Pharmacology of Heparin and Related Drugs: An Update

Heparin has been used extensively as an antithrombotic and anticoagulant for close to 100 years. This anticoagulant activity is attributed to the pentasaccharide sequence which potentiates the inhibitory action of antithrombin, a major inhibitor of the coagulation cascade. More recently it has been determined that heparin also has antithrombotic action through interference of the formation of neutrophil extracellular traps which have been determined to play a role in thrombosis. This demonstrated a well-known observation that heparin, given it is a highly negatively charged polysaccharide, interacts with a broad range of biomolecules demonstrating attenuating effect. Since our previous review, there has been an increased interest in these non-anticoagulant effects of heparin, with the beneficial role in patients infected with sars2-coronavirus a highly topical example. This article provides an update on our previous review with more recent developments and observations made for these novel uses of heparin and an overview of the development status of heparin-based drugs. Significance Statement This state of the art review covers recent developments in the use of heparin and heparin-like materials as anticoagulant, now including immuno-thrombosis observations, and as non-anticoagulant including a role in the treatment of sars-coronavirus and inflammatory conditions

Comparison of Oral, Intranasal and Aerosol Administration of Amiodarone in Rats as a Model of Pulmonary Phospholipidosis.

‘Foamy’ alveolar macrophages (FAM) observed in nonclinical toxicology studies during inhaled drug development may indicate drug-induced phospholipidosis, but can also derive from adaptive non-adverse mechanisms. Orally administered amiodarone is currently used as a model of pulmonary phospholipidosis and it was hypothesized that aerosol administration would produce phospholipidosis-induced FAM that could be characterized and used in comparative inhalation toxicology. Han-Wistar rats were given amiodarone via (1) intranasal administration (6.25 mg/kg) on two days, (2) aerosol administration (3 mg/kg) on two days, (3) aerosol administration (10 mg/kg) followed by three days of 30 mg/kg or (4) oral administration (100 mg/kg) for 7 days. Alveolar macrophages in bronchoalveolar lavage were evaluated by di_erential cell counting and high content fluorescence imaging. Histopathology and mass-spectrometry imaging (MSI) were performed on lung slices. The higher dose aerosolised amiodarone caused transient pulmonary inflammation (p < 0.05), but only oral amiodarone resulted in FAM (p < 0.001). MSI of the lungs of orally treated rats revealed a homogenous distribution of amiodarone and a putative phospholipidosis marker, di-22:6 bis-monoacylglycerol, throughout lung tissue whereas aerosol administration resulted in localization of both compounds around the airway lumen. Thus, unlike oral administration, aerosolised amiodarone failed to produce the expected FAM responses.Peer reviewedFinal Published versio

Pharmacological characterization of the interaction between aclidinium bromide and formoterol fumarate on human isolated bronchi

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Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: a meta-analysis

In order to clarify the possible role of N-acetylcysteine (NAC) in the treatment of patients with chronic bronchitis and chronic obstructive pulmonary disease (COPD), we have carried out a meta-analysis testing the available evidence that NAC treatment may be effective in preventing exacerbations of chronic bronchitis or COPD and evaluating whether there is a substantial difference between the responses induced by low (≤600 mg per day) and high (>600 mg per day) doses of NAC.The results of the present meta-analysis (13 studies, 4155 COPD patients, NAC n=1933; placebo or controls n=2222) showed that patients treated with NAC had significantly and consistently fewer exacerbations of chronic bronchitis or COPD (relative risk 0.75, 95% CI 0.66–0.84; p<0.01), although this protective effect was more apparent in patients without evidence of airway obstruction. However, high doses of NAC were also effective in patients suffering from COPD diagnosed using spirometric criteria (relative risk 0.75, 95% CI 0.68–0.82; p=0.04). NAC was well tolerated and the risk of adverse reactions was not dose-dependent (low doses relative risk 0.93, 95% CI 0.89–0.97; p=0.40; high doses relative risk 1.11, 95% CI 0.89–1.39; p=0.58).The strong signal that comes from this meta-analysis leads us to state that if a patient suffering from chronic bronchitis presents a documented airway obstruction, NAC should be administered at a dose of ≥1200 mg per day to prevent exacerbations, while if a patient suffers from chronic bronchitis, but is without airway obstruction, a regular treatment of 600 mg per day seems to be sufficient

Large-Scale Polarized Foreground Component Separation for Planck

We use Bayesian component estimation methods to examine the prospects for large-scale polarized map and cosmological parameter estimation with simulated Planck data assuming simplified white noise properties. The sky signal is parametrized as the sum of the CMB, synchrotron emission, and thermal dust emission. The synchrotron and dust components are modelled as power-laws, with a spatially varying spectral index for synchrotron and a uniform index for dust. Using the Gibbs sampling technique, we estimate the linear polarisation Q and U posterior amplitudes of the CMB, synchrotron and dust maps as well as the two spectral indices in ~4 degree pixels. We use the recovered CMB map and its covariance in an exact pixel likelihood algorithm to estimate the optical depth to reionization tau, the tensor-to-scalar ratio r, and to construct conditional likelihood slices for the EE and BB spectra. Given our foreground model, we find sigma(tau)~0.004 for tau=0.1, sigma(r)~0.03 for a model with r=0.1, and a 95% upper limit of r<0.02 for r=0.0.Comment: 15 pages, 12 figures, submitted to MNRA

Predicting the Fine Particle Fraction of Dry Powder Inhalers Using Artificial Neural Networks

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Pharmaceutical Sciences after peer review and technical editing by the publisher. Under embargo. Embargo end date: 9 November 2017. The version of record, Joanna Muddle, Stewart B. Kirton, Irene Parisini, Andrew Muddle, Darragh Murnane, Jogoth Ali, Marc Brown, Clive Page and Ben Forbes, ‘Predicting the Fine Particle Fraction of Dry Powder Inhalers Using Artificial Neural Networks’, Journal of Pharmaceutical Sciences, Vol 106(1): 313-321, first published online on 9 November 2016, is available online via doi: http://dx.doi.org/10.1016/j.xphs.2016.10.002 0022-3549/© 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.Dry powder inhalers are increasingly popular for delivering drugs to the lungs for the treatment of respiratory diseases, but are complex products with multivariate performance determinants. Heuristic product development guided by in vitro aerosol performance testing is a costly and time-consuming process. This study investigated the feasibility of using artificial neural networks (ANNs) to predict fine particle fraction (FPF) based on formulation device variables. Thirty-one ANN architectures were evaluated for their ability to predict experimentally determined FPF for a self-consistent dataset containing salmeterol xinafoate and salbutamol sulfate dry powder inhalers (237 experimental observations). Principal component analysis was used to identify inputs that significantly affected FPF. Orthogonal arrays (OAs) were used to design ANN architectures, optimized using the Taguchi method. The primary OA ANN r2 values ranged between 0.46 and 0.90 and the secondary OA increased the r2 values (0.53-0.93). The optimum ANN (9-4-1 architecture, average r2 0.92 ± 0.02) included active pharmaceutical ingredient, formulation, and device inputs identified by principal component analysis, which reflected the recognized importance and interdependency of these factors for orally inhaled product performance. The Taguchi method was effective at identifying successful architecture with the potential for development as a useful generic inhaler ANN model, although this would require much larger datasets and more variable inputs.Peer reviewe

Pulmonary Perspective b 2 -Agonist Therapy in Lung Disease

b 2 -Agonists are effective bronchodilators due primarily to their ability to relax airway smooth muscle (ASM). They exert their effects via their binding to the active site of b 2 -adrenoceptors on ASM, which triggers a signaling cascade that results in a number of events, all of which contribute to relaxation of ASM. There are some differences between b 2 -agonists. Traditional inhaled short-acting b 2 -agonists albuterol, fenoterol, and terbutaline provide rapid as-needed symptom relief and short-term prophylactic protection against bronchoconstriction induced by exercise or other stimuli. The twice-daily b 2 -agonists formoterol and salmeterol represent important advances. Their effective bronchodilating properties and long-term improvement in lung function offer considerable clinical benefits to patients. More recently, a newer b 2 -agonist (indacaterol) with a longer pharmacodynamic half-life has been discovered, with the hopes of achieving once-daily dosing. In general, b 2 -agonists have an acceptable safety profile, although there is still controversy as to whether long-acting b 2 -agonists may increase the risk of asthma mortality. In any case, they can induce adverse effects, such as increased heart rate, palpitations, transient decrease in Pa O 2 , and tremor. Desensitization of b 2 -adrenoceptors that occurs during the first few days of regular use of b 2 -agonist treatment may account for the commonly observed resolution of the majority of these adverse events after the first few doses. Nevertheless, it can also induce tolerance to bronchoprotective effects of b 2 -agonists and has the potential to reduce bronchodilator sensitivity to them. Some novel once-daily b 2 -agonists (olodaterol, vilanterol, abediterol) are under development, mainly in combination with an inhaled corticosteroid or a long-acting antimuscarinic agent