Novel medications for asthma: a look at the future

The principal components of the asthmatic response are airways hyper-responsiveness, persistent inflammation and mucus hypersecretion. Although these components are inter-related, any of these can predominate at different times and for different patients and each requires a different approach to therapy. As a result of the inflammation and epithelial damage, there can be abnormal repair mechanisms leading to fixed airflow obstruction that has been termed ‘airways remodeling’. Although there are a number of highly effective therapeutic agents used to treat asthma today, novel therapies are being designed to more specifically and safely target these different components and better meet the needs of patients with asthma.     

静脉注射沙丁胺醇治疗哮喘急性发作20例

本文选择20例支气管哮喘急性发作患者,用沙丁胺醇,按4μg/kg的负荷量作静脉推注。经用药前、后的肺通气功能测定比较,于用药后即刻、15min,30min,1h,2h的FEV_1均比用药前有明显的改善(P<0.001),其药效高峰时间为用药后15min左右,作用时间维持在2h以上。用药后20例患者的FEV_1比用药前均可增加≥20％,其中13例(65％)增加达≥40％。患者在用药后肺通气功能改善的同时,其胸闷,气急和咳嗽等临床症状好转,哮鸣音减少或消失。作者认为沙丁胺醇静脉注射治疗支气管哮喘急性发作患者,具有临床疗效好,起效快,药效高峰出现早等优点。     

福莫特罗治疗支气管哮喘的多中心临床研究

目的:比较2种长效肾上腺素β2受体激动药福莫特罗治疗支气管哮喘的疗效和安全性。方法:采用多中心、随机、双盲、双模拟、平行对照试验方法,临床研究共分为2部分。(1)连续2 wk用药观察:试验组59例和对照组64例,分别口服福莫特罗试验药或对照药及模拟药40μg,bid,疗程14 d。观察病人症状、体征、肺功能(FEV1和PEF)的变化。(2)即刻疗效观察:试验组和对照组各24例,分别口服单一剂量的福莫特罗试验药或对照药40μg及模拟药。观察病人服药后FEV1和PEF改善达15％的时间和改善≥15％的疗效持续时间。结果: (1)治疗2 wk后,试验组哮鸣音的改善优于对照组(P< 0．05),咳嗽、痰量、喘息、呼吸困难及FEV1和PEF的2组间比较,无显著差异(P>0．05)。试验组临床有效率为95％,对照组为92％。试验组FEV1及PEF有效率分别为66％,75％,对照组FEV1及PEF有效率分别为55％,72％。2组间比较无显著差异(P>0．05)。(2)服用单一剂量药物后,试验组FEV1和PEF改善达15％的起始时间分别为(2．0±s 2．1)h, (2．6±2．8)h,对照组分别为(2．3±2．7)h,(3±4)h。试验组FEV1和PEF改善≥15％的疗效持续时间分别为(6±4)h, (6±4)h,对照组分别为(6±4)h,(5±4)h。2组间比较均无显著差异(P>0．05)。(3)2组治疗耐受性均较好,不良反应发生率均为30％。结论:2种福莫特罗治疗支气管哮喘均具有较好的临床疗效、肺功能疗效及安全性,且两者疗效和安全性相似。     

机械通气救治重症哮喘32例临床分析

目的探讨机械通气在救治重症哮喘中的作用,评价机械通气治疗重症哮喘的方法和疗效。方法对32例重症哮喘患者适时进行机械通气治疗,采用面罩无创正压通气和（或）有创机械通气,尽量减少有创机械通气的时间。结果32例患者在24小时内症状明显缓解,缺氧伴二氧化碳潴留迅速改善,一周内基本脱离呼吸机,机械通气前后心率、呼吸频率、血气变化（P〈0．01）,有统计学意义;29例患者抢救成功,3例患者因并发多脏器功能衰竭死亡。结论机械通气是治疗重症哮喘的有效方法,可适时应用。     

苏葶止喘汤联合西医治疗小儿支气管哮喘急性发作期(痰热阻肺证) 38例

目的探讨苏葶止喘汤联合西医治疗小儿支气管哮喘急性发作期(痰热阻肺证)临床疗效。方法收集 2020年 2月至 2022年 3月河北省沧州中西医结合医院就诊的急性发作期的支气管哮喘病儿 78例,根据随机数字表法分为对照组与治疗组各 39例,对照组病儿给予硫酸沙丁胺醇、异丙托溴铵、布地奈德雾化吸入等西医治疗,治疗组在对照组基础上给予苏葶止喘汤治疗,观察两组治疗前后的临床疗效,症状缓解时间(咳痰消失时间、哮鸣音消失时间、咳嗽消失时间、喘息消失时间)肺功能指标［用力肺活量(FVC)第 1秒用力呼吸容积(FEV1)第 1秒用力呼气量占所有呼气量的比例(FEV1/FVC)最大呼气流量(,PEF)气中断流速( PEF25%)、、呼吸中期瞬间流速( PEF50%、)、呼吸后期瞬间流速( PEF75%)］血清炎症因子指、标［C反应蛋白(CRP)、呼、白细胞介素 -22(IL-22)、白细胞介素 -4(IL-4)］,Toll样受体 2(TLR2)Toll样受体 4(TLR4),表达水平。结果治疗后治疗组总有效率 94.74%显著高于对照组 71.05%(P<0.05);治疗组症状缓解时间快、于对照组( P<0.05);治疗后两组 FVC、FEV1、FEV1/FVC、PEF、PEF25%、PEF50%、PEF75%值均较治疗前升高且治疗组高于对照组( P<0.05);治疗后两组血清 CRP、IL-22、IL-4、TLR2、 TLR4水平均较治疗前降低,且治疗组 CRP［( 10.23±3.26)mg/L比( 15.25±5.37)mg/L］、 IL-22［( 37.13±9.84)ng/L比( 45.46±11.08) ng/L］、IL-4［(48.15±12.28)ng/L比( 56.07±14.36)ng/L］、 TLR2［(16.78±1.91)ng/L比( 21.15±2.08)ng/L］、 TLR4［(18.05±2.53)ng/L比     

Law,medicines and the doctor: a critical look at drug regulation

Summary

The current status of medicines regulation and legislation throughout the world is reviewed. The basic task of drug regulatory agencies is to ensure that the medicines available to the physician are sufficiently safe and effective, and that the information supplied on these medicines is adequate and reliable; the final choice of drug remains the physician's task. By examining the way in which regulatory agencies have dealt with different problems it is possible to identify many of the norms which are emerging. By and large these would seem to be reasonable, and it appears unlikely that drug regulation has, in fact, impeded the development of valuable new medicines. Such problems as do arise are due in part to marked differences in national control systems. It is suggested that these problems may be more readily resolved by informal international co-operation than by formalized international control of medicines.     

Intracellular immune dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome: state of the art and therapeutic implications

Background: Evidence in support of intracellular immune dysfunctions in people with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is accumulating, but few studies have addressed intracellular immunity as a potential therapeutic target. Objective: To provide an overview of our present understanding of intracellular immunity in ME/CFS, to relate the intracellular immune dysfunctions to other aspects of the illness like decreased natural killer cell function, the presence of infections and poor exercise performance, and to point to potential therapeutic targets. Methods: An in-depth review of the scientific literature of intracellular immunity in people with ME/CFS was performed. Results/conclusion: From the scientific literature it is concluded that proteolytic cleavage of the native RNase L enzyme is characteristic of the dysregulation of intracellular immunity in people with ME/CFS, but the origin of the dysregulation is speculative. There is increasing evidence for immune cell apoptosis and upregulation of various aspects of the 2′-5′ oligoadenylate (2-5A) synthetase/RNase L pathway in ME/CFS. This review provides the theoretical rationale for conducting studies examining the effectiveness of direct or indirect drug targeting of the 2-5A synthetase/RNase L pathway in ME/CFS patients.     

Effects of inhaled beclomethasone dipropionate on beta2-receptor function in the airways and adrenal responsiveness in bronchial asthma

Summary Sixteen patients suffering from bronchial astham, with or without chronic bronchitits, sufficiently severe to be treated with inhaled corticosteroids, were studied in a single-blind trial (blind observer) of beclomethasone dipropionate (BDP) given in three randomized dosage regimens: 500, 1000 and 2000 µg per day, each for 4 weeks. The ₂-adrenergic agoinst response curve showed a dose-dependent increase in FEV₁ which was not affected by different doses of BDP. A small but significant reduction in basal cortisol levels was observed after BDP 500 µg/day. There was no significant difference between the various doses of BDP in reducting cortisol level and stimulation with tetracosactide remained unchanged. The study showed a gradual, dose-dependent improvement in lung function, statistically significant for morning peak expiratory flow rate at BDP 2000 µg/day. Dyspnoea score and ₂-agonist use decreased, reflecting the anti-asthmatic effects. An increase in total leukocyte count was observed, together with a decrease in the eosinophil count. Oral candidiasis was seen in 2 out of 16 patients. It is concluded that the clinical anti-asthmatic effects of corticosteroid treatment by inhalation are not due to modulation of ₂-receptor function in the airways.     

综合外治法治疗小儿哮喘96例

目的:观察综合外治法治疗小儿哮喘的疗效。方法:运用针灸、中药贴敷及穴位注射治疗小儿哮喘96例,并观察其临床疗效。结果:显效60例,有效19例,无效17例,总有效率为82.4%。结论:此方法简便易行,疗效可靠,值得推广。     

Effect of omalizumab on the need for rescue systemic corticosteroid treatment in patients with moderate-to-severe persistent IgE-mediated allergic asthma: a pooled analysis

ABSTRACT

Background: Allergic asthma is an immunoglobulin E (IgE)-mediated disease characterized by frequent exacerbations following exposure to relevant allergens that leads to the development of chronic airway inflammation. Omalizumab, an anti-IgE antibody, reduces asthma exacerbation and hospitalization rates in patients with IgE-mediated allergic asthma. We investigated the effect of omalizumab on asthma outcomes in a retrospective pooled analysis of data from phase III clinical trials in patients (≥ 12 years) with moderate-to-severe persistent IgE-mediated allergic asthma.

Methods: Systemic corticosteroid bursts and physician and patient overall assessments of asthma control were assessed in patients who received add-on omalizumab or current asthma therapy (control). The association of physician and patient overall assessments with the number of steroid bursts were also evaluated.

Results: The analysis encompassed 4308 patients with moderate-to-severe persistent IgE-mediated allergic asthma (93% met GINA 2002 criteria for severe persistent asthma) from seven clinical trials. The number of systemic corticosteroid bursts was significantly lower in omalizumab-treated patients than in the control group (relative risk [95% CI]: 0.57 [0.48–0.66], p < 0.001). In addition, 58.5% of omalizumab recipients had complete/marked improvement in asthma control according to the physician's overall assessment (responders) vs. 36.9% in the control group (?p < 0.001). Similarly, 64.2% of omalizumab patients vs. 43.9% of control patients had complete/marked improvement according to the patient's overall assessment (?p < 0.001). There were statistically significant associations between systemic corticosteroid bursts and physician (Goodman–Kruskal gamma [95% CI]: 0.32 [0.26–0.38]) and patient (gamma [95% CI]: 0.29 [0.23–0.36]) overall assessments. This pooled analysis has limitations as it was not pre-specified.

Conclusions: Omalizumab therapy reduced the need for systemic corticosteroid bursts and improved effectiveness of asthma treatment as judged by both physicians and patients.     

高敏肌钙蛋白T诊断急性冠脉综合征及其危急值医学决定水平的研究

目的：探讨高敏肌钙蛋白T对急性冠脉综合征（ACS）诊断及其危急值的的临界值（cutoff）。方法采用化学发光法检测857例研究对象,其中307例ACS患者和550例正常对照者血浆高敏心肌肌钙蛋白T（cTnT-hs）和高敏心肌肌钙蛋白I（cTnI-hs）,应用受试者工作特征曲线（ROC）进行分析。结果cTnT-hs为0.030ng/mL时,其诊断ACS的ROC曲线下面积为0.912,敏感度为89.6%,特异度为83.8%,阴性预测值为92.6%,阳性预测值为94.4%,正确诊断指数为0.734。当以cTnT-hs为0.10ng/mL作为ACS危急界限值时,ROC曲线下面积为0.927,敏感度为90.9%,特异度为87.9%,阴性预测值为89.3%,阳性预测值为86.5%,正确诊断指数为0.788。结论cTnT-hs是诊断ACS敏感而特异的指标,当cutoff值分别为0.03ng/mL、0.10ng/mL时,cTnT-hs诊断ACS及其危急值的cutoff值综合评价最佳。     

Solid lipid nanoparticles for applications in gene therapy: a review of the state of the art

Importance of the field: Gene therapy represents a new paradigm in the prevention and treatment of many inherited and acquired diseases, including genetic disorders, such as cystic fibrosis, haemophilia and many somatic diseases, such as tumours, neurodegenerative diseases and viral infections, such as AIDS.

Areas covered in this review: Among a large array of non-viral transfection agents used for in-vitro applications, cationic SLNs are the topic of this review, being recently proposed as an alternative carrier for DNA delivery, due to many technological advantages such as large-scale production from substances generally recognized as safe, good storage stability and possibility of steam sterilization and lyophilisation.

What the reader will gain: The authors give some information on the knowledge of intracellular trafficking and SLNs-DNA complex chemical-physical properties reported until now in the literature.

Take home message: The future success of cationic SLNs for administration of genetic material will depend on their ability to efficiently cross the physiological barriers, selectively targeting a specific cell type in vivo and expressing therapeutic genes.     

Intranasal insulin therapy for cognitive impairment and neurodegeneration: current state of the art

Introduction: Growing evidence supports the concept that insulin resistance plays an important role in the pathogenesis of cognitive impairment and neurodegeneration, including in Alzheimer's disease (AD). The metabolic hypothesis has led to the development and utilization of insulin- and insulin agonist-based treatments. Therapeutic challenges faced include the ability to provide effective treatments that do not require repeated injections and also the ability to minimize the potentially hazardous off-target effects.

Areas covered: This review covers the role of intranasal insulin therapy for cognitive impairment and neurodegeneration, particularly AD. The literature reviewed focuses on data published within the past 5 years as this field is evolving rapidly. The review provides evidence that brain insulin resistance is an important and early abnormality in AD, and that increasing brain supply and utilization of insulin improves cognition and memory. Emphasis was placed on discussing outcomes of clinical trials and interpreting discordant results to clarify the benefits and limitations of intranasal insulin therapy.

Expert opinion: Intranasal insulin therapy can efficiently and directly target the brain to support energy metabolism, myelin maintenance, cell survival and neuronal plasticity, which begin to fail in the early stages of neurodegeneration. Efforts must continue toward increasing the safety, efficacy and specificity of intranasal insulin therapy.     

Lipid nanoparticles for cancer therapy: state of the art and future prospects

Introduction: Cancer is a leading cause of death worldwide and it is estimated that deaths from this disease will rise to over 11 million in 2030. Most cases of cancer can be cured with surgery, radiotherapy or chemotherapy if they are detected at an early stage. However, current cancer therapies are commonly associated with undesirable side effects, as most chemotherapy treatments are cytotoxic and present poor tumor targeting.

Areas covered: Lipid nanoparticles (LN) are one of the most promising options in this field. LN are made up of biodegradable generally recognized as safe (GRAS) lipids, their formulation includes different techniques, and most are easily scalable to industrial manufacture. LN overcome the limitations imposed by the need for intravenous administration, as they are mainly absorbed via the lymphatic system when they are administered orally, which improves drug bioavailability. Furthermore, depending on their composition, LN present the ability to cross the blood–brain barrier, thus opening up the possibility of targeting brain tumors.

Expert opinion: The drawbacks of chemotherapeutic agents make it necessary to invest in research to find safer and more effective therapies. Nanotechnology has opened the door to new therapeutic options through the design of formulations that include a wide range of materials and formulations at the nanometer range, which improve drug efficacy through direct or indirect tumor targeting, increased bioavailability and diminished toxicity.     

Tiotropium for the treatment of asthma: a drug safety evaluation

ABSTRACT

Introduction: Tiotropium, a once-daily long-acting anticholinergic bronchodilator, has recently been approved for use in the treatment of asthma in a number of countries, including the EU and the USA, and was incorporated into the 2015 update of the Global Initiative for Asthma treatment guidelines. Here we review safety data from published clinical trials to help inform the use of tiotropium in the treatment of patients with asthma.

Areas covered: Safety data from recently published clinical trials, which compared tiotropium with placebo or an active control, were reviewed. Trials included children, adolescents, and adults across severities of symptomatic asthma, and assessed tiotropium delivered via the Respimat and HandiHaler devices.

Expert opinion: Based on the reviewed scientific evidence, tiotropium is a safe and well-tolerated long-acting anticholinergic bronchodilator for use in the treatment of asthma. In the trials assessed, the safety of tiotropium was found to be comparable with that of placebo and alternative therapeutic options, including a doubling in the dose of inhaled corticosteroids and the long-acting β₂-agonist salmeterol.     

Genotype-based therapeutic approach for colorectal cancer: state of the art and future perspectives

Background: There is a considerable need to increase efforts in maximizing clinical outcome in the treatment of colorectal cancer, and the identification of genetic factors underlying drug response seems to be one of the most promising areas in this research field. Methods: Clinical trials and pharmacogenetic association studies were reviewed to offer an overview of the most commonly reported polymorphisms in candidate genes critically involved in the response to the chemotherapeutics used at present in the management of colorectal cancer. Results: Several studies investigating the association between genotype and therapeutic results show contrasting data, thus determining increasing uncertainty in the identification of reliable predictive genetic markers of drug response. However, some of the genetic variations identified in genes encoding thymidylate synthase, dihydropyrimidine dehydrogenase, glutathione S-transferase pi, and uridine diphosphate glucosyltransferase 1A1 seem to be promising predictors of drug efficacy and/or toxicity. Conclusion: Additional investigation is needed to validate fully the clinical relevance of individual genetic differences in the variability of drug response. It is hoped that this knowledge base will offer, in the not too distant future, the opportunity to overcome the empirical trial-and-error method in favor of therapeutic drug optimization based on individual genetic make-up.