外用磷酸二酯酶4抑制剂软膏治疗斑秃一例附文献复习

斑秃既往治疗包括局部外用药物治疗(糖皮质激素、米诺地尔等)、系统药物治疗(口服糖皮质激素、甲氨蝶呤、环孢素等)以及物理疗法(如光化学疗法PUVA、308 nm准分子激光等)。磷酸二酯酶4(PDE-4)抑制剂通过增加细胞内环磷酸腺苷(cAMP)水平,进而调节一系列细胞因子发挥免疫调节作用。国外曾有口服PDE-4抑制剂治疗斑秃的动物模型研究和病例报道,但存在较多的不良反应。克立硼罗软膏是近年来新研发的外用磷酸二酯酶4(PDE-4)抑制剂,曾报道用于特应性皮炎、银屑病和白癜风等皮肤病的治疗,其治疗斑秃的二期临床试验正在开展,目前国内外尚无治疗斑秃的正式报道。我们报道一例外用磷酸二酯酶4抑制剂治疗斑秃的患者,取得良好治疗效果,未见明显不良反应。     

银屑病患者外周血白细胞磷酸二酯酶活性检测及临床意义

目的通过检测正常人群和银屑病患者外周血白细胞磷酸二酯酶（phosphodiesterase,PDEs）活性,探讨PDEs活性在银屑病发病中的作用。方法对50例银屑病患者及60名健康对照者外周血白细胞应用高效液相色谱法（HPLC）检测PDEs活性。结果银屑病患者外周血白细胞PDEs活性为（10．40±3．54）％,健康对照者为（8．60±2．25）％,两者差异有统计学意义（P〈0．05）。结论外周血白细胞PDEs活性与银屑病的发病可能具有相关性。     

银屑病发病机制中免疫学研究进展

银屑病的发病机制与免疫关系密切,近几年研究倾向于银屑病是Th1/Th17混合途径的免疫性疾病.银屑病的发病中除了有树突细胞、T细胞、角质形成细胞以及Tb1型的细胞因子如白介素12、白介素18等参与外,还有Th17型细胞因子,如白介素23及白介素22等的参与,Th17型免疫反应可能在银屑病发病中起到重要的作用.     

5型磷酸二酯酶抑制剂对精液质量影响的研究进展

磷酸二酯酶-5抑制剂(phosphodiesterase-5 inhibitor,PDE5i)常用于阴茎勃起功能障碍的治疗,也越来越多的被用于肺动脉高压、心脏移植、肿瘤、良性前列腺增生引起的下尿路症状、早泄、不孕症等的临床治疗。研究表明,PDE5抑制剂可能会影响精液质量,在动物研究和人群研究中各有不同的结果。本文将结合国内外相关文献对PDE5抑制剂对精液参数的影响的相关研究进展进行综述。     

银屑病瘙痒机制及治疗研究进展

瘙痒是银屑病患者的一种常见症状,严重影响患者的生活质量.但其瘙痒的机制尚不清楚,许多常规治疗瘙痒的药物并不能有效缓解银屑病的瘙痒.目前认为,银屑病皮损中神经分布异常增多和敏感性增加,炎症细胞在病灶中聚集、活化并释放炎症介质是银屑病瘙痒的主要原因.抗组胺药不能有效控制银屑病瘙痒,而神经肽受体拮抗剂、免疫抑制剂及光疗等为治疗银屑病瘙痒的有效方法.

Abstract：

Pruritus is an important symptom of psoriasis.It seriously affects the quality of life of psoriatic patients,but its pathogenesis remains unanswered.Many routine treatments cannot relieve the pruritus in psoriasis effectively.It has been demonstrated that the pruritus in psoriasis is mainly attributed to the abnormally increased innervation and sensitivity of sensory nerves,as well as the aggregation,activation of and release of inflammatory mediators by inflammatory cells.Antihistamine drugs are usually ineffective for the treatment of pruritus in psoriasis,while antagonists of neuropeptide receptors,immunosuppressants and phototherapy have shown favorable efficacy.     

银屑病免疫学的研究进展

银屑病是一种基因、环境、精神心理等多种体内外因素导致的慢性炎症性皮肤病,各种免疫细胞特别是各型CD4+辅助性T细胞及其分泌的细胞因子形成复杂的调控网络,调节银屑病的发病及转归,如IL-23/Th17轴、IL-4/Th2轴等信号通路.抗原提呈细胞、自然杀伤细胞等介导的固有免疫和T细胞介导的获得性免疫是维持免疫稳态的基础,综合银屑病相关的免疫细胞、获得性免疫细胞及其信号传导的最新研究成果,进一步阐述银屑病的免疫学发病机制.     

蛋白激酶C、JAK、磷酸二脂酶的小分子抑制剂在银屑病治疗中的研究进展

银屑病是一种慢性复发性炎症性疾病,临床表现为皮肤的鳞屑性红斑,部分患者可累及关节。尽管目前针对特异性炎症性细胞因子和免疫细胞的生物制剂在银屑病治疗中取得了较为满意的疗效,但仍缺乏长期安全有效而经济的治疗药物。小分子抑制剂是一些相对分子质量〈1000的化合物,主要针对一些细胞内信号通路或分子靶点,如蛋白激酶C、JAK通路、磷酸二酯酶等。小分子抑制剂最初在一些自身免疫性疾病和炎症性疾病中应用,现已进入寻常性银屑病和关节病性银屑病的Ⅱ期和Ⅲ期临床试验并取得了较为满意的疗效。因此,小分子抑制剂有望成为治疗银屑病的选择之一。     

外用磷酸二酯酶4抑制剂在特应性皮炎中的研究进展

特应性皮炎(AD)是一种反复发作的炎症性皮肤病,患者往往有剧烈瘙痒,严重影响生活质量。在过去,AD的治疗主要是外用糖皮质激素或钙调神经磷酸酶抑制剂。以上药物在治疗的同时常有一些显著的不良反应和局限性。因此,需开发一种更加安全有效且副作用小的药物。环核苷酸磷酸二酯酶4(phosphodiesterase 4, PDE4)是炎症细胞和免疫细胞中水解环磷腺苷(cAMP)的关键细胞内酶。AD患者白细胞中PDE4活性增加可使cAMP降解,导致促炎症因子的激活。因此,靶向抑制PDE4可以下调促炎症因子的产生,实现AD的治疗。PDE4外用制剂可以避免口服药物及传统外用药引起的不良反应,提高安全性和有效性。本文就目前已发表的相关文献对外用PDE4抑制剂治疗特应性皮炎作一综述。     

A comparison of the stimulatory effects of cytokines on normal and psoriatic keratinocytes in vitro

Keratinocytes from normal and psoriatic skin were tested for their in vitro proliferative response to a range of concentrations of rIL-6, rTGF, rIL-8 and rGM-CSF using a serum-free culture system. With one exception, all normal cultures (11/12) were stimulated by 1000 ng/ml IL-6 (P<0.001). Six out of ten psoriatic keratinocyte cultures were also stimulated at this concetration, but this just failed to reach significance (P=0.05). As a group, the response by psoriatic keratinocytes to IL-6 was significantly less than that of normal keratinocytes (P=0.02). TGF at 1 ng/ml induced proliferation in approximately 60% of both normal (8/12,P<0.05) and psoriatic (6/10,P<0.1) keratinocyte cultures; there was no significant difference between the responses of the two groups to this cytokine. In addition, small numbers of both normal and psoriatic cultures responded to TGF over a concentration range of 0.1 to 100 ng/ml. Approximately half of the normal and psoriatic cultures were stimulated by 10–1000 ng/ml IL-8. However, the effect was not significant for the group at any of the concentrations tested. GM-CSF had minimal to no effect on most of the normal and psoriatic cultures tested. This study showed that psoriatic keratinocytes are equally responsive to the stimulatory effects of TGF and IL-8, but are less susceptible to IL-6 compared to keratinocytes from normal skin. These findings are consistent with a role for these cytokines in the maintenance of a hyperproliferative epidermis in psoriasis.     

某些治疗银屑病药物对PAF致皮肤炎症反应的影响

研究局部应用蒽林、地塞米松、氮芥对豚鼠皮肤内注射血小板活化因子（ＰＡＦ）致炎症反应的影响。结果发现，蒽林、地塞米松均能抑制血小板活化因子致皮肤炎症反应，以蒽林作用更强，氮芥则对皮肤炎症细胞浸润无抑制作用。提示，蒽林、糖皮质激素抑制炎症细胞浸润可能是其抗银屑病的机制之一。     

Newer treatments of psoriasis regarding IL‐23 inhibitors,phosphodiesterase 4 inhibitors,and Janus kinase inhibitors

The rapid progress of genetic engineering furthermore opens up new prospects in the therapy of this difficult‐to‐treat disease. IL‐23 inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and Janus kinase (JAK) inhibitors are currently encouraging further research. Two drugs which are IL‐23 inhibitors are now in phase III of clinical trials. The aim of the action of both drugs is selective IL‐23 inhibition by targeting the p19 subunit. Guselkumab is a fully human monoclonal antibody. Tildrakizumab is a humanized monoclonal antibody, which also belongs to IgG class and is targeted to subunit p19 of interleukin 23 (IL‐23). Phosphodiesterase inhibitors exert an anti‐inflammatory action and their most common group is the PDE4 family. PDE4 inhibits cAMP, which reduces the inflammatory response of the pathway of Th helper lymphocytes, Th17, and type 1 interferon which modulates the production of anti‐inflammatory cytokines such as IL‐10 interleukins. The Janus kinase (JAK) signaling pathway plays an important role in the immunopathogenesis of psoriasis. Tofacitinib suppresses the expression of IL‐23, IL‐17A, IL‐17F, and IL‐22 receptors during the stimulation of lymphocytes. Ruxolitinib is a selective inhibitor of JAK1 and JAK2 kinases and the JAK‐STAT signaling pathway. This article is a review of the aforementioned drugs as described in the latest available literature.     

The antipsoriatic activity of IL-10 is rather caused by effects on peripheral blood cells than by a direct effect on human keratinocytes

Abstract IL-10 is a promising candidate for the treatment of cutaneous disorders. Antipsoriatic efficacy of systemic IL-10 treatment has been already demonstrated. This includes histomorphological changes in the epidermis, suggesting effects on keratinocytes. However, less is known about direct effects of IL-10 on this cell population, although effects are likely since IL-10 receptor expression on keratinocytes has been demonstrated recently. Therefore we analysed the effects of IL-10 on keratinocytes in vitro, using concentrations of human recombinant IL-10 corresponding to those detectable in plasma during therapy. Proliferation, cytokine formation (IL-6, IL-8, IL-1ra), and expression of surface molecules (MHC class I and II, costimulatory molecules CD80 and CD86, CD29, CD54, CD95) were measured in stimulated and unstimulated cells. Although stimulation influenced the expression levels of certain surface markers, no or only slight effects of IL-10 were found. In contrast considerable inhibitory effects of IL-10 on surface molecule expression and cytokine secretion by peripheral blood human monocytes were observed. Our results suggest that the antipsoriatic activity of IL-10 is rather caused by modulatory effects on circulating immune cells, which subsequently might infiltrate the skin, than by direct effects on human keratinocytes. Considering the remarkable antipsoriatic activity of IL-10 and the observation that IL-10 seem to act on peripheral blood mononuclear cells but not on keratinocytes provide further evidence that circulating immune cells play a key role in the pathology of psoriasis. Finally, our results argue against the value of IL-10 therapy in dermatoses strictly limited to keratinocyte involvement. Received: 19 July 1999 / Revised: 6 December 1999 / Accepted: 10 December 1999     

Non-invasive assessment of the antipsoriatic activity of fumaric acid derivatives

Background/aims: Noninvasive methods are introduced for the monitoring of healing of psoriasis. Fumaris acid derivatives (FAD) were used in the treatment of psoriasis vulgaris for more than 30 years, but the effectiveness of these drugs has remained controversial. The object was to study the efficacy of FAD in a prospective study including noninvasive techniques, which may allow more accurate assessment in a smaller patient group.
Methods: High-frequency ultrasound including image analysis, and colorimetry was employed. 14 patients were treated for 20 weeks.
Results: In the ultrasound image, acanthosis and inflammatory infiltrate of active psoriasis cause an echopoor area under the entry echo. Under theray, this echo area diminishes while its density increases. During healing, the decrease in redness could be quantified.
Conclusions: Monitoring of the healing of psoriasis is possible with ultrasonography and colorimetry. Fumaric acid was found efficient and safe in the treatment of psoriasis.     

消银汤联合卡泊三醇软膏对血热型寻常性银屑病疗效及相关细胞因子水平的影响

目的 探讨消银汤联合卡泊三醇软膏治疗进展期血热型轻/中度（PASI评分 < 10）寻常性银屑病疗效和对IL-17、IL-22、TNF-α水平影响。方法 60例进展期血热型轻/中度寻常性银屑病患者分为治疗组及对照组,每组各30例。治疗组予消银汤口服;对照组予安慰剂口服,2组同时外用卡泊三醇软膏;另选志愿者30例作为健康对照组;疗程12周。记录治疗前、后PASI评分,检测治疗前、后Th17细胞、TNF-α、IL-22、IL-17水平。结果 治疗前,与健康对照组相比,治疗组及对照组在Th17细胞水平及血清IL-17、IL-22和TNF-α水平差异有统计学意义（P ＜ 0.05）,治疗组及对照组水平高于健康对照组;治疗后,上述指标与治疗前比较,差异有统计学意义（P ＜ 0.05）。治疗组治疗后PASI评分为（1.83 ± 1.28）,对照组为（2.91 ± 1.42）,差异有统计学意义（P ＜ 0.05）。治疗组总有效率为93.33%,与对照组总有效率73.33%比较差异有统计学意义（P ＜ 0.05）。治疗组在PASI评分,治疗总有效率及细胞因子水平改善方面优于对照组。结论 Th17细胞及血清IL-17、IL-22和TNF-α水平在轻/中度寻常性银屑病患者存在异常,消银汤联合卡泊三醇软膏对此有改善作用。     

T淋巴细胞及细胞因子与银屑病的发病关系

近年来一些新的研究发现，银屑病患者外周血的T细胞表面的CD80和天然杀伤细胞受体的表达明显上调，单核细胞的活性也有所改变，而T细胞还可以影响正常皮肤的表皮通过时间，皮损中调节性T淋巴细胞亚群也有变化，白介素-23、20、19以及α-干扰素对银屑病的发病均有促进作用。一些新的免疫学研究发现，CD11α单抗、LFA-3／IgGl融合蛋白、TNF—α已经成为银屑病免疫治疗中较为成熟的疗法，而粒细胞-巨噬细胞集落刺激因子单抗IgGl，CD4单抗及补体受体3抗体的治疗作用在动物实验中已得到初步验证，有望为银屑病的治疗提供新的突破点。