Corticosteroids: the mainstay in asthma therapy

Inflammation is now marked as a central feature of asthma pathophysiology and aims of current asthma management are not only to treat acute symptoms of wheezing, breathlessness, chest tightness, cough but also to suppress the underlying inflammatory component. Despite the availability of a number of drugs, corticosteroids remain the mainstay in the management of all types of asthma as these are the most potent and effective antiinflammatory agents available so far. Corticosteroids suppress virtually every step in inflammation. However therapeutic doses of oral glucocorticoids are associated with a range of adverse reactions. To overcome these side effects, inhalations have been developed to deliver glucocorticoids directly to the lungs and in the process a number of aerosol preparations have become available, which have advantage of significantly lower toxicity due to low systemic absorption from the respiratory tract and rapid inactivation. Despite considerable efforts by pharmaceutical industry, it has been difficult to develop novel therapeutic agents for asthma management, which could surpass inhaled corticosteroids. Currently the data favours using inhaled corticosteroids as monotherapy in the majority of patients in all kinds of asthma. If combination therapy is recommended to achieve additional control in severe asthma cases, other drugs such as beta-agonists, antileukotrienes, theophylline, etc. are considered as adjunct therapies to corticosteroids. This review discusses the importance of corticosteroids as first line therapy for asthma treatment with the availability of inhaled corticosteroids for chronic treatment and oral formulations for treating acute exacerbations of moderate to severe asthma.     

From bedside to bench to clinic trials: identifying new treatments for severe asthma

Asthmatics with a severe form of the disease are frequently refractory to standard medications such as inhaled corticosteroids, underlining the need for new treatments to prevent the occurrence of potentially life-threatening episodes. A major obstacle in the development of new treatments for severe asthma is the heterogeneous pathogenesis of the disease, which involves multiple mechanisms and cell types. Furthermore, new therapies might need to be targeted to subgroups of patients whose disease pathogenesis is mediated by a specific pathway. One approach to solving the challenge of developing new treatments for severe asthma is to use experimental mouse models of asthma to address clinically relevant questions regarding disease pathogenesis. The mechanistic insights gained from mouse studies can be translated back to the clinic as potential treatment approaches that require evaluation in clinical trials to validate their effectiveness and safety in human subjects. Here, we will review how mouse models have advanced our understanding of severe asthma pathogenesis. Mouse studies have helped us to uncover the underlying inflammatory mechanisms (mediated by multiple immune cell types that produce Th1, Th2 or Th17 cytokines) and non-inflammatory pathways, in addition to shedding light on asthma that is associated with obesity or steroid unresponsiveness. We propose that the strategy of using mouse models to address clinically relevant questions remains an attractive and productive research approach for identifying mechanistic pathways that can be developed into novel treatments for severe asthma.     

Cytokine-directed therapies for the treatment of chronic airway diseases

Multiple cytokines play a critical role in orchestrating and perpetuating inflammation in asthma and chronic obstructive pulmonary disease (COPD) and several specific cytokine and chemokine inhibitors now in development as future therapy for these diseases. Anti-IL-5 antibody markedly reduces peripheral blood and airway eosinophils, but does not appear to be effective in symptomatic asthma. Inhibition of IL-4 despite promising early results in asthma has been discontinued and blocking IL-13 might be more effective. Inhibitory cytokines, such as IL-10, interferons and IL-12 are less promising, as systemic delivery produces side effects. Inhibition of TNF-alpha may be useful in severe asthma and for treating severe COPD with systemic features. Many chemokines are involved in the inflammatory response of asthma and COPD and several small molecule inhibitors of chemokine receptors (CCR) are in development. CCR3 antagonists (which block eosinophil chemotaxis) and CXCR2 antagonists (which block neutrophil and monocyte chemotaxis) are in clinical development for asthma and COPD, respectively. Because so many cytokines are involved in asthma, drugs that inhibit the synthesis of multiple cytokines may prove to be more useful; several such classes of drug are now in clinical development and any risk of side effects with these non-specific inhibitors may be reduced by the inhaled route.     

Emerging trends in COVID-19 treatment: learning from inflammatory conditions associated with cellular therapies

Coronavirus disease 2019 (SARS-CoV2) is an active global health threat for which treatments are desperately being sought. Even though most people infected experience mild to moderate respiratory symptoms and recover with supportive care, certain vulnerable hosts develop severe clinical deterioration. While several drugs are currently being investigated in clinical trials, there are currently no approved treatments or vaccines for COVID-19 and hence there is an unmet need to explore additional therapeutic options. At least three inflammatory disorders or syndromes associated with immune dysfunction have been described in the context of cellular therapy. Specifically, Cytokine Release Syndrome (CRS), Immune Reconstitution Inflammatory Syndrome (IRIS), and Secondary Hemophagocytic Lymphohistiocytosis (sHLH) all have clinical and laboratory characteristics in common with COVID19 and associated therapies that could be worth testing in the context of clinical trials. Here we discuss these diseases, their management, and potential applications of these treatment in the context of COVID-19. We also discuss current cellular therapies that are being evaluated for the treatment of COVID-19 and/or its associated symptoms.     

Targeted therapy and immunotherapy: Emerging biomarkers in metastatic melanoma

Targeted therapy directed against oncogenic BRAF mutations and immune checkpoint inhibitors have transformed melanoma therapy over the past decade and prominently improved patient outcomes. However, not all patients will respond to targeted therapy or immunotherapy and many relapse after initially responding to treatment. This unmet need presents two major challenges. First, can we elucidate novel oncogenic drivers to provide new therapeutic targets? Second, can we identify patients who are most likely to respond to current therapeutic strategies in order to both more accurately select populations and avoid undue drug exposure in patients unlikely to respond? In an effort to evaluate the current state of the field with respect to these questions, we provide an overview of some common oncogenic mutations in patients with metastatic melanoma and ongoing efforts to therapeutically target these populations, as well as a discussion of biomarkers for response to immune checkpoint inhibitors—including tumor programmed death ligand 1 expression and the future use of neoantigens as a means of truly personalized therapy. This information is becoming important in treatment decision making and provides the framework for a treatment algorithm based on the current landscape in metastatic melanoma.     

Progress in the use of mesenchymal stromal cells for osteoarthritis treatment

Literature review of MSCs in the treatment of osteoarthritis in the past five yearsOsteoarthritis (OA) is one of the most common chronic joint diseases, with prominent symptoms caused by many factors. However, current medical interventions for OA have resulted in poor clinical outcomes, demonstrating that there are huge unmet medical needs in this area. Cell therapy has opened new avenues of OA treatment. Different sources of mesenchymal stromal cells (MSCs) may have different phenotypes and cellular functions. Pre-clinical and clinical studies have demonstrated the feasibility, safety and efficacy of MSC therapy. Mitogen-activated protein kinase, Wnt and Notch signaling pathways are involved in the chondrogenesis of MSC-mediated treatments. MSCs may also exert effective immunoregulatory and paracrine effects to stimulate tissue repair. Therapy with extracellular vesicles containing cytokines, which are secreted by MSCs, might be a potential treatment for OA.     

Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension

Atopic asthma is a chronic inflammatory pulmonary disease characterised by recurrent episodes of wheezy, laboured breathing with an underlying Th2 cell-mediated inflammatory response in the airways. It is currently treated and, more or less, controlled depending on severity, with bronchodilators e.g. long-acting beta agonists and long-acting muscarinic antagonists or anti-inflammatory drugs such as corticosteroids (inhaled or oral), leukotriene modifiers, theophyline and anti-IgE therapy. Unfortunately, none of these treatments are curative and some asthmatic patients do not respond to intense anti-inflammatory therapies. Additionally, the use of long-term oral steroids has many undesired side effects. For this reason, novel and more effective drugs are needed. In this review, we focus on the CD4+ Th2 cells and their products as targets for the development of new drugs to add to the current armamentarium as adjuncts or as potential stand-alone treatments for allergic asthma. We argue that in early disease, the reduction or elimination of allergen-specific Th2 cells will reduce the consequences of repeated allergic inflammatory responses such as lung remodelling without causing generalised immunosuppression.     

Treatment of allergic asthma: Modulation of Th2 cells and their responses

Atopic asthma is a chronic inflammatory pulmonary disease characterised by recurrent episodes of wheezy, laboured breathing with an underlying Th2 cell-mediated inflammatory response in the airways. It is currently treated and, more or less, controlled depending on severity, with bronchodilators e.g. long-acting beta agonists and long-acting muscarinic antagonists or anti-inflammatory drugs such as corticosteroids (inhaled or oral), leukotriene modifiers, theophyline and anti-IgE therapy. Unfortunately, none of these treatments are curative and some asthmatic patients do not respond to intense anti-inflammatory therapies. Additionally, the use of long-term oral steroids has many undesired side effects. For this reason, novel and more effective drugs are needed. In this review, we focus on the CD4+ Th2 cells and their products as targets for the development of new drugs to add to the current armamentarium as adjuncts or as potential stand-alone treatments for allergic asthma. We argue that in early disease, the reduction or elimination of allergen-specific Th2 cells will reduce the consequences of repeated allergic inflammatory responses such as lung remodelling without causing generalised immunosuppression.     

The hookworm pharmacopoeia for inflammatory diseases

In the developed world, declining prevalence of parasitic infections correlates with increased incidence of allergic and autoimmune disorders. Current treatments for these chronic inflammatory conditions have little to no effect on their prevalence and are referred to as “controllers” rather than cures. There has been limited success in therapeutically targeting allergic and autoimmune pathways, leaving an unmet need for development of effective anti-inflammatories. We discuss the benefit of hookworm infections and the parasite’s ability to condition the immune system to prevent allergic asthma and inflammatory bowel diseases. We then examine the immunomodulatory properties of selected hookworm-derived proteins in these two models of inflammation. While hookworm protein therapy has yet to be fully exploited, the identification of these proteins and the mechanisms by which they skew the immune system will provide new avenues for controlling and optimally reversing key pathological processes important in allergic and inflammatory bowel diseases.     

Therapies for allergic inflammation: refining strategies to induce tolerance

Current therapies for asthma and allergy are relatively safe and effective at controlling symptoms but do not change the chronic course of disease. There is no established method to prevent asthma and allergy, and major unmet needs in this area include the better control of the severe forms of these diseases and the developments of curative therapies. Two major therapeutic strategies for asthma and allergy are currently being developed, and I here discuss the advances and challenges for future therapeutic development in these two areas. The first approach, allergen-specific immunotherapy, aims to induce specific immune tolerance and has a long-term disease-modifying effect. The second approach is the use of biological immune response modifiers to decrease pathological immune responses. Combination strategies using both of these approaches may also provide a route for addressing the unmet clinical needs in allergic diseases.     

Beclomethasone dipropionate dry-powder inhalation compared with conventional aerosol in chronic asthma.

In a double-blind study beclomethasone dipropionate inhaled as a dry powder in doses of 100 microgram four times daily and 150 microgram four times daily was compared with the conventional aerosol dose of 100 microgram four times daily in 20 outpatients with chronic asthma. Each of the three treatments was given for four weeks. The dry powder in a dose of 150 microgram four times daily had advantages over the other two treatments in terms of FEV1 and the number of exacerbations of asthma during the study. There were no adverse reactions to inhaling dry-powder beclomethasone. It was concluded that this new way of administering the drug was effective in chronic asthma, and should allow most patients with chronic asthma who cannot use conventional pressurised aerosols efficiently to benefit from inhaled corticosteroid treatment.     

Identification and management of adults with asthma prone to exacerbations: can we do better?

Exacerbations are a major cause of morbidity in asthma and generate high health costs. Identification and management of adults with asthma who are prone to exacerbations is of considerable importance as by this means it should be possible to reduce the number of patients who currently experience inadequately controlled disease. Exacerbations occur most frequently in individuals with severe disease. Other risk factors include a history of a recent exacerbation, co-morbidities such as a raised body mass index and psychological problems as well as current smoking and lower socio-economic status. A low FEV₁, particularly if combined with the additional information from questionnaires helps predict exacerbations. Despite the association between these risk factors and exacerbations it remains difficult to accurately predict in an individual patient with asthma whether they will go on to develop an exacerbation in the future. A major aim of international guidelines on the management of asthma is to prevent future risks of exacerbations, but some patients, particularly those with severe disease, respond poorly to current therapies and continue to experience recurrent exacerbations. There is an unmet need for improved management strategies and drugs targeted at preventing asthma exacerbations. Monitoring induced sputum eosinophil cell counts is helpful in preventing exacerbations in some patient with severe asthma. Future developments are likely to include the identification of better biomarkers to predict exacerbations or the cause of exacerbations, augmentation of the immunological response to viruses at the time of the exacerbation, the use of telemonitoring in patients with severe asthma and the development of improved therapies targeted at reducing exacerbations.     

Evolution of a pulmonary insulin delivery system (Exubera) for patients with diabetes

Many patients with diabetes fail to meet recommended glycemic goals regardless of the recognition of optimal glycemic control as a key component for improving clinical outcomes and quality of life in patients with diabetes. Patient- and physician-related barriers to the adoption of insulin therapy include fear and anxiety about injecting insulin, concerns about side effects, and personal health beliefs in regard to the use of insulin. There is an unmet need for an alternative insulin therapy that provides optimal glycemic control, is well tolerated, and improves patient adherence. Of the several inhaled insulin devices that are in various stages of development, the Exubera (INH) formulation is the first to be approved for use in the United States and in Europe. Exubera is a novel, rapid-acting inhaled human insulin formulation that has been developed for prandial insulin use. Clinical studies have shown that INH consistently improves glycemic control, in combination with longer-acting subcutaneous (SC) insulin regimens in patients with type 1 or type 2 diabetes, or is used to supplement or replace oral antidiabetic therapy in patients with type 2 diabetes. INH has demonstrated long-term safety and tolerability, with a risk for hypoglycemia similar to that of SC insulin, and no clinically meaningful changes in pulmonary function have been noted with its use. Patients treated with INH in clinical studies reported high levels of satisfaction with treatment, and many patients with diabetes choose inhaled insulin when it is offered as a treatment option. Taken together, these findings suggest that INH represents an important new development in the treatment of diabetes that may improve glycemic control in many patients with diabetes.     

Theophylline in the management of airflow obstruction. 2. Difficult drugs to use,few clinical indications.

The narrow therapeutic index, potential toxicity, and need to monitor plasma concentrations make theophyllines difficult to use. Other drugs provide comparable or better bronchodilator and prophylactic efficacy. In asthma theophyllines should be considered for chronic stable asthma when treatment with optimal doses of inhaled steroids and bronchodilators fails to provide adequate control; for nocturnal asthma; and for prophylaxis and relief of symptoms in children and adults when inhaled treatment cannot be given. In general, theophyllines cannot be recommended for chronic airflow obstruction. A trial of theophylline is reasonable in individual patients whose symptoms remain troublesome despite a trial of steroids and optimal doses of inhaled bronchodilators.     

Modeling HIV-associated neurocognitive disorders in mice: new approaches in the changing face of HIV neuropathogenesis

It is well established that infection with the human immunodeficiency virus (HIV) leads to immune suppression. Less well known is the fact that long-term, progressive HIV disease is associated with the development of cognitive deficits. Since the introduction of combined antiretroviral therapy (cART), the clinical presentation of HIV infection has evolved into a chronic illness with very low levels of viral replication and chronic immune activation, with compliant affected individuals surviving for decades with a high quality of life. Despite these advances, many HIV-infected individuals develop some degree of neurodegeneration and cognitive impairment. The underlying pathophysiological mechanisms are not well understood, and there are no effective treatments. Thus, there is an unmet need for animal models that enable the study of HIV-associated neurocognitive disorders (HAND) and the testing of new therapeutic approaches to combat them. Here, we review the pros and cons of existing mouse models of HIV infection for addressing these aims and propose a detailed strategy for developing a new mouse model of HIV infection.     

Renal stem cell reprogramming: Prospects in regenerative medicine

Stem cell therapy is a promising future enterprise for renal replacement in patients with acute and chronic kidney disease, conditions which affect millions worldwide and currently require patients to undergo lifelong medical treatments through dialysis and/or organ transplant. Reprogramming differentiated renal cells harvested from the patient back into a pluripotent state would decrease the risk of tissue rejection and provide a virtually unlimited supply of cells for regenerative medicine treatments, making it an exciting area of current research in nephrology. Among the major hurdles that need to be overcome before stem cell therapy for the kidney can be applied in a clinical setting are ensuring the fidelity and relative safety of the reprogrammed cells, as well as achieving feasible efficiency in the reprogramming processes that are utilized. Further, improved knowledge about the genetic control of renal lineage development is vital to identifying predictable and efficient reprogramming approaches, such as the expression of key modulators or the regulation of geneactivity through small molecule mimetics. Here, we discuss several recent advances in induced pluripotent stem cell technologies. We also explore strategies that have been successful in renal progenitor generation, and explore what these methods might mean for the development of cell-based regenerative therapies for kidney disease.     

Predementia Alzheimer's disease. Benefits of early diagnosis

Given population aging and the rise in the number of persons with Alzheimer's disease, measures that aim not only to delay but also to prevent the development of this disease are increasingly required. Advances in the diagnosis of Alzheimer's disease support the need for a review of current clinical standards for mild cognitive impairment and provide new goals in the early treatment of this disease. The current diagnostic process should be refocussed toward the pathological substrate of this disease rather than symptoms in order to initiate therapeutic measures as soon as possible without waiting for clinical manifestations to appear. Such an approach is essential in patients with greater cognitive reserve, in whom the lesions are usually more severe at diagnosis and treatment is less effective. To identify disease-modifying therapies to delay the onset of the clinical symptoms of Alzheimer's disease in cognitively intact persons at high risk, biomarkers for this disease must be validated. A single biomarker is unlikely to provide the required diagnostic accuracy and therefore a multimodal approach, incorporating biochemical, neuropathological and anatomical and metabolic neuroimaging methods, should be employed. To optimize the results of drugs under investigation, a combination of biomarkers should be used to select appropriate participants in the earliest phases of the disease, and disease progression should be followed-up. Early diagnosis might clarify essential questions in the care of patients with Alzheimer's disease, such as the possibility of distinguishing among various subtypes, thus encouraging the development of optimal treatments for each. The ultimate goal is to develop disease-modifying treatments that could be initiated early, while patients are asymptomatic or only minimally symptomatic, to maintain their quality of life.     

Late stage antibacterial drugs in the clinical pipeline

Bacterial resistance to antimicrobial agents is a growing problem worldwide. Not only is issue compounded by the fact that there are fewer pharmaceutical companies conducting research to discover novel antimicrobials than in the past but development time lines have stretched so that a dozen years from discovery to the market is now the standard. Eleven antibacterial drugs in late stage clinical development are discussed. Whereas many of these may successfully deal with resistant strains of Gram-positive pathogens, there is very little in development to address the gorwing unmet medical need of multi-drug resistant Gram-negative infections.     

Effect of long-term treatment with salmeterol on asthma control: a double blind,randomised crossover study.

OBJECTIVES: To determine the effect of adding salmeterol 50 micrograms twice daily for six months to current treatment in subjects with asthma who control their inhaled corticosteroid dose according to a management plan. DESIGN: A double blind, randomised crossover study. SETTING: Nottingham. SUBJECTS: 101 subjects with mild or moderate asthma taking at least 200 micrograms twice daily of beclomethasone dipropionate or budesonide. INTERVENTIONS: Salmeterol 50 micrograms twice daily and placebo for six months each, with a one month washout. Subjects adjusted inhaled steroid dose according to guidelines. MAIN OUTCOME MEASURE: Reduction in inhaled steroid use, exacerbations of asthma, and use of oral steroids. RESULTS: Data were available for 87 subjects. When compared with placebo salmeterol treatment was associated with a 17% reduction in inhaled steroid use (95% confidence interval 12% to 22%) with no significant difference in the number of subjects who had an exacerbation (placebo 25%, salmeterol 16%) or use of oral steroids. For secondary end points salmeterol treatment was associated with higher morning and evening peak expiratory flow and forced expiratory volume in one second; a reduction in symptoms, bronchodilator use and airway responsiveness to methacholine; and no effect on serum potassium concentration, 24 hour heart rate, or the final forced expiratory volume in one second achieved during a salbutamol dose-response study. CONCLUSIONS: In subjects who adjusted their inhaled steroid treatment according to guidelines the addition of salmeterol 50 micrograms twice daily was associated with a reduction in inhaled steroid use and improved lung function and symptom control.     

Severe asthma and the omalizumab option

Atopic diseases and asthma are increasing at a remarkable rate on a global scale. It is now well recognized that asthma is a chronic inflammatory disease of the airways. The inflammatory process in many patients is driven by an immunoglobulin E (IgE)-dependent process. Mast cell activation and release of mediators, in response to allergen and IgE, results in a cascade response, culminating in B lymphocyte, T lymphocyte, eosinophil, fibroblast, smooth muscle cell and endothelial activation. This complex cellular interaction, release of cytokines, chemokines and growth factors and inflammatory remodeling of the airways leads to chronic asthma. A subset of patients develops severe airway disease which can be extremely morbid and even fatal. While many treatments are available for asthma, it is still a chronic and incurable disease, characterized by exacerbation, hospitalizations and associated adverse effects of medications. Omalizumab is a new option for chronic asthma that acts by binding to and inhibiting the effects of IgE, thereby interfering with one aspect of the asthma cascade reviewed earlier. This is a humanized monoclonal antibody against IgE that has been shown to have many beneficial effects in asthma. Use of omalizumab may be influenced by the cost of the medication and some reported adverse effects including the rare possibility of anaphylaxis. When used in selected cases and carefully, omalizumab provides a very important tool in disease management. It has been shown to have additional effects in urticaria, angioedema, latex allergy and food allergy, but the data is limited and the indications far from clear. In addition to decreasing exacerbations, it has a steroid sparing role and hence may decrease adverse effects in some patients on high-dose glucocorticoids. Studies have shown improvement in quality of life measures in asthma following the administration of omalizumab, but the effects on pulmonary function are surprisingly small, suggesting a disconnect between pulmonary function, exacerbations and quality of life. Anaphylaxis may occur rarely with this agent and appropriate precautions have been recommended by the Food and Drug Administration (FDA). As currently practiced and as suggested by the new asthma guidelines, this biological agent is indicated in moderate or severe persistent allergic asthma (steps 5 and 6).