Plasminogen activator and its inhibitor in cancer patients treated with tumor necrosis factor.

BACKGROUND: We noted the presence of plasma fibrin degradation products in patients treated with recombinant human tumor necrosis factor (TNF) in a phase I trial. PURPOSE: To further define this observation, we investigated the effects of TNF on the fibrinolytic system in patients entered in the same trial. METHODS: In the 14 patients studied, fibrinolytic parameters were measured by analyzing blood samples for tissue plasminogen activator and inhibitor at 0, 1, 2, 4, 6, and 18-24 hours after initiation of TNF treatment. We used a chromogenic substrate method to determine activity of plasminogen activator and its inhibitor and an enzyme-linked immunosorbent assay (ELISA) to determine levels of antigen (tissue-type plasminogen activator). Molecular weight was determined by zymographic assay. RESULTS: TNF treatment was associated with tissue-type plasminogen activator induction within 1 hour of TNF initiation. The plasminogen activator produced was consistent with tissue-type plasminogen activator derived from endothelium as evidenced by molecular weight analysis and ELISA. Moreover, induction of plasminogen activator inhibitor occurred following the release of tissue-type plasminogen activator, and our data suggest a dose-response effect for TNF. At high doses (i.e., 200 and 240 micrograms/m2), there was a more rapid and prolonged release of plasminogen activator inhibitor, which had an inverse relationship with the level of antigenic tissue-type plasminogen activator. Zymographic analysis showed urokinase-type plasminogen activator activity in 13 of 14 patients. In three patients, simultaneous measurements of white blood cells and tissue-type plasminogen activator revealed a temporal association between the TNF-associated rapid granulocytopenia at 30 minutes after TNF initiation and release of tissue-type plasminogen activator antigen. CONCLUSIONS: The results suggest a positive association between TNF and rapid induction of plasminogen activator activity that is consistent with an endothelial product. It is possible that, at high doses, TNF may interact directly with vascular endothelium, leading to rapid and prolonged production of plasminogen activator inhibitor. There was a dose-response effect between TNF and release of tissue-type plasminogen activator. The release of tissue-type plasminogen activator was preceded by granulocytopenia, which may indicate an association between a proposed TNF-induced granulocyte-endothelial interaction in vivo and release of tissue-type plasminogen activator. IMPLICATIONS: These findings demonstrating the effects of TNF on the fibrinolytic system can be analyzed further in experimental systems to determine the implications for use of this agent as a biological response modifier in cancer therapy.

A double-blind, placebo-controlled trial of fluoxetine plus behavior modification in the treatment of obese binge-eaters and non-binge-eaters.

To determine whether fluoxetine is effective in the long-term treatment of obesity and whether it is particularly useful in the treatment of obese binge-eaters, the authors randomly assigned 45 obese subjects (22 with binge-eating problems and 23 without binge-eating) to fluoxetine (60 mg/day) or placebo in a 52-week double-blind trial. The 21 subjects who completed the trial made 13 clinic visits and were taught basic behavior modification strategies. Patients treated with fluoxetine plus behavior modification lost significantly more weight than those treated with placebo plus behavior modification. However, the drug did not appear to have a differential benefit for binge-eaters.

Variables associated with weight loss and improvements in glycemic control in type II diabetic patients in behavioral weight control programs.

Because weight loss is difficult to achieve, it would be helpful to determine whether there are subgroups of obese type II diabetic patients who benefit most from participation in a behavioral weight loss program. We studied 178 obese patients with type II diabetes, who participated in a 12-20 week behavioral weight loss program and were followed for 1 year after the program to determine whether age, gender, percent overweight, medication, duration of diabetes or fasting glucose were related to weight loss and/or to the magnitude of improvement in glycemic control experienced with weight loss. Gender was the only variable related to weight loss; males lost more weight and had greater decreases in percent overweight than females. The variable most strongly related to improvement in glycemic control was pretreatment fasting glucose level; patients with higher initial glucose levels experienced the greatest improvements in control. There was no evidence to support the belief that patients on insulin have poorer weight losses or that patients with long-duration diabetes benefit less from weight reduction than those with recent-onset diabetes.

Long-term effects of modest weight loss in type II diabetic patients.

Since most obese patients with type II diabetes are unable to achieve ideal body weight, this study examined whether more modest weight losses would provide a long-term benefit. Type II diabetic patients (N = 114) were treated in a behavioral weight control program and followed up for one year. Weight loss was significantly correlated with improvements in glycosylated hemoglobin values at posttreatment (r = .55) and one year (r = .51). Patients who lost more than 6.9 kg or had more than 5% reduction in body weight had significant improvements in glycosylated hemoglobin values at one year, while patients losing less weight had nonsignificant changes and those gaining weight had significant worsening. Thus, modest weight loss can have a long-term impact on glycemic control. However, the improvement in glycemic control for a given weight loss was greater initially than at one year, suggesting that energy restriction, in addition to weight loss, may contribute to initial improvement. Neither percent overweight nor diabetes treatment affected weight loss.