Safety assessment of single-bolus administration of TNK tissue-plasminogen activator in acute myocardial infarction: the ASSENT-1 trial. The ASSENT-1 Investigators.

BACKGROUND: To evaluate the safety of several doses of a new thrombolytic, TNK tissue-plasminogen activator (tPA), given as a single bolus to patients with acute myocardial infarction. METHODS AND RESULTS: A total of 3235 patients were given TNK-tPA: 1705 received 30 mg, 1457 received 40 mg, and 73 received 50 mg. The 50-mg dose was discontinued and replaced by 40 mg because of increased bleeding observed in the Thrombolysis In Myocardial Infarction (TIMI)-10B study, the phase II angiographic efficacy trial conducted in parallel with this study. The total stroke rate at 30 days in the trial was 1.5%. An intracranial hemorrhage was observed in 25 patients (0.77%): 16 in the 30-mg group (0.94%) and 9 in the 40-mg group (0.62%). No strokes occurred in the 73 patients treated with 50 mg TNK-tPA. In patients treated within 6 hours after symptom onset the rates of intracranial hemorrhage were 0.56% (30 mg TNK-tPA) and 0.58 (40 mg TNK-tPA). Death, death or nonfatal stroke, or severe bleeding complications occurred in a low proportion of patients: 6.4%, 7.4%, and 2.8%, respectively, without significant differences among the treatment groups. CONCLUSIONS: The overall safety profile of a single bolus of 30 to 50 mg TNK-tPA is comparable to that of accelerated r-tPA observed in other large trials. The safety data from this trial and the patency data of TIMI-10B were the basis for a decision to conduct a large phase III mortality trial comparing weight-adjusted single-bolus TNK-tPA with accelerated r-tPA (ASSENT-2).

Randomised, controlled study of intratumoral recombinant gamma-interferon treatment in newly diagnosed glioblastoma.

The effect of intratumoral recombinant interferon gamma (rIFN-gamma) as adjuvant to open cytoreduction and external irradiation of 60 Gy on survival in adults with a newly diagnosed high-grade cerebral glioma was studied. The patients were randomised during surgery into the rIFN-gamma group (n = 14) or the control group (n = 17), and the latter received a subcutaneous reservoir of rIFN-gamma injections. Intratumoral rIFN-gamma was given three times a week for 4 weeks until radiotherapy, escalating the dose from 5 micrograms to 50 micrograms. Both groups received external whole-brain irradiation of 40 Gy and a local boost of 20 Gy. After radiotherapy, rIFN-gamma was continued with 50 micrograms twice a week up to 9 weeks. The patients received no chemotherapy. Intratumoral rIFN-gamma was tolerated well with transient fever only. There were 12 glioblastomas (GBs) in the control group and nine in the rIFN-gamma group with completed irradiation. The patients were followed clinically and by computerised tomography (CT) every third month until death. Tumour responses were seen in three interferon-treated (one still alive 45 months after operation) and in two conventionally treated patients. The progression of the tumour volumes on CT did not differ between the IFN-treated and control groups. There were no differences in the survival times. Median survival of the rIFN-gamma-treated patients was 54 weeks (95% CI 35-68) and of the control patients 55 weeks (95% CI 41-77). Intratumoral rIFN-gamma given in the study doses does not seem to inhibit tumour growth or improve the prognosis of patients with high-grade glioma.

Induction of cytotoxic capacity by recombinant gamma interferon in human myelomonocytic leukaemia cell lines.

We have investigated the ability of human recombinant gamma interferon (IFN-gamma) to induce functional differentiation in three human myelomonocytic cell lines U937, RC2A, and ML-2. Treatment with IFN-gamma induced natural killer (NK) cell like cytotoxicity against K-562 cells in ML-2 and RC2A but not in U937. U937 and RC2A displayed a spontaneous antibody-dependent cell-mediated cytotoxicity (ADCC), which against nucleated target cells was significantly increased in U937 but not in RC2A after treatment with IFN-gamma. ML-2 did not display ADCC against nucleated targets either before or after IFN-gamma treatment, but lysed efficiently antibody-coated erythrocytes. All three cell lines displayed enhanced ADCC against erythrocytes after IFN-gamma treatment. Spontaneous phagocytosis of erythrocytes was seen in U937, and this was enhanced by IFN-gamma treatment, while ML-2 and RC2A were phagocytically inactive before and after treatment with IFN-gamma. The differentiated functions induced by IFN-gamma treatment in this panel of phenotypically closely related cell lines offers an interesting model for further studies on the IFN-gamma regulated gene expression. Moreover, the increased cytolytic capacity after exposure to IFN-gamma might have implications on the use of IFN-gamma for treatment of myelomonocytic malignancies. In such cases, IFN-gamma might even increase the aggressiveness of the tumour.

Pirenzepine in the treatment of reflux oesophagitis. A placebo-controlled, double-blind study.

The efficacy of 50 mg pirenzepine twice daily in the treatment of reflux oesophagitis was compared with that of placebo in 47 patients over a period of 12 weeks. The 23 patients receiving pirenzepine experienced decreases in symptoms after 4 weeks (p less than 0.001) and 12 weeks (p less than 0.02) of treatment significantly greater than those in the 24 patients receiving placebo. The decreases in symptoms were associated with significantly less use of antacids by the pirenzepine group (p less than 0.01) during the first 4 weeks. Endoscopically, oesophagitis was healed or improved in 54.5% of patients receiving pirenzepine and in 18.2% of patients receiving placebo (p less than 0.05) after 4 weeks of treatment. After 12 weeks of treatment healing or improvement was seen in 55.0% and 35.0% of patients, respectively (difference not significant). Histologic improvement did not differ significantly between the groups. Our results suggest that pirenzepine is useful in the management of reflux oesophagitis.

Cyclosporine in treatment of corticosteroid-resistant episodes of rejection.

We used cyclosporine (formerly called cyclosporin A) to treat established episodes of kidney-transplant rejection in six patients in whom the use of corticosteroids either was ineffective or was precluded by preestablished side effects. All patients were followed up by using fine-needle aspiration biopsy and transplant aspiration cytology. In four episodes of rejection with typical blast cell--dominated inflammation, the response to cyclosporine was apparently favorable: the inflammatory cells disappeared within days and the transplant resumed its normal function. One episode of acute rejection was overcome within a week after discontinuing treatment with cyclosporine. In one episode of chronic rejection that was devoid of any distinct blastogenic component, no effect of cyclosporine could be detected. We believe that cyclosporine can be used to treat established episodes of rejection, but what type or types of inflammatory episodes are susceptible to cyclosporine must first be clarified through prerandomized clinical trials.