New targets for drug development in asthma

Asthma is a chronic inflammatory disease that affects about 300 million people worldwide, a total that is expected to rise to about 400 million over the next 15-20 years. Most asthmatic individuals respond well to the currently available treatments of inhaled corticosteroids and beta-adrenergic agonists; however, 5-10% have severe disease that responds poorly. Improved knowledge of asthma mechanisms has led to the recognition of different asthma phenotypes that might reflect distinct types of inflammation, explaining the effectiveness of anti-leucotrienes and the anti-IgE monoclonal antibody omalizumab in some patients. However, more knowledge of the inflammatory mechanisms within the airways is required. Improvements in available therapies-such as the development of fast-onset, once-a-day combination drugs with better safety profiles-will occur. Other drugs, such as inhaled p38 MAPK inhibitors and anti-oxidants, that target specific pathways or mediators could prove useful as monotherapies, but could also, in combination with corticosteroids, reduce the corticosteroid insensitivity often seen in severe asthma. Biological agents directed against the interleukin-13 pathway and new immunoregulatory agents that modulate functions of T-regulatory and T-helper-17 cells are likely to be successful. Patient-specific treatments will depend on the development of discriminatory handprints of distinct asthma subtypes and are probably over the horizon. Although a cure is unlikely to be developed in the near future, a greater understanding of disease mechanisms could bring such a situation nearer to reality.     

Inhalation therapy for bronchial asthma: strategies and targets

Bronchial asthma is associated with symptoms, reversible airflow obstruction, airway hyper-responsiveness and inflammation along large and small airways. Inhalation therapy with bronchodilators (relievers) and anti-inflammatory agents (controllers) forms the basis of treatment for most patients with asthma of different severities. Conventionally, therapeutic efficacy is assessed on the basis of improvements in symptoms and lung function. However, airway hyper-responsiveness as a primary outcome may change therapeutic strategies. There are problems associated with this concept which need to be addressed, such as the heterogeneity of airway inflammation in the asthmatic lung. The goals for inhalation therapy should be to determine the site of airway inflammation for each degree of asthma severity, to improve inhaler technology, ensuring that the drug can reach the site of inflammation, and to improve compliance. New inhalers need to do the following: contain appropriate therapeutic agents; have particle dimensions small enough to be deposited in distal airways; and minimize the effects of incorrect inhalation and low compliance.     

New targets for modifying mast cell activation in asthma

Mast cells play a central role in innate immunity and in orchestrating the asthmatic response. Current medication relies on β-agonists to relieve bronchoconstriction and steroids to reduce inflammation. However, recently drugs such as leukotriene-receptor antagonists and anti-immunoglobulin E have come on to the market. In this paper, a number of potential targets for modifying mast cell activation in asthma are reviewed. Some are already under study, including clinical trials (eg, tryptase inhibitors); others are more speculative (eg, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity). In each case, where data are available, the action of the agents on human lung mast cells is described.     

可望用于临床的治疗难治性哮喘的新药物和新方法

"获得哮喘最佳控制(GOAL)"研究结果显示,采用吸入性糖皮质激素(ICS)联合长效β2受体激动剂(LABA)治疗,2/3以上的中重度哮喘患者均可获得良好的临床控制,但仍有5%～10%的患者经全球哮喘防治指南(GINA)推荐的第4步治疗方案,即采用两种或两种以上的控制药物仍不能达到可接受的哮喘控制水平,称为难治性哮喘.     

New targets for CAR T therapy in hematologic malignancies

As we expand our acumen of the intricacies of hematological malignancies at a genetic and cellular level, we have paved the way in advancing novel targeted therapeutic avenues such as chimeric antigen receptor T-cell therapies (CAR T). Engineering cells to target a specific antigen has led to dramatic remission rates in cases of relapsed/refractory non-Hodgkin lymphoma, acute lymphoblastic leukemia as well as multiple myeloma thus far with trials in place to further advance targeted therapies in other hematological malignancies. Most currently available CAR T therapies target CD19 antigen. Studies are underway exploring novel CAR T products aimed at other tumor-specific antigens with potential to improve the efficacy and reduce the toxicities. Early studies have confirmed safety and efficacy of CD22 and BCMA targeted CAR T therapies. Moreover, various other targets including CD20, CD30, CD123, kappa, and lambda light chains among others are under clinical investigation as potential avenues of targeted therapy. This review highlights the shift in the treatment paradigm in pursuing diverse antigen targets while addressing the challenges in terms of the efficacy and toxicity of current CAR T-cell therapies.     

New targets for antiviral therapy of chronic hepatitis C

Until recently, chronic hepatitis C caused by persistent infection with the hepatitis C virus (HCV) has been treated with a combination of pegylated interferon-alpha (PEG-IFNα) and ribavirin (RBV). This situation has changed with the development of two drugs targeting the NS3/4A protease, approved for combination therapy with PEG-IFNα/RBV for patients infected with genotype 1 viruses. Moreover, two additional viral proteins, the RNA-dependent RNA polymerase (residing in NS5B) and the NS5A protein have emerged as promising drug targets and a large number of antivirals targeting these proteins are at different stages of clinical development. Although this progress is very promising, it is not clear whether these new compounds will suffice to eradicate the virus in an infected individual, ideally by using a PEG-IFNα/RBV-free regimen, or whether additional compounds targeting other factors that promote HCV replication are required. In this respect, host cell factors have emerged as a promising alternative. They reduce the risk of development of antiviral resistance and they increase the chance for broad-spectrum activity, ideally covering all HCV genotypes. Work in the last few years has identified several host cell factors used by HCV for productive replication. These include, amongst others, cyclophilins, especially cyclophilinA (cypA), microRNA-122 (miR-122) or phosphatidylinositol-4-kinase III alpha. For instance, cypA inhibitors have shown to be effective in combination therapy with PEG-IFN/RBV in increasing the sustained viral response (SVR) rate significantly compared to PEG-IFN/RBV. This review briefly summarizes recent advances in the development of novel antivirals against HCV.     

New immunological approaches and cytokine targets in asthma and allergy.

The aims of current asthma treatment are to suppress airway inflammation and control symptoms, and corticosteroids maintain a commanding position in this role. Steroids effectively suppress inflammation in the majority of patients but have little impact on the natural history of this disease. In severe asthmatics, corticosteroids may have relatively less beneficial effects. Recent advances in understanding the inflammatory and immunological mechanisms of asthma have indicated many potential therapeutic avenues that may prevent or reverse abnormalities that underlie asthma. As the roles of effector cells, and of signalling and adhesion molecules are better understood, the opportunities to inhibit or prevent the inflammatory cascade have increased. In addition, there have been advances in the synthesis of proteins, monoclonal antibodies and new small molecule chemical entities, which may provide valuable flexibility in the therapeutic approach to asthma. The novel immunological approaches include the prevention of T-cell activation, attempts to influence the balance of T-helper cell (Th) populations to inhibit or prevent Th2-derived cytokine expression, and the inhibition or blockade of the downstream actions of these cytokines such as effects on immunoglobulin-E and eosinophils. These approaches provide broad as well as highly specific targeting, and also prospects for prevention and reversal of immunological and inflammatory abnormalities associated with asthma. Hopefully, the development of effective antiasthma agents with effects beyond those provided by current therapies coupled with lesser side-effects will further address the unmet needs of asthma.     

Aerosol therapy for asthma

Inhaled drugs play an important role in asthma management. The correct use of an appropriate delivery device is necessary to achieve the desired therapeutic effects of the drug. Currently, chlorofluorocarbon-propelled metered-dose inhalers, with or without spacers, are the most popular aerosol delivery devices. With the planned phase out of the chlorofluorocarbon metered-dose inhalers, the use of other delivery devices is being emphasized. To achieve optimal therapeutic effects, the drug and the delivery device should be considered a "couple". Aerosol delivery devices should provide an adequate "drug dose to the lung", be cost effective, simple to operate, minimize oropharyngeal deposition and systemic side effects, and match the patient's requirements. A new generation of aerosol delivery devices, incorporating the latest advances in aerosol technology, is likely to fulfill many of the goals mentioned above.     

Targets for asthma therapy

Most asthma is allergic in origin, the disease involves four distinct phases of response: the sensitization phase and the activation phase, followed by the effector phase, initiated by the release of pharmacologically active agents, the growth and repair phase, characterized by proliferation of tissues as "remodeling" of the airway wall, altering structure and function.     

支气管哮喘的免疫疗法

支气管哮喘(简称哮喘)是常见的呼吸系统疾病.随着对哮喘发病机制的了解,哮喘的治疗已取得很大进展,针对免疫机制的治疗是哮喘治疗的重要方面.本文重点阐述特异性免疫治疗、免疫球蛋白E单克隆抗体、细胞因子调节剂在哮喘方面的治疗作用.     

Anti-immunoglobulin E therapy for asthma

The role of immunoglobulin E (IgE) in allergic asthmatic disease is well established. Allergen-specific IgE binds to its cognate receptors, thus triggering a series of cellular events. These events include presentation of antigen by dendritic cells and the degranulation of mast cells and basophils to release numerous factors that play an integral part in potentiating the disease symptoms. Studies in the mouse indicate that a reduction in IgE levels could lead to significant attenuation of the allergic inflammatory response associated with diseases such as asthma, making IgE a target for the development of new therapeutic agents. Omalizumab (Xolair, a recombinant humanized monoclonal anti-IgE antibody that blocks the interaction of IgE with its receptors, is the first anti-IgE agent to undergo clinical development. Several clinical studies have been performed in adults and children with moderate-to-severe allergic asthma to evaluate the efficacy and safety of this agent. Treatment with omalizumab was well tolerated and showed clinical benefit in terms of a reduction in the frequency and number of asthma exacerbation episodes and lower usage of corticosteroids and other medications to control disease, along with improved quality of life. Such findings indicate that omalizumab represents a promising new treatment option for allergic asthma.     

Corticosteroid therapy for acute asthma

Asthma is a chronic inflammatory disease, which is characterised by reversible airflow obstruction in response to a variety of stimuli. Exacerbations in response to airway irritants are part of the natural history of asthma, but often they also represent a failure in chronic treatment. Presentations to emergency departments and other acute care settings are common and frequently lead to hospitalisation and other complications. After treatment, however, most patients are discharged to the care of their primary care physician for further management. This review highlights the role of systemic and inhaled corticosteroids as mainstays of treatment in the acute and sub-acute phase of an exacerbation. These agents form the basis of most current clinical practice guidelines, yet their use is not universal. We will review the evidence for the use of these agents that arises from the Cochrane Collaboration of Systematic Reviews contained in the Cochrane Library.     

Initial corticosteroid therapy for asthma

PURPOSE OF REVIEW: This review examines the commencement of maintenance pharmacotherapy for asthma: inhaled corticosteroids alone or in combination with long-acting beta2 agonists. RECENT FINDINGS: A systematic review of randomized controlled trials has examined the starting dose of inhaled corticosteroids (high, moderate, low) and the dose regimen (step down versus constant) in asthma. There was no significant difference in key asthma outcomes for step down compared with a constant inhaled corticosteroid dose. There was no significant difference between high or moderate dose inhaled corticosteroid groups (n=11) for morning peak expiratory flow, symptoms and rescue medication use. There may be a benefit from high-dose inhaled corticosteroids for airway hyperresponsiveness. There was a significant improvement in peak expiratory flow and nocturnal symptoms in favour of a moderate inhaled corticosteroid dose compared with low-dose treatment. Long-acting beta2 agonists combined with inhaled corticosteroids as initial asthma therapy has been examined in a systematic review of nine randomized controlled trials. Inhaled corticosteroids combined with long-acting beta2 agonists led to significant improvements in forced expiratory volume in 1 s, morning peak expiratory flow, symptom score and symptom-free days but no difference in exacerbations requiring oral corticosteroids. A randomized controlled trial of patients with uncontrolled asthma found a benefit of escalating doses of salmeterol/fluticasone compared with fluticasone on asthma control. SUMMARY: Initial inhaled corticosteroid therapy should begin with a constant, moderate dose. Initial therapy with long-acting beta2 agonist and inhaled corticosteroids achieves superior improvement in symptoms and lung function, and at a quicker rate than inhaled corticosteroids alone. There is no benefit in terms of reduced exacerbations unless an escalating inhaled corticosteroid dose strategy is used.     

New treatments for asthma

It has proved to be very difficult to develop new classes of antiasthma therapy, partly because existing drugs, and particularly inhaled corticosteroids are so effective. The only new class of drug developed in 25 years have been the antileukotrienes which are less effective than inhaled corticosteroids. There is a need to develop new treatments for asthma, since patients with severe asthma are not well controlled on doses of corticosteroids that are safe, and there is a problem of poor compliance with existing inhaler therapy. Several drugs are now in development for asthma. New bronchodilators have been difficult to develop as new drugs are less effective than β₂-agonists and have more side effects. Mediator antagonists have proved disappointing as so many mediators are involved in asthma. Inhibitors of cytokines, such as interleukin (IL)-5, IL-4 and eotaxin, which may inhibit eosinophilic inflammation, are now in clinical development. Other approaches include more selective immunomodulation, anti-IgE antibodies, adhesion molecule blockers and kinase inhibitors. Preventive treatments in the future may include drugs that alter the immune abnormalities in atopy by stimulating a protective Th1 immunity. A cure for asthma does not seem likely in the near future.     

胸腺和活化调节趋化因子与支气管哮喘

胸腺和活化调节趋化因子(TARC)是一种新的CC趋化因子,具有选择性诱导T细胞的迁移,尤其是将Th2细胞从外周募集至炎症部位,参与了多种过敏性疾病的发生和发展。近年研究显示TARC在哮喘的气道炎症细胞浸润和气道高反应性的发生发展中起了重要作用。本文就TARC的生物学特点及其与支气管哮喘的关系作一综述,以探讨通过抑制TARC的作用为治疗哮喘提供新方法和新策略。     

Cancer therapy: new targets for chemotherapy

The number two cause of mortality in developed countries is cancer. Despite the enormous effort put into cancer prevention, early diagnosis and treatment, it is likely that the incidence of the cancer morbidity and mortality will increase for the foreseeable future. This is due to various factors such as increased life expectancy, changes in environment and also the socio-economic situation around the world. Some cancer attracts more attention than others and increasingly epidemiological information is reaching the general public and is beginning to influence behavior. It is now well recognized that, for example, 1 of 8 women in the industrialized world will be diagnosed with breast cancer. Additionally, a strong correlation was established between lung cancer incidence and smoking and it is broadly accepted that the incidence of colon cancer is directly related to age and diet, and has been increasing over time. The current failure of preventive measures to significantly reduce the increasing incidence of these common tumors illustrates the importance of effective cancer treatment strategies, including chemotherapy. The combination of various anticancer drugs, given together with surgery and radiotherapy, gives hope to many patients. There has been recent evidence of improved therapeutic outcome with recent approaches and newer agents but for continuing effective chemotherapeutic treatment there is a need for a detailed understanding of their mechanisms of action and on the rationale of their application. This review attempts to provide up-to-date information regarding the development of new and innovative treatment strategies for cancer chemotherapy. Virtually, every year several of new targets for cancer therapy on both, cellular and molecular levels, are identified and new drugs enter not only clinical trials but also are included in well accepted and documented therapeutic protocols. As this review is in addition to our review published previously (Medical Principles and Practice 11, 2002, 117-125), we have tried to include new and innovative targets and drugs that attract attention at present. Although it is not possible to provide a complete list of all achievements and cover all work done in this field, we hope to be able to give some insight into this rapidly developing area.