美洛昔康栓剂的制备及质量控制

目的制备美洛昔康栓剂及质量控制。方法以S-40和PEG-400为基质,热熔法制备栓剂。结果栓剂稳定性良好。结论该制剂制备工艺可行,性质稳定,质控方法简单可靠。     

美洛昔康片联合七味通痹口服液治疗强直性脊柱炎肝肾亏虚证40例临床研究

目的 观察美洛昔康片联合七味通痹口服液治疗强直性脊柱炎(AS)肝肾亏虚证的临床疗效。方法 将80例AS患者随机分为治疗组和对照组,各40例。治疗组患者口服美洛昔康片和七味通痹口服液,对照组患者口服柳氮磺胺嘧啶和双氯芬酸钠肠溶片。观察治疗后两组患者的关节疼痛、肿胀及整体功能分级、Keitel试验、双侧4字试验、Schober试验、肌腱附着点炎症情况;实验室指标包括血沉(ESR),C反应蛋白(CRP)、X射线常规骶髂关节正位片或CT扫描及HLA-B27。结果 治疗组的总有效率为85.00%,明显高于对照组的60.00%(P<0.05);治疗组髋疼痛、膝疼痛、膝肿胀、踝疼痛、踝肿胀评分均较对照组改善显著(P<0.05或P<0.01);治疗组前屈、侧屈、晨僵和Keitel试验评分均较对照组变化显著(P<0.05或P<0.01);治疗组体征及关节外症状各项指标与对照组比较,差异均有统计学意义(P<0.05或P<0.01);ESR,CRP,HLA-B27阳性及X线改变比较,治疗组各项指标变化均较对照组显著(P<0.05或P<0.01);治疗组不良反应明显少于对照组(P<0.05)。结论 美洛昔康片结合七味通痹口服液治疗AS肝肾亏虚证疗效肯定且不良反应小。     

美洛昔康急性毒性研究

目的:观察美洛昔康(meloxicam)经两种给药途径对大、小鼠的急性毒性反应,评价其安全性。方法:以小鼠和大鼠为对象,将美洛昔康按灌胃和腹腔注射两种给药方式进行急性毒性试验,用Bliss法测得LD50及95％置信限。结果:小鼠ig给药LD50:840．0(668．0～1057．0)mg·kg-1。小鼠ip给药LD50:143．9(111．7～185．5)mg·kg-1。大鼠ig给药LD50:219．9 (186．1～259．9)mg·kg-1。大鼠ip给药LD50:116．4(98．3～137．9)mg·kg-1。结论:美洛昔康属于低等毒性物质。     

美洛昔康的合成

糖精钠与氯乙酸甲酯缩合得 3-氧代 - 1,2 -苯并异噻唑 - 2 -乙酸甲酯 1,1-二氧化物 (2 ) ,再加甲醇钠在激烈条件下扩环 ,经 N -甲基化 ,所得 4-羟基 - 2 -甲基 - 2 H- 1,2 -苯并噻嗪 - 3-羧酸甲酯 1,1-二氧化物 (4 )再与 2 -氨基 - 5 -甲基噻唑反应得美洛昔康 (1) ,总收率为 48.6 %     

美洛昔康的合成

美洛昔康（ｍｅｌｏｘｉｃａｍ,１）,商品名Ｍｏｂｉｃ,化学名４－羟基－２－甲基－Ｎ－（５－甲基－２－噻唑基）－２Ｈ－１,２－苯并噻嗪－３－甲酰胺１,１－二氧化物,是德国ＢｏｅｈｒｉｎｇｅｒＩｎｇｅｌｈｅｉｍ公司于１９９６年上市的一种烯醇酸非甾体抗炎药,对环氧合酶－２（Ｃｏｘ－２）有高度选择性。与双氯芬酸、吲哚美辛、萘丁美酮、萘普生和吡罗昔康相比较,１对Ｃｏｘ－２比对Ｃｏｘ－１具更强的抑制作用,胃肠道刺激不良反应的发生率低,副作用小,剂量小且长效,主要用于骨关节炎和类风湿性关节炎［１］。文献［２～…     

美洛昔康治疗骨关节炎临床疗效

目的:对骨关节炎应用美洛昔康治疗的临床疗效进行观察.方法:将我院在2015年2月~2016年2月接受的70例骨关节炎患者,按照治疗举措分为观察组与对照组,两组各35例.对照组以双氯芬酸钠治疗,观察组则用美洛昔康进行治疗,对比两组临床效果、指标改善情况.结果:观察组临床总有效率为97.14%,不良反应发生率5.71%;对照组分别为77.14%、25.71%,组间数据对比均存在明显差异(P<0.05).另外,在临床具体特征及临床指标改善方面,观察组显著优于对照组,差异显著,具有统计学意义(P<0.05).结论:运用美洛昔康药物治疗骨关节炎,临床效果明显,可有效促使快速康复,且出现不良反应的概率低,值得临床推广.     

美洛昔康的合成

糖精钠与氯乙酸乙酯缩合得到的3-氧代-1,2-苯并异噻唑啉-2-乙酸乙酯1,1-二氧化物,在乙醇钠存在下扩环重排、甲基化一锅反应得到4-羟基-2-甲基-2H-1,2-苯并噻嗪-3-羧酸乙酯1,1-二氧化物,再与2-氨基-5-甲基噻唑缩合制得非甾体抗炎药美洛昔康,总收率53%.     

美洛昔康凝胶的制备

目的:对美洛昔康凝胶的制备及质量控制方法进行了研究.方法:以卡波姆为辅料,制备美洛昔康凝胶;采用紫外分光光度法测定美洛昔康凝胶中美洛昔康的含量.结果:辅料对含量测定结果无干扰,平均回收率为99.3%,RSD为0.98%(n=6).结论:该制剂的制备工艺简单,检测方法简便,结果准确.     

美洛昔康贴片抗炎作用实验研究

目的观察局部用美洛昔康贴剂(Mel T)的抗炎作用及其对胃肠道的刺激性。方法采用二甲苯致腹腔毛细血管通透性增加法和二甲苯致耳肿胀法,角叉菜胶诱发足肿胀法以及完全佐剂诱导佐剂性关节炎等实验方法。结果Mel T局部粘贴小鼠20、105、mg/kg,明显抑制二甲苯所致的小鼠耳肿胀和二甲苯引起的皮肤毛细血管通透性的增加,大鼠足部粘贴14、7、3.5 mg/kg,明显抑制角叉菜胶致大鼠足肿胀;对AA大鼠原发性和继发性炎症均有抑制作用,且大鼠胃肠道粘膜出血和溃疡比Mel灌胃组少。结论Mel T有明显的抗炎作用,不良反应小于口服给药。     

依那西普治疗强直性脊柱炎的安全性研究

目的：观察依那西普治疗强直性脊柱炎（ankylosing spondylitis，AS）出现的不良反应。方法：本研究采用随机、双盲、安慰剂平行对照的方案，2005年4月至2006年1月对52例活动性AS患者随机分入依那西普组及安慰剂组，每组患者各26例，依那西普组平均年龄（27．7±8．5）岁，安慰剂组平均年龄（29．7±8．1）岁。整个研究持续12周，前6周为双盲治疗期，后6周为开放治疗期。在双盲期，依那西普组给予依那西普25mg／次，皮下注射，每周2次，连续用药6周；安慰剂组给予非活性物质25mg／次，皮下注射，每周2次，连续用药6周。开放治疗期，2组均使用依那西普25mg／次，皮下注射，每周2次，连续用药6周。于第0、1、2、4、6、7、8、10、12周进行血常规检查，观察分析注射部位皮肤反应、其他的皮肤及附属器官的反应、感染的发生情况、血液系统反应、肝酶水平、自身抗体反应及其他不良反应。结果：依那西普组和安慰剂组的不良反应发生率分别为23％和38％。差异无统计学意义（P〉0．05）；无严重不良事件发生。双盲期内依那西普组有26．9％的患者出现注射部位皮肤红肿、硬结和瘙痒反应，安慰剂组无l例出现该反应，2组差别有统计学意义（P〈0．05）。试验期间注射部位皮肤反应的发生率为34．6％。双盲期依那西普组有6例患者（23．1％）出现中性粒细胞减少，而安慰剂组无1例发生该反应，2组之间差异有统计学意义（P〈0．05）。依那西普组和安慰组的其他不良反应如上呼吸道感染（分别为5例与7例）、皮肤及附属器官反应（分别为6例和3例）、肝酶升高（分别为5例和8例）等，差异均无统计学意义（均P〉0．05）。结论：依那西普是一种较为安全的治疗AS的药物。     

Efficacy and safety of adalimumab treatment in patients with rheumatoid arthritis,ankylosing spondylitis and psoriatic arthritis

Introduction: In the last couple of years, the number of patients with chronic inflammatory rheumatic diseases being treated with TNF α antagonist has increased dramatically. Adalimumab, a fully human monoclonal antibody against TNF α, is one of the most frequently administered TNF α antagonists. Yet, unresolved issues are the long-term safety of TNF α antagonists and high treatment costs.

Areas covered: The authors summarize the available data on short- and long-term efficacy and safety of adalimumab in the treatment of rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. The reader will find a comprehensive overview on the safety and efficacy of adalimumab for these conditions. Clinically relevant questions of adalimumab therapy are discussed. A special focus of this review is on the safety of adalimumab therapy.

Expert opinion: Adalimumab is effective and reasonably safe in the short- and long-term treatment of patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis who do not respond to the standard therapy. It inhibits radiographic progression in rheumatoid and psoriatic arthritis. Treatment with a TNF α inhibitor such as adalimumab is associated with high treatment costs.     

强直性脊柱炎的药物治疗进展

探讨慢作用药物、细胞毒性药物、非甾体抗炎药、其他药物如反应停、帕米膦酸钠及中药的治疗和治疗策略。药物对强直性脊柱炎的治疗是安全有效的。早期治疗和恰当的选用药物，可以延缓强直性脊柱炎的疾病进程，提高患者的生活质量，降低致残率。对强直性脊柱炎的治疗应选用不同类药物的联合应用疗效会更满意。     

Adalimumab for the treatment of ankylosing spondylitis

Ankylosing spondylitis is a chronic inflammatory disease, with a prevalence of ～ 0.5%, which starts in the third decade of life. Treatment was, until recently, limited. Conventional disease-modifying drugs are not effective for the spinal manifestations, and NSAIDs and physical therapy were the standard treatment, without any other options for patients who did not respond to this treatment. Therefore, the high efficacy of the new group of TNF-blockers for the treatment of active ankylosing spondylitis represents a breakthrough for NSAID-refractory patients. Following the introduction of the two TNF-blockers, infliximab and etanercept, the fully humanized, anti-TNF monoclonal antibody adalimumab is now the third product that has been approved for the treatment of ankylosing spondylitis. Adalimumab is given subcutaneously every 2 weeks at a dose of 40 mg. In open and placebo-controlled trials, the drug was shown to be safe and effective in ankylosing spondylitis patients. Long-term treatment data of up to 2 years are now available, confirming efficacy and acceptable safety.     

强直性脊柱炎79例临床特点分析

目的 总结强直性脊柱炎(AS)发病的一般情况及临床特点,进一步提高对AS的认识.方法 收集2002～2004年在南京医科大学第一附属医院住院的79例强直性脊柱炎病例,对79例患者的一般资料、临床表现、体征及辅助检查等进行回顾性分析.结果 AS患者男女比为3.16∶1,平均年龄28岁,平均病程5年.腰痛、外周关节炎、"4"字试验阳性、骶髂关节压痛和腰椎压痛为常见症状和体征.腰背痛者占79.75%,足跟痛者占17.72%,普通X线及CT诊断III级以上骶髂关节炎者占62.03%,86.08%患者HLA-B27阳性,53.16%患者免疫球蛋白升高,15.19%患者有心脏损害,主要累及二尖瓣.结论 AS主要以腰背痛及骶髂关节炎为临床特征,临床上需注意AS的关节外表现,与骨关节炎、类风湿性关节炎等相鉴别,避免误诊.     

Therapeutic advances in ankylosing spondylitis

Ankylosing spondylitis (AS) is a systemic inflammatory rheumatic disease involving spinal and sacroiliac joints. This condition is responsible for back pain, stiffness, but also loss of functional capacity with socio-economic consequences. The management of AS includes patient education, rest, a programme of regular physical exercise, together with the use of NSAIDs. Second-line treatments are required in cases of severe or refractory AS, however only sulfasalazine has proven to benefit AS patients with peripheral arthritis. In spite of this management, the disease may not be adequately controlled, mainly for patients with refractory axial disease, enthesopathy or extra-articular features. Thus, new innovative treatments are needed for AS. It is likely that the new NSAIDs or COX-2 specific inhibitors will certainly take the place of the conventional NSAIDs, with regard to their superior tolerability. Methotrexate is a therapeutic option for AS treatment, but its usefulness in this disease remains to be established in adequate controlled studies. Finally, the TNF-α targeting drugs, namely thalidomide and the anti-TNF-α mAb, infliximab, have given promising results in the treatment of severe and/or refractory AS patients, however further controlled studies are required. In addition, the long-term use (efficacy and tolerability) of these two agents deserves attention.     

Treatment of ankylosing spondylitis with flurbiprofen or phenylbutazone

Summary Flurbiprofen (150–200 mg daily) and phenylbutazone (300–400 mg daily) were compared in the management of 27 patients with active ankylosing spondylitis. This was a parallel, double-blind, and randomized trial of 6 weeks duration. Both drugs were equally effective in the relief of pain and tenderness of the affected joints. Overall subjective improvement, assessed by the patient and the investigator at the end of the trial, favored phenylbutazone, but it did not reach a statistically significant level. The mean values of the endpoint parameters of spinal motion showed statistically significant improvement in both groups, except in the Schober test in the flurbiprofen group and chest expansion in the phenylbutazone group. Untoward effects characteristic of these drugs were found in a few patients.     

通痹灵治疗强直性脊柱炎临床疗效评价

目的:评价通痹灵治疗活动期强直性脊柱炎(AS)的临床疗效及毒副反应。方法:采用随机对照单盲双模拟的方法,将69例活动期AS分为通痹灵治疗组(36例)和吲哚美辛对照组(33例)。通痹灵组口服通痹灵A,每次6片,每日3次,吲哚美辛组口服通灵A(含吲哚美辛25mg)每次6片,每日3次。结果:总有效率两组间差异无显著性(P>0.05),但通痹灵组控显率优于吲哚美辛组(P<0.01);两组治疗前后疼痛积分、晨僵时间和指地距离改善明显(P<0.01或<0.05),扩胸度和枕墙距均无改善(P>0.05)。通痹灵组关节肿胀积分、Schober试验、整体功能、实验指标(ESR、CRP、PLT、IgG、IgA、IgM)和骶髂关节影像积分均有明显改善(P<0.01);吲哚美辛组关节肿胀积分、整体功能、实验指标和骶骼关节影像积分无改善(P>0.05)。两组治疗后比较:通痹灵组改善肿胀积分、晨僵时间、指地距离、整体功能和实验指标(除CRP外)优于吲哚美辛组(P<0.01或<0.05);通痹灵组未发现明显不良反应。结论:通痹灵对活动期AS具有改善临床症状、体征和实验指标的作用,且对AS骨质损害具有保护作用,未发现不良反应。     

Novel approaches in the treatment of ankylosing spondylitis and other spondyloarthritides

The therapeutic options for patients suffering from severe forms of spondyloarthritis (SpA) have been rather limited in recent decades. There is now accumulating evidence that anti-TNF therapy is highly effective in SpA, especially in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Based on the data recently published on what is now several hundred AS and PsA patients, this treatment seems to be even more effective than the same therapy in rheumatoid arthritis (RA). The anti-TNF-α agents currently available, infliximab (Remicade^®; Centocor), etanercept (Enbrel^®; Amgen) and adalimumab (Humira?; Abbott), are approved for the treatment of RA in the US; infliximab and etanercept are approved in Europe. The situation in SpA is different to RA because there is an unmet medical need, especially in AS, since no therapies with disease-controlling antirheumatic drugs are available for severely affected patients, especially with spinal disease. Thus, TNF blockers might even be considered as first-line immunosuppressive agents in patients with active AS and PsA who are not sufficiently treated by non-steroidal anti-inflammatory drugs and sulfasalazine, if peripheral arthritis is present. For infliximab, a dosage of 5 mg/kg at intervals between 6 and 12 weeks was necessary to constantly suppress disease activity; this is also a major aim of long-term treatment. No dose-finding studies have yet been performed. The standard dose of etanercept is 25 mg s.c. twice-weekly. No studies on adalimumab (standard RA dose 20 – 40 mg s.c. every 2 weeks) have yet been conducted in SpA. The efficacy of etanercept was first demonstrated in PsA and etanercept is now approved for this indication. A double-blind study has also been performed in AS, with similarly clearcut efficacy. There is preliminary evidence that both agents do also work in other SpA such as undifferentiated SpA. Infliximab has recently been approved for short-term treatment of severe uncontrolled AS; the approval for etanercept is pending. Studies should be performed to document the long-term efficacy of this treatment. There is hope that ankylosis might be preventable but it remains to be shown whether patients benefit from long-term anti-TNF therapy and whether radiological progression and ankylosis can be stopped. Severe adverse events have remained rare. Complicated infections including tuberculosis have been reported. Tuberculosis can be mostly prevented if patients are checked for previous contact with tuberculosis. Currently, the benefits of anti-TNF therapy in AS seem to outweigh these shortcomings.     

Influence of methotrexate on infliximab pharmacokinetics and pharmacodynamics in ankylosing spondylitis

AIMS

Infliximab, an anti-tumour necrosis factor α monoclonal antibody, has profoundly modified the treatment of several inflammatory diseases. The objective was to assess the influence of methotrexate on the variability of infliximab pharmacokinetics and concentration–effect relationship in axial ankylosing spondylitis (AAS) patients.

METHODS

Twenty-six patients with AAS were included in a prospective study. They were treated by infliximab 5 mg kg⁻¹ infusions at weeks 0, 2, 6, 12 and 18. Infliximab concentrations were measured before, and 2 and 4 h after each infusion, and at each intermediate visit (weeks 1, 3, 4, 5, 8, 10 and 14). Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was measured at each visit. Infliximab pharmacokinetics was described using a two-compartment model with first-order distribution and elimination constants. A population approach was used. Infliximab pharmacodynamics was described using the area under the BASDAI curve.

RESULTS

A total of 507 blood samples and 329 BASDAI measurements were collected. The following pharmacokinetic parameters were obtained (interindividual coefficient of variation): volumes of distribution for the central compartment = 2.4 l (9.6%) and peripheral compartment = 1.8 l (26%), systemic clearance = 0.23 l day⁻¹ (22%) and intercompartment clearance = 2.3 l day⁻¹. Methotrexate influenced neither pharmacokinetic nor BASDAI variability.

CONCLUSIONS

Using the present dosage, the clinical efficacy of infliximab is only weakly influenced by its serum concentrations. The results do not support the combination of methotrexate with infliximab in ankylosing spondylitis.