Human tissue urokinase type plasminogen activator(Yuhuaneng Biological)

The aim of our study was to investigate the pharmacokinetics and safety of human tissue urokinase type plasminogen activator (HTUPA) in healthy Chinese subjects after intravenous administration. Thirty-two subjects were given intravenous injection doses of 5-35 mg of HTUPA for safety evaluation. Twenty-four subjects were given 10, 20 or 30 mg HTUPA for pharmacokinetic assessment. Safety and tolerance were evaluated by monitoring adverse events, laboratory parameters, electrocardiography and vital signs. HTUPA concentration in human serum samples was determined by an enzyme-linked immunosorbent assay (ELISA) method. The main pharmacokinetic parameters were calculated by DAS software. HTUPA was generally well tolerated and in the whole study course no serious adverse events occurred. The main pharmacokinetic parameters were as follows: geometric mean [95% confidence interval, CI] for t1/2 were 1.5 (1.4, 1.6), 1.3 (1.2, 1.4), and 1.2 (1.2, 1.3) h, AUC0-t were 1.0 (0.7, 1.3), 2.1 (1.5, 2.7), and 5.6 (4.7, 6.6) mg h L(-1), AUC0-∞ were 1.1 (0.8, 1.3), 2.1 (1.5, 2.7), and 5.8 (4.7, 6.7) mg h L(-1) for 10, 20, and 30 mg group, respectively. The main pharmacokinetic parameters were not significantly different between males and females (P>0.05). No serious adverse events were reported by the subjects or revealed by clinical or laboratory examinations, suggesting the given doses were safe and well tolerated.

Adopting thrombolytic therapy with tissue plasminogen activator (tPA) in clinical practice presents many challenges. One major factor is the restrictive time window of 0-3 hours after symptom onset, for the commencement of treatment.

To test the efficacy of a newly developed plasminogen activator (human tissue urokinase type plasminogen activator [HTUPA]) for the treatment of acute ischaemic stroke within 5 hours of symptom onset.

An open-label, dose escalation trial. The initial dose was 0.3 mg/kg and could be increased or decreased depending on tolerability.

Three teaching hospitals in Taiwan.

Thirty-three patients who presented with National Institute of Health Stroke Scale (NIHSS) scores of between 9 and 20, who had evidence of ischaemic stroke confirmed by CT.

Efficacy was assessed by the NIHSS, the Modified Rankin Scale (MRS), the Barthel Index and the Glasgow Outcome Scale. Preliminary efficacy endpoints included major neurological improvement at 24 hours and favourable outcome at 90 days after administration of HTUPA.

Of the 33 patients who received HTUPA, 29 received 0.3 mg/kg, 3 received 0.35 mg/kg and 1 received 0.4 mg/kg. Major neurological improvement, defined as improvement of > or =4 points on the NIHSS 24 hours after treatment, was observed in 45% of all patients treated (15/33) and in 48% (14/29) of those treated with 0.3 mg/kg. Ninety days after symptom onset, in those who received HTUPA 0.3 mg/kg, the proportion of patients with a favourable outcome was 34% on the NIHSS (< or =1), 45% on the MRS (0 or 1), 41% on the Barthel Index (> or =95) and 45% on the Glasgow Outcome Scale (1). Eighty six percent of the patients treated with 0.3 mg/kg within 0-3 hours of symptom onset reached scores of 0-1 on both the NIHSS and the MRS.

Approximately 50% of patients treated with HTUPA 0.3 mg/kg within a 5-hour window after symptom onset experienced major neurological improvement within 24 hours of drug administration. Thrombolytic agents, in this case HTUPA, may be suitable for Taiwanese or Asian patients with acute ischaemic stroke who meet the inclusion criteria.