Human urinary kallidinogenase in treating acute ischemic stroke patients: analyses of pooled data from a randomized double-blind placebo-controlled phase IIb and phase III clinical trial.

Objectives: Intravenous thrombolysis and thrombectomy are recommended for patients whose stroke onsets are within first 6 h, and very few options are available for patients whose stroke onset is more than 6 h, which includes most ischemic stroke patients. Human urinary kallidinogenase (HUK) showed potential clinical benefits in acute ischemic stroke patients. This study aims to investigate the safety and clinical benefits of HUK in ischemic stroke patients.Patients and methods: Patients were recruited for a multicenter double-blind, placebo-controlled phase II b and phase III trial. Neurophysiological outcomes were assessed by the European Stroke Scale (ESS) and the functional outcomes were assessed by the activity of daily living scale (ADL). Safety was monitored by recording adverse events.Results: The improvements in ESS scores and ADL scores in the HUK group were significantly greater than that in patients receiving placebo. Furthermore, HUK treatment was also associated with a lower rate of disable, according to ADL. HUK-related adverse events occurred at a low rate, in 1.73% of HUK-treated patients.Conclusion: HUK is safe and provides potential clinical benefits as a treatment for acute ischemic stroke. Further large post-marketing observational studies are needed.

Pharmacokinetics, distribution, and excretion of 125I-labeled human plasma-derived-FVIIa and -FX with MC710 (FVIIa/FX mixture) in rats.

INTRODUCTION: MC710 is a mixture agent consisting of plasma-derived activated factor VII (FVIIa) and factor X (FX) at a weight ratio of 1:10 developed as a novel bypassing agent for the management of the bleeding of hemophilia patients with inhibitors. The pharmacokinetics, distribution, and excretion of (125)I-labeled-FVIIa ((125)I-FVIIa) and -FX ((125)I-FX) were studied in male rats after a single intravenous administration of (125)I-FVIIa or (125)I-FX combined with MC710. METHODS: (125)I-FVIIa or (125)I-FX was administered intravenously with MC710 to male rats in a single dosage (FVIIa 0.4 mg and FX 4 mg/kg body weight) and radioactivity and antigen levels in plasma were quantified for 24h. Urine and feces were sampled to study the excretion of radioactivity during 168 h after dosing. Whole-body autoradiography was performed to evaluate the qualitative distribution of radioactivity 168 h after dosing. RESULTS AND CONCLUSIONS: The half-life (t(1/2)α and t(1/2)ß) of radioactivity and FVIIa antigen were 0.704 and 6.27 h, and 0.496 and 1.66 h, respectively and the area under the plasma concentration-time curve (AUC(0-∞)) of radioactivity and FVIIa antigen were 17,932 and 8671 ng·h/mL, respectively. The t(1/2) of radioactivity and FX antigen were 4.06 and 3.05 h, respectively, and the AUC(0-∞) of radioactivity and FX antigen were 320,143 and 395,794 ng·h/mL, respectively. About 80% of the administered dose of radioactivity was excreted in urine and feces by 168 h after administration. Tissue distribution experiments showed that FVIIa- and FX-related (125)I accumulated in bone and bone marrow, and disappeared slowly.

Human urinary kallidinogenase suppresses cerebral inflammation in experimental stroke and downregulates nuclear factor-kappaB.

The purpose of this study is to investigate the possible mechanism and the neuroprotective effect of human urinary kallidinogenase (HUK) in cerebral ischemia. The mouse middle cerebral artery occlusion (MCAO) model was used. Mice were treated with HUK (20 PNAU/g per day, intravenous) or saline as control, from the beginning of reperfusion to 72 h. Neurological deficits, infarct size, and BWC were measured at 6, 24, 48, and 72 h after MCAO, respectively. Pathological changes of brain were observed by TUNEL assay. Inflammatory factors were measured by real-time PCR and western blotting. Activation of MAPKs, Akt, and nuclear factor-kappaB (NF-kappaB) was detected by western blotting. Our results indicated that HUK significantly improved neurofunction, decreased infarct size, and suppressed edema, as well as inflammatory mediators as compared with the vehicle group. Furthermore, HUK inhibited the NF-kappaB pathway and activated the MAPK/ERK pathway in this neuroprotection.

[On the normalization of the content of human urine of procoagulant after renal transplantation (author's transl)]. / Uber die Normalisierung des Gehaltes menschlichen Urins an Prokoagulans nach Nierenübertragung.

With human urine a very active procoagulant is excreted which converts prothrombin into thrombin in the presence of factor V, phospholipids and calcium chloride. In kidney diseases, its excretion is considerably reduced or totally absent. A negative correlation exists between these diseases and protein excretion. Kidney transplantation results in a normalization, however showing a trend which is not always parallel with the normalization of the blood creatinine levels. During the post-transplantation period, an occasional temporary, but very clear reduction with abnormal values of the kidney function tests can be observed. It is presumed that the procoagulant excretion could represent a hitherto unexplored function of the tubuli.