Changes in plasma lipids after a non-lethal dose of cycloheximide in rats.

This paper describes a study of the effect of a single intraperitoneal non-lethal dose of cycloheximide (CHM; 2.0 mg/kg body weight) on the concentration of plasma lipids and lipoproteins in male rats killed one, two, three, four and nine days after receiving the dose. The concentration of triglycerides, total cholesterol, high-density lipoproteins (HDL)-cholesterol and low-density lipoproteins (LDL)-cholesterol was measured in treated and control animals. The effect of CHM on the concentration of triglycerides, total cholesterol, HDL-cholesterol, and LDL-cholesterol was visible in rat plasma throughout the study. Total cholesterol and HDL-cholesterol concentrations showed the same pattern of changes, probably due to the reversible inhibition of apolipoprotein apo A-I synthesis by CHM. The concentration of triglycerides decreased after a lag period of three days when the reserves of apolipoprotein apo B, the main apolipoprotein of very low-density lipoproteins (VLDL)-cholesterols produced in the liver, were consumed.

Plasma cholinesterase activity in patients with uterine cervical cancer during radiotherapy.

The objectives of this study were to investigate: 1) the activity of pseudocholinesterase (PChE) in patients with uterine cervical cancer in different stages (uterine cervical carcinoma in stages II b and III and recurrent cervical carcinoma in stages III and IV a,b) and to compare it to the enzyme activity in patients with benign tumour of the uterus, and 2) the effects of radiotherapy on enzyme activity in those patients with uterine cervical carcinoma for which the chosen treatment was radical radiotherapy. Thirty patients with uterine cervical carcinoma in stages II b and III (Group A), sixteen patients with recurrent cervical carcinoma in stages III and IV a,b (Group B) and thirty-eight patients with benign tumours of the uterus (control, Group C) were evaluated and their PChE activity was determined prior to any treatment (pre-therapy enzyme activity). All eighty-four patients were free of any liver disease. The results have shown that the patients of Group A had the pre-therapy PChE activity practically identical to those in group C, but patients of Group B had significantly lower values of PChE with respect to enzyme activities of Groups A and C (p < 0.001). That is to say, PChE activity was influenced by the extent to which the malignancy had spread. Radical radiotherapy (up to 8 weeks in doses higher than 50 Gy into point A; average 80 Gy) which was the chosen treatment only for patients from group A did not cause a significant inhibition of PChE activity in any patients in comparison with their control values. With regard to the role of PChE in hydrolysis of succinylcholine, our results about the influence of the malignant disease and the radiotherapy on PChE activity are clinically significant.

Effects of oxprenolol treatment on pseudocholinesterase and lipids in rats.

The effect of chronic treatment with the non-selective beta-blocker oxprenolol (CAS 6452-71-7) administered orally in two different doses (15 or 30 mg/kg/day for 6, 10 and 12 weeks) on plasma cholinesterase (PChE) activity and on the plasma level of triglyceride and total cholesterol were studied in normal rats. In all treated groups a significant increase (approximately 27-51%) of PChE activity was obtained (p < 0.05 vs. control group). The plasma concentration of total cholesterol was significantly increased as well (21-48%, p < 0.05 vs. control) but oxprenolol exerted no significant effect on plasma triglyceride levels. The increase of enzyme activity and total cholesterol were not time- or dose-dependent. According to these results which showed a direct relationship between PChE activity and total cholesterol it is supposed that the increase of enzyme activity is initially due to the action of oxprenolol on total cholesterol metabolism but that it does not have a direct effect on the enzyme. The results contribute to the hypothesis that PChE plays a role in lipoprotein metabolism although this has not yet been proven.

A phase II trial of cardioprotection with Cardioxane (ICRF-187) in patients with advanced breast cancer receiving 5-fluorouracil, doxorubicin and cyclophosphamide.

From January 1991 to August 1993, 237 women with metastatic breast cancer were recruited into a multicentric phase II clinical trial designed to assess the cardioprotective activity of Cardioxane (ICRF-187). All patients were treated with 5-fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 (FDC) and Cardioxane 1000 mg/m2, in cycles repeated every 3-4 weeks. Cardiac functions were assessed at baseline by physical examination, ECG, and resting ultrasound left ventricle ejection fraction (LVEF). The same tests were repeated regularly after the 3rd, 6th, 8th cycle and every additional 100 mg/m2 of doxorubicin. At the end of the study there were 212 evaluable patients. Prior to analysis, patients were stratified according to the presence of cardiac risks at study entry. One hundred thirty-three patients (63%) bore one or more cardiac risks. The average total cumulative dose of doxorubicin administered to the group was 311 mg/m2 (range: 200-900 mg/m2). Overall response (CR + PR) was 49.5% (105/212), with 12% of patients entering complete remission. General toxicity (WHO grading) was mild and tolerable; no excessive myelosuppression or related symptoms were observed. Three patients from the risk group experienced cardiotoxicity, with an LVEF fall below 45%, and had to be removed from the study. Another 3 patients (1 from the risk group) were removed from the study due to clinically documented congestive heart failure after 200, 300 and 400 mg/m2 of doxorubicin. In our study, Cardioxane (ICRF-187) did not influence the antitumor efficacy of FDC chemotherapy, nor did concomitant administration of Cardioxane and chemotherapy result in any other or severer toxicity than that already known for this regimen. Finally, the observation that 51% of patients with preexisting cardiac risks received doxorubicin at dose range of 450-900 mg/m2 without significant clinical or laboratory signs of cardiotoxicity supports the evidence that Cardioxane provided cardiac protection offering the possibility of longer doxorubicin chemotherapy.

Plasma cholinesterase activity in patients during therapy with dexamethasone or prednisone.

We have studied the effects of i.v. dexamethasone and oral prednisone on plasma cholinesterase (ChE) activity in 13 male and 10 female patients during long-term treatment with dexamethasone or prednisone. A decrease in ChE activity--probably due to inhibition of ChE synthesis in the liver--was seen in all the patients. In individual patients there was a drop in enzyme activity of 14-57% (dexamethasone) and 23-69% (prednisone) respectively, compared with individual control values. After withdrawal of dexamethasone, ChE activity in most cases increased to above control values and the period necessary for complete restoration of ChE activity was variable (between 25-70 days). Our results suggest that the decrease in ChE activity in patients treated with dexamethasone or prednisone depends on the initial dose of the drug as well as on the duration of treatment.

Effect of glucocorticoids on plasma cholinesterase in the rat.

Changes in plasma cholinesterase (ChE) activity after administration of glucocorticoids (prednisone, methyl-prednisolone and dexamethasone) were studied in male and female rats. The decrease of ChE activity-probably due to inhibition of ChE synthesis in the liver-was more marked in female than in male rats. This difference could be explained by the more rapid metabolism of glucocorticoids in male than in female rats or by the decreased stimulatory effect of estrogens on ChE synthesis after administration of glucocorticoids. The inhibitory effect of dexamethasone on ChE synthesis was significantly greater than the effect of equivalent antiinflammatory doses of the other two glucocorticoids investigated. The inhibitory effect of glucocorticoids on ChE activity increased with the duration of their administration. Decrease of ChE activity was more marked after the p.o. than after the i.p. route of application, indicating that inhibition of ChE synthesis after p.o. administration of glucocorticoids occurs partially during the first pass of these drugs in the liver.