Efficacy and safety of mizolastine 10 mg in a placebo-controlled comparison with loratadine in chronic idiopathic urticaria: results of the MILOR Study.

BACKGROUND: Mizolastine is a novel histamine H1-antagonist registered in Europe for the management of allergic rhinitis and urticaria. OBJECTIVES: To compare the clinical efficacy and safety of mizolastine with loratadine and placebo in patients with chronic idiopathic urticaria (CIU). METHODS: A multicentre, double-blind, parallel group study was designed in which 247 patients with CIU were randomised after a 1-week placebo run-in period to 10 mg daily mizolastine (n = 88), 10 mg daily loratadine (n = 79), or placebo (n = 80) for a 4-week treatment period. RESULTS: Mizolastine and loratadine both relieved symptoms of CIU. After 2 weeks' treatment, the severity of pruritus (visual analogue score (VAS) assessed by patients) decreased significantly in both the mizolastine and loratadine groups compared with placebo (mizolastine: -36.7 mm, P = 0.0001; loratadine: -29.8, P = 0.0071; placebo: -16.3); this improvement with both active treatments was maintained throughout the treatment period, the difference being significant only for the mizolastine group (P = 0.0090). Both active treatments were also associated with reduced weekly episodes of urticaria compared with placebo, which was significant after 2 weeks' treatment (mizolastine: 7.9 episodes, P = 0.0061; loratadine: 8.3, P = 0.0221; placebo: 13.3). Angioedema was improved to a clinically significant extent with mizolastine, and loratadine compared with placebo in those patients who had this symptom before treatment. Overall tolerability of both treatments was similar to placebo, and there were no clinically relevant effects on cardiac repolarisation with either mizolastine or loratadine. CONCLUSION: Mizolastine (10 mg daily) is confirmed as an effective and well tolerated agent, comparable to loratadine and superior to placebo, for the management of CIU. Mizolastine acted as rapidly as loratadine in improving urticarial symptoms from the first day of treatment.     

3种抗组胺药抗组胺及抗花生四烯酸作用的比较研究

目的:比较咪唑斯汀、氯雷他定、西替利嗪3种抗组胺药的抗组胺及抗花生四烯酸的作用。方法:给大鼠左、右爪分别皮下注射花生四烯酸(1.0g/L,0.1mL)和组胺(10g/L,0.1mL)构建鼠爪水肿炎性模型。在注射花生四烯酸和组胺2h前分别给予咪唑斯汀、氯雷他定、西替利嗪(0.6mg/kg)灌胃,注射后应用体积测量仪分别测定给药后鼠爪体积在不同时间点的变化。结果:咪唑斯汀可抑制花生四烯酸所致的鼠爪水肿(P<0.05),西替利嗪、氯雷他定对其无明显抑制作用;咪唑斯汀对组胺所致的鼠爪水肿有抑制作用(P<0.05),抑制作用强于氯雷他定组,但与西替利嗪组比较无统计学差异(P>0.05)。结论:咪唑斯汀具有抗组胺和抗花生四烯酸的作用,且其抗组胺作用强于氯雷他定;与氯雷他定、西替利嗪相比,咪唑斯汀表现出其独特的抗花生四烯酸的作用。     

咪唑斯汀抑制多形核白细胞白三烯LTB4合成的实验研究

目的：研究咪唑斯汀的抗炎机制。方法：采用皮下植入0．5％花生四烯酸浸泡的海绵做为抗原刺激剂的方法。各组分别在植入前、后2h灌胃给药地塞米松（0．1mg／kg）、咪唑斯汀高剂量（0．3mg／kg）、咪唑斯汀低剂量（0．1mg／kg）、氯雷他定（0．3mg／kg）,结合高效液相的分析方法,定量检测炎症关键产物——白三烯LTB4的生成量。结果：与模型对照组比较,地塞米松组、咪唑斯汀高剂量组有较强的抑制作用（P＜0．01）、咪唑斯汀低剂量组显示出抑制作用（P＜0．05）、而氯雷他定组无抑制作用（P＞0．01）。结论：咪唑斯汀可有效抑制多形核白细胞合成LTB4,咪唑斯汀的抗炎作用机制可能主要通过抑制5-脂氧合酶活性发挥作用。     

咪唑斯汀和氯雷他定抗炎作用的比较研究

目的:检测咪唑斯汀的抗炎活性,探讨咪唑斯汀抗炎症的作用机制。方法:建立花生四烯酸诱导小鼠耳部肿胀的模型,了解咪唑斯汀和氯雷他定对花生四烯酸诱导的耳部肿胀的抑制作用;同时用酶免疫法检测小鼠血液中的白三烯浓度。建立角叉菜胶诱导的大鼠鼠爪肿胀模型,了解咪唑斯汀和氯雷他定对角叉菜胶诱导的炎症的抑制作用。结果:咪唑斯汀可抑制花生四烯酸诱导的耳部水肿,对角叉菜胶诱导的鼠爪水肿无抑制作用;但氯雷他定对两种致炎剂诱导的水肿均无抑制作用。结论:咪唑斯汀具有显著的抗炎作用,其机制是抑制5-脂氧合酶的活性,阻止白三烯的产生而发挥其抗炎活性。     

One-year treatment of chronic urticaria with mizolastine: efficacy and safety

AIM: To assess the long-term safety and efficacy of the H1-receptor antagonist mizolastine in the symptomatic treatment of chronic urticaria (CU). BACKGROUND: Mizolastine is a novel second generation antihistamine with additional anti-inflammatory properties which has been shown to be effective in this condition as well as in allergic rhinitis. As the drug is used for chronic treatment, a detailed study of its efficacy and safety over a prolonged period was warranted. METHODS: This open label multicentre trial recruited 211 patients suffering from CU (67% female; mean age 40+/-13 years), with > or = 1 episode/week if untreated. After a 7-day placebo run-in period, patients received mizolastine (10 or 15 mg) for 12 months. Efficacy was assessed by the patient using daily diary cards and overall condition evaluation at study visits. Clinicians also assessed the same parameters at each visit, and gave a global assessment at study termination. Safety was assessed by monitoring adverse events and laboratory parameters. Cardiac safety was monitored every 4 months using 12-lead ECGs, with particular attention to QT intervals. RESULTS: The trial was completed by 127 patients. Mizolastine reduced overall discomfort from the second week of therapy, and reduced itching and the number and size of wheals, as assessed by the patients. The clinician's assessment of the proportion of patients with > 10 wheals decreased from 42% to 28% after 2 months. Clinical assessment also indicated that itch intensity and angioedema were improved by mizolastine, and the improvement was sustained throughout the trial. The investigators estimated that 70% of patients benefited from therapy. There were no drug-related serious adverse events during the study. The cardiac repolarization assessed according to the QTc intervals was not modified during prolonged administration. CONCLUSION: Mizolastine improves CU symptoms, and these improvements are sustained over 12 months with no loss of drug sensitivity. No specific side-effects are associated with its long-term use in the current study.     

咪唑斯汀治疗慢性荨麻疹的随机双盲研究

目的 评价咪唑斯汀治疗慢性荨麻疹的疗效和安全性,并与氯雷他定进行比较。方法 多中心、随机双盲、平行对照临床试验。结果 5个研究中心共入选慢性荨麻疹患者213例,纳入疗效分析共206例,其中咪唑斯汀组104例,氯雷他定组102例。治疗结束时,咪唑斯汀组总有效率(痊愈+显效)为80.8%,氯雷他定组为74.5%,两组差异无显著性(χ²=1.16,P=0.28)。咪唑斯汀组于治疗后第1周时,对控制风团大小、每周发作次数及直观模拟标尺法(VAS)瘙痒程度平均值明显优于对照组,两组差异均有显著性(P=0.05,P=0.03和P=0.02)。至第2、4周时,两组间比较差异无显著性(P>0.05)。咪唑斯汀组不良事件发生率为28.6%,对照组为25.5%,差异无显著性(χ²=0.25,P=0.62)。结论 口服咪唑斯汀或氯雷他定10mg/d治疗慢性荨麻疹疗效相似,但咪唑斯汀似乎比氯雷他定组起效更快,两组不良事件发生率及表现无明显差异。     

咪唑斯汀对花生四烯酸诱导的鼠爪水肿的影响

目的 探讨咪唑斯汀抗炎活性的产生机制。方法 大鼠鼠爪皮下注射0.1 mL的花生四烯酸(体积分数为0.003)诱导鼠爪水肿炎性动物模型。注射前灌胃分别给予咪唑斯汀、氯雷他定、西替利嗪(0.3 mg/kg),用千分尺测量肿胀足爪厚度,比较不同抗组胺药对鼠爪肿胀抑制程度的高低。分别给予大鼠5-脂氧合酶的直接抑制剂齐留通(3 mg/kg)和咪唑斯汀(0.3 mg/kg),比较2种药物对鼠爪肿胀抑制程度的高低。结果 咪唑斯汀显著抑制花生四烯酸诱导的鼠爪水肿,氯雷他定、西替利嗪对鼠爪水肿无抑制作用(P<0.01);齐留通显著抑制鼠爪水肿(P<0.01),对鼠爪水肿的抑制率与咪唑斯汀比较差异无显著性(P>0.05)。结论 咪唑斯汀可能通过抑制5-脂氧合酶活性的途径发挥其抗炎活性。     

咪唑斯汀治疗急性荨麻疹起效时间及疗效的观察

目的:探讨咪唑斯汀(皿治林)治疗急性荨麻疹的疗效及起效时间。方法:对35例急性荨麻疹患者给予皿治林10mg口服,观察2h内瘙痒、红晕及风团的变化和起效情况。结果:服药1h内起效的有28.6％,在第2h内起效的有42.9％。其余的28.6％在2h内虽然没有达到起效的积分,但均有明显好转。在服药后的1.5h内,有71.4％患者的瘙痒、62.9％的风团数量及91.4％的红晕均有减轻;服药后2h内所有患者的症状均有不同程度的减轻。结论:皿治林是一种起效快、疗效好、不良反应少的长效抗组胺药物。     

咪唑斯汀抗炎作用的实验研究

目的了解咪唑斯汀的抗炎活性及抗炎机制。方法建立花生四烯酸诱导耳部肿胀的小鼠模型,了解咪唑斯汀对花生四烯酸诱导的耳部肿胀的抑制作用;酶免疫法检测小鼠血液中的白三烯浓度。结果咪唑斯汀可抑制花生四烯酸诱导的小鼠耳部水肿,但氯雷他定和西替利嗪均不能;白三烯可减弱咪唑斯汀在花生四烯酸诱导小鼠耳部水肿中的抗炎作用,但前列腺素不能。结论咪唑斯汀具有抗炎症作用,其机制可能是抑制5-脂氧合酶的活性,阻止白三烯的产生而抑制炎症。     

咪唑斯汀、氯雷他定及西替利嗪对小鼠变应性接触性皮炎作用的比较研究

目的:比较咪唑斯汀、氯雷他定及西替利嗪对小鼠变应性接触性皮炎(ACD)的抑制作用。方法:建立小鼠ACD模型,采用致敏前及诱发后两种给药方法,口服不同剂量咪唑斯汀、氯雷他定及西替利嗪,观察抑制作用。结果:致敏前开始给药,3种药物均能明显抑制ACD小鼠耳肿胀(P<0.05),但咪唑斯汀的抑制作用强于氯雷他定及西替利嗪(P<0.05);诱发后开始给药,咪唑斯汀组小鼠耳肿胀消退快于氯雷他定及西替利嗪(P<0.05)。结论:咪唑斯汀对小鼠ACD抑制作用强于氯雷他定和西替利嗪。     

咪唑斯汀治疗急、慢性荨麻疹70例疗效观察

目的:探讨咪唑斯汀(皿治林)治疗急、慢性荨麻疹的疗效。方法:对急性荨麻疹40例患者给予口服皿治林10mg,2h后观察疗效;慢性荨麻疹30例患者给予口服皿治林10mg,每日1次,治疗14d。结果:急性荨麻疹患者70％在2h内起效,1h内88％患者瘙痒开始减轻,86％患者风团数开始减少,83％患者红晕程度开始减轻;慢性荨麻疹患者治疗1w临床总有效率为86.6％,2w总有效率100％。结论:使用皿治林口服治疗急、慢性荨麻疹快速起效、持续时间长、安全有效。     

润燥止痒胶囊联合咪唑斯汀缓释片治疗慢性湿疹疗效观察

目的观察润燥止痒胶囊联合咪唑斯汀治疗慢性湿疹的临床疗效。方法将80例临床确诊的慢性湿疹患者随机分为两组,治疗组40例口服润燥止痒胶囊4粒,3次/d,同时口服咪唑斯汀缓释片10mg,外用复方薄荷脑软膏,2次/d;对照组40例口服咪唑斯汀缓释片10mg,外用复方薄荷脑软膏,2次/d;连续治疗4周,根据评分标准进行疗效比较。结果治疗组有效率为87.5%,对照组为67.5%。两组有效率差异有显著性(P<0.05)。结论润燥止痒胶囊联合咪唑斯汀可有效治疗慢性湿疹。     

Influence of mizolastine on antigen-induced activation of signalling pathways in murine mast cells

BACKGROUND: There is accumulating evidence that some antihistamines can interrupt intermediate signalling events that regulate cell function. The effect of mizolastine on both the generation and release process of many cytokines in mast cells further implies that the inhibition by mizolastine may target signalling pathways. AIM: To observe the influence of mizolastine on antigen-induced activation of signalling pathways in murine mast cells. METHODS: Western blot analysis and enzyme assay were performed. Immunoblots were prepared from whole cell lysates and probed with antibodies against Fyn, Akt, ERK, p38, phospho-Fyn, phospho-Akt, phospho-ERK and phospho-p38, respectively. RESULTS: Our study showed that signalling molecules such as IP3, Fyn, p38 and ERK were enhanced when mast cells were stimulated by antigen, and that this was not inhibited by treatment with mizolastine. Mizolastine at concentrations from 10(-9) to 10(-5) mol/L could inhibit activation of the PI3K kinase downstream signalling molecule Akt to antigen stimulation. The study also demonstrated that mizolastine exerted inhibitory ability on protein kinase C (PKC) activation in a dose-dependent manner. CONCLUSION: PKC-mediated phosphorylation of Akt can be blocked by mizolastine. There may be a PKC-independent pathway effectively activating MAPK pathways in mast cells in response to antigen induction, which cannot be affected by mizolastine.     

咪唑斯汀对致敏小鼠脾淋巴细胞释放LTB_4和IL-5的抑制作用

目的　观察咪唑斯汀对卵蛋白(OVA)致敏的小鼠脾淋巴细胞释放白三烯B4 (LTB4)和白介素5 (IL 5)的影响。方法　实验第1天及第15天给小鼠腹腔注射OVA,构建致敏动物模型,分离实验小鼠脾淋巴细胞进行培养,以不同浓度咪唑斯汀及对照药物预处理,加入OVA再次刺激,采用竞争酶联免疫吸附法(CompetitiveELISA)检测培养细胞上清液中LTB4及IL 5水平。结果　致敏组小鼠脾淋巴细胞培养上清液中LTB4和IL 5水平分别为1 1 1. 0 6±1 5. 9 8pg/ml和333. 54±24. 76pg/ml,较正常组小鼠显著升高(P<0. 01)。1. 0μmol/L和10μmol/L的咪唑斯汀可显著抑制致敏小鼠脾淋巴细胞产生LTB4和IL 5。对照药物为1. 0μmol/L的地塞米松,对LTB4和IL 5的释放均具显著抑制效应;而10μmol/L的扑尔敏及氯雷他定对LTB4和IL 5的抑制不明显。结论　咪唑斯汀对致敏小鼠脾淋巴细胞LTB4和IL 5的释放具有剂量依赖性的抑制作用。     

咪唑斯汀治疗6970例慢性荨麻疹临床研究

目的观察咪唑斯汀治疗慢性荨麻疹的疗效和安全性。方法口服咪唑斯汀10mg,每日1次,连服14d为1个疗程。结果用咪唑斯汀治疗6970例慢性荨麻疹患者,总有效率治疗7d为49.0%,14d达85.0%。治疗后患者的瘙痒、风团大小和数量均有明显改善,治疗7d和14d时分别与治疗前比较,治疗14d时与治疗7d时比较,差异均有非常显著性(P<0.001)。治疗1d后半数患者的症状和体征开始缓解,3d后80%以上出现改善。不良反应少,主要表现为困倦(6.8%,与一般安慰剂的发生率相同)和头晕(1.4%)。结论咪唑斯汀治疗慢性荨麻疹有效而安全。     

咪唑斯汀对小鼠接触性变态反应模型的作用研究

目的探讨咪唑斯汀对小鼠变应性接触性皮炎(ACD)的治疗作用及可能机制。方法以2,4-二硝基氟苯(DNFB)诱发的小鼠ACD为模型,设立两个不同阶段用药组观察3种剂量咪唑斯汀对小鼠耳肿胀、真皮内炎性细胞浸润、血清IL-4,IL-12和IFN-γ水平的影响。结果两个不同阶段用药组咪唑斯汀均能显著抑制ACD小鼠的耳肿胀及真皮炎症细胞浸润,并呈剂量依赖性。咪唑斯汀可降低诱发后24h和72h小鼠血清IL-12和诱发后72hIFN-γ水平。结论咪唑斯汀对小鼠ACD具有治疗作用,这种作用可能与下调致炎性细胞因子的水平有关。     

3种抗组胺药抗花生四烯酸致炎性的比较

目的:观察不同抗组胺药是否具有抗炎作用。方法:给大鼠鼠爪皮下注射花生四烯酸(1.0 g/L,0.1 mL)构建鼠爪水肿炎性模型,在注射花生四烯酸2 h前分别灌胃给予咪唑斯汀、地氯雷他定、依巴斯汀3种抗组胺药(0.3 mg/kg),注射后1、2、3、4h,应用体积测量仪分别测定给药后鼠爪体积的改变。结果:咪唑斯汀(0.3 mg/kg)显著抑制花生四烯酸诱导的鼠爪水肿(P<0.05),地氯雷他定、依巴斯汀对花生四烯酸诱导的鼠爪水肿均无抑制作用(P>0.05)。结论:0.3 mg／kg的咪唑斯汀在体内具有抗炎作用,相同剂量的地氯雷他定、依巴斯汀无抗炎作用。     

咪唑斯汀治疗慢性荨麻疹前后患者血清白三烯B4含量的变化

目的探讨白三烯B4在慢性荨麻疹发病中的意义及咪唑斯汀在治疗慢性荨麻疹中的抗炎作用。方法采用酶联免疫法测定42例慢性荨麻疹患者在咪唑斯汀治疗前后血清中白三烯B4的含量。结果患者治疗前血清白三烯B4水平较正常对照组高,差异有显著性;症状缓解后白三烯B4含量下降,与对照组间差异无显著性;咪唑斯汀治疗前后患者血清白三烯B4水平差异有显著性。结论咪唑斯汀能降低患者血清白三烯B4水平。     

Mizolastine in primary acquired cold urticaria

BACKGROUND: Treatment of primary acquired cold urticaria (CU) is quite difficult because of variable clinical effectiveness and side effects of classic antihistamines. OBJECTIVE: The objective of the study was to assess the efficacy and safety of mizolastine, an antihistaminic with antiallergic properties, versus placebo in primary acquired CU. METHODS: This study was a phase II, multicenter, randomized, double-blind, crossover, placebo-controlled study of mizolastine (10 mg, once daily) versus placebo in 28 patients with primary acquired CU. Efficacy was measured by the cold-stimulation time test, the wheal response, and pruritus intensity after an ice-cube test. RESULTS: Mizolastine delayed the cold-induced wheal reaction, reduced wheal response at 3 and 10 minutes, and reduced pruritus intensity. Statistically significant differences were observed versus placebo for the cold-stimulation time test, wheal response at 3 and 10 minutes, and pruritus intensity (P =.006,.015,.009, and.005, respectively). No clinically relevant adverse events were reported. CONCLUSIONS: Mizolastine (10 mg, once daily) was shown to be superior to placebo for both delaying and reducing the cold-induced wheal reaction without significant adverse events. Results suggest that mizolastine may be effective in the treatment of CU.     

咪唑斯汀治疗荨麻疹多中心临床研究

目的:观察咪唑斯汀治疗慢性荨麻疹的临床疗效的安全性。方法:采用多中心、开放、临床研究方法,人选病例每日日服一片咪唑斯汀(每片10mg),疗程为14d。结果:共治疗858例,其中男400例,女458例。用药后第7 d的有效率为 85．1%,第 14 d的有效率为 95．0%。药物不良反应较轻,发生率为4．1%。结论:咪唑斯汀是一种治疗慢性荨麻疹安全有效的药物。