Challenges in the management of asthma associated with smoking-induced airway diseases

ABSTRACT

Introduction: Smoking-induced airway diseases such as chronic bronchitis, emphysema, and small airway dysfunction contribute to the chronic respiratory symptoms experienced by adults with asthma, including those with spirometric chronic obstructive pulmonary disease (COPD), termed asthma-COPD overlap (ACO). Drug treatment of symptomatic smokers with asthma or ACO is uncertain due to their exclusion from most clinical trials.

Areas covered: This review summarizes evidence for the efficacy of small molecule drugs used in the clinic to treat current and former smokers with a diagnostic label of asthma or ACO. Other therapeutic interventions are reviewed, including smoking cessation and biologics.

Expert opinion: Clinical trials and observational studies suggest that smoking cessation and approved drugs used to treat non-smokers with asthma produce clinical benefits in smokers with asthma or ACO, although the overall quality of evidence is low. The efficacy of some treatments for asthma is altered in current smokers, including reduced responsiveness to short-term inhaled corticosteroids and possibly improved responsiveness to leukotriene receptor antagonists. Preliminary findings suggest that low-dose theophylline, statins, and biologics, such as omalizumab, mepolizumab, and dupilumab, may improve clinical outcomes in smokers with asthma or ACO. Improved phenotyping and endotyping of asthma and smoking-induced airway diseases should lead to better targeted therapies.     

Istradefylline for the treatment of Parkinson’s disease: is it a promising strategy?

ABSTRACT

Introduction: Istradefylline (ISD) is a new drug developed for the treatment of Parkinson’s disease (PD). It is an adenosine receptor A_2A antagonists that will represent an important option for patients with advanced PD where it has been demonstrated efficacy in decreasing daily OFF time and is well tolerated. ISD has been marketed in Japan since May 2013.

Areas covered: The objective of this review is to summarize evidences emerged from clinical studies that have demonstrated the efficacy of ISD in advanced parkinsonian patients. It will then focus on the potential role in treating non-motor symptoms (NMS) and cognitive decline, which heavily affect quality of life for PD patients. Its putative role as neuroprotective agent will also be discussed.

Expert opinion: ISD might represent an alternative option for patients with advanced PD. The reduction of OFF time highlighted in pivotal trials is comparable to that obtained with different levodopa adjunct therapies. The low profile of side effects makes ISD a more suitable drug for advanced patients whose illness is complicated by depression or cognitive impairment. Future studies are warranted to investigate the possible effects of this drug to delay the occurrence of dyskinesia and to impact significantly on NMS.     

Memantine in dementia: a review of the current evidence

Introduction: As the world's population ages, the incidence of Alzheimer's disease (AD) is projected to double every 20 years. Understanding the pathogenesis of AD and developing effective treatments is a public health imperative. Memantine is a low- to moderate-affinity, non-competitive NMDA receptor antagonist that is currently approved for the treatment of moderate to severe AD.

Areas covered: We discuss the current evidence, emphasizing more recent studies examining the effects of memantine in AD. We also look at the gaps in the current knowledge; the studies that will be required to fill these gaps are also discussed. The present paper reviews: the pharmacology of memantine; evidence for its use in moderate to severe AD, as well as in mild to moderate AD; adverse events related to memantine use; its effects specifically on behaviours including aggression and agitation; the pharmacoeconomics of memantine; and the use of memantine in other dementias. Memantine has shown modest benefits in cognition, function, global and behavioural measures, and has shown little potential for drug-drug interactions.

Expert opinion: For the treatment of moderate to severe AD, memantine should be offered as a therapeutic option, either on its own, or in combination with a cholinesterase inhibitor.     

Agonists of luteinizing hormone-releasing hormone in prostate cancer

Introduction: Androgen deprivation therapy (ADT) has been the first-line standard of care for treating patients with hormone-sensitive advanced prostate cancer (PCa) for many decades. The agonists of luteinizing hormone-releasing hormone (LHRH), also called gonadotropin-releasing hormone, are still the most frequently used form of medical ADT.

Areas covered: This article reviews the available data and most recent information concerning the use of LHRH agonists in advanced PCa. This article also reviews the discovery and development of LHRH agonists and summarizes the clinical evidence for their efficacy in PCa.

Expert opinion: The introduction and application of agonists of LHRH has modernized and improved the treatment of advanced PCa. The life-saving benefits of LHRH agonists are well established, yet underestimated. Despite their efficacy, agonists of LHRH have several disadvantages or drawbacks including disease flare. The approach to ADT has been recently further refined with the development of the LHRH antagonist degarelix. Degarelix, a highly clinically effective third-generation LHRH antagonist, is currently available in most countries for therapy of advanced PCa. This new drug offers attractive alternatives to LHRH agonists for treatment of advanced PCa. A therapy for castration-resistant PCa based on a targeted cytotoxic analog of LHRH, AEZS-108, is also emerging.     

Small molecule inhibitors in the treatment of cerebral ischemia

Introduction: Stroke is the world's second leading cause of death. Although recombinant tissue plasminogen activator is an effective treatment for cerebral ischemia, its limitations and ischemic stroke's complex pathophysiology dictate an increased need for the development of new therapeutic interventions. Small molecule inhibitors (SMIs) have the potential to be used as novel therapeutic modalities for stroke, since many preclinical and clinical trials have established their neuroprotective capabilities.

Areas covered: This paper provides a summary of the pathophysiology of stroke as well as clinical and preclinical evaluations of SMIs as therapeutic interventions for cerebral ischemia. Cerebral ischemia is broken down into four mechanisms in this article: thrombosis, ischemic insult, mitochondrial injury and immune response. Insight is provided into preclinical and current clinical assessments of SMIs targeting each mechanism as well as a summary of reported results.

Expert opinion: Many studies demonstrated that pre- or post-treatment with certain SMIs significantly ameliorated adverse effects from stroke. Although some of these promising SMIs moved on to clinical trials, they generally failed, possibly due to the poor translation of preclinical to clinical experiments. Yet, there are many steps being taken to improve the quality of experimental research and translation to clinical trials.     

Drugs in the medical treatment of Cushing's syndrome – an update on mifepristone and pasireotide

Introduction: The prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing along with the worldwide epidemic of obesity and their strong association with metabolic syndrome. Currently existing pharmacological therapies include anti-oxidants, insulin-sensitizing agents, lipid-lowering drugs and cytoprotective agents, but there is a lack of consensus regarding the most effective and appropriate pharmacologic therapies for NASH. Clinical trials examining new therapeutic drugs for NASH that act via various mechanisms are being performed in several countries, and these drugs may strongly influence current NASH treatment.

Areas covered: This article provides a review of recent data on the safety and efficacy of existing and emerging agents for the treatment of NASH.

Expert opinion: Ideally, treatment for NASH should not only improve liver disease, but also reduce the risks of adverse cardiovascular outcomes and the development of diabetes and cancers. However, this goal is likely to be too high in the context of clinical trials designed to obtain approval for the treatment of liver disease. The only way to achieve the goal is to accumulate the results of these relatively short-term clinical trials.     

Melanin-concentrating hormone functions in the nervous system: food intake and stress

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide, which centrally regulates food intake and stress. MCH induces food intake in rodents and, more generally, acts as an anabolic signal in energy regulation. In addition, MCH seems to be activatory on the stress axis. Two receptors for MCH in humans have very recently been characterised, namely, MCH-R1 and MCH-R2. MCH-R1 has received considerable attention, as potent and selective antagonists acting at that receptor display anxiolytic, antidepressant and/or anorectic properties. Feeding and affective disorders are both debilitating conditions that have become serious worldwide health threats. There are as yet no efficient and/or safe cures that could contain the near-pandemia phenomen of both diseases. Thus, the discovery of MCH-R1 antagonists may lead to the development of valuable drugs to treat obesity, anxiety and depressive syndromes. In addition, it opens wide avenues to probe additional functions of the peptide, both in the brain and in the peripheral nervous system.     

Respiratory Effects of Cocaine Freebasing Among Habitual Cocaine Users

Smoking of alkaloidal cocaine ("crack") has become increasingly prevalent in our society. Recent evidence suggests that crack smoking can cause acute respiratory symptoms, abnormalities in lung function and, in some instances, sever, life-threatening acute lung unjury. To evalute further the relationship between frequent cocaine smoking and respiratory symptoms and lyng dysfunction, we studied a sample of 177 heavy, habitual smokers of freebase cocaine (mean 6.6 gm/wk for an average of 27 months) with or without concomitant smoking of tobacco and/or marijuana. Results in this sample were compared with those in a control sample of 75 age-, sex- and race-matched nonsmokers of cocaine who did or did not also smoke tobacco and/or marijuana. After controlling for the use of other smoked substances, heavy, habitual cocaine smoking was associated with the following: (1) a high frequency of acute respiratory symptoms (cough, black sputum, chest pain) in temporal association with freebase use; (2) an obstructive ventilatory abnormality involving the large airways; and (3) a mild but significant impairment in the diffusing capacity of the lung. These findings suggest that heavy, habitual crack smoking produces (1) respiratory tract injury manifested by acute respiratory symptoms and evidence of chronic airflow obstruction in large airways, and (2) an abnormality in diffusion of has at the alveolar-capillary level. The mechanism of the diffusion defect is unknown but could reflect damage to the alveolar-capillary membrane. Further study of the magnitude, persistence, reversibility, mechanism and clinical significance of the abnormality in diffusing capacity is needed.     

新型内皮素受体拮抗剂马西替坦

内皮素受体拮抗剂与内皮素受体结合后,可以抑制由内皮素引起的血管收缩,同时还可减轻由内皮素活化造成的血管平滑肌的增殖和纤维化,从而达到治疗与内皮素相关疾病的目的.马西替坦是由瑞士Actelion公司研发的新型内皮素受体拮抗剂,具有组织靶向性,对ETA受体、ETB受体具有双重抑制作用,可用于治疗肺动脉高压、肺纤维化等疾病,在一系列临床研究中显示出良好的治疗前景,且安全性及耐受性均较好.     

The discovery of dabigatran etexilate for the treatment of venous thrombosis

ABSTRACT

Introduction: Venous thromboembolism (VTE) can be life-threatening and requires anticoagulant treatment; for many years, vitamin K antagonists, e.g. warfarin, were the only oral anticoagulants available for long-term treatment. Although highly effective, they have many limitations including a slow onset, a multitude of drug–drug and drug–food interactions, and a narrow therapeutic range. These limitations spurred the search for non-vitamin K antagonist oral anticoagulants (NOACs), such as dabigatran etexilate.

Areas covered: The authors illustrate the progression of preclinical and clinical studies leading to the development of dabigatran, the only approved NOAC to act by direct thrombin inhibition. They focus on molecule discovery, animal models of thrombosis, clinical trials and post-launch activities in VTE treatment.

Expert opinion: Dabigatran demonstrated comparable efficacy to the highly effective warfarin, and a more favourable safety profile in trials of VTE treatment. A favourable anticoagulant safety profile in addition to efficacy is essential for VTE treatment. Availability of the dabigatran-specific reversal agent, idarucizumab, provides a means of rapidly reversing the anticoagulant effect if required. Future investigations into the optimal duration of VTE treatment and an evaluation of the impact of idarucizumab, in real-world studies, could provide valuable information to help optimise treatment for selected patients.