ACCELERATED DOSING FREQUENCY OF A PULMONARY FORMULATION OF TISSUE PLASMINOGEN ACTIVATOR IS WELL-TOLERATED IN MICE

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72578/1/j.1440-1681.2008.05011.x.pd

The Reactome pathway Knowledgebase

The Reactome Knowledgebase (www.reactome.org) provides molecular details of signal transduction, transport, DNA replication, metabolism and other cellular processes as an ordered network of molecular transformations-an extended version of a classic metabolic map, in a single consistent data model. Reactome functions both as an archive of biological processes and as a tool for discovering unexpected functional relationships in data such as gene expression pattern surveys or somatic mutation catalogues from tumour cells. Over the last two years we redeveloped major components of the Reactome web interface to improve usability, responsiveness and data visualization. A new pathway diagram viewer provides a faster, clearer interface and smooth zooming from the entire reaction network to the details of individual reactions. Tool performance for analysis of user datasets has been substantially improved, now generating detailed results for genome-wide expression datasets within seconds. The analysis module can now be accessed through a RESTFul interface, facilitating its inclusion in third party applications. A new overview module allows the visualization of analysis results on a genome-wide Reactome pathway hierarchy using a single screen page. The search interface now provides auto-completion as well as a faceted search to narrow result lists efficiently

Gamma Hydroxybutyric Acid (GHB) for the Treatment of Alcohol Dependence: A Review

Gamma-hydroxybutyric acid (GHB) is a short-chain fatty acid structurally similar to the inhibitory neurotransmitter γ-aminobutyric acid. Clinical trials have demonstrated that 50–100 mg/kg of GHB fractioned into three or six daily doses is able to suppress alcohol withdrawal symptoms and facilitates the maintenance of abstinence from alcohol. These studies have also shown that GHB craving episodes are a very limited phenomenon (about 10–15%). Thus, physicians with access should consider the clinical efficacy of GHB as a valid pharmacological tool for the treatment of alcohol addiction

Glibenclamide—10-h Treatment Window in a Clinically Relevant Model of Stroke

Glibenclamide improves outcomes in rat models of stroke, with treatment as late as 6 h after onset of ischemia shown to be beneficial. Because the molecular target of glibenclamide, the sulfonylurea receptor 1 (Sur1)-regulated NCCa-ATP channel, is upregulated de novo by a complex transcriptional mechanism, and the principal pathophysiological target, brain swelling, requires hours to develop, we hypothesized that the treatment window would exceed 6 h. We studied a clinically relevant rat model of stroke in which middle cerebral artery occlusion (75% < reduction in LDF signal ≤90%) was produced using an intra-arterial occluder. Recanalization was obtained 4.5 h later by removing the occluder. At that time, we administered recombinant tissue plasminogen activator (rtPA; 0.9 mg/kg IV over 30 min). Immunolabeling showed modest expression of Sur1 5 h after onset of ischemia, with expression increasing 7- to 11-fold (P < 0.01) by 24 h. Rats were administered either vehicle or glibenclamide (10 μg/kg IP loading dose plus 200 ng/h by constant subcutaneous infusion) beginning 4.5 or 10 h after onset of ischemia. In rats treated at 4.5 or 10 h, glibenclamide significantly reduced hemispheric swelling at 24 h from (mean ± SEM) 14.7 ± 1.5% to 8.1 ± 1.6% or 8.8 ± 1.1% (both P < 0.01), respectively, and significantly reduced 48-h mortality from 53% to 17% or 12% (both P < 0.01), and improved Garcia scores at 48 h from 3.8 ± 0.62 to 7.6 ± 0.70 or 8.4 ± 0.74 (both P < 0.01). We conclude that, in a clinically relevant model of stroke, the treatment window for glibenclamide extends to 10 h after onset of ischemia

Mutant Prourokinase with Adjunctive C1-Inhibitor Is an Effective and Safer Alternative to tPA in Rat Stroke

A single-site mutant (M5) of native urokinase plasminogen activator (prouPA) induces effective thrombolysis in dogs with venous or arterial thrombosis with a reduction in bleeding complications compared to tPA. This effect, related to inhibition of two-chain M5 (tcM5) by plasma C1-inhibitor (C1I), thereby preventing non-specific plasmin generation, was augmented by the addition of exogenous C1I to plasma in vitro. In the present study, tPA, M5 or placebo +/− C1I were administered in two rat stroke models. In Part-I, permanent MCA occlusion was used to evaluate intracranial hemorrhage (ICH) by the thrombolytic regimens. In Part II, thromboembolic occlusion was used with thrombolysis administered 2 h later. Infarct and edema volumes, and ICH were determined at 24 h, and neuroscore pre (2 h) and post (24 h) treatment. In Part I, fatal ICH occurred in 57% of tPA and 75% of M5 rats. Adjunctive C1I reduced this to 25% and 17% respectively. Similarly, semiquantitation of ICH by neuropathological examination showed significantly less ICH in rats given adjunctive C1I compared with tPA or M5 alone. In Part-II, tPA, M5, and M5+C1I induced comparable ischemic volume reductions (>55%) compared with the saline or C1I controls, indicating the three treatments had a similar fibrinolytic effect. ICH was seen in 40% of tPA and 50% of M5 rats, with 1 death in the latter. Only 17% of the M5+C1I rats showed ICH, and the bleeding score in this group was significantly less than that in either the tPA or M5 group. The M5+C1I group had the best Benefit Index, calculated by dividing percent brain salvaged by the ICH visual score in each group. In conclusion, adjunctive C1I inhibited bleeding by M5, induced significant neuroscore improvement and had the best Benefit Index. The C1I did not compromise fibrinolysis by M5 in contrast with tPA, consistent with previous in vitro findings

Preclinical stroke research - advantages and disadvantages of the most common rodent models of focal ischaemia

This review describes the most commonly used rodent models and outcome measures in preclinical stroke research and discusses their strengths and limitations. Most models involve permanent or transient middle cerebral artery occlusion with therapeutic agents tested for their ability to reduce stroke-induced infarcts and improve neurological deficits. Many drugs have demonstrated preclinical efficacy but, other than thrombolytics, which restore blood flow, none have demonstrated efficacy in clinical trials. This failure to translate efficacy from bench to bedside is discussed alongside achievable steps to improve the ability of preclinical research to predict clinical efficacy: (i) Improvements in study quality and reporting. Study design must include randomization, blinding and predefined inclusion/exclusion criteria, and journal editors have the power to ensure statements on these and mortality data are included in preclinical publications. (ii) Negative and neutral studies must be published to enable preclinical meta-analyses and systematic reviews to more accurately predict drug efficacy in man. (iii) Preclinical groups should work within networks and agree on standardized procedures for assessing final infarct and functional outcome. This will improve research quality, timeliness and translational capacity. (iv) Greater uptake and improvements in non-invasive diagnostic imaging to detect and study potentially salvageable penumbral tissue, the target for acute neuroprotection. Drug effects on penumbra lifespan studied serially, followed by assessment of behavioural outcome and infarct within in the same animal group, will increase the power to detect drug efficacy preclinically. Similar progress in detecting drug efficacy clinically will follow from patient recruitment into acute stroke trials based on evidence of remaining penumbra

Applicability of percutaneous transluminal coronary angioplasty to patients with recombinant tissue plasminogen activator mediated thrombolysis

To test the utility and safety of percutaneous transluminal coronary angioplasty (PTCA) after recombinant tissue plasminogen activator (t-PA), we performed the procedure in all suitable candidates with acute myocardial infarction (MI) who had successful t-PA mediated coronary thrombolysis. Twenty consecutive patients with MI received t-PA after coronary angiographic conformation of total occlusion. Successful recanalization with t-PA was achieved in 13 patients, leaving a residual obstruction of 84 ± 6% in the nine patients for whom PTCA was attempted at a mean of 21.6 h. Success was achieved in seven patients, leading to a residual lesion of 29 ± 7%. In the two patients for whom PTCA was unsuccessful, total reocclusion occurred prior to the attempt despite therapy with heparin, aspirin, dipyridamole, and nifedipine. All PTCA procedures were uncomplicated. Serial two-dimensional echocardiography at 10 days, compared to admission, demonstrated infarct zone wall motion index improvement in the patients with successful PTCA (group A, 0.83 ± 0.36 to 1.46 ± 0.49) as compared to the 13 patients without thrombolysis or successful PTCA (group B, 0.61 ± 0.26 to 0.66 ± 0.39), (P < 0.05). One patient of group A sustained a massive stroke at 2 weeks after hospital discharge. In the remaining six patients, follow-up exercise testing and/or coronary arteriography demonstrated a negative treadmill test and/or patent infarct vessel, respectively. After successful PTCA, no patient had clinical signs of reocclusion, reinfarction, postinfarction angina, or congestive heart failure. At 9.4 ± 2 months, all six patients are asymptomatic and have returned to work. Thus, sequential PTCA after t-PA can be performed safely and successfully in patients with MI and this approach may be associated with improved regional function and a favorable post-MI course.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38212/1/1810110402_ftp.pd