Formulation and Evaluation of Tramadol HCl Matrix Tablets Using Carbopol 974P and 934 as Rate-Controlling Agents

Purpose: To formulate and prepare controlled release (CR) matrix tablets of tramadol HCl using Carbopol 974P and 934 polymers as rate-controlling agents.Methods: The tablets were prepared by direct compression method using various drug to polymer (D:P) ratios. Co-excipients, including carboxymethylcellulose, starch and/or hydroxypropyl methylcellulosewere also used to modulate the formulations. Various physical tests and in vitro dissolution studies were carried out on the formulations. The dissolution data were subjected to various release modelsResults: As the concentration of the polymer (rate-controlling agent) increased, dissolution rate decreased, For the formulation containing Carbopol 974P at D:P ratio of 10:7, drug release decreased to 83 % compared with the release rate of 99 % for the formulation with D:P ratio of 10:3. Kinetic analysis indicates that drug release mechanism was anomalous non-Fickian diffusion.Conclusion: Both Carbopol 974P and 934 can be used as rate-controlling agents in the formulation of tramadol HCl CR tablets. Appropriate selection of drug/polymer ratio can be applied effectively to modulate the dissolution rate of the drug.Keywords: Tramadol, Carbopol, Carboxymethylcellulose (CMC), Hydroxypropyl methylcellulose, Controlled releas

A controlled trial of natalizumab for relapsing multiple sclerosis.

Background: In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein (alpha)(sub 4) integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an (alpha)(sub 4) integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis.Methods: In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being.Results: There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram).Conclusions: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis

Analysis of Restrained Composite Perforated Beams during Fire Using a Hybrid Simulation Approach

This paper is concerned with the behavior of restrained perforated beams acting compositely with a profiled slab during a fire. These members are increasingly popular in the construction of long-span floor systems because they provide a structurally and materially efficient design solution and provide space for placement of building services. However, their response during a fire has received little attention from the research community until recently. In the current work, a hybrid simulation-type numerical approach is adopted using a combination of the OpenSEES, ABAQUS, and OpenFresco software. The accuracy of the model is validated using available fire test data whereby the temperatures measured during the experiments are directly applied in the numerical model at various locations. The effect of axial and rotational restraint due to the connections between the beams and columns is also investigated following validation of the model. Furthermore, the hybrid simulation approach is employed to study a number of salient parameters, including load ratios, material grade, and the location of the openings. The variation in axial force during the fire is also examined. Various failure modes were observed during the analysis, including flexural and shear failure, failure of the web-post, concrete crushing, and also a Vierendeel mechanism. The fire resistance of the analyzed beams is compared with the values obtained from the most common design codes. Because of the consideration of restraint forces, which are not included in the design codes, the resistances predicted by the finite-element simulations were more favorable. It was found that the location of the openings along the span and also the boundary conditions had a considerable effect on the time-displacement behavior, axial reactions, and web-post buckling behavior, as well as the fire performance of the perforated beam

Clinical and cost-effectiveness analysis of an open label, single-centre, randomised trial of spinal cord stimulation (SCS) versus percutaneous myocardial laser revascularisation (PMR) in patients with refractory angina pectoris: The SPiRiT trial.

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.BACKGROUND: Patients with refractory angina have significant morbidity. This study aimed to compare two of the treatment options, Spinal Cord Stimulation (SCS) and Percutaneous Myocardial Laser Revascularisation (PMR) in terms of clinical outcomes and cost-effectiveness. METHODS: Eligible patients were randomised to PMR or SCS and followed up for exercise tolerance time (ETT), Canadian Cardiovascular Society (CCS) classification and the quality of life measures SF-36, Seattle Angina Questionnaire and the EuroQoL at 3, 12 and 24 months. Utilities were calculated using the EQ-5D and these and costs were compared between groups. The incremental cost-effectiveness ratio (ICER) per QALY for SCS compared to PMR was also calculated. RESULTS: At 24 months post-randomisation, patients that had SCS and PMR had similar ETT (mean difference 0.05, 95% CI -2.08, 2.18, p = 0.96) and there was no difference in CCS classification or quality of life outcomes. The difference in overall mean costs when comparing SCS to PMR was GBP5,520 (95% CI GBP1,966 to GBP8,613; p < 0.01) and the ICER of using SCS was GBP46,000 per QALY. CONCLUSION: Outcomes after SCS did not differ appreciably from those after PMR, with the former procedure being less cost-effective as currently applied. Larger studies could clarify which patients would most benefit from SCS, potentially increasing cost-effectiveness. TRIAL REGISTRATION: Current Controlled Trials ISRCTN09648950.Published versio

Survey of Predatory Coccinellids (Coleoptera: Coccinellidae) in the Chitral District, Pakistan

An extensive survey of predatory Coccinellid beetles (Coleoptera: Coccinellidae) was conducted in the Chitral District, Pakistan, over a period of 7 months (April through October, 2001). A total of 2600 specimens of Coccinellids were collected from 12 different localities having altitudes from 1219.40–2651.63 m. Twelve different species belonging to 9 genera of 3 tribes and 2 sub-families were recorded. Two sub-families, viz, Coccinellinae Latreille, 1807 and Chilocorinae Mulsant, 1846 were identified. The following 8 species belonged to family Coccinellinae Latreille 1807 and tribe Coccinellini Latreille 1807: Coccinella septempunctata Linnaeus, 1758, Hippodamia (Adonia) variegata Goeze, 1777, Calvia punctata (Mulsant, 1846), Adalia bipunctata (Linnaeus, 1758),Adalia tetraspilota (Hope, 1831), Aiolocaria hexaspilota Hope 1851, Macroilleis (Halyzia) hauseri Mader, 1930,Oenopia conglobata Linnaeus, 1758. Only one species namely Halyzia tschitscherini Semenov, 1965 represented tribe Psylloborini of the sub-family Coccinellinae Latreille, 1807. Three species occurred from sub-family Chilocorinae Mulsant 1846 and tribe Chilocorini Mulsant 1846: Chilocorus rubidus Hope, 1831, Chilocorus circumdatus (Gyllenhal, 1808), Priscibrumus uropygialis (Mulsant, 1853). From the aforementioned species 6 were recorded for the first time from Pakistan: Chilocorus circumdatus, Calvia punctata, Adalia bipunctata, Macroilleis (Halyzia) hauseri, Priscibrumus uropygialis, and Oenopia conglobata

Analysis of restrained composite beams exposed to fire using a hybrid simulation approach

Obtaining an accurate simulation of the boundary conditions is very challenging but it is essential in order to represent the true behaviour of the whole structure in fire. In recent years, hybrid simulation has been emerging as an efficient and economical method for simulating realistic boundary conditions in the field of earthquake engineering. This technique can be used to study the load redistribution that may occur in a structural system as a result of locally elevated temperatures. In this paper, the fire-exposed element will be modelled in one analysis (a 3D model) and the rest of the structure in another analysis (a 2D model). This kind of sub-structuring enables the behaviour of the structural system as a whole to be studied. A hybrid simulation (HS) approach is presented and successfully implemented using the OpenFresco and OpenSees software. This approach enables the simulation of the correct restraint provided by the cold structure to the fire affected structural element. The HS analysis of a composite beam is compared with an unrestrained or simply supported version to highlight the difference in behaviour. Finally, the Cardington restrained beam test is modelled to demonstrate the potential of HS technique. Good agreement with the test results highlights that HS approach can be an effective method for studying the behaviour of the whole structural system

A hybrid model combining neural networks and decision tree for comprehension detection

The Artificial Neural Network is generally considered to be an effective classifier, but also a “Black Box” component whose internal behavior cannot be understood by human users. This lack of transparency forms a barrier to acceptance in high-stakes applications by the general public. This paper investigates the use of a hybrid model comprising multiple artificial neural networks with a final C4.5 decision tree classifier to investigate the potential of explaining the classification decision through production rules. Two large datasets collected from comprehension studies are used to investigate the value of the C4.5 decision tree as the overall comprehension classifier in terms of accuracy and decision transparency. Empirical trials show that higher accuracies are achieved through using a decision tree classifier, but the significant tree size questions the rule transparency to a human

Learning and attention increase visual response selectivity through distinct mechanisms

Selectivity of cortical neurons for sensory stimuli can increase across days as animals learn their behavioral relevance and across seconds when animals switch attention. While both phenomena occur in the same circuit, it is unknown whether they rely on similar mechanisms. We imaged primary visual cortex as mice learned a visual discrimination task and subsequently performed an attention switching task. Selectivity changes due to learning and attention were uncorrelated in individual neurons. Selectivity increases after learning mainly arose from selective suppression of responses to one of the stimuli but from selective enhancement and suppression during attention. Learning and attention differentially affected interactions between excitatory and PV, SOM, and VIP inhibitory cells. Circuit modeling revealed that cell class-specific top-down inputs best explained attentional modulation, while reorganization of local functional connectivity accounted for learning-related changes. Thus, distinct mechanisms underlie increased discriminability of relevant sensory stimuli across longer and shorter timescales

Mild Behavioral Impairment as a Marker of Cognitive Decline in Cognitively Normal Older Adults

This is the author accepted manuscript. the final version is available from Elsevier via the DOI in this recordObjective: Mild Behavioral Impairment (MBI) is a neurobehavioural syndrome characterized by later life emergent neuropsychiatric symptoms (NPS) which represent an at-risk state for incident cognitive decline and dementia in people with Mild Cognitive Impairment. We undertook a study to determine whether MBI was associated with progressive changes in neuropsychological performance in people without significant cognitive impairment. Methods: 9,931 older adults enrolled in the PROTECT study who did not have MCI or dementia undertook a comprehensive neuropsychological battery measuring attention, reasoning, executive function and working memory at baseline and one year. MBI was ascertained using self-administration of the MBI-C at one year, and participants grouped according to MBI status: no symptoms, intermediate neuropsychiatric symptoms and MBI. All assessments were completed online and data analyzed using MMRM ANOVA. Results: 949 (10%) people had MBI. These individuals had significantly worse cognitive performance at baseline and significantly greater decline over one year in the four composites cognitive scores measuring attentional intensity (F(2,8578)=3.97,p=0.019), sustained attention (F(2,8578)=18.63, p<.0001), attentional fluctuation (F(2,8578)=10.13, p=<.0001) and working memory F(2,9895)=13.1, p<.0001. Conclusions: Our novel findings show that MBI is associated with faster decline in attention and working memory in this cognitively normal sample. MBI may be an earlier marker of neurodegenerative disease than MCI, captured at the stage of SCD or before, raising the possibility that MBI represents a novel target for dementia clinical trials or prevention strategies.National Institute for Health Research (NIHR