Dataset Information

Reperfusion half-life: a novel pharmacodynamic measure of thrombolytic activity.

ABSTRACT: BACKGROUND AND PURPOSE:We hypothesized that the probability of reperfusion can be modeled by an exponential decay (ie, half-life) function and that this reperfusion half-life is decreased by thrombolytic treatment. METHODS:Serial perfusion MRI scans were evaluated for evidence of reperfusion in intravenous tissue plasminogen activator-treated (n=45) and untreated (n=103) patients. The cumulative probability of reperfusion for each group was fit with exponential decay functions. The resulting reperfusion half-life (ie, the time it takes half the sample to reperfuse) was calculated. RESULTS:In untreated patients, a monoexponential decay function fit the data well (R(2)=0.95) with a half-life of 29.1 hours. In tissue plasminogen activator-treated patients, the data were best fit with a biexponential decay function (R(2)=0.99) that had a fast and a slow component. The fast component is attributable to tissue plasminogen activator therapy and has a half-life of 0.71 hours, whereas the slow component was similar to that of the untreated group. Approximately 3.5 hours after the start of treatment, the effect of tissue plasminogen activator on the probability of reperfusion was negligible. CONCLUSIONS:The probability of reperfusion can be well described by the reperfusion half-life. Determination of the fast component reperfusion half-life may be an approach to compare the relative potency of different thrombolytic agents.

SUBMITTER: Merino JG

PROVIDER: S-EPMC2749694 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Reperfusion half-life: a novel pharmacodynamic measure of thrombolytic activity.

Merino José G JG Latour Lawrence L LL An Li L Hsia Amie W AW Kang Dong-Wha DW Warach Steven S

Stroke 20080501 7

<h4>Background and purpose</h4>We hypothesized that the probability of reperfusion can be modeled by an exponential decay (ie, half-life) function and that this reperfusion half-life is decreased by thrombolytic treatment.<h4>Methods</h4>Serial perfusion MRI scans were evaluated for evidence of reperfusion in intravenous tissue plasminogen activator-treated (n=45) and untreated (n=103) patients. The cumulative probability of reperfusion for each group was fit with exponential decay functions. Th ...[more]

PMID: 18451344

Similar Datasets

Project description:Purpose: Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including AKT, p70S6 kinase, PKA, SGK and Rho kinase, is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component. Experimental Design: We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148. Results: AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK and SGK substrate phosphorylation and induced apoptosis in a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate cancer and PTEN-deficient MES-SA uterine tumor xenografts was demonstrated. We show for the first time that induction of AKT phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of AKT, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on apoptosis genes, whereas the selective AKT inhibitor CCT128930 modulates cell cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 due to compensatory feedback loops was observed. Conclusions: The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which demonstrates a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human Phase I trial. The PTEN-deficient U87MG glioblastoma cell line was treated for 6 hours with vehicle control (DMSO) or to different concentrations of AT13148 and CCT128930 (0.1uM, 1xGI50 and 3XGI50).

Project description:Recombinant urate oxidase (UOX, E.C.1.7.3.3) is an important therapeutic enzyme used in preventing and treating chemotherapy-induced hyperuricemia and severe gout. However, UOX use is limited due to the poor stability and short plasma half-life. To solve this problem, we designed three PASylated variants of Aspergillus flavus UOX with different PAS sequences at the C- or N-terminus. The genes of native and PASylated variants (UOX-PAS20, PAS24-UOX, and UOX-PAS100) were designed and produced in Escherichia coli strain BL21 (DE3). The expressed recombinant native and PASylated enzymes were compared in terms of biophysical properties, kinetics parameters, and pharmacokinetics behavior using standard methods. PASylation of UOX with PAS100 polymer caused a 1.24-fold reduction in K m to 52.61 μM, and a 3.87-fold increase in K cat/K m for uric acid compared to the native variant. UOX-PAS100 retained its activity in different temperatures (20-55 °C); however, other variants lost nearly 50% of their original activity at 55 °C. UOX-PAS100 exhibited a 1.78-fold increase in hydrodynamic radius and a 1.64-fold larger apparent molecular size in comparison to the native UOX. Circular dichroism (CD) spectroscopy demonstrated that the addition of the PAS tag does not change the secondary structure of the fusion enzyme. The tryptophan fluorescence emission spectra for PASylated enzymes showed a significant modification in the conformational state of UOX by the PAS polymer presence. UOX-PAS100 retained 89.0% of the original activity following 72 h incubation in the presence of plasma at 37 °C. However, only about 61.0%, 57.0%, 50.0%, and 52.0% of activity from PAS24-UOX, UOX-PAS20, native UOX, and rasburicase (Fasturtec, Italy) remained, respectively, at the identical time. UOX-PAS100 had an increased biological half-life (8.21 h) when compared with the rasburicase (3.12 h) and native UOX (2.87 h) after being injected into a rat. Having considering everything, our results suggest that the UOX-PAS100, an A. flavus UOX fused with a C-terminally 100 amino acid PAS-residue, is a proper candidate with enhanced biological activity and extended plasma half-life for clinical therapy in patients suffering from hyperuricemia.

Dataset Information

Reperfusion half-life: a novel pharmacodynamic measure of thrombolytic activity.

Publications

Reperfusion half-life: a novel pharmacodynamic measure of thrombolytic activity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets