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

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

“Switching on” the single-molecule magnet properties within a series of dinuclear cobalt( iii )–dysprosium( iii ) 2-pyridyloximate complexes

The use of 2-pyridinealdoxime (paoH), methyl 2-pyridyl ketone oxime (mepaoH), phenyl 2-pyridyl ketone oxime (phpaoH) and pyridine-2-amidoxime (NH2paoH) for the synthesis of dinuclear CoIII/DyIII complexes is described in the absence or presence of an external base. Complexes [CoDy(pao)3(NO3)3] (1), [CoDy(mepao)3(NO3)3] (2), [CoDy(phpao)3(NO3)3] (3) and [CoDy(NH2pao)3(NO3)3]·3MeOH (4·3MeOH) have been isolated and their structures have been determined by single-crystal X-ray crystallography. The complexes crystallize in non-centrosymmetric (2, 3) or centrosymmetric (1, 4·3MeOH) trigonal space groups and form a family of triply-oximate bridged dinuclear Co(III)–Dy(III) complexes. The crystals of 1, 3 and 4·3MeOH contain mixtures of Δ and Λ enantiomers, whereas complex 2 is enantiomerically pure (Λ). A 3-fold crystallographic axis (C3) passes through two metal ions in all complexes. The low-spin CoIII and DyIII ions are bridged by three oximate groups belonging to the η1:η1:η1:μ 2-pyridyloximate ligands. The CoIII centre is octahedrally coordinated by the six nitrogen atoms of the deprotonated organic ligands in a facial arrangement. The DyIII centre is bound to an O9 set of donor atoms, its coordination sphere being completed by three bidentate chelating nitrato groups. The coordination polyhedron around DyIII in 1 is best described as the Johnson tricapped trigonal prism, while the coordination geometries of the DyIII centres in 2, 3 and 4·3MeOH are best described as consisting of spherical tricapped trigonal prismatic coordination polyhedra. The spectroscopic data of the complexes are also reported and discussed in the infra-red region in terms of the coordination modes of the ligands involved. The magnetic properties of these complexes were studied between 300 and 1.8 K revealing mainly the depopulation of the DyIIImj sublevels of the ground 6H15/2 state. The intrinsic magnetic anisotropy of the DyIII centers is clearly observed by the non-superimposed magnetization (M) versus H/T data, but single-molecule magnet (SMM) properties were detected only for the mepao−-containing complex 2. The origin of these properties in 2 is critically discussed and supported by computational studies