Intra-arterial administration of recombinant tissue-type plasminogen activator (rt-PA) causes more intracranial bleeding than does intravenous rt-PA in a transient rat middle cerebral artery occlusion model

<p>Abstract</p> <p>Background</p> <p>Intra-arterial (IA) administration of rt-PA for ischemic stroke has the potential for greater thrombolytic efficacy, especially for a large thrombus in the M1 or M2 segment of the middle cerebral artery (MCA). Intracranial hemorrhage (ICH) is a concern with IA or intravenous (IV) administration especially as the therapeutic window is extended. However, because IA administration delivers a higher local concentration of agent, the incidence and severity of ICH may be greater than with similar doses IV. We investigated the safety of rt-PA administration by IA compared to IV infusion following 6 hours of MCA occlusion (MCAo) with reflow in the spontaneously hypertensive rat (SHR).</p> <p>Methods</p> <p>Male SHRs were subjected to 6 hours MCAo with 18 hours reflow using a snare ligature model. They were treated with IA saline, IA rt-PA (1, 5, 10, 30 mg/kg), or IV rt-PA (10 and 30 mg/kg) by a 10 to 60 minute infusion beginning approximately 1 minute before reflow. The rats were recovered for 24 hours after MCAo onset at which time Bleeding Score, infarct volume, and Modified Bederson Score were measured.</p> <p>Results</p> <p>Greater hemorrhagic transformation occurred with 10 and 30 mg/kg rt-PA administered IA than IV. The IV 10 mg/kg rt-PA dosage induced significantly less bleeding than did the 1 or 5 mg/kg IA groups. No significant increase in infarct volume was observed after IA or IV treatment. Rats treated with 30 mg/kg rt-PA by either the IA or IV route had greater neurological dysfunction compared to all other groups.</p> <p>Conclusions</p> <p>Administration of rt-PA by the IA route following 6 hours of MCAo results in greater ICH and worse functional recovery than comparable dosages IV. Significantly greater bleeding was observed when the IA dose was a tenth of the IV dose. The increased bleeding did not translate in larger infarct volumes.</p

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The Knee Society Short Form Reduces Respondent Burden in the Assessment of Patient-reported Outcomes

BACKGROUND: The patient’s own evaluation of function and satisfaction is a fundamental component of assessing outcomes after total knee arthroplasty (TKA). The new Knee Society Knee Score was introduced in 2012 and has been shown to be a valid and reliable instrument for measuring the outcome of TKA. This score combines an objective, physician-derived component and a patient-reported component to characterize the expectations, satisfaction, and functional activities of diverse lifestyles of contemporary patients undergoing TKA. However, in the routine clinical setting, the administration and scoring of outcome measures is often resource-intensive, as the expenditure of time and budget for outcome measurement increase with the length and complexity of the instrument used, and so a short-form assessment can help to reduce the burden the assessment of outcomes. QUESTIONS/PURPOSES: The purposes of this study were (1) to develop a short-form version of the new Knee Society Knee Score; (2) to validate the short form against the full Knee Society Knee Score; and (3) to evaluate the responsiveness to treatment (TKA) of the new Knee Society short-form assessment. METHODS: To develop the short form, data from the sample of 497 patients recruited during validation of the original long form the new Knee Society Knee Score were used. The multicenter study was approved by the institutional review boards at 15 participating medical institutions within the United States and Canada. An analytic item reduction approach was applied simultaneously but separately to preoperative and postoperative patient-reported data to select a subset of items from the original form that had good measurement properties and closely reflected the scores obtained using the original form. RESULTS: Expectations and satisfaction were reflected by a single item in the newly developed short form compared with a total of five satisfaction and three expectation items in the long form. The functional activities subscale was reduced from 17 to six items. An excellent correlation was demonstrated between function scores derived from the functional activities subscale of the original long-form score (17 items) and the six-item short form (r = 0.97; p < 0.01). The sample mean difference between the two scores was less than 4 points with a SD of 6.7 points. The short form was capable of discriminating clinically different groups of patients before and after TKA with virtually the same estimated effect size as the original functional activities subscale of the new Knee Society Knee Score. CONCLUSIONS: The Knee Society Knee Score long form is still recommended for research studies and for more sensitive measurement of the outcomes of individual patients. However, for general clinical use with large patient populations, the short form is expected to improve the rate of patient completion while also being easier to administer. In this study, we found the short-form version of the Knee Society Knee Score to be practical, valid, reliable, and responsive for assessing the functional outcome of TKA. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11999-015-4370-2) contains supplementary material, which is available to authorized users

Safety evaluation of a recombinant plasmin derivative lacking kringles 2-5 and rt-PA in a rat model of transient ischemic stroke

AbstractBackgroundTissue type plasminogen activator is the only approved thrombolytic agent for the treatment of ischemic stroke. However, it carries the disadvantage of a 10-fold increase in symptomatic and asymptomatic intracranial hemorrhage. A safer thrombolytic agent may improve patient prognosis and increase patient participation in thrombolytic treatment. A novel direct-acting thrombolytic agent, Δ(K2-K5) plasmin, promising an improved safety profile was examined for safety in the snare ligature model of stroke in the rat.MethodsMale spontaneously hypertensive rats were subjected to 6 hours middle cerebral artery occlusion followed by 18 hours reflow. Beginning 1 minute before reflow, they were dosed with saline, vehicle, Δ(K2-K5) plasmin (0.15, 0.5, 1.5, and 5 mg/kg) or recombinant tissue-type plasminogen activator (10 and 30 mg/kg) by local intra-arterial infusion lasting 10 to 60 minutes. The rats were assessed for bleeding score, infarct volume, modified Bederson score and general behavioral score. In a parallel study, temporal progression of infarct volume was determined. In an in vitro study, whole blood clots from humans, canines and rats were exposed to Δ(K2-K5). Clot lysis was monitored by absorbance at 280 nm.ResultsThe main focus of this study was intracranial hemorrhage safety. Δ(K2-K5) plasmin treatment at the highest dose caused no more intracranial hemorrhage than the lowest dose of recombinant tissue type plasminogen activator, but showed at least a 5-fold superior safety margin. Secondary results include: temporal infarct volume progression shows that the greatest expansion of infarct volume occurs within 2–3 hours of middle cerebral artery occlusion in the spontaneously hypertensive rat. A spike in infarct volume was observed at 6 hours ischemia with reflow. Δ(K2-K5) plasmin tended to reduce infarct volume and improve behavior compared to controls. In vitro data suggests that Δ(K2-K5) plasmin is equally effective at lysing clots from humans, canines and rats.ConclusionsThe superior intracranial hemorrhage safety profile of the direct-acting thrombolytic Δ(K2-K5) plasmin compared with recombinant tissue type plasminogen activator makes this agent a good candidate for clinical evaluation in the treatment of acute ischemic stroke