A phase II trial of homoharringtonine and caracemide in the treatment of patients with advanced large bowel cancer.

Twenty-four previously untreated, ambulatory patients with advanced colorectal carcinoma were treated with either caracemide (11 patients) or homoharringtonine (13 patients). No objective responses were observed in any of the treatment cohorts. Caracemide was well tolerated with the exception of one death due to sepsis. On the homoharringtonine arm one patient died of pulmonary sepsis, one patient experienced grade 4 leukopenia requiring more than 4 weeks of recovery, and an additional patient developed grade 4 renal failure. These severe and unexpected complications caused early termination of accrual to the homoharringtonine arm of the study. These agents have no activity in the treatment of advanced colorectal carcinoma.

Combined intravenous and oral mesna in outpatients treated with ifosfamide.

PURPOSE: To prevent hemorrhagic cystitis, mesna is typically injected intravenously (i.v.) at the time of an ifosfamide dose and 4 and 8 h later. To simplify outpatient ifosfamide therapy, we gave the second and third mesna doses orally. METHODS: The mesna doses (400 or 600 mg/m2) were 40% (w/w) of each ifosfamide dose (1.0 or 1.5 g/m2), which was given daily for 5 days. We evaluated urinary mesna excretion and plasma concentrations in ten patients from the beginning of mesna infusion until the time of the second oral dose. The first oral dose was administered at hour 2 in the last six patients to allow time for absorption of mesna. RESULTS: The rate and amount of mesna excretion was less variable over time and among patients after oral than after i.v. administration. No macrohematuria was observed in these ten patients nor in an additional 50 patients given oral mesna at hours 2 and 8 during at least two cycles of ifosfamide therapy. CONCLUSION: These pharmacokinetic and clinical efficacy data support the use of a combined regimen of i.v. and oral mesna to simplify outpatient ifosfamide administration.

Pharmacokinetics of very high-dose oral melphalan in cancer patients.

The pharmacokinetics and systemic availability of melphalan after high-dose oral administration with and without 1,3-bis(2-Chloroethyl)-1-nitrosourea (BCNU) or etoposide were examined in three patients undergoing autologous bone marrow transplantation. Patient 1 (advanced melanoma) received melphalan at 80 mg/m2/day p.o. on days -6, -5, and -4, followed by BCNU at 300 mg/m2/day i.v. on days -3, -2, and -1 prior to bone marrow transplantation. Patient 2 (advanced colon carcinoma) received melphalan at 75 mg/m2/day p.o. on days -3, -2, and -1. Patient 3 (advanced refractory lymphoma) received etoposide at 800 mg/m2/day i.v. on days -7, -5, and -3, followed by melphalan at 157 mg/m2/day p.o. on days -2 and -1. Melphalan was administered as a bolus oral dose, using 2-mg tablets. Blood samples were collected at 0, 5, 10, 15, 30, and 45 min and 1, 2, 3, 4, 6, 8, 12, and 24 h after each dose of melphalan. Peak plasma melphalan concentrations in the three patients ranged from 0.354 (patient 2) to 1.768 micrograms/ml (patient 1). Plasma melphalan concentration X time products (C x Ts) showed extreme variability in one patient (patient 2), ranging from 0.76 to 4.48 micrograms.h/ml. To determine the relative systemic availability of orally administered melphalan, i.v. C X Ts proportional to the p.o. doses were extrapolated from previously reported i.v. bolus pharmacokinetic data. The p.o.:i.v. plasma C X T ratios for high-dose melphalan ranged between 0.09 (patient 3) and 0.58 (patient 2). Although these C X T data suggest a dose-response for orally administered melphalan, the systemic availability of these high p.o. melphalan doses was extremely variable, both within and between study patients. Thus, we cannot recommend the use of high-dose p.o. melphalan regimens in patients undergoing autologous bone marrow transplantation.

Prevention of venous thrombosis after total hip arthroplasty. Antithrombin III and low-dose heparin compared with dextran 40.

The anticoagulant action of heparin is mediated through antithrombin III, and the postoperative decrease in the plasma concentration of antithrombin III may contribute to the relative ineffectiveness of prophylaxis with low-dose heparin in preventing venous thrombosis after total hip arthroplasty. We conducted a prospective, randomized trial to compare the effectiveness of a regimen of antithrombin III, given intravenously once daily, and low-dose heparin with a regimen of dextran 40, given intravenously, in preventing venographically documented venous thrombosis after total hip arthroplasty. The results demonstrated an incidence of venous thrombosis of 4.9 per cent in patients who received antithrombin III and heparin; this was significantly lower than the incidence (28.6 per cent) in patients who received dextran 40 (p less than 0.005). Venous thrombosis occurred only in patients who had total hip arthroplasty with a cemented prosthesis (fourteen of fifty-seven patients, or 24.6 per cent); none of the twenty-six patients in whom a non-cemented prosthesis was used had venous thrombosis (p less than 0.01). Of the patients in whom a cemented prosthesis had been inserted, the incidence of venous thrombosis was lower in those who were treated with antithrombin III and heparin (7.4 per cent) than in those who were treated with dextran 40 (40 per cent) (p less than 0.005). Postoperative levels of antithrombin III were maintained at more than 90 per cent of the baseline level in patients who received it; this was significantly higher than in patients who received dextran 40.(ABSTRACT TRUNCATED AT 250 WORDS)

Leukemic dermal infiltrates as a complication of central venous catheter placement.

A leukemic dermal infiltrate at the site of a central venous catheter placement was the first manifestation of relapse in a 58-year-old woman in clinical remission of acute myelomonocytic leukemia. The patient developed a large hematoma around the site of an unsuccessful attempt to place a central venous (CV) catheter. Although the hematoma resolved completely by the time that complete remission was achieved, an indurated, erythematous mass subsequently developed, which when biopsied revealed leukemic cells in the dermis. The patient had a relapse in her peripheral blood shortly thereafter. The authors reviewed recent literature and their own experience with CV catheters and report on localized dermal relapse as a previously unpublished risk of CV catheter placement. They also speculate on the role of the dermis as a sanctuary for leukemic cells and a potential source for relapsing disease.

Elevated factor Xa activity in the blood of asymptomatic patients with congenital antithrombin deficiency.

The presence of congenital antithrombin deficiency has been consistently shown to predispose patients to venous thrombosis. We have utilized the prothrombin fragment F1+2 radioimmunoassay to quantitate factor Xa activity in the blood of 22 asymptomatic individuals with this clinical disorder not receiving antithrombotic therapy. The mean level of F1+2 was significantly elevated in these patients as compared to normal controls (3.91 vs. 1.97 nM, P less than 0.001). The metabolic behavior of 131 I-F1+2 was found to be similar in antithrombin-deficient subjects and normal individuals. The hemostatic system hyperactivity as measured by the F1+2 assay could be specifically corrected by raising the plasma antithrombin levels of the above asymptomatic individuals into the normal range. This study provides the first demonstration that the prethrombotic state can be biochemically defined as an imbalance between the production and inhibition of factor Xa enzymatic activity within the human circulation. It is known that antithrombin and alpha 1-proteinase inhibitor (PI) are the major inhibitors of factor Xa in human plasma in the absence of heparin. To further evaluate the mechanism by which antithrombin functions as an inhibitor of factor Xa in humans, we studied five patients who exhibited severe congenital deficiencies of alpha 1-PI. Our results indicated that the plasma of these subjects showed virtually identical decreases in plasma antifactor Xa activity in the absence of heparin when compared to antithrombin-deficient individuals, but the plasma F1+2 levels in the alpha 1-PI deficient population were not significantly different than normal. This data suggests that alpha 1-PI does not function as a major inhibitor of factor Xa in vivo, and that a tonically active heparin-dependent mechanism exists in humans for accelerating the neutralization of this enzyme by antithrombin.

Laboratory observations and clinical implications of monitoring the effect of heparin by bioassay.

Laboratory and clinical experience in the monitoring of circulating heparin concentration of bioassay shows that the whole blood clotting time and the activated partial thromboplastin time differ in their reflection of the state of anticoagulation. The decay of biologic activity may be as short as 30 minutes in one patient or as long as 360 minutes in another. This fact may drastically affect patient response to the drug. Safe and rational clinical heparinization is dependent upon periodic monitoring of the circulating heparin concentration. The success of this method was illustrated in two representative patients.