Pharmacology & therapeutics
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Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel expressed in epithelial cells throughout the body. In the lungs, absence or dysfunction of CFTR results in altered epithelial salt and water transport eventuating in impaired mucociliary clearance, chronic infection and inflammation, and tissue damage. CF lung disease is the major cause of morbidity and mortality in CF despite the many therapies aimed at reducing it. However, recent technological advances combined with two decades of research driven by the discovery of the CFTR gene have resulted in the development and clinical testing of novel therapies aimed at the principal underlying defect in CF, thereby ushering in a new age of therapy for CF.
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Migraine is a highly prevalent neurovascular disorder that can be provoked by infusion of calcitonin gene-related peptide (CGRP). CGRP, a neuropeptide released from activated trigeminal sensory nerves, dilates intracranial and extracranial blood vessels and centrally modulates vascular nociception. On this basis, it has been proposed that: (i) CGRP may play an important role in the pathophysiology of migraine; and (ii) blockade of CGRP receptors may abort migraine. ⋯ However, recent data reported elevated liver transaminases when telcagepant was dosed twice daily for three months for the prevention of migraine rather than acutely. The potential for a specific acute antimigraine drug, without producing vasoconstriction or vascular side effects and with an efficacy comparable to triptans, is enormous. The present review will discuss the role of CGRP in the pathophysiology of migraine and the various treatment modalities that are currently available to target this neuropeptide.
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Review
Modulation of sensory nerve function and the cough reflex: understanding disease pathogenesis.
To cough is a protective defence mechanism that is vital to remove foreign material and secretions from the airways and which in the normal state serves its function appropriately. Modulation of the cough reflex pathway in disease can lead to inappropriate chronic coughing and an augmented cough response. Chronic cough is a symptom that can present in conjunction with a number of diseases including chronic obstructive pulmonary disease (COPD) and asthma, although often the cause of chronic cough may be unknown. ⋯ Therefore, in the hope of identifying novel antitussives, much research has focused on understanding the neural mechanisms of cough provocation. Experimentally this has been undertaken using chemical or mechanical tussive stimuli in conjunction with animal models of cough and clinical cough assessments. This review will discuss the neural mechanisms involved in the cough, changes that occur under pathophysiological conditions and and how current research may lead to novel therapeutic opportunities for the treatment of cough.
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Review
Inflammatory mechanisms and treatment of obstructive airway diseases with neutrophilic bronchitis.
Obstructive airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) are major global health issues. Although considered as distinct diseases, airway inflammation is a key underlying pathophysiological process in asthma, COPD and bronchiectasis. Persistent neutrophilic airway inflammation (neutrophilic bronchitis) occurs with innate immune activation and is a feature of each of these airway diseases. ⋯ Current therapies are limited for the treatment of neutrophilic bronchitis; possible treatments being investigated include theophylline, statins, antagonists of pro-inflammatory cytokines and macrolide antibiotics. Macrolides have shown great promise in their ability to reduce airway inflammation, and can reduce airway neutrophils, levels of CXCL8 and neutrophil proteases in the airways. Studies also show improvements in quality of life and exacerbation rates in airways diseases.
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Known treatments of type 2 diabetes mellitus have limitations such as weight gain, and hypoglycaemias. A new perspective is the use of incretin hormones and incretin enhancers. Incretins are defined as being responsible for the higher insulin release after an oral glucose load compared to an intravenous glucose load. ⋯ Their differences from incretin mimetics include: oral bioavailability, less side effects with overdose, no direct CNS effects (nausea and vomiting) and no effect on weight. In rodent models of diabetes, but not yet in humans, GLP-1 receptor agonists and DPP-4 inhibitors increase islet mass and preserve beta-cell function. Incretin mimetics and enhancers expand type 2 diabetes treatment, are still not first line therapy and it is discussed if they are to be prophylactically used.