23,668 research outputs found
Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial.
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs. An incomplete response to the anti-inflammatory effects of inhaled corticosteroids is present in COPD. Preclinical work indicates that 'low dose' theophylline improves steroid responsiveness. The Theophylline With Inhaled Corticosteroids (TWICS) trial investigates whether the addition of 'low dose' theophylline to inhaled corticosteroids has clinical and cost-effective benefits in COPD. METHOD/DESIGN: TWICS is a randomised double-blind placebo-controlled trial conducted in primary and secondary care sites in the UK. The inclusion criteria are the following: an established predominant respiratory diagnosis of COPD (post-bronchodilator forced expiratory volume in first second/forced vital capacity [FEV1/FVC] of less than 0.7), age of at least 40 years, smoking history of at least 10 pack-years, current inhaled corticosteroid use, and history of at least two exacerbations requiring treatment with antibiotics or oral corticosteroids in the previous year. A computerised randomisation system will stratify 1424 participants by region and recruitment setting (primary and secondary) and then randomly assign with equal probability to intervention or control arms. Participants will receive either 'low dose' theophylline (Uniphyllin MR 200 mg tablets) or placebo for 52 weeks. Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1-5 mg/l. A dose of theophylline MR 200 mg once daily (or placebo once daily) will be taken by participants who do not smoke or participants who smoke but have an ideal body weight (IBW) of not more than 60 kg. A dose of theophylline MR 200 mg twice daily (or placebo twice daily) will be taken by participants who smoke and have an IBW of more than 60 kg. Participants will be reviewed at recruitment and after 6 and 12 months. The primary outcome is the total number of participant-reported COPD exacerbations requiring oral corticosteroids or antibiotics during the 52-week treatment period. DISCUSSION: The demonstration that 'low dose' theophylline increases the efficacy of inhaled corticosteroids in COPD by reducing the incidence of exacerbations is relevant not only to patients and clinicians but also to health-care providers, both in the UK and globally. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014
The influence of fillers on theophylline release from clay matrices
Abstract: The objectives of this study were to investigate the suitability of magnesium aluminium silicate (MAS) (Veegum®) to control drug release of a model drug, theophylline, from tablet matrices. To this end, the performance of three commonly used fillers namely: lactose, microcrystalline cellulose (Avicel PH102; MCC), and pre-gelatinized starch, Starch 1500 PGS), were evaluated against Veegum®. The physico-mechanical properties of the tablet matrices were studied along with dissolution studies to determine the effect of single or binary mixtures of the excipients on the drug release pattern. A DSC hydration methodology was also employed to characterize the states of water present in the tablet matrices and to determine any impact on drug release. Formulations containing MAS alone produced compacts with the lowest hardness (4.5 kp) whereas formulations containing MCC alone produced the hardest tablets (17.2 kp). Dissolution studies suggested that matrices containing MAS alone released the theophylline quickest as compared to lactose, MCC or PGS. It was difficult to establish a trend of the bound and free water states in the tablet matrices; however the formulation containing only MAS had the highest bound water at 29 %. The results therefore show that theophylline does not interact with MAS. As such the dominant factor in controlling drug release using MAS requires interaction or intercalation with a cationic drug. In the absence of this however, other excipients can play a role in controlling drug release.
Keywords: Veegum, clay matrices, DSC hydration, Magnesium aluminium silicate, filler
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Pulmonary outcomes following specialized respiratory management for acute cervical spinal cord injury: a retrospective analysis.
Study designRetrospective analysis.ObjectivesTo identify multivariate interactions of respiratory function that are sensitive to spinal cord injury level and pharmacological treatment to promote strategies that increase successful liberation from mechanical ventilation.SettingUnited States regional spinal cord injury (SCI) treatment center.MethodsRetrospective chart review of patients consecutively admitted to Santa Clara Valley Medical Center between May 2013 and December 2014 for ventilator weaning with C1-C5 American Spinal Injury Association Impairment Scale (AIS) A or B SCI, <3 months from injury and who had a tracheostomy in place. A nonlinear, categorical principal component analysis (NL-PCA) was performed to test the multivariate interaction of respiratory outcomes from patients (N=36) being weaned off ventilator support after acute SCI with (N=15) or without (N=21) theophylline treatment.ResultsIn total, 36 patients met inclusion criteria (2 C1, 5 C2, 11 C3, 14 C4 and 4 C5). The NL-PCA returned three independent components that accounted for 95% of the variance in the data set. Multivariate general linear models hypothesis tests revealed a significant syndromic interaction between theophylline treatment and SCI level (Wilks' Lambda, P=0.028, F (12,64)=2.116, η2=0.256, 1-β=0.838), with post hoc testing demonstrating a significant interaction on PC1, explained by a positive correlation between improved forced vital capacity and time it took to reach 16 h of ventilator-free breathing. Thirty-three patients (92%) achieved 16 h of ventilator-free breathing (VFB) and 30 patients (83%) achieved 24 h of VFB.ConclusionsWe suspect that some portion of the high success rate of ventilator weaning may be attributable to theophylline use in higher cervical SCI, in addition to our aggressive regimen of high volume ventilation, medication optimization and pulmonary toilet (positive pressure treatments and mechanical insufflation-exsufflation)
Loss of PopZ At activity in Agrobacterium tumefaciens by Deletion or Depletion Leads to Multiple Growth Poles, Minicells, and Growth Defects.
Agrobacterium tumefaciens grows by addition of peptidoglycan (PG) at one pole of the bacterium. During the cell cycle, the cell needs to maintain two different developmental programs, one at the growth pole and another at the inert old pole. Proteins involved in this process are not yet well characterized. To further characterize the role of pole-organizing protein A. tumefaciens PopZ (PopZ At ), we created deletions of the five PopZ At domains and assayed their localization. In addition, we created a popZAt deletion strain (ΔpopZAt ) that exhibited growth and cell division defects with ectopic growth poles and minicells, but the strain is unstable. To overcome the genetic instability, we created an inducible PopZ At strain by replacing the native ribosome binding site with a riboswitch. Cultivated in a medium without the inducer theophylline, the cells look like ΔpopZAt cells, with a branching and minicell phenotype. Adding theophylline restores the wild-type (WT) cell shape. Localization experiments in the depleted strain showed that the domain enriched in proline, aspartate, and glutamate likely functions in growth pole targeting. Helical domains H3 and H4 together also mediate polar localization, but only in the presence of the WT protein, suggesting that the H3 and H4 domains multimerize with WT PopZ At , to stabilize growth pole accumulation of PopZ AtIMPORTANCEAgrobacterium tumefaciens is a rod-shaped bacterium that grows by addition of PG at only one pole. The factors involved in maintaining cell asymmetry during the cell cycle with an inert old pole and a growing new pole are not well understood. Here we investigate the role of PopZ At , a homologue of Caulobacter crescentus PopZ (PopZ Cc ), a protein essential in many aspects of pole identity in C. crescentus We report that the loss of PopZ At leads to the appearance of branching cells, minicells, and overall growth defects. As many plant and animal pathogens also employ polar growth, understanding this process in A. tumefaciens may lead to the development of new strategies to prevent the proliferation of these pathogens. In addition, studies of A. tumefaciens will provide new insights into the evolution of the genetic networks that regulate bacterial polar growth and cell division
Real-time assessment of critical quality attributes of a continuous granulation process
There exists the intention to shift pharmaceutical manufacturing of solid dosage forms from traditional batch production towards continuous production. The currently applied conventional quality control systems, based on sampling and time-consuming off-line analyses in analytical laboratories, would annul the advantages of continuous processing. It is clear that real-time quality assessment and control is indispensable for continuous production. This manuscript evaluates strengths and weaknesses of several complementary Process Analytical Technology (PAT) tools implemented in a continuous wet granulation process, which is part of a fully continuous from powder-to-tablet production line. The use of Raman and NIR-spectroscopy and a particle size distribution analyzer is evaluated for the real-time monitoring of critical parameters during the continuous wet agglomeration of an anhydrous theophylline− lactose blend. The solid state characteristics and particle size of the granules were analyzed in real-time and the critical process parameters influencing these granule characteristics were identified. The temperature of the granulator barrel, the amount of granulation liquid added and, to a lesser extent, the powder feed rate were the parameters influencing the solid state of the active pharmaceutical ingredient (API). A higher barrel temperature and a higher powder feed rate, resulted in larger granules
Design of small molecule-responsive microRNAs based on structural requirements for Drosha processing
MicroRNAs (miRNAs) are prevalent regulatory RNAs that mediate gene silencing and play key roles in diverse cellular processes. While synthetic RNA-based regulatory systems that integrate regulatory and sensing functions have been demonstrated, the lack of detail on miRNA structure–function relationships has limited the development of integrated control systems based on miRNA silencing. Using an elucidated relationship between Drosha processing and the single-stranded nature of the miRNA basal segments, we developed a strategy for designing ligand-responsive miRNAs. We demonstrate that ligand binding to an aptamer integrated into the miRNA basal segments inhibits Drosha processing, resulting in titratable control over gene silencing. The generality of this control strategy was shown for three aptamer–small molecule ligand pairs. The platform can be extended to the design of synthetic miRNAs clusters, cis-acting miRNAs and self-targeting miRNAs that act both in cis and trans, enabling fine-tuning of the regulatory strength and dynamics. The ability of our ligand-responsive miRNA platform to respond to user-defined inputs, undergo regulatory performance tuning and display scalable combinatorial control schemes will help advance applications in biological research and applied medicine
Assessment and prediction of tablet properties using transmission and backscattering Raman spectroscopy and transmission NIR spectroscopy
This study investigated whether Raman and Near Infrared (NIR) spectroscopy could predict tablet properties. Granules were produced on a continuous line by varying granulation parameters. Tableting process parameters were adjusted to obtain uniform tablet weight and thickness. Spectra were collected offline and tablet properties determined with traditional analyzing methods. Partial Least Squares (PLS) regression was used to correlate spectral information to tablet properties, but predictive models couldn't be established. Principal component analysis (PCA) was effectively used to distinguish theophylline concentrations and hydration levels and multiple linear regression (MLR) analysis allowed insight on how granulation parameters affect granule and tablet properties
Engineering ligand-responsive RNA controllers in yeast through the assembly of RNase III tuning modules
The programming of cellular networks to achieve new biological functions depends on the development of genetic tools that link the presence of a molecular signal to gene-regulatory activity. Recently, a set of engineered RNA controllers was described that enabled predictable tuning of gene expression in the yeast Saccharomyces cerevisiae through directed cleavage of transcripts by an RNase III enzyme, Rnt1p. Here, we describe a strategy for building a new class of RNA sensing-actuation devices based on direct integration of RNA aptamers into a region of the Rnt1p hairpin that modulates Rnt1p cleavage rates. We demonstrate that ligand binding to the integrated aptamer domain is associated with a structural change sufficient to inhibit Rnt1p processing. Three tuning strategies based on the incorporation of different functional modules into the Rnt1p switch platform were demonstrated to optimize switch dynamics and ligand responsiveness. We further demonstrated that these tuning modules can be implemented combinatorially in a predictable manner to further improve the regulatory response properties of the switch. The modularity and tunability of the Rnt1p switch platform will allow for rapid optimization and tailoring of this gene control device, thus providing a useful tool for the design of complex genetic networks in yeast
Model-guided design of ligand-regulated RNAi for programmable control of gene expression
Progress in constructing biological networks will rely on the development of more advanced components that can be predictably modified to yield optimal system performance. We have engineered an RNA-based platform, which we call an shRNA switch, that provides for integrated ligand control of RNA interference (RNAi) by modular coupling of an aptamer, competing strand, and small hairpin (sh) RNA stem into a single component that links ligand concentration and target gene expression levels. A combined experimental and mathematical modelling approach identified multiple tuning strategies and moves towards a predictable framework for the forward design of shRNA switches. The utility of our platform is highlighted by the demonstration of fine-tuning, multi-input control, and model-guided design of shRNA switches with an optimized dynamic range. Thus, shRNA switches can serve as an advanced component for the construction of complex biological systems and offer a controlled means of activating RNAi in disease therapeutics
Calculation of absolute free energy of binding for theophylline and its analogs to RNA aptamer using nonequilibrium work values
The massively parallel computation of absolute binding free energy with a
well-equilibrated system (MP-CAFEE) has been developed [H. Fujitani, Y. Tanida,
M. Ito, G. Jayachandran, C. D. Snow, M. R. Shirts, E. J. Sorin, and V. S.
Pande, J. Chem. Phys. , 084108 (2005)]. As an application, we
perform the binding affinity calculations of six theophylline-related ligands
with RNA aptamer. Basically, our method is applicable when using many compute
nodes to accelerate simulations, thus a parallel computing system is also
developed. To further reduce the computational cost, the adequate non-uniform
intervals of coupling constant , connecting two equilibrium states,
namely bound and unbound, are determined. The absolute binding energies thus obtained have effective linear relation between the computed and
experimental values. If the results of two other different methods are
compared, thermodynamic integration (TI) and molecular mechanics
Poisson-Boltzmann surface area (MM-PBSA) by the paper of Gouda [H.
Gouda, I. D. Kuntz, D. A. Case, and P. A. Kollman, Biopolymers , 16
(2003)], the predictive accuracy of the relative values is
almost comparable to that of TI: the correlation coefficients (R) obtained are
0.99 (this work), 0.97 (TI), and 0.78 (MM-PBSA). On absolute binding energies
meanwhile, a constant energy shift of -7 kcal/mol against the
experimental values is evident. To solve this problem, several presumable
reasons are investigated.Comment: 23 pages including 6 figure
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