Clinical advantages of dual activity in allergic rhinitis

Symptoms of allergic rhinitis include sneezing; itching of the eyes, nose, and throat; nasal obstruction; and rhinorrhoea; they may be seasonal or perennial, depending on the causative allergen. The major symptom of perennial allergic rhinitis is nasal obstruction. Sneezing and rhinorrhoea are often present, but are less troublesome than in seasonal allergic rhinitis. Symptom relief is a priority in allergic rhinitis because patients have a severely impaired quality of life. The nasal vascular system is complex. Histamine acts on postcapillary venules during both the immediate and late phase of reactivity and causes plasma extravasation. Other inflammatory mediators can also induce this reaction. Thus, histamine antagonists that also have some additional antiallergic properties have advantages in the treatment of allergic rhinitis. Mizolastine is a second-generation antihistamine that has been shown, in experimental studies, to possess 5-lipoxygenase inhibitory properties in addition to its H₁-receptor antagonistic activity. In the treatment of seasonal allergic rhinitis, mizolastine 10 mg/day has been shown to be effective in reducing nasal and ocular symptoms. It has been shown to be significantly more effective than placebo with a greater percentage of responders. Another study has shown that symptoms of seasonal allergic rhinitis in mizolastine-treated patients were reduced more significantly than in cetirizine-treated patients on the second and third days of treatment. In perennial allergic rhinitis, mizolastine significantly improved symptoms of nasal obstruction compared with placebo and also significantly reduced nasal membrane colour, nasal secretions, and mucosal swelling as shown by rhinoscopy. These effects were maintained over a 5-month treatment period. Mizolastine has also been shown to be at least as effective as loratadine, and in one trial even superior in the treatment of perennial allergic rhinitis.     

两种咪唑斯汀缓释制剂体内生物利用度和药动学研究

目的 对两种上市的咪唑斯汀缓释制剂进行人体药动学的研究,以评价两厂家生产的咪唑斯汀缓释片是否具有生物等效性.方法 采用随机交叉试验设计,10名男性健康受试者单剂量口服咪唑斯汀缓释片(皿治林和尼乐)10 mg后于规定时间点取血,用高效液相法测定血药浓度,计算两种缓释制剂的主要药动学参数,进行人体生物利用度的比较.结果 10名男性健康受试者单剂量口服咪唑斯汀缓释片皿治林后的药动学参数分别为tmax为(1.70±0.59)h,cmax为(276.99±67.58)ng/mL,t1/2为(12.68±1.97)h,MRT为(15.29±2.67)h,AUC0→t为(2 555.89±777.52)ng/mL·h,AUC0→∞为(2 724.07±852.60)ng/mL·h;单剂量口服参比制剂尼乐后的药动学参数分别为tmax为(1.95±0.64)h,cmax为(344.56±93.96)ng/mL,t1/2为(12.42±1.89)h,MRT为(13.49±1.60)h,AUC0→t为(2 532.28±776.06)ng/mL·h,AUC0→∞为(2 659.16±818.06)ng/mL·h.统计结果表明药动学参数t1/2、MRT、tmax、AUC0→T、AUC0→∞受试制剂皿治林与参比制剂尼乐相比没有显著性差异,cmax具有显著性差异,与参比制剂cmax相比有所降低.AUC0→t、AUC0→∞、cmax、t1/2和MRT生物等效,tmax生物不等效.受试制剂的相对生物利用度平均为(101.26±9.82)%(n=10,以AUC0→t计算)和(102.52±8.61)%(n=10,以AUC0→∞计算);药动学参数cmax的比值为(82.17±15.32)%.结论 受试制剂皿治林与参比制剂尼乐二者生物等效,但皿治林制剂咪唑斯汀峰浓度略低,达峰时间tmax略短.     

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。     

3种抗组胺药治疗慢性特发性荨麻疹的临床研究

目的:评价第2代抗组胺药咪唑斯汀、西替利嗪、氯雷他定治疗慢性特发性荨麻疹的疗效和安全性。方法:采用随机开放平行对照的方法,对96例慢性特发性荨麻疹患者进行随机分组,分别予以咪唑斯汀10mg、西替利嗪10mg、氯雷他定10mg,均每日1次口服,观察治疗第14天、第28天的临床疗效及停药1周后的复发率。结果:三者治疗慢性特发性荨麻疹第14天和第28天的有效率分别为:咪唑斯汀组90.0%和96.7%,西替利嗪组85.3%和94.2%,氯雷他定组90.6%和93.8%,三者之间差异无显著性(P>0.05)。停药1周后的复发率,咪唑斯汀组为40.0%,西替利嗪组为35.3%,氯雷他定组为28.1%。整个试验过程中均无明显严重不良反应出现。结论:咪唑斯汀、西替利嗪和氯雷他定治疗慢性特发性荨麻疹临床疗效好,安全性高,在改善临床症状及控制复发方面各有所长。     

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。     

Efficacy of mizolastine, a new antihistamine, compared with placebo in the treatment of chronic idiopathic urticaria

A two-centre, double-blind, randomized, placebo (P)-controlled, parallel-group study was conducted in the UK to examine the efficacy and safety of mizolastine (M), a new H₁-receptor antagonist, as a once-daily 10-mg dose in chronic idiopathic urticaria. Fifty-six outpatients (M: n = 28; P: n = 28) with a mean age of 38 ± 15 years, a duration of disease of more than 3 years, and symptoms of urticaria at least twice a week in the absence of treatment were recruited. After a single-blind placebo run-in period, patients were allocated to one of two treatment groups and were evaluated after 7 and 28 days. The main characteristics (age, duration of disease, number of urticarial episodes, and total score) of the two groups were comparable at inclusion. Mizolastine was shown to improve the urticaria symptoms: at the end of the study, mizolastine produced a significantly greater decrease in the global symptom score comprising itch, wheals, and erythema (M: 2.1 ± 2.1 vs P: 0.4 ± 2.0; P = 0.002). The patient-rated global discomfort from symptoms measured by visual analog scale was significantly improved with mizolastine (M: 31.4 ± 36.7) compared to placebo (P: 5.4 ± 27.6; P = 0.003), with respectively more M responders (74.1%) than P responders (28.6%, P = 0.001), a responder being a patient with a ≥50% decrease in VAS. Premature dropouts due to lack of efficacy and loss to follow-up mainly occurred at the first evaluation (day 7) and were more often observed in patients in the placebo group ( n = 17) than in the mizolastine group ( n = 8) ( P = 0.031). No serious adverse events were recorded. Somnolence was reported in two mizolastine patients, one of whom discontinued the study. Thus, mizolastine may be considered a new treatment option for the symptoms of chronic urticaria.     

咪唑斯汀、依巴斯汀和地氯雷他定的实验性抗组胺强度比较

目的:比较咪唑斯汀(皿治林)与依巴斯汀(开思亭)、地氯雷他定(芙必叮)的抗组胺强度与时效之间的关系。方法:36名志愿者分为3组,皿治林组12例、开思亭组12例和芙必叮组12例。在服药前和服药后的12d中,以及停药1周后皮内注射组胺100μg,诱导观察局部风团、红晕的反应强度。结果:皿治林组服药后12d内组胺诱导局部风团和红晕面积的反应强度在各时间点显著低于其他两组(P<0.01或0.05)。结论:皿治林的起效速度、抗组胺作用强度均优于和芙必叮。     

Population Pharmacokinetic Analysis of Mizolastine and Validation from Sparse Data on Patients Using the Nonparametric Maximum Likelihood Method

A population analysis of the kinetics of mizolastine was performed from concentrations on 449 allergic patients, using the nonparametric maximum likelihood method (NPML). A two-compartment open model with zero-order absorption was used to describe the kinetics of mizolastine after oral administration. A heteroscedastic variance model was assumed for the error. To explain the kinetic variability, eight covariates were introduced in the analysis: gender, pharmaceutical dosage form, age, body weight, serum creatinine concentration, creatinine renal clearance, plasma levels of hepatic transaminases ASAT and ALAT. Their relationships to the kinetic parameters were studied by means of the estimated distribution of each kinetic parameter conditional on different levels of each covariate. An important interindividual kinetic variability was found for all parameters. Moreover, several kinetic parameters among which the duration of absorption were found to be influenced by pharmaceutical dosage form and gender. Body weight and creatinine renal clearance were found to have a little influence on the oral clearance and the smallest disposition rate constant. This population analysis was validated on a separate group of 247 other patients. For each observed concentration of this sample, a predictive distribution was computed using the individual covariates. Predicted concentrations and standardized prediction errors were deduced. The mean and variance of the standardized prediction errors were, respectively, 0.21 and 2.79. Moreover, in the validation sample, the predicted cumulative distribution function of each observed concentration was computed. Empirical distribution of these values was not significantly different from a uniform distribution, as expected under the assumption that the population model estimated by NPML is adequate.     

对花生四烯酸人皮肤炎症模型和咪唑斯汀抗炎作用的研究

目的探讨咪唑斯汀对花生四烯酸(AA)人体皮肤炎症模型的抗炎作用。方法以20%、4%浓度的AA在25名健康志愿者前臂屈侧做点刺试验,并在其服用抗过敏药(咪唑斯汀/氯雷他定)前1h及服药后1h、2h进行AA点刺试验,分别记录点刺试验30min后的红斑面积和风团面积。用氯雷他定作为对照组。结果20?人体皮肤点刺试验中,服用咪唑斯汀前与服用后1h红斑面积及风团面积变化显著(P<0.01),显著优于氯雷他定组(P<0.05);服用咪唑斯汀前与服用后2h红斑面积及风团面积变化显著(P<0.01),显著优于氯雷他定组(P<0.01);4%点刺试验中,咪唑斯汀组用药前与服用后2h风团面积存在显著性差异(P<0.05),显著优于氯雷他定组(P<0.01);咪唑斯汀2h抗炎效果优于1h。结论咪唑斯汀具有明显的拮抗AA引起的人体皮肤炎症反应作用。