。
(3)消炎止瘁凝胶剂皮肤接触对豚鼠的致敏率为0%,提示消炎止痒凝胶剂无致敏性。
(4)消炎止痒凝胶剂多次给药对兔完整和破损皮肤无明显刺激作用。
结论:通过动物急性、长期毒性、局部皮肤过敏和刺激实验,未发现消炎止痒凝胶具有毒性、致过敏和皮肤刺激作用。
三、临床研究
目的:客观评价消炎止痒凝胶治疗亚急性、慢性湿疹(湿热未尽、余毒未清证)的有效性与安全性。方法:将120例符合亚急性、慢性湿疹(湿热未尽、余毒未清证)的患者随机分成试验组和对照组,其中试验外用消炎止痒凝胶适量(约0.1克/cm2)涂敷患处,每日2-3次;对照组外用艾洛松适量(约0.1克/cm2)涂敷患处,每日2-3次。疗程为4周。不足4周已经痊愈者可提前结束,治疗期间不得合并其它具有治疗本病相关的中西医药物。主要观察察皮肤瘙痒情况(瘙痒分级、瘙痒程度、瘙痒频率)、皮损性状(干燥、鳞屑、抓痕和血痂、丘疹和苔藓化)、皮损面积等主要疗效指标,并观察局部及全身不良事件。结果:消炎止痒凝胶治疗亚急性、慢性湿疹的痊愈率及总有效率分别为37.5%和91.07%对照组艾洛松痊愈率及总有效率分别为47.27%和94.54%,两组痊愈率及总有效率比较其差异无显著性意义(P＞0.05)。二组止痒效果、皮损面积疗效方面比较也无无显著性意义(P＞0.05)。两组临床未见不良事件发生。
结论:研究结果表明消炎止痒凝胶临床疗效是比较肯定的,临床使用也是安全的。
四、结论
(1)实验研研究提示:消炎止痒凝胶具有良好的抗炎、止痒、抗过敏等作用:
(2)临床研究表明:消炎止痒凝胶对中医辨证属湿热未清、余毒未尽之证型的慢性湿疹有显著效果;
(3)安全性研究表明:对动物无急性、长期毒性及对皮肤无刺激、致过敏等副作用;临床试用过程未发出有副作用。
实验和临床研究结果提示:消炎止痒凝胶值得进一步开发研究。
Background
The anti-inflammatory and relieving itching creme,which was developed by the famous Professor XuanGuowei(as well as the academic leader in the dermatology department of Guangdong Provincial hospital of Traditional Chinese Medicine,) for fourty years,as a medical prescription for treating eczema,cutaneous pruritus and other skin disorders,the curative effect was determined,steroids ointment accounted for a prodigious proportion in the external used medicine for treating eczema at present.Although the steroids showed a good clinical effect in anti-inflammatory,relieving itching and decreasing exudation,,the disease recurred when the drug withdrew,and what's more,other side effects would arised such as pachylosis,enlarged pore, pigmentation after a long term usage.There were various treatment methods in traditional chinese medicine,but the external used medicine was limited,in addition to,other defects were also exist such as lagged dosage form, inconvenient to use,poor transdermal absorption and bioavailability, caducous and aesthetic problems,so how to develope efficient,easy-to-use external formulations was an urgent need.in view of this,we have studied the following aspects:
literature search
Eczema was an acute or chronic skin inflammation which result from various internal and external factors.In the acute stage,the Symptoms were red rash, herpes Hill pleomorphic damage and they have exudational tendency;while in the chronic phase,hypertrophy and Lichenoid skin are change-oriented,often recurrentin many years and intense itching.The causes are very complicated, for example,the external factors such as sunlight,ultraviolet radiation,cold, heat,drying,scratch and all kinds of animal fur,plants,chemical substances,that can aggravate the eczema,and the internal factors such as chronic digestive system diseases,gastrointestinal disorders,mental tension, insomnia,fatigue,focal infections,endocrine dysfunction,that may also worsen the disease.As for the pathogenesis,with both foreign-related research, we mainly focus on the genetic,allergic source of infection,immunization, and other neuropsychiatric research,it is generally acknowledged the pathogenesis was mainly caused by the complicated internal and external factors of a delayed hypersensitivity.
Currently,the main treatment of the disease was to relieve the Symptoms.The main methods are anti-allergic,anti-inflammatory,antipruritic and so on.but there are some problems in use,suchas:(1) antihistamines aere generally significant in the acute phase,but their effect declined with time in the chronic phase;long-term application of antihistamines may be dependent on drugs and mental effects.In the same time,sudden withdrawal may result in obvious adverse drug reaction;and what's more,antihistamine drugs have obvious central inhibition and other side effects.(2) Although Glucocorticoid can control symptoms rapidly,but the drug is easy to relapse even worsen in general,and taking it by oral is not suggested.(3)The adverse reactions of immunomodulators are obvious,such as long-term use or excessive doses of cyclosporine can lead to renal toxicity;azathioprine may cause severe bone marrow suppression,neutropenia,aplastic anemia,even toxic hepatitis and other serious adverse reactions.
Chinese medicine has a long history of be familiar with the eczema,the disease belong to "immersed sores," "wet wound","Hydrangea Wind," "Spin sore ears";chronic eczema is equivalent to "stubborn ringworm" in Chinese medicine. Chinese medicine practitioners believe that the occurrence of eczema are because of dysplasia and wind,moisture,thermal are Mixed in the skin,and intemperance of taking food,over-eating spicy and Smelly food due to spleen injury,Kin Yun-loss Secretary humid endogenous,internal and external pathogens involved,rheumatic fever immersed skin caused by this evil disease. The treatment of the eczema were recorded in document before the Ming and Qing dynasties are prior to external-oriented major,physicians have come to realize all above will be not enough to cure the diseas fundamentally,and begin to retrieve the disordered state of the body in the Ming and Qing Dynasties:At the same time,people start using acupuncture and physical therapy to cure the disease,and the methods of treatment gradually enriched; Now the Chinese medicine has done a large number of clinical and experimental research in the treatment of this disease,covering many aspects,and the current clinical researches focuse on simple Syndrome differentiation, specific drug research,pure external research and the intergration of internal-external therapy,the efficacy was various,by summarizing the cases, the efficiency is more than 80%,and some even 100%,which demonstrates the beautiful future of the treatment of eczema by the Chinese medicine.
However,according to their clinical experience,different doctors carry on different researches,because of regional differences and personal factors, modern medicine has diffrent understanding about eczema;it is difficult to make a unified objective evaluation,the results of these studies encounter great difficulties when they are used to guide clinical work.
animal experiment research
Pharmacodynamic Study:
we carried out six animal experiments in all:(1)we coated DNCB in the inner ear of guinea pigs so as to sensitize,stimulate and prepare the eczema model,while local administration of the auricle and observe drugs effect on the ear Profile swelling values and the impact of pathological changes simultaneously.(2)DNCB skin sensitization and ear to stimulate delayed-typehypersensitivity model preparation,abdominal skin of localized drug delivery to observe the impact of drugs on ear edema of guinea pigs and immune organs such as spleen,thymus.(3) the guineapig itching model were acquired through Oroupammonia(HA) method,and we observed The drugs effect on the HA of guineapig itch threshold by local administration;(4)using carrageenin to induce guinea pig feet proinflammatory,then observe the drugs effect on foot swelling rates by local administration(5)p-xylene-induced ear inflammation,observing the impact of drugs on guinea pig ear edema NIH value the capillary permeability were measured by Evansblue,and the drugs effect on animal skin Evansblue exudation volume were observed by local skin administration
The animal experimental research shows that:
(1)The anti-inflammatory and relieving itching gel has a significant effect to relieve itching reduced ear edema model inguinea pigs eczema values and dermal infiltration of inflammatory cells,auricleepi dermal thickening,dermal inflammatory cell
infiltrationina,and decrease invascularendothelial cells swelling significantly.
(2) The anti-inflammatory and relieving itching gel can relieve DNCB-induced delayed-type hypersensitivity;this shows that the gel have the therapeutic effects on eczema.
(3)The anti-inflammatory and relieving itching gel enhances itching threshold inguineapigs induced by histamine significantly,which means that it has antipruritic effect.
(4)The anti-inflammatory and relieving itching gel can be significantly reduced carrageenan-induced rat foot swelling rate and xylene-induced mouse ear edema values this means the gel has anti-inflammatory effects.
(5)The anti-inflammatory and relieving itching gel can reduce medication partial skin graft in rats lixivium in the concentration of Evansblue that has reduced the role of capillary permeability.
Conclusion:The animal experiments confirmed that The anti-inflammatory and relieving itching gel has anti-inflammatory,antiallergic,antipruritic effects.
Drug Toxicology study:
We carried out the following four tests:(1)with 8%sodium sulfide to the back of the spine on both sides of the rabbit hair removal,with an area equal to about 10%of body surface area,so as to conduct acute toxicity test on the intact and damaged skin.(2)The anti-inflammatory and relieving itching gel pharmacognostic considerable amount of 0.91g/g and 3.64g/g two concentrations by 0.91g/kg and 3.64g/kg to rabbit skin and damaged skin integrity of local administration,drug-coated thickness of about for 0.1mm,the daily administration of one times,to maintain six hours,a total of 3 months of administration,observe two weeks after drug withdrawal,both sides of shearing on guinea pig back,with an area of each side of the 3×3cm~2,complete allergic skin tests,observe local medication when anaphylactic reaction on the skin.(4)rabbit spine on both sides of the back hair removal,with an area equal to about 10%of body surface area,inact and damaged skin irritation tests were conducted afterwards.
Drug Toxicology Results:
(1)The local administration of rabbit skin and damaged skin,we did not observe that local skin and animal acute toxicity:
(2)The anti-inflammatory and relieving itching gel has no significant effect on animal behavior,activity,fur,urine,diet,drinking water and eye,nose,oral cavity;one week after administration of local damaged skin scab,after two weeks decrustation:it has no significant effect on animal body weight,organcoefficient,and histopathology;it has no significant effect on peripheral blood cells,blood biochemistry and liver and kidney function.
(3)Skin contact sensitization of guinea pigs was 0%,suggesting that the anti-inflammatory and relieving itching gel has no hypersensitization.
(4)The anti-inflammatory and relieving itching gel has no obvious stimulus on skin and damaged skin of rabbit.
Conclusion:the anti-inflammatory and relieving itching gel has no toxicity,hypersensitization,and skin stimulation in our acute,long-term toxicity,skin allergies and local stimulation animal experiment. Clinical Research
Objective:To objectively evaluate the the effectiveness and safety of anti-inflammatory and relieving itching gel in treating subacute and chronic eczema.Methods:120 patients sufferring from subacute or chronic eczema we recollected and randomly divided into treatment group and control group;the treatment group:anti-inflammatory relieving itching gel,topical,coverring the affected area 2-3 times daily by appropriate dose(about 0.1 grams /cm~2). Control group:Eloson paste,external use,take appropriate amount(about 0.1 grams/cm2) coating the affected area 2-3 times daily.The period of Treatment is 4 weeks,they may have been recovered in advance for less than four weeks; During the period of treatment,other treatment of the disease-related drugs can not be combined,we observe the situation of skin itching(pruritus grading, the degree of itching,pruritus frequency),lesions traits(dry,dander, scratch and blood scab,Papules and moss),lesions size,and observe the local and systemic adverse events.Results:the cure rate and total effective rate were 37.5%and 91.07%;In the control group,the cure rate and total effective rates were 47.27%and 94.54%,The treatment group Compared with the control group,both of them was not significant(P＞0.05).Antipruritic effect of two groups,lesion area reducement were not significant(P＞0.05).Clinical adverse events did not occur.Conclusion:The results showed that the clinical efficacy of anti-inflammatory and relieving itching gel was more positive, clinical use was safe.
Conclusion:
(1)Experimental research suggests that The anti-inflammatory and relieving itching gel are good at anti-inflammatory,antipruritic,anti-allergic effect and so on;
(2)Clinical research shows that the anti-inflammatory and relieving itching gel have an outstanding effect in treating chronic eczema.
(3)Security study shows that The gel has no acute and long-term toxicity to the animals,no irritation to the skin,and other side effects;the side effects was not observed in the process of clinical trials.
Both the experimental and clinical study suggest that The anti-inflammatory and relieving itching gel is worthy of further research and development.
一、文献研究
湿疹是各种内外因素引起的一种急性或慢性皮肤炎症。在急性期以红斑丘疹、丘疱疹为主的多形性损害,有渗出倾向,在慢性期以皮肤肥厚和苔藓样变为主,常反复发作,多年不愈,瘙痒剧烈,其发病原因复杂,外在因素如日光,紫外线、寒冷、炎热、干燥、搔抓及各种动物皮毛、植物、化学物质的刺激均可使湿疹加重。内在因素如慢性消化道系统疾病,胃肠道障碍、精神紧张、失眠、过劳、病灶感染、内分泌功能失调等也可加重病情。关于其发病机理,国外内都有相关的研究,主要在遗传、过敏源、感染、免疫、神经精神等方面的研究,但一般认为:本病的发病机理主要是复杂的内外因素引起的一种迟发型变态反应。
治疗上,目前主要是对症治疗,予以抗过敏,抗炎,止痒等治疗,但在使用的过程中也存在一些问题如:(1)抗组胺药一般对急性期作用显著,而慢性期疗效随时间延长而下降;长期应用抗组胺药可出现对药物的依赖性和精神影响,突然撤药可出现明显不良反应;该药的抗中枢抑制作用明显,副作用较大。(2)激素类药物虽然能迅速控制症状,但停药易复发甚至加重,一般不主张内服。(3)免疫调节剂如环孢素长期使用或剂量过大可导致肾中毒,硫唑嘌呤可有严重的骨髓抑制,导致粒细胞减少,甚至发生再障及中毒性肝炎等严重不良反应。
祖国医学对湿疹的认识由来已久,本病属于中医“浸淫疮”、“湿疮”、“绣球风”、“旋耳疮”等范畴,其中慢性湿疹相当于中医所称的“顽癣”范畴。中医认为湿疹的发生是由于禀赋不耐,风、湿、热阻于肌肤而致,或因饮食失节,过食辛辣荤腥之品而致脾胃损伤,健运失司,湿热内生,内外相搏,风湿热邪浸淫肌肤所致本病。在湿疹的治疗上,明清之前的文献记载主要以外治法为主。到了明清,医家们逐渐认识到单靠外用药治疗湿疹不能解决根本问题,开始重视针对内因的辨证论治,并用针灸及物理疗法以解郁毒,治疗方法逐渐丰富;现在中医在治疗本病方面做了大量的临床及实验研究,内容涉及多个方面,目前临床研究主要集中在单纯辨证分型、专方专药研究、单纯外治疗法研究及内服和外治结合治疗本病的研究,疗效各有差别,从收集的病例总结来看,有效率一般在80%以上,有的甚至达到100%,展示了中医药治疗湿疹的美好前景。但由于不同医家在总结各自临床经验的基础上进行各种各样的研究,因地区的差异及个人的主观因素的影响,现代医家对湿疹的认识各有差异,很难做出统一的客观的评价,把这些研究成果用于指导临床时遇到了很大的困难。
二、动物试验研究
药效学研究:
共进行了以下六个动物试验:(1)在豚鼠右耳廓内侧外涂二硝基氯苯(DNCB)以致敏与激发、制备湿疹模型,同时耳廓局部给药,观察药物对耳廓肿胀值和病理改变的影响。(2)DNCB局部皮肤致敏与耳廓激发制备迟发型超敏反应模型,腹部皮肤局部给药,观察药物对小鼠耳廓肿胀度和免疫器官脾脏、胸腺的影响。(3)组氨(HA)法制备豚鼠瘙痒模型,局部给药,观察药物对豚鼠HA致痒阈的影响。(4)用角叉菜胶致大鼠足跖致炎,局部给药,观察药物对足跖肿胀率的影响。(5)二甲苯耳廓致炎,观察药物对取NIH小鼠耳廓肿胀值的影响。(6)伊文思蓝法测毛细血管通透性,皮肤局部给药,观察药物对动物皮肤伊文思蓝渗出量的影响。
动物试验研究表明:
(1)消炎止痒凝胶剂能明显降低豚鼠湿疹模型耳廓肿胀值和真皮浸润炎性细胞数,耳廓表皮增厚、真皮内炎性细胞浸润明显减少,血管内皮细胞肿胀明显减轻;
(2)消炎止痒凝胶剂能抑制小鼠DNCB引起的迟发型超敏反应;表明消炎止痒凝胶剂对湿疹有治疗作用。
(3)消炎止痒凝胶剂能明显提高豚鼠磷酸组织胺致痒阈,表明有止痒作用;
(4)能明显降低角又菜胶所致大鼠足跖肿胀率和二甲苯所致小鼠耳廓肿胀值,表明有抗炎作用;
(5)能降低大鼠用药局部皮片浸泡液中伊文思蓝浓度,表明有降低毛细血管通透性的作用。
结论:通过动物实验,证实消炎止痒凝胶具有抗炎、抗过敏、止痒等作用。
药物毒理研究:
共进行了以下四个试验:(1)用8%硫化钠将兔背部脊柱两侧脱毛,面积约相当于体表面积的10%。进行完整皮肤和破损皮肤急性毒性试验。(2)消炎止痒凝胶剂相当生药量0.91g/g和3.64g/g2种浓度,按0.91g/kg和3.64g/kg给兔完整皮肤和破损皮肤局部用药,涂药厚度约为0.1mm,每天给药1次,维持6小时,共给药3个月,停药观察2周。(3)豚鼠背部两侧剪毛,面积每侧3×3cm~2,进行皮肤过敏性试验,观察局部用药时对皮肤的过敏反应。(4)兔脊柱两侧背部脱毛,面积约相当于体表面积的10%,进行完整皮肤和破损皮肤刺激性试验。
药物毒理研究结果:
(1)消炎止痒凝胶剂兔完整皮肤和破损皮肤局部给药,未观察到药物对皮肤局部和动物全身的急性毒性反应;
(2)消炎止痒凝胶剂对动物行为、活动、毛色、大小便、饮食、饮水和眼、鼻、口腔无明显影响;给药1周后破损皮肤局部结痂,2周后脱落;对动物体重、脏器系数、组织病理学无明显影响;对外周血细胞、血液生化和肝、肾功能指标无明显影响。
(3)消炎止瘁凝胶剂皮肤接触对豚鼠的致敏率为0%,提示消炎止痒凝胶剂无致敏性。
(4)消炎止痒凝胶剂多次给药对兔完整和破损皮肤无明显刺激作用。
结论:通过动物急性、长期毒性、局部皮肤过敏和刺激实验,未发现消炎止痒凝胶具有毒性、致过敏和皮肤刺激作用。
三、临床研究
目的:客观评价消炎止痒凝胶治疗亚急性、慢性湿疹(湿热未尽、余毒未清证)的有效性与安全性。方法:将120例符合亚急性、慢性湿疹(湿热未尽、余毒未清证)的患者随机分成试验组和对照组,其中试验外用消炎止痒凝胶适量(约0.1克/cm2)涂敷患处,每日2-3次;对照组外用艾洛松适量(约0.1克/cm2)涂敷患处,每日2-3次。疗程为4周。不足4周已经痊愈者可提前结束,治疗期间不得合并其它具有治疗本病相关的中西医药物。主要观察察皮肤瘙痒情况(瘙痒分级、瘙痒程度、瘙痒频率)、皮损性状(干燥、鳞屑、抓痕和血痂、丘疹和苔藓化)、皮损面积等主要疗效指标,并观察局部及全身不良事件。结果:消炎止痒凝胶治疗亚急性、慢性湿疹的痊愈率及总有效率分别为37.5%和91.07%对照组艾洛松痊愈率及总有效率分别为47.27%和94.54%,两组痊愈率及总有效率比较其差异无显著性意义(P＞0.05)。二组止痒效果、皮损面积疗效方面比较也无无显著性意义(P＞0.05)。两组临床未见不良事件发生。
结论:研究结果表明消炎止痒凝胶临床疗效是比较肯定的,临床使用也是安全的。
四、结论
(1)实验研研究提示:消炎止痒凝胶具有良好的抗炎、止痒、抗过敏等作用:
(2)临床研究表明:消炎止痒凝胶对中医辨证属湿热未清、余毒未尽之证型的慢性湿疹有显著效果;
(3)安全性研究表明:对动物无急性、长期毒性及对皮肤无刺激、致过敏等副作用;临床试用过程未发出有副作用。
实验和临床研究结果提示:消炎止痒凝胶值得进一步开发研究。
Background
The anti-inflammatory and relieving itching creme,which was developed by the famous Professor XuanGuowei(as well as the academic leader in the dermatology department of Guangdong Provincial hospital of Traditional Chinese Medicine,) for fourty years,as a medical prescription for treating eczema,cutaneous pruritus and other skin disorders,the curative effect was determined,steroids ointment accounted for a prodigious proportion in the external used medicine for treating eczema at present.Although the steroids showed a good clinical effect in anti-inflammatory,relieving itching and decreasing exudation,,the disease recurred when the drug withdrew,and what's more,other side effects would arised such as pachylosis,enlarged pore, pigmentation after a long term usage.There were various treatment methods in traditional chinese medicine,but the external used medicine was limited,in addition to,other defects were also exist such as lagged dosage form, inconvenient to use,poor transdermal absorption and bioavailability, caducous and aesthetic problems,so how to develope efficient,easy-to-use external formulations was an urgent need.in view of this,we have studied the following aspects:
literature search
Eczema was an acute or chronic skin inflammation which result from various internal and external factors.In the acute stage,the Symptoms were red rash, herpes Hill pleomorphic damage and they have exudational tendency;while in the chronic phase,hypertrophy and Lichenoid skin are change-oriented,often recurrentin many years and intense itching.The causes are very complicated, for example,the external factors such as sunlight,ultraviolet radiation,cold, heat,drying,scratch and all kinds of animal fur,plants,chemical substances,that can aggravate the eczema,and the internal factors such as chronic digestive system diseases,gastrointestinal disorders,mental tension, insomnia,fatigue,focal infections,endocrine dysfunction,that may also worsen the disease.As for the pathogenesis,with both foreign-related research, we mainly focus on the genetic,allergic source of infection,immunization, and other neuropsychiatric research,it is generally acknowledged the pathogenesis was mainly caused by the complicated internal and external factors of a delayed hypersensitivity.
Currently,the main treatment of the disease was to relieve the Symptoms.The main methods are anti-allergic,anti-inflammatory,antipruritic and so on.but there are some problems in use,suchas:(1) antihistamines aere generally significant in the acute phase,but their effect declined with time in the chronic phase;long-term application of antihistamines may be dependent on drugs and mental effects.In the same time,sudden withdrawal may result in obvious adverse drug reaction;and what's more,antihistamine drugs have obvious central inhibition and other side effects.(2) Although Glucocorticoid can control symptoms rapidly,but the drug is easy to relapse even worsen in general,and taking it by oral is not suggested.(3)The adverse reactions of immunomodulators are obvious,such as long-term use or excessive doses of cyclosporine can lead to renal toxicity;azathioprine may cause severe bone marrow suppression,neutropenia,aplastic anemia,even toxic hepatitis and other serious adverse reactions.
Chinese medicine has a long history of be familiar with the eczema,the disease belong to "immersed sores," "wet wound","Hydrangea Wind," "Spin sore ears";chronic eczema is equivalent to "stubborn ringworm" in Chinese medicine. Chinese medicine practitioners believe that the occurrence of eczema are because of dysplasia and wind,moisture,thermal are Mixed in the skin,and intemperance of taking food,over-eating spicy and Smelly food due to spleen injury,Kin Yun-loss Secretary humid endogenous,internal and external pathogens involved,rheumatic fever immersed skin caused by this evil disease. The treatment of the eczema were recorded in document before the Ming and Qing dynasties are prior to external-oriented major,physicians have come to realize all above will be not enough to cure the diseas fundamentally,and begin to retrieve the disordered state of the body in the Ming and Qing Dynasties:At the same time,people start using acupuncture and physical therapy to cure the disease,and the methods of treatment gradually enriched; Now the Chinese medicine has done a large number of clinical and experimental research in the treatment of this disease,covering many aspects,and the current clinical researches focuse on simple Syndrome differentiation, specific drug research,pure external research and the intergration of internal-external therapy,the efficacy was various,by summarizing the cases, the efficiency is more than 80%,and some even 100%,which demonstrates the beautiful future of the treatment of eczema by the Chinese medicine.
However,according to their clinical experience,different doctors carry on different researches,because of regional differences and personal factors, modern medicine has diffrent understanding about eczema;it is difficult to make a unified objective evaluation,the results of these studies encounter great difficulties when they are used to guide clinical work.
animal experiment research
Pharmacodynamic Study:
we carried out six animal experiments in all:(1)we coated DNCB in the inner ear of guinea pigs so as to sensitize,stimulate and prepare the eczema model,while local administration of the auricle and observe drugs effect on the ear Profile swelling values and the impact of pathological changes simultaneously.(2)DNCB skin sensitization and ear to stimulate delayed-typehypersensitivity model preparation,abdominal skin of localized drug delivery to observe the impact of drugs on ear edema of guinea pigs and immune organs such as spleen,thymus.(3) the guineapig itching model were acquired through Oroupammonia(HA) method,and we observed The drugs effect on the HA of guineapig itch threshold by local administration;(4)using carrageenin to induce guinea pig feet proinflammatory,then observe the drugs effect on foot swelling rates by local administration(5)p-xylene-induced ear inflammation,observing the impact of drugs on guinea pig ear edema NIH value the capillary permeability were measured by Evansblue,and the drugs effect on animal skin Evansblue exudation volume were observed by local skin administration
The animal experimental research shows that:
(1)The anti-inflammatory and relieving itching gel has a significant effect to relieve itching reduced ear edema model inguinea pigs eczema values and dermal infiltration of inflammatory cells,auricleepi dermal thickening,dermal inflammatory cell
infiltrationina,and decrease invascularendothelial cells swelling significantly.
(2) The anti-inflammatory and relieving itching gel can relieve DNCB-induced delayed-type hypersensitivity;this shows that the gel have the therapeutic effects on eczema.
(3)The anti-inflammatory and relieving itching gel enhances itching threshold inguineapigs induced by histamine significantly,which means that it has antipruritic effect.
(4)The anti-inflammatory and relieving itching gel can be significantly reduced carrageenan-induced rat foot swelling rate and xylene-induced mouse ear edema values this means the gel has anti-inflammatory effects.
(5)The anti-inflammatory and relieving itching gel can reduce medication partial skin graft in rats lixivium in the concentration of Evansblue that has reduced the role of capillary permeability.
Conclusion:The animal experiments confirmed that The anti-inflammatory and relieving itching gel has anti-inflammatory,antiallergic,antipruritic effects.
Drug Toxicology study:
We carried out the following four tests:(1)with 8%sodium sulfide to the back of the spine on both sides of the rabbit hair removal,with an area equal to about 10%of body surface area,so as to conduct acute toxicity test on the intact and damaged skin.(2)The anti-inflammatory and relieving itching gel pharmacognostic considerable amount of 0.91g/g and 3.64g/g two concentrations by 0.91g/kg and 3.64g/kg to rabbit skin and damaged skin integrity of local administration,drug-coated thickness of about for 0.1mm,the daily administration of one times,to maintain six hours,a total of 3 months of administration,observe two weeks after drug withdrawal,both sides of shearing on guinea pig back,with an area of each side of the 3×3cm~2,complete allergic skin tests,observe local medication when anaphylactic reaction on the skin.(4)rabbit spine on both sides of the back hair removal,with an area equal to about 10%of body surface area,inact and damaged skin irritation tests were conducted afterwards.
Drug Toxicology Results:
(1)The local administration of rabbit skin and damaged skin,we did not observe that local skin and animal acute toxicity:
(2)The anti-inflammatory and relieving itching gel has no significant effect on animal behavior,activity,fur,urine,diet,drinking water and eye,nose,oral cavity;one week after administration of local damaged skin scab,after two weeks decrustation:it has no significant effect on animal body weight,organcoefficient,and histopathology;it has no significant effect on peripheral blood cells,blood biochemistry and liver and kidney function.
(3)Skin contact sensitization of guinea pigs was 0%,suggesting that the anti-inflammatory and relieving itching gel has no hypersensitization.
(4)The anti-inflammatory and relieving itching gel has no obvious stimulus on skin and damaged skin of rabbit.
Conclusion:the anti-inflammatory and relieving itching gel has no toxicity,hypersensitization,and skin stimulation in our acute,long-term toxicity,skin allergies and local stimulation animal experiment. Clinical Research
Objective:To objectively evaluate the the effectiveness and safety of anti-inflammatory and relieving itching gel in treating subacute and chronic eczema.Methods:120 patients sufferring from subacute or chronic eczema we recollected and randomly divided into treatment group and control group;the treatment group:anti-inflammatory relieving itching gel,topical,coverring the affected area 2-3 times daily by appropriate dose(about 0.1 grams /cm~2). Control group:Eloson paste,external use,take appropriate amount(about 0.1 grams/cm2) coating the affected area 2-3 times daily.The period of Treatment is 4 weeks,they may have been recovered in advance for less than four weeks; During the period of treatment,other treatment of the disease-related drugs can not be combined,we observe the situation of skin itching(pruritus grading, the degree of itching,pruritus frequency),lesions traits(dry,dander, scratch and blood scab,Papules and moss),lesions size,and observe the local and systemic adverse events.Results:the cure rate and total effective rate were 37.5%and 91.07%;In the control group,the cure rate and total effective rates were 47.27%and 94.54%,The treatment group Compared with the control group,both of them was not significant(P＞0.05).Antipruritic effect of two groups,lesion area reducement were not significant(P＞0.05).Clinical adverse events did not occur.Conclusion:The results showed that the clinical efficacy of anti-inflammatory and relieving itching gel was more positive, clinical use was safe.
Conclusion:
(1)Experimental research suggests that The anti-inflammatory and relieving itching gel are good at anti-inflammatory,antipruritic,anti-allergic effect and so on;
(2)Clinical research shows that the anti-inflammatory and relieving itching gel have an outstanding effect in treating chronic eczema.
(3)Security study shows that The gel has no acute and long-term toxicity to the animals,no irritation to the skin,and other side effects;the side effects was not observed in the process of clinical trials.
Both the experimental and clinical study suggest that The anti-inflammatory and relieving itching gel is worthy of further research and development.
引文
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