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香莲栓治疗复发性外阴阴道念珠菌病的临床和实验研究
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摘要
背景
     随着复发性外阴阴道念珠菌病(recurrent vulvovaginal candidiasis, RVVC)研究的不断深入,众多学者逐渐认识到,虽然念珠菌是本病的致病菌,但RVVC反复发作的原因考虑与患者阴道局部免疫功能的紊乱密切相关。RVVC患者的阴道局部普遍存在着Thl/Th2细胞极化失衡的现象,局部的免疫功能紊乱会降低对念珠菌感染的抵抗力。
     虽然RVVC的传染性和临床症状同其他的感染性性传播疾病(sexually transmitted disease,STD)相比,其临床症状程度较轻,但患者在生存质量方面依然呈现受抑制状态,包括性功能和情感生活等。遗憾的是,到目前为止,RVVC患者的心理健康和生存质量等相关问题尚未受到国内学者的关注。国外少数学者已经对此进行了小样本量、局域性的相关研究,并在其研究成果的基础上呼吁应进行大样本量、纵向的研究。加强对患者生存质量的关注,也是对疾病的系统治疗提出的新的要求,并将有助于增强患者的依从性,提高临床疗效。
     中医药外用治疗皮肤粘膜真菌病能充分体现中医的特色和优势。根据前期研究报道,中药香莲外洗液外用治疗念珠菌性外阴阴道炎或复发性念珠菌性外阴阴道炎的临床疗效显著;实验室方面,香莲洗液能够明显抑制多种真菌,包括念珠菌的生长。目前国内外针对RVVC的推荐治疗方案均立足于抗真菌治疗,但单纯抗真菌对大多数RVVC患者的疗效是不理想的。究其原因,一方面,抗真菌药物可能诱导耐药菌株及交叉耐药菌株的出现,另一方面,患者阴道局部存在免疫功能异常,从而导致对念珠菌的易感性和病情的反复发作。中药抗真菌治疗的副作用小、来源广、很少出现耐药、适合于长期及预防性应用,同时中草药复方可以有效发挥抗真菌和调节免疫力的的协同作用。
     目的
     首先,评价香莲栓治疗RVVC的临床疗效。其次,观察RVVC对广东地区患者生存质量的影响。最后,以阴道局部免疫因子为指标,探讨香莲栓是否能对患者阴道局部的免疫功能起到一定的调节作用。
     方法
     采用前瞻性、随机、双盲/双模拟,平行对照临床试验的原则,将纳入的60例患者随机分为治疗组和对照组。治疗组给予香莲栓和达克宁模拟剂,对照组予达克宁栓和香莲模拟栓剂。用药方法和疗程两组相同,均是借鉴RVVC的推荐治疗方案,强化治疗6天,巩固治疗3天。主要观察指标包括患者的症状、体征、生存质量、病原学和阴道局部免疫因子等。
     纳入符合真菌镜检阴性等标准的健康对照受试者16名。主要观察生存质量和阴道局部的免疫因子等相关指标,并与RVVC患者的检测结果进行比较,分析差异是否具有统计学意义。
     结果
     16名健康对照组与60名RVVC患者间平均年龄的差异无统计学意义。30名治疗组和30名对照组患者间的年龄进行分段比较,差异无统计学意义。
     强化治疗阶段,香莲栓组治疗RVVC的有效率为26.67%(n=8),达克宁栓组的有效率为43.33%(n=13),两组间有效率差异无统计学意义。在后续的第一次巩固治疗后,香莲栓组和达克宁栓组的有效率均达到53.33%(n=16),两组间有效率的差异无统计学意义。
     RVVC患者在对6个维度的生存质量进行评估过程中发现患者的生存质量明显下降。所有评估项目中,患者对心理压力的感受最为明显,平均分达到3.12分。心理压力包括了缺乏自信(1.25分),影响着装(0.98分)、购物(0.88分)等方面。对患者社交活动的影响平均分值为1.72,其中对社交休闲的影响为0.88,而对运动的影响为0.87。对患者日常工作和学习造成影响的平均分值为1.10分,说明本病对患者的工作学习虽有一定的影响,但并不会造成患者无法进行必须的工作。在家庭生活方面,平均分值为2.65,仅次于对心理健康的影响。其中,限制其对家人的照顾和性生活方面的分值分别为1.18和1.47。而治疗对生活的影响仅为1.00,是所有影响因素里最不明显的一项。
     29例香莲栓组患者经过6天的强化治疗,生存质量在自觉症状和家庭生活方面得到一定的改善。外阴阴道自觉症状(瘙痒、疼痛)的分值由1.6667降至1.3000,差异具有统计学意义,P<0.05。家庭生活方面平均分值由2.8667降至2.4000,差异具有统计学意义,P<0.05。但治疗前后,患者在心理、社交、工作和治疗等方面的影响差异不显著,无统计学意义。
     28名达克宁栓组患者经过6天的达克宁栓的强化治疗,生存质量方面得到一定的改善。首先,患者主观症状(瘙痒、疼痛)的平均分由1.607下降至1.0714,差异具有统计学意义,P<0.05。其次,家庭生活方面也得到改善,分值由2.3571下降至1.7500,差异具有统计学意义,P<0.05。而治疗前后,患者在心理、社交、工作和治疗等方面的影响差异不显著,无统计学意义。
     治疗前RVVC患者阴道分泌物中总蛋白、IL-4和IL-10的含量明显高于健康对照者,IL-12和IL-23的含量则显著低于健康对照组,差异均具有统计学意义(P<0.05),而IL-25的含量与健康对照者间的差异无统计学意义(P>0.05)。香莲栓组和达克宁栓组的患者在治疗前,阴道局部各项免疫指标间的免疫水平无显著差异,无统计学意义(P>0.05)。
     经过6天的强化治疗,香莲栓组患者阴道局部总蛋白的含量显著减少,平均值由0.22934641减至0.16027714,差异具有统计学意义,P<0.05;其余白介素指标均无显著差异,P>0.05。与健康对照组进行比较,香莲栓组的总蛋白和IL-25的含量虽然高于健康对照组,但差异不具有统计学意义,P>0.05。其余白介素指标均仍存在显著差异,P<0.05。达克宁栓组患者阴道局部的总蛋白定量显著减少,平均值由0.23479095减至0.15410034,差异具有统计学意义,P<0.05。其余白介素指标均无显著差异,P>0.05;再与健康对照组阴道局部的免疫因子进行比较,总蛋白和IL-25的含量虽然高于健康对照组,但差异不具有统计学意义,P>0.05。其余白介素指标均仍存在显著差异,P<0.05。香莲栓组与达克宁栓组间进行相互比较,香莲栓组的IL-10含量显著低于达克宁栓组,差异具有统计学意义,P<0.05。其余免疫指标指标均未发现显著差异,P>0.05。
     经过6天的强化治疗和3天的巩固治疗后,香莲栓组阴道分泌物检测的总蛋白含量明显降低,有统计学意义P<0.05.其它免疫因子含量的变化不显著,无统计学意义,P>0.05。达克宁栓组患者阴道检测总蛋白和IL-23的含量显著降低,均值差异分别由0.24074957降至0.15068855和21.81750降至21.61740,差异具有统计学意义,P<0.05。其余白介素指标未见显著差异。与健康对照组相比,香莲栓组IL-12和IL-23的含量低于健康对照组,差异有统计学意义,P<0.05;IL-10的含量显著高于健康对照组,差异有统计学意义,P<0.05;但总蛋白和IL-4和IL-25的含量无明显差异,无统计学意义,P>0.05。达克宁栓组与健康对照组相比,IL-23的含量显著低于健康对照组,IL-4和IL-10的含量则明显高于健康对照组,差异均具有统计学意义。但总蛋白、IL-12和IL-25的含量无明显差异,无统计学意义,P>0.05。此时,香莲栓组IL-4的水平显著高于达克宁栓组,而IL-10的水平则明显低于达克宁栓组,差异具有统计学意义,P<0.05;其余免疫指标在两组间无显著差异。
     结论
     香莲栓治疗RVVC的临床疗效同达克宁栓相当。RVVC患者在6个维度的生存质量方面均受到显著的负面影响。通过香莲栓或达克宁栓的治疗,患者在自觉症状和家庭生活两个维度方面均能得到一定的改善。通过强化治疗和巩固治疗,香莲栓在一定程度上对RVVC患者阴道局部免疫因子的水平起到有效的调节作用。
Introduct ion
     Vaginal candidiasis is seen predominantly in women of childbearin g age, and frequently in the absence of obvious predisposing factors. Recurrent vulvovaginal candidiasis (RVVC) is defined as at least four discrete episodes of symptomatic infection occurring in a year. It i s estimated that 5% of all women who have a single episode of vaginal candidiasis will experience chronic or recurrent infection.
     Scholars have gradually realized although candida is the pathogen, but vaginal local immune function disorder are closely related with repeated attacks from patients. Th1/Th2 cell polarization in vaginal is one of the most important reason for unbalance of local immune fun ction. Type 1 immune response is protective, while IL-12 is the repre sentative cytokine. IL-23 is a newly identified member in the family of IL-12, which is structurally related to IL-12. The ability of IL-2 3 to stimulate CD4+T cells to produce IL-17 plays a dominant role in the development and persistence of autoimmunity. Type 2 immune respo nse is suppressive, while IL-4 and IL-10 are the representative cytok ines. IL-25 is a newly identified member in the family of IL-17. All of them are found to induce the proliferation of eosnophilis and prom ote inflammatory response.
     Although vaginal candidiasis may be regarded ans a minor conditio n in that it is transitory and its physical effects are not seriously damaging, many authors report that recurrent vaginal candidiasis can result in "significant morbidity",serious social consequences and profoundly distressing deterioration in quality of life, including em otional relationships and sexual functioning. This may lead to excess ive demands on healthcare system and if the women's perception of th e illness is not appreciated by the medical practitioner this can add a further frustrating dimension to the clinical problem.
     Traditional Chinese medicine has its unique advantages on treatme nt of dermal mucous fungal disease. According to the previous researc h, Xiang Lian outside lotion is a Chinese traditional medicine. It ha s a significant effect on vaginal candidiasis and other dermal mucous fungal disease. There is a need for novel antifungal drugs, as some of the currently available antimycotics are frequently toxic at thera peutic dosage, and there have been several reports of the isolation o f strains of important fungal pathogens which are resistant to antifu ngals. On the other hand, dysfunction of immunity in vaginal may be t he main reason for recurrent vulvovaginal candidiasis. Traditional Ch inese medicine antifungal lacks host toxicity, it has extensive sourc es and rarely resistance. It's suitable for long and preventive appl ication. Compound Chinese herbs can play synergistic effect of antifu ngal activity and regulating the immunity function.
     Objective
     First, to evaluate the clinical effectiveness of Xiang Lian suppositories for recurrent vulvovaginal candidiasis. Secondly, to evaluate quality of life (QOL) of recurrent vulvovaginal candidiasis patients. Finally, to explore whether Xiang Lian suppositories play a regulatory role in local vaginal immune function of the patients.
     Method
     In this study, block random, double-bland, donble dummy and contrast clinical research methods were applied.60 cases of reccurent valvaginal candidiasis were divided randomly into two groups including 30 cases in trial group and 20 cases in contral group. The patients of trial group were given the Xiang Lian suppositories and Miconazole Nitrate simulating agents, while those in control groups were given Miconazole Nitrate suppositories and Xiang Lian simulating agents. All of the patients are prescribed 2 suppositories in the night and 2 simulating agents during the day. The intensive treatment lasts for 6 days, and consolidate 3 days of medication treatment. Symptoms, signs, etiology quality of live, etiology and vaginal local immune factors are main evaluating index for clinical effects.
     16 cases of health control group were included by negeative leucorrhea routine test. Quality of live and vaginal local immune factors are main evaluating index for comparing with reccurrent vulvovaginal patients.
     Result
     60 patients and 16 healthy controls have no significant differences between ages. Trial groups and control groups were compared between age sections, the differences are not statistical significant.
     Quality of life evaluation results show that patients were suffering from recurrent vulvovaginal candidaisis. The negative influences are remarkable in six dimensions. Psychological pressure is the most obvious factor for patients, Average score can reach 3.12 points. The mental pressure includes lack of confidence (1.25 points), dress affecting (0.98 points), shopping (0.88 points), etc. The influence of social activities for patients is 1.72 scored, including social leisure (0.88 points), and exercise (0.87 points). Though the disease may influence patients'daily life and work, but wouldn't cause patients unable to do, and the average score is 1.10 points. Influence on family life is 2.65 points, which is second only to mental pressure. Among the family life, limit for family care and sexual function respectively score 1.18 and 1.47 points. Influence for treatment is only 1.00 points, and it's the least negative factors.28 control patients had improved their some living quality after 6 days'intensive therapy. First, subjective symptoms (vulva vaginal prutitus and pain) have been improved, and average score fell to 1.0714 from 1.607 significantly. Secondly, quality of family life also has been improved from 2.3571 score dropped significantly to 1.7500. However, there were no significant differences between psychological, social, work and treatment effect.29 trial patients also had improved their qualities of symptoms and family life after 6 days'intensive therapy. The score of Vulvar vaginal consciously itch and pain fall to 1.3000 from 1.6667. Average score of family life dropped significantly from 2.8667 to 2.4000. However, patients have not significant differences between paychological, social, work and treatment effect.
     After the intensive treatment phase, efficient rate of Xiang Lian suppositories is 26.67%(n=8), while Miconazole Nitrate suppositories therapy is 43.33%(n=13). The difference between two groups is not significant, but efficiency of trail group is lower than the control group. After subsequent consolidate treatment, both of two treatment groups have efficiency of 53.33% (n=16).
     There were higher contents of immunological factors (total protein, IL-4 and IL-10) in vaginal fluide of Recurrent vulvovaginal candidiasis patients before treatment, compared with the healthy controls. However, contents of IL-23 and IL-12 were significantly lower than the healthy group. Besides, contents of IL-25 had no significant difference between two groups. There were not significant differences of immunological factors between trial groups and control groups. After the intensive treatment phase, contents of total protein had been reduced significantly from 0.23479095 to 0.15410034, and other factors had no significant differences. Contents of total protein and IL-25 is higher than healthy groups, but differences were not significant. However, other factors had significant differences. Meanwhile, trial groups reduced content of total protein significantly from 0.22934641 to 0.16027714 after intensive therapy, and other factor's content had no significant differences. Then compared with healthy groups, contents of total protein and IL-25 is higher than healthy groups, but differences were not significant. However, other factors had significant differences. Contents of IL-10 of trail group is significant lower than control groups'. After 3 days' consolidating treatment, contents of total protein and IL-23 reduced in control groups, while other factors had no significant differences, meanwhile, total protein of trial groups had reduced significantly, and other factors had no significant differences. After intensive and consequent consolidating treatment, control groups had a lower contents of IL-23 and higher contents of IL-4 and IL-10 than healthy groups', while other factors had no significant differences. Trail groups had lower contents of IL-12 and IL-23 but higher contents of IL-10 than healthy groups after intensive and consequent consolidating treatment, while other factors had no significant differences. Compared two treatment groups, trial groups had higher content of IL-4 and lower content of IL-10 than control groups significantly, and other factors had no significant differences.
     Conelusion
     Effective rates of the Xiang Lian suppositories and Miconazole Nitrate suppositories'are similar. Recurrent vulvovaginal candidiasis patients suffered negative effects from the disease in six dimensions of the living quality. Symptoms and family life among living quality can be improved after therapy in both treatment groups. Xiang Lian suppositories may played a part in regulating vaginal local immune factors.
引文
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