Dosing patterns of three tumor necrosis factor blockers among patients with rheumatoid arthritis in a large United States managed care population

Abstract

Objective:

To describe dosing patterns of etanercept, adalimumab, and infliximab in rheumatoid arthritis (RA) patients in US managed care.     

肿瘤坏死因子抑制剂的研究进展

类风湿性关节炎(rheumatoid arthritis,RA)、节段性肠炎(Crohn′s disease,CD)等疾病具有类似的发病机制。肿瘤坏死因子(tumor necrosis factor,TNF)在这些疾病的发生发展中具有非常重要的作用。TNF分子在细胞因子免疫调节网络中位于中枢环节,是重要的炎症介质,过量的TNF导致炎症的发生。目前上市的TNF抑制剂种类繁多,治疗效果显著。然而随着TNF抑制剂广泛应用,这类药物的安全性逐渐受到重视。本文综述了TNF与疾病关系、上市的TNF蛋白抑制剂分子结构、临床应用等方面,重点关注药物潜在的不良反应,并对近期新型TNF抑制剂的研究开发进行总结。     

蛋白激酶C激活剂和抑制剂对肿瘤坏死因子杀瘤活性的影响

以小鼠成纤维细胞瘤L929细胞为靶细胞,研究蛋白激酶C(PKC)的激活剂和抑制剂对人重组肿瘤坏死因子(rHuTNF)杀瘤活性的影响.各种药物与rHuTNF 10 ng·ml~(-1)和放线菌素D 1 μg·ml~(-1)温育18 h,结果表明PKC的激活剂佛波醇-12-肉豆蔻酸盐-13-乙酸盐(PMA)2.5～160ng·ml~(-1)可浓度依赖性地抑制rHuTNF的杀瘤活性.Sc-10(1～16μg·ml~(-1))单独作用很弱,但可浓度依赖地增强PMA 10 ng·ml~(-1)或A23187 0.5μg·ml~(-1)的抑制作用,PKC抑制剂1-(5-异喹啉磺酰基)-2-甲基哌嗪(H-7)单独作用对rHuTNF杀瘤活性无影响,但可减弱PMA 50ng·ml~(-1)的抑制作用.槲皮囊2～16μg·ml~(-1)则可直接抑制rHuTNF的杀瘤活性,钙调蛋白抑制剂N-(6-氨己基)-5-氯-1-萘磺酰胺(W-7)及其同系物也有微弱的抑制作用.结果提示PKC在rHuTNF杀瘤作用中起着重要作用.     

Safety and treatment patterns of angiogenesis inhibitors in patients with advanced renal cell carcinoma in Spain

Objective: To examine real-world safety and treatment patterns of angiogenesis inhibitors for advanced renal cell carcinoma (aRCC) using observational data from two Spanish hospitals.

Methods: A retrospective medical record review was performed for 93 patients with a histological diagnosis of aRCC who received sunitinib, sorafenib, bevacizumab or temsirolimus as first-line angiogenesis inhibitor therapy, between January 2005 and September 2010 at two Spanish hospitals. Data were collected on adverse events (AEs), dosing to calculate relative dose intensity (RDI), treatment modifications and reasons for modifications.

Results: Sixty patients received sunitinib, 23 received sorafenib, 6 received bevacizumab, 1 received temsirolimus and 3 received a bevacizumab-temsirolimus combination. 91.7 and 100.0% of patients receiving sunitinib and sorafenib, respectively, experienced ≥ 1 AE; 40.0% and 43.5% had ≥ 1 grade 3/4 AE. Mean RDI for sunitinib and sorafenib were 0.866 (standard deviation (std) = 0.903) and 0.798 (std = 2.154), respectively. Among patients receiving sunitinib, 15.0% discontinued treatment, 43.3% had an interruption and 33.3% had a reduction due to AEs. For sorafenib, these rates were 4.3, 56.5 and 34.8%, respectively.

Conclusions: High rates of AEs were observed which resulted in high rates of treatment interruptions and dose reductions. These results suggest the need for additional treatment options for aRCC with improved tolerability.     

氯沙坦对心力衰竭病人肿瘤坏死因子的影响

目的 :研究氯沙坦对心力衰竭 (CHF)病人血肿瘤坏死因子 (TNF α)、内皮素 (ET 1)、醛固酮(Ald)水平的影响。方法 :采用放免法测定CHF病人 (5 4例 )及健康志愿者 (2 8例 )血TNF α ,Ald及ET 1水平。 5 4例CHF病人分为 2组 ,非氯沙坦组给予常规抗心力衰竭治疗 ;氯沙坦组在非氯沙坦组药物治疗基础上加氯沙坦 2 5～ 5 0mg·d- 1,共 1mo。结果 :CHF病人TNF α ,Ald及ET 1水平分别为(2 .7±s 0 .8) μg·L- 1,(195± 33)ng·L- 1,(90±16)ng·L- 1,显著高于健康对照组 [(1.2± 0 .2 ) μg·L- 1,(117± 38)ng·L- 1,(5 9± 11)ng·L- 1,P <0 .0 1];氯沙坦组经治疗后TNF ,Ald及ET 1水平显著降低 ;非氯沙坦组治疗后血Ald水平明显降低(P <0 .0 1)。结论 :氯沙坦可明显降低心力衰竭病人血TNF α及ET 1水平     

硼替佐米辅助治疗老年骨肿瘤对患者血清肿瘤坏死因子-α水平的影响

目的 探讨硼替佐米辅助治疗老年骨肿瘤对患者血清肿瘤坏死因子-α（TNF-α）水平的影响。方法 采用回顾性、抽样调查研究方法,2014年3月—2017年1月选择在重庆市开州区人民医院诊治的老年膝关节周围骨肿瘤患者118例作为研究对象,所有患者都给予人工假体置换治疗,对照组给予地塞米松和环磷酰胺辅助治疗,环磷酰胺200 mg/m²在治疗的第1~4 d静脉推注;地塞米松20 mg/d,在术后第1~2、4~5、8~9、11~12 d静脉滴注;观察组在对照组治疗的基础上辅助硼替佐米治疗,剂量为1.3 mg/m²,在治疗第1、4、8、11 d静脉推注,其他治疗方法同对照组。在术前与术后6个月进行膝关节主动屈曲活动度的评定,观察与记录关节退变、囊性变、关节面塌陷、坏死等并发症发生情况;在术前与术后6个月检测TNF-α的浓度;随访至今,对比两组的无进展生存时间。结果 观察组与对照组术后6个月膝关节主动屈曲活动度都显著高于术前（P<0.05）,观察组也显著高于对照组（P<0.05）。观察组术后6个月的关节退变、囊性变、关节面塌陷、坏死等并发症发生率显著低于对照组（P<0.05）。观察组与对照组术后6个月的血清TNF-α值都显著低于术前（P<0.05）,术后6个月观察组的血清TNF-α值也显著低于对照组（P<0.05）。随访至今,观察组与对照组的无进展生存时间（15.77±2.14）个月和（10.87±3.14）个月,观察组显著长于对照组（P<0.05）。结论 硼替佐米辅助治疗老年膝关节周围骨肿瘤能有效降低患者的血清TNF水平,促进膝关节功能的恢复,减少术后并发症的发生,从而延长患者的生存时间。     

罗格列酮对2型糖尿病病人肿瘤坏死因子和瘦素的影响

目的 :探讨罗格列酮治疗 2型糖尿病对肿瘤坏死因子 (TNF)和瘦素的影响及其治疗糖尿病的可能机制。方法 :4 8例 2型糖尿病病人 ,男性 2 4例 ,女性 2 4例 ,年龄 (5 8±s 8)a ,随机分为 2组 ,每组 2 4例 ,对照组维持原磺酰脲类和双胍类药物降糖治疗 ,治疗组在原治疗基础上加用罗格列酮 4mg·d- 1,疗程 3mo。测定治疗前后 2组血糖、胰岛素、糖化血红蛋白及TNF和瘦素水平。结果 :治疗后 ,治疗组空腹和餐后 2h血糖下降 (1.0± 1.0 )和 (4±3)mmol·L- 1,TNF和瘦素下降 (0 .8± 0 .4 )和 (10±7) μg·L- 1,空腹和餐后 2h胰岛素下降 (3± 4 )和(8± 7)mU·L- 1,与治疗前及对照组相比 ,差异有显著或非常显著意义 (P <0 .0 5或P <0 .0 1)。结论 :罗格列酮可明显改善 2型糖尿病病人的血糖和胰岛素抵抗 ,可能与降低TNF和瘦素有关     

The effects of tumor necrosis factor inhibitors on cardiovascular risk in rheumatoid arthritis

There is abundant evidence that rheumatoid arthritis (RA), a chronic inflammatory disorder, is associated with an increased risk for cardiovascular (CV) disease. While there may be several mechanisms contributing to a higher CV risk in RA patients, inflammation is considered to be the main cause explaining the excess CV burden. Inflammatory processes appear pivotal to the atherothrombotic process and are linked to endothelial dysfunction, fatty streak initiation and progression, deterioration of fatty streaks into (unstable) plaques, and plaque rupture. Moreover, systemic inflammation, through tumor necrosis factor (TNF) or related cytokines, appears to accelerate atherothrombosis either directly or via effects on conventional and novel CV risk factors, such as lipids and lipoproteins, blood pressure, haemostatic factors, and insulin resistance. New and highly specific therapeutic agents (TNF inhibitors) may significantly lower CV risk in RA. This review summarizes the evidence base supporting the notion that TNF inhibitors confer benefit CV disease risk in RA.     

肿瘤坏死因子相关凋亡诱导配体临床治疗应用前景

肿瘤坏死因子相关凋亡诱导配体(TRAIL)具有选择性细胞毒性,不仅诱导肿瘤细胞凋亡,还诱导肝和脑细胞凋亡,也诱导病毒感染的细胞凋亡,但对机体正常组织无毒性。TRAIL已成为全球新药研究的热点。本文从TRAIL的凋亡通路及其调控、肿瘤细胞对TRAIL抵抗的原因综述TRAIL在难治性疾病治疗中的应用。     

Effects of tumor necrosis factor alpha on replication of varicella-zoster virus.

Replication of varicella-zoster virus (VZV) and expression of VZV nuclear antigen are inhibited in human embryonic lung fibroblast (HEL) cells pretreated with recombinant tumor necrosis factor (TNF) alpha for 24 h. This antiviral activity is completely blocked by the addition of monoclonal antibodies against TNF. TNF acts synergistically with interferons alpha and gamma. When TNF is added to HEL cells after VZV adsorption, virus replication is still inhibited. When VZV-infected HEL cells are co-cultured with HEL cells which have been pretreated with TNF or grown in the presence of TNF, spread of VZV from VZV-infected HEL cells to uninfected cells is unaffected. No interferon is detected in the supernatants or cell lysates of HEL cells cultured with TNF and antibodies to alpha-, beta- and gamma-interferon have no effect on the antiviral action of TNF.     

肿瘤坏死因子-α对骨关节炎滑膜细胞增殖和RNA表达的影响

目的探讨肿瘤坏死因子 α（ＴＮＦ α）对骨关节炎（ＯＡ）滑膜细胞增殖和ＲＮＡ表达的效应，以及ＯＡ治疗药物和生物制剂对这种作用的调节。方法分离、培养晚期ＯＡ滑膜细胞，采用ＭＴＴ比色法、放射自显影和液体闪烁技术，检测ＴＮＦ α对滑膜细胞增殖及ＲＮＡ表达的影响，以及非甾体类和甾体类药物、生物制剂作用后的滑膜细胞对这种影响的反应性。结果ＴＮＦ α可诱导滑膜成纤维细胞样细胞增殖，以ＴＮＦ α浓度为５×１０５Ｕ·Ｌ－１作用２４ｈ最为明显（增殖率提高３７８％）；促进滑膜细胞摄取［３Ｈ］ ＵＲ，使ＲＮＡ表达量增加。吲哚美辛作用后的滑膜细胞对ＴＮＦ α的反应性未发生明显改变，而地塞米松和干扰素 α高浓度时有拮抗ＴＮＦ α促滑膜细胞增殖的作用。结论ＴＮＦ α可促使ＯＡ滑膜细胞进一步变性，抗炎类药物和细胞因子对此无明显拮抗作用。     

血脂康对不稳定型心绞痛患者血浆基质金属蛋白酶9和肿瘤坏死因子仪水平的影响

目的研究血脂康对不稳定型心绞痛（UAP）患者血浆基质金属蛋白酶（MMP-9）和肿瘤坏死因子d（TNF-α）的影响,探讨其抗炎抗氧化治疗效果。方法采用酶联免疫吸附测定（ELISA）法测定65例UAP患者（UAP组）服药持续时间前后（血脂康胶囊0．6g／d,治疗1个月）及冠状动脉造影正常者（对照组,40例）血浆MMP-9及TNF-α浓度。结果UAP组治疗前MMP-9、TNF—α血浆水平为（24±6）mg／L、（22±4）μg／L,与对照组[（20±6）mg／L和（16-4-4）μg／L]比较,差异有统计学意义（P〈0．01）,服用血脂康4周后UAP组血浆MMP-9及TNF-α水平[分别为（21±6）mg／L和（19±4）μg／L]较治疗前明显下降（均P〈0．01）。结论血脂康在抑制UAP患者炎症反应、稳定动脉粥样斑块,减少急性心血管事件方面可能有-定的作用。     

老年原发性高血压患者肿瘤坏死因子-α与高敏C反应蛋白 同型半胱氨酸相关性分析

目的观察各级老年原发性高血压(EH)患者肿瘤坏死因子(TNF)-α、高敏C反应蛋白(hs-CRP)和同型半胱氨酸(Hcy)的水平变化,以及TNF-α与hs-CRP、Hcy之间的相关性。方法分别测定39例各级老年EH患者血清TNF-α、hs-CRP和血浆Hcy水平以及血压和一般项目检查,以13名健康老年人作对照。结果①血清TNF-α和血浆Hcy水平在老年EH患者组明显高于老年对照组(P<0.01),且各级老年EH患者组间两两比较差异有统计学意义(P<0.01);血清hs-CRP水平在老年EH1级组升高不明显(P>0.05),在老年EH2级和3级组显著升高(P<0.01),且老年EH2级和3级组hs-CRP的水平与老年EH1级组比较差异有统计学意义(P<0.01)。②老年EH组TNF-α与hs-CRP(r=0.863,P<0.01)、Hcy(r=0.809,P<0.001)呈正相关。③以TNF-α为应变量,年龄、体重指数(BMI)、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL-c)、低密度脂蛋白(LDL-c)、hs-CRP、Hcy为自变量进行多元线性回归分析,TNF-α指标值的变化与hs-CRP和Hcy有线性回归关系,其中hs-CRP对TNF-α指标值影响最多。结论TNF-α、hs-CRP、Hcy浓度的升高,可能参与了老年原发性高血压发生的病理生理过程。TNF-α指标值的变化与hs-CRP和Hcy有线性回归关系,提示三者之间可能相互调节、相互作用,共同参与原发性高血压的病理生理过程。     

大米α-球蛋白肽YGEGSSEEG对TNF-α诱导的血管内皮细胞损伤的影响

目的研究从大米α-球蛋白中获取的活性肽发挥抗动脉粥样硬化功效的机制。方法大米α-球蛋白经体外消化产物,采用外翻肠囊法收集可吸收组分,利用凝胶色谱和半制备高效液相色谱分离纯化,液相质谱串联测定氨基酸序列。利用TNF-α诱导人脐静脉内皮细胞损伤模型来评价肽的功效。检测细胞存活率,筛选肽的合适剂量;流式细胞仪检测细胞凋亡率;蛋白质印迹检测Bcl-2、Bax、p-p38、血管细胞黏附分子及NF-κB信号通路等蛋白表达水平;酶联免疫检测谷胱甘肽过氧化物酶等氧化应激因子含量。结果从可吸收组分中获得肽YGEGSSEEG。50 mg·L~(-1)合成肽能够明显抑制TNF-α引起的细胞凋亡,调控Bcl-2/Bax蛋白表达以及阻碍p38蛋白的磷酸化;同时,明显抑制HUVEC产生黏附分子、阻碍NF-κB信号通路的激活;此外,肽对细胞中的氧化应激水平并无明显影响。结论大米α-球蛋白肽YGEGSSEEG可通过抑制细胞凋亡和降低黏附分子表达,发挥血管内皮细胞保护作用。     

Impact of non-medical switching on clinical and economic outcomes,resource utilization and medication-taking behavior: a systematic literature review

Objective: To evaluate current knowledge of the impact of non-medical switching on clinical and economic outcomes, resource utilization and medication-taking behavior. Methods: The literature was searched (Medline and Web of Science, January 2000–November 2015) to identify United States’ studies evaluating ≥25 patients and measuring the impact of non-medical switching of drugs (switching to a chemically distinct but similar medication for reasons other than lack of clinical efficacy/response, side effects or poor adherence) on ≥1 clinical, economic, resource utilization or medication-taking behavior outcome. The direction of association between non-medical switching and outcomes was classified as negative or positive if a statistically significant worsening or improvement was reported, or neutral if no significant difference was observed. Results: Twenty-nine studies contributed 96 outcomes (60.4% clinical; 21.9% resource utilization; 13.5% economic; 4.2% medication-taking behavior) within six disease categories (cardio-metabolic, immune-mediated, acid suppression, psychiatric, hormone replacement therapy and pain). The direction of association was more frequently negative (33.3%) or neutral (55.2%) than it was positive (11.5%). Stratified by outcome type, non-medical switching was negatively associated with clinical, economic, healthcare utilization and medication-taking behavior outcomes in 20.7%, 69.2%, 38.1% and 75.0% of cases, respectively; and positively in only 4.8%–17.2% of outcomes subgroups. Of 32 outcomes in patients demonstrating stable/well controlled disease, 68.8% and 31.3% had a negative and neutral direction of association. In patients without demonstrated disease stability, outcomes were negatively, neutrally and positively impacted by non-medical switching in 15.6%, 67.2% and 17.2% of 64 outcomes. Limitations: Our inability to evaluate specific disease state categories and studies/outcomes received equal weight regardless of sample size or magnitude of effect. Conclusions: Non-medical switching was more often associated with negative or neutral effects than positive effects on an array of important outcomes. Among patients with stable/well controlled disease, non-medical switching was associated with mostly negative effects.     

阿托伐他汀对急性冠脉综合征患者外周血单核细胞合成组织因子和TNF-α的影响

目的：研究阿托伐他汀对急性冠脉综合征患者外周血单核细胞表达TNF-α、组织因子水平及组织因子活性的影响。方法：分离急性冠脉综合征患者外周血单核细胞,分别以不同浓度的阿托伐他汀（0,0．1,1,10μmol／L）干预,共同孵育24h后．用夹心酶联免疫吸附测定法检测细胞培养上清液TNF-α及细胞膜组织因子水平,用逆转录聚合酶联链反应测定它们mRNA的表达,同时用底物发光法检测组织因子的活性。结果：不同浓度的阿托伐他汀（0,0．1,1,10μmol／L）干预后急性冠脉综合征患者外周血单核细胞合成TNF-α分别为（306±40）、（264±54）、（229±24）、（189±44）ng／L,合成组织因子分别为（5．8±1．3）、（4．6±0．8）、（3．7±0．9）、（2．7±0．5）ng／L及组织因子的活性分别为（16．2±3．2）、（7．7±2．8）、（4．3±0．8）、（3．8±0．8）pmol／L（均P〈0．05）。结论：阿托伐他汀呈药物浓度依赖性地减少急性冠脉综合征患者外周血单核细胞合成TNF氓组织因子及组织因子活性。阿托伐他汀通过抗炎、抗血栓形成而在急性冠脉综合征防治中起重要作用。     

Clinical interest: a study of the influence on general practitioners' prescribing

PURPOSE: To analyse the association between general practitioners' clinical interest and prescribing rates in four clinical areas: dyspepsia, depression, headache and diabetes. METHODS: Data concerning general practitioners' prescribing during 2004 were retrieved from a pharmacy database and linked with data from a physician questionnaire and the National Health Insurance Register. To counterbalance differences in practice populations all 1-year prevalences of prescribing were standardised according to age and gender. Participants were asked 'To what extent do you find the following areas interesting from a professional point-of- view?' Four rating categories were used. The association between clinical interest and standardised prescribing rates was investigated using logistic regression, the Kruskal-Wallis test and a trend test. RESULTS: A total of 68 (72%) single-handed general practitioners representative of the total group completed the questionnaire. We observed a two-fold ratio between the 90% and the 10% percentiles of the 1-year prevalences of antisecretory drugs, antidepressants, migraine drugs as well as anti-diabetics. The variation in prescribing of antidepressant and antisecretory drugs was far above chance level. No significant association with clinical interest could, however, be observed for any of the four clinical areas. CONCLUSION: General practitioners' prescribing of the four classes of medical drugs varied considerably. However, only part of this variation was based on chance. This study did not confirm our hypothesis that general practitioners' level of clinical interest in one area corresponds with their prescribing of drugs used within that area.     

慢性阻塞性肺疾病患者营养状况与瘦素及肿瘤坏死因子α和甲状腺激素关系的研究

目的探讨血清瘦素、肿瘤坏死因子α（TNF—α）和甲状腺激素在慢性阻塞性肺疾病（COPD）患者营养不良发生中的意义。方法观察COPD临床稳定期患者148例,根据体质指数（BMI）、理想体质量百分比（NW％）、三头肌皮皱厚度（TSF）、上臂中点臂围（MAC）、血清白蛋白（ALB）、总淋巴细胞（LYM）等营养参数,分为COPD营养不良组（COPDⅠ组）47例,COPD非营养不良组（COPDⅡ组）101例,另选健康人30例为对照组。采用双抗体夹心酶联免疫吸附法检测血清瘦素、TNF-α,采用放射免疫法测定甲状腺激素（T3、T4、FT3、FT4、TSH）,并探讨上述因素在COPD营养不良患者中的作用及相互之间的相关性。结果COPDI组BMI、NW％、TSF、MAC、ALB、LYM与COPDⅡ组、对照组比较差异均有统计学意义（P〈0．01）,COPDⅡ组与对照组比较差异无统计学意义（P〉0．05）;COPDⅠ组瘦素水平分别与COPDⅡ组、对照组比较差异均有统计学意义（P〈0．01）,COPDⅡ组与对照组比较差异无统计学意义（P〉0．05）;COPDⅠ组、COPDⅡ组TNF-α水平分别与对照组比较差异有统计学意义（均P〈0．01）,而COPDⅠ组与COPDⅡ组比较差异无统计学意义（P〉0．05）;COPDI组T3、T4分别与COPDⅡ组、对照组比较差异有统计学意义（均P〈0．01）;COPDⅡ组T4与对照组比较差异有统计学意义（均P〈0．01）。COPDⅠ组、COPDⅡ组BMI、NW％、TSF与瘦素水平呈正相关（P〈0．01）,瘦素水平与TNF—α、TSH呈正相关（P〈0．05）。结论COPD患者营养不良与血清瘦素水平、TNF-α及甲状腺激素有关,瘦素受TNF—α系统调控,瘦素与下丘脑-垂体-甲状腺轴之间存在相互调节关系,三者共同参与了COPD患者营养不良的发生。