Radiation worker mortality: intersociety call for survey participation.
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Air Pollution, Radioactive↗
Biomedical subjects
John Barr
Publications and source records attributed to John Barr.
Biochronomer technology.
Biochronomer (AP Pharma) is a fourth-generation poly(ortho ester) prepared by the condensation of diols and a diketene acetal. The polymer contains a copolymerised latent acid whose concentration controls erosion rate. The polymer has been shown to undergo a surface erosion process and a number of applications have been explored. Among these, the delivery of plasmid DNA for vaccines is currently of most interest. This application takes advantage of the acid-labile nature of the polymer, which leads to rapid polymer hydrolysis and hence rapid release of plasmid DNA once internalised in the acidic environment within the endosomes, and the non-acidic environment within the polymer that conserves plasmid DNA conformation. A low molecular semisolid polymer is now in Phase II clinical trials for the delivery of mepivacaine to control postoperative pain, and in Phase I clinical trials for the systemic delivery of granisetron to control nausea.
Anesthetics, Local↗
Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic stroke.
BACKGROUND AND PURPOSE: The National Institutes of Health (NIH) estimates that stroke costs now exceed 45 billion dollars per year. Stroke is the third leading cause of death and one of the leading causes of adult disability in North America, Europe, and Asia. A number of well-designed randomized stroke trials and case series have now been reported in the literature to evaluate the safety and efficacy of thrombolytic therapy for the treatment of acute ischemic stroke. These stroke trials have included intravenous studies, intra-arterial studies, and combinations of both, as well as use of mechanical devices for removal of thromboemboli and of neuroprotectant drugs, alone or in combination with thrombolytic therapy. At this time, the only therapy demonstrated to improve outcomes from an acute stroke is thrombolysis of the clot responsible for the ischemic event. There is room for improvement in stroke lysis studies. Divergent criteria, with disparate reporting standards and definitions, have made direct comparisons between stroke trials difficult to compare and contrast in terms of overall patient outcomes and efficacy of treatment. There is a need for more uniform definitions of multiple variables such as collateral flow, degree of recanalization, assessment of perfusion, and infarct size. In addition, there are multiple unanswered questions that require further investigation, in particular, questions as to which patients are best treated with thrombolysis. One of the most important predictors of clinical success is time to treatment, with early treatment of <3 hours for intravenous tissue plasminogen activator and <6 hours for intra-arterial thrombolysis demonstrating significant improvement in terms of 90-day clinical outcome and reduced cerebral hemorrhage. It is possible that improved imaging that identifies the ischemic penumbra and distinguishes it from irreversibly infarcted tissue will more accurately select patients for therapy than duration of symptoms. There are additional problems in the assessment of patients eligible for thrombolysis. These include being able to predict whether a particular site of occlusion can be successfully revascularized, predict an individual patient's prognosis and outcome after revascularization, and in particular, to predict the development of intracerebral hemorrhage, with and without clinical deterioration. It is not clear to assume that achieving immediate flow restoration due to thrombolytic therapy implies clinical success and improved outcome. There is no simple correlation between recanalization and observed clinical benefit in all ischemic stroke patients, because other interactive variables, such as collateral circulation, the ischemic penumbra, lesion location and extent, time to treatment, and hemorrhagic conversion, are all interrelated to outcome. METHODS: This article was written under the auspices of the Technology Assessment Committees for both the American Society of Interventional and Therapeutic Neuroradiology and the Society of Interventional Radiology. The purpose of this document is to provide guidance for the ongoing study design of trials of intra-arterial cerebral thrombolysis in acute ischemic stroke. It serves as a background for the intra-arterial thrombolytic trials in North America and Europe, discusses limitations of thrombolytic therapy, defines predictors for success, and offers the rationale for the different considerations that might be important during the design of a clinical trial for intra-arterial thrombolysis in acute stroke. Included in this guidance document are suggestions for uniform reporting standards for such trials. These definitions and standards are mainly intended for research trials; however, they should also be helpful in clinical practice and applicable to all publications. This article serves to standardize reporting terminology and includes pretreatment assessment, neurologic evaluation with the NIH Stroke Scale score, imaging evaluation, occlusion sites, perfusion grades, follow-up imaging studies, and neurologic assessments. Moreover, previously used and established definitions for patient selection, outcome assessment, and data analysis are provided, with some possible variations on specific end points. This document is therefore targeted to help an investigator to critically review the scales and scores used previously in stroke trials. This article also seeks to standardize patient selection for treatment based on neurologic condition at presentation, baseline imaging studies, and utilization of standardized inclusion/exclusion criteria. It defines outcomes from therapy in phase I, II, and III studies. Statistical approaches are presented for analyzing outcomes from prospective, randomized trials with both primary and secondary variable analysis. A discussion on techniques for angiography, intra-arterial thrombolysis, anticoagulation, adjuvant therapy, and patient management after therapy is given, as well as recommendations for posttreatment evaluation, duration of follow-up, and reporting of disability outcomes. Imaging assessment before and after treatment is given. In the past, noncontrast CT brain scans were used as the initial screening examination of choice to exclude cerebral hemorrhage. However, it is now possible to quantify the volume of early infarct by using contiguous, discrete (nonhelical) images of 5 mm. In addition, CT angiography by helical scanning and 100 mL of intravenous contrast agent can be used expeditiously to obtain excellent vascular anatomy, define the occlusion site, obtain 2D and 3D reformatted vascular images, grade collateral blood flow, and perform tissue-perfusion studies to define transit times of a contrast bolus through specific tissue beds and regions of interest in the brain. Dynamic CT perfusion scans to assess the whole dynamics of a contrast agent transit curve can now be routinely obtained at many hospitals involved in these studies. The rationale, current status of this technology, and potential use in future clinical trials are given. Many hospitals are also performing MR brain studies at baseline in addition to, or instead of, CT scans. MRI has a high sensitivity and specificity for the diagnosis of ischemic stroke in the first several hours from symptom onset, identifies arterial occlusions, and characterizes ischemic pathology noninvasively. Case series have demonstrated and characterized the early detection of intraparenchymal hemorrhage and subarachnoid hemorrhage by MRI. Echo planar images, used for diffusion MRI and, in particular, perfusion MRI are inherently sensitive for the susceptibility changes caused by intraparenchymal blood products. Consequently, MRI has replaced CT to rule out acute hemorrhage in some centers. The rationale and the potential uses of MR scanning are provided. In addition to established criteria, technology is continuously evolving, and imaging techniques have been introduced that offer new insights into the pathophysiology of acute ischemic stroke. For example, a better patient stratification might be possible if CT and/or MRI brain scans are used not only as exclusion criteria but also to provide individual inclusion and exclusion criteria based on tissue physiology. Imaging techniques might also be used as a surrogate outcome measure in future thrombolytic trials. The context of a controlled study is the best environment to validate emerging imaging and treatment techniques. The final section details reporting standards for complications and adverse outcomes; defines serious adverse events, adverse events, and unanticipated adverse events; and describes severity of complications and their relation to treatment groups. Recommendations are made regarding comparing treatment groups, randomization and blinding, intention-to-treat analysis, quality-of-life analysis, and efficacy analysis. This document concludes with an analysis of general costs associated with therapy, a discussion regarding entry criteria, outcome measures, and the variability of assessment of the different stroke scales currently used in the literature is also featured. CONCLUSIONS: In summary, this article serves to provide a more uniform set of criteria for clinical trials and reporting outcomes used in designing stroke trials involving intra-arterial thrombolytic agents, either alone or in combination with other therapies. It is anticipated that by having a more uniform set of reporting standards, more meaningful analysis of the data and the literature will be able to be achieved.
Acute Disease↗
Trial design and reporting standards for intraarterial cerebral thrombolysis for acute ischemic stroke.
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Journal Article↗
Poly(ortho esters): synthesis, characterization, properties and uses.
Over the last 30 years, poly(ortho esters) have evolved through four families, designated as POE I, POE II, POE III and POE IV. Of these, only POE IV has been shown to have all the necessary attributes to allow commercialization, and such efforts are currently underway. Dominant among these attributes is synthesis versatility that allows the facile and reproducible production of polymers having the desired mechanical and thermal properties as well as desired erosion rates and drug release rates that can be varied from a few days to many months. Further, the polymer is stable at room temperature when stored under anhydrous conditions and undergoes an erosion process confined predominantly to the surface layers. Important consequences of surface erosion are controlled and concomitant drug release as well as the maintenance of an essentially neutral pH in the interior of the matrix because acidic hydrolysis products diffuse away from the device. Two physical forms of such polymers are under development. One form, solid materials, can be fabricated into shapes such as wafers, strands, or microspheres. The other form are injectable semi-solid materials that allow drug incorporation by a simple mixing at room temperature and without the use of solvents. GMP toxicology studies on one family of POE IV polymers has been concluded, an IND filed and Phase I clinical trials are in progress. Important applications under development are treatment of post-surgical pain, osteoarthritis and ophthalmic diseases as well as the delivery of proteins, including DNA. Block copolymers of poly(ortho ester) and poly(ethylene glycol) have been prepared and their use as a matrix for drug delivery and as micelles, primarily for tumor targeting, are being explored.
Animals↗
Post surgical pain management with poly(ortho esters).
Poly(ortho esters), POE, are synthetic bioerodible polymers that can be prepared as solid materials, or as viscous, injectable polymers. These materials have evolved through a number of families, and the latest member of this family, POE IV, is particularly well suited to drug delivery since latent acid is integrated into the polymer backbone, thereby, modulating surface erosion. POE IV predominantly undergoes surface erosion and is able to moderate drug release over periods from days to many months. One indication in which the POE IV polymer is currently being investigated is in sustained post-surgical pain management. The local anesthetic agent, mepivacaine, has been incorporated into a viscous, injectable POE IV and its potential to provide longer-acting anesthesia has been explored in non-clinical models.
Animals↗
Development of poly(ortho esters) and their application for bovine serum albumin and bupivacaine delivery.
The preparation of drug delivery devices using solventless fabrication procedures is of significant interest and two such procedures are described. In one such procedure, powdered polymer and micronized protein are intimately mixed and then extruded into 1 mm strands that are cut to the desired length. The polymers used were specifically designed to allow extrusion at temperatures where proteins maintain activity in the dry state. In vitro erosion and BSA release show that BSA release and polymer erosion occur concomitantly indicating an erosion-controlled process. There is a lag-time, but that can be eliminated by the addition to the mixture prior to extrusion small amounts of poly(ethylene glycol) or its methoxy derivatives. The lag-time could also be eliminated by using an AB-block copolymer where A is poly(ortho ester) and B is poly(ethylene glycol). Another means of using solventless fabrication methods is to use a semi-solid material into which drugs can be mixed at room temperature and the semi-solid injected. Data on BSA and bupivacaine release are presented.
Bupivacaine↗
Approved IFCC reference method for the measurement of HbA1c in human blood.
HbA1C is the stable glucose adduct to the N-terminal group of the beta-chain of HbA0. The measurement of HbA1c in human blood is most important for the long-term control of the glycaemic state in diabetic patients. Because there was no internationally agreed reference method the IFCC Working Group on HbA1c Standardization developed a reference method which is here described. In a first step haemoglobin is cleaved into peptides by the enzyme endoproteinase Glu-C, and in a second step the glycated and non-glycated N-terminal hexapeptides of the beta-chain obtained are separated and quantified by HPLC and electrospray ionisation mass spectrometry or in a two-dimensional approach using HPLC and capillary electrophoresis with UV-detection. Both principles give identical results. HbA1c is measured as ratio between the glycated and non-glycated hexapeptides. Calibrators consisting of mixtures of highly purified HbA1c and HbA0 are used. The analytical performance of the reference method has been evaluated by an international network of reference laboratories comprising laboratories from Europe, Japan and the USA. The intercomparison studies of the network showed excellent results with intra-laboratory CVs of 0.5 to 2% and inter-laboratory CVs of 1.4 to 2.3%. Possible interferences have been carefully investigated. Due to the higher specificity of the reference method the results are lower than those generated with most of the present commercial methods which currently are calibrated with unspecific designated comparison methods. The new reference method has been approved by the member societies of the International Federation of Clinical Chemistry and Laboratory Medicine and will be the basis for the future uniform standardization of HbA1c routine assays worldwide.
Blood Chemical Analysis↗
Poly(ortho esters)--from concept to reality.
The development of poly(ortho esters) dates back to the early 1970s, and during that time, four distinct families were developed. These polymers can be prepared by a transesterification reaction or by the addition of polyols to diketene acetals, and it is the latter method that has proven to be preferred one. The latest polymer, now under intense development, incorporates a latent acid segment in the polymer backbone that takes advantage of the acid-labile nature of the ortho ester linkages and allows control over erosion rates. By use of diols having selected chain flexibility, polymers that range from hard, brittle materials to materials that have a gel-like consistency at room temperature can be obtained. Drug release from solid materials will be illustrated with 5-fluorouacil and bovine serum albumin, and drug release from gel-like materials will be illustrated with mepivacaine, now in Phase II clinical trials as a delivery system to treat post-operative pain. A brief summary of preclinical toxicology studies is also presented.
Animals↗