Phase I and pharmacokinetic study of NSC 655649, a rebeccamycin analog with topoisomerase inhibitory properties.

PURPOSE: To assess the feasibility of administering NSC 655649, a water-soluble, rebeccamycin analog with topoisomerase inhibitory properties, as a brief intravenous (IV) infusion once every 3 weeks and to determine the maximum-tolerated dose (MTD) of NSC 655649, characterize its pharmacokinetic behavior, and seek preliminary evidence of antitumor activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of NSC 655649 administered over 30 to 60 minutes IV once every 3 weeks. An accelerated dose-escalation method was used to guide dose escalation. After three patients were treated at the first dose level, doses were escalated in increments that ranged up to 150% using single patient cohorts until moderate toxicity was observed, when a more conservative dose-escalation scheme was invoked. MTD was defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%. MTD was determined for both minimally pretreated (MP) and heavily pretreated (HP) patients. Plasma and urine were sampled to characterize the pharmacokinetic and excretory behavior of NSC 655649. RESULTS: Forty-five patients were treated with 130 courses of NSC 655649 at doses ranging from 20 mg/m(2) to 744 mg/m(2). Myelosuppression was the principal toxicity. Severe neutropenia, which was often associated with thrombocytopenia, was unacceptably high in HP and MP patients treated at 572 mg/m(2) and 744 mg/m(2), respectively. Nausea, vomiting, and diarrhea were common but rarely severe. The pharmacokinetics of NSC 655649 were dose dependent and fit a three-compartment model. The clearance and terminal elimination half-lives for NSC 655649 averaged 7.57 (SD = 4.2) L/h/m(2) and 48.85 (SD = 23.65) hours, respectively. Despite a heterogeneous population of MP and HP patients, the magnitude of drug exposure correlated well with the severity of myelosuppression. Antitumor activity was observed in two HP ovarian cancer patients and one patient with a soft tissue sarcoma refractory to etoposide and doxorubicin. CONCLUSION: Recommended phase II doses are 500 mg/m(2) and 572 mg/m(2) IV once every 3 weeks for HP and MP patients, respectively. The absence of severe nonhematologic toxicities, the encouraging antitumor activity in HP patients, and the unique mechanism of antineoplastic activity of NSC 655649 warrant further clinical development.

Phase I and pharmacokinetic study of BMS-184476, a taxane with greater potency and solubility than paclitaxel.

PURPOSE: To assess the feasibility, toxicity, pharmacokinetics, and preliminary activity of BMS-184476 administered as a 1-hour intravenous (IV) infusion every 3 weeks. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of BMS-184476 as a 1-hour IV infusion every 3 weeks without premedication to prevent hypersensitivity reactions (HSR). Plasma sampling and urine collections were performed to characterize the pharmacokinetics and pharmacodynamics of BMS-184474. RESULTS: Thirty-four patients were treated with 78 courses of BMS-184476 at five dose levels ranging from 20 to 80 mg/m2. Dose-limiting toxicity (DLT), consisting of severe neutropenia with fever, severe diarrhea, and/or severe mucositis, was experienced during course 1 by six of nine minimally pretreated patients treated at the 70 and 80 mg/m2 dose level. In contrast, of 15 assessable patients treated at the 60 mg/m2 dose level, which is the maximum-tolerated dose (MTD) of BMS-184476 on this administration schedule, only one heavily pretreated patient developed DLT (grade 4 neutropenia with fever and grade 3 diarrhea). One patient developed a grade 2 HSR during a second course of BMS-184476 at the 40 mg/m2 dose level. A previously untreated patient with an advanced cholangiocarcinoma experienced a partial response, and a patient with an untreated carcinoma of the gastroesophageal junction had a minor response. The pharmacokinetics of BMS-184476 seemed linear in the dose range studied. Mean +/- SD values for clearance, volume of distribution at steady-state, and terminal half-life were 220 +/- 89 mL/min/m2, 402 +/- 231 L/m2, and 40.8 +/- 21.8 hours, respectively. CONCLUSION: The MTD and recommended dose for phase II evaluations of BMS-184476 is 60 mg/m2 as a 1-hour IV infusion every 3 weeks. The results of this study suggest that BMS-184476 may have several advantages compared with paclitaxel in terms of toxicity, pharmacokinetics, pharmaceutics, and administration and warrants further clinical development.

A phase I study of rhizoxin (NSC 332598) by 72-hour continuous intravenous infusion in patients with advanced solid tumors.

BACKGROUND: Rhizoxin (NSC 332598) is a novel macrolide antitumor antibiotic that inhibits microtubule assembly and also depolymerizes preformed microtubules. In preclinical evaluations, rhizoxin demonstrated broad antitumor activity in vitro and in vivo including both vincristine- and vindesine-resistant human lung cancers. Prolonged exposure schedules in xenograft models demonstrated optimal efficacy indicating schedule-dependent antitumor activity. The early phase I and II evaluations a five-minute bolus infusion schedule was studied, however, only modest anti-tumor activity was noted, possibly due to rapid systemic clearance. To overcome these limitations and to exploit the potential for schedule-dependent behavior of rhizoxin, the feasibility of administering rhizoxin as a 72-hour continuous intravenous (i.v.) infusion was evaluated. PATIENTS AND METHODS: Patients with advanced solid malignancies were entered into this phase I study, in which both the infusion duration and dose of rhizoxin were increased. The starting dose was 0.2 mg/m2 over 12 hours administered every 3 weeks. In each successive dose level, the dose and infusion duration were incrementally increased in a stepwise fashion. Once a 72-hour i.v. infusion duration was reached, rhizoxin dose-escalations alone continued until a maximum tolerated dose (MTD) was determined. RESULTS: Nineteen patients were entered into the study. Rhizoxin was administered at doses ranging from 0.2 mg/m2 i.v. over 12 hours to 2.4 mg/m2 i.v. over 72 hours every 3 weeks. The principal dose-limiting toxicities (DLT) were severe neutropenia and mucositis, and the incidence of DLT was unacceptably high at rhizoxin doses above 1.2 mg/m2, which was determined to be the MTD and dose recommended for phase II studies. At these dose levels, rhizoxin could not be detected in the plasma by a previously validated and sensitive high-performance liquid chromatography assay with a lower limit of detection of 1 ng/ml. No antitumor responses were observed. CONCLUSIONS: Rhizoxin can be safely administered using a 72-hour i.v. infusion schedule. The toxicity profile is similar to that observed previously using brief infusion schedules. Using this protracted i.v. infusion schedule the maximum tolerated dose is 1.2 mg/m2/72 hours.

Phase I and pharmacologic study of the specific matrix metalloproteinase inhibitor BAY 12-9566 on a protracted oral daily dosing schedule in patients with solid malignancies.

PURPOSE: To evaluate the feasibility of administering BAY 12-9566, a matrix metalloproteinase (MMP) inhibitor with relative specificity against MMP-2, MMP-3, and MMP-9, on a protracted oral daily dosing schedule in patients with advanced solid malignancies. The study also sought to determine the principal toxicities of BAY 12-9566, whether plasma BAY 12-9566 steady state concentrations (C(ss)) of biologic relevance could be sustained for prolonged periods, and whether BAY 12-9566 affected plasma concentrations of MMP-2, MMP-9, and tissue inhibitor of MMP-2 (TIMP-2). PATIENTS AND METHODS: Patients with solid malignancies were treated with BAY 12-9566 at daily oral doses ranging from 100 to 1,600 mg. BAY 12-9566 dose schedules included 100 mg once daily, 400 mg once daily, 400 mg twice daily, 400 mg three times daily, 400 mg four times daily, and 800 mg twice daily. Plasma was collected to study the range of BAY 12-9566 C(ss) values achieved, and exploratory studies were performed to assess the effects of BAY 12-9566 on plasma concentrations of MMP-2, MMP-9, and TIMP-2. RESULTS: Twenty-one patients were treated with 47 28-day courses of BAY 12-9566. The most common side effects were headache, nausea, vomiting, abnormalities in hepatic functions, and thrombocytopenia, which were rarely clinically significant. BAY 12-9566 was well tolerated on all dose schedules, and there was no consistent dose-limiting toxicity that precluded treatment in the range of dose schedules evaluated. Instead, dose escalation was terminated because BAY 12-9566 plasma C(ss) values increased less than proportionately and plateaued as the daily dose was increased within the dose range of 100 to 1,600 mg/d, suggesting saturable drug absorption. Mean plasma C(ss) values achieved with all dose schedules exceeded BAY 12-9566 concentrations required to inhibit MMPs in vitro and in vascular invasion and tumor proliferation in vivo models. There were no consistent effects of BAY 12-9566 on the plasma concentrations of MMP-2 and MMP-9 over the continuous dosing period at any dose schedule level. However, plasma levels of TIMP-2 seemed to increase in a dose-dependent manner (r(2) =.50, P =.046). CONCLUSIONS: The recommended dose of BAY 12-9566 for subsequent disease directed studies is 800 mg twice daily, which resulted in biologically relevant plasma C(ss) values and an acceptable toxicity profile. Although exploratory studies of MMPs in plasma were not revealing, it is conceivable that some tumor types and disease settings are more likely to produce more readily quantifiable levels of activated MMPs than others. Therefore, attempts to identify and quantify surrogate markers of MMP inhibitory effects should continue to be performed in disease-directed studies in more homogenous patient populations.

A phase I study of docetaxel and 5-fluorouracil in patients with advanced solid malignancies.

PURPOSE: This study was undertaken to evaluate the feasibility of administering docetaxel (Taxotere; Rhône-Poulenc-Rorer) as a one-hour intravenous (i.v.) infusion on day 1 combined with 5-fluorouracil (5-FU) as a bolus i.v. injection for five (days 1-5) or three (days 1-3) consecutive days every four weeks. PATIENTS AND METHODS: Thirty-seven patients with advanced solid malignancies were treated with 115 total courses involving seven dose levels of the two regimens of docetaxel and 5-FU (docetaxel/5-FU [mg/m2]/mg/m2/d]). In an effort to reduce fluid retention and hypersensitivity phenomena related to docetaxel, patients received premedication with dexamethasone 8 mg orally twice daily for three consecutive days beginning 24 hours before treatment. RESULTS: Severe (grade 4) neutropenia lasting longer than seven days with or without fever and/or severe mucositis, precluded further dose escalation above docetaxel 60 mg/m2 on day 1 and 5-FU 300 mg/m2/day administered on days 1-5 every four weeks. The rates of these toxic effects were also unacceptably high above docetaxel 60 mg/m2 on day 1 and 5-FU 300 mg/m2/day administered on days 1-3 every four weeks. Nine patients experienced various manifestations of fluid-retention that were potentially related to study drugs. However, neither treatment delay nor discontinuation of treatment was required. Nausea, vomiting, diarrhea, and fatigue, were mild to modest in severity and occurred infrequently (< 10% of courses). Two patients with metastatic breast cancer experienced complete responses and a partial response occurred in a patient with metastatic non-small-cell lung cancer. CONCLUSION: Based on the results of this study, the regimen of docetaxel 60 mg/m2 on day 1 followed by 5-FU 300 mg/m2/d i.v. for three or five days every four weeks is well tolerated and these doses are recommended for further evaluations. The feasibility of administering docetaxel 60 mg/m2 followed by 5-FU 300 mg/m2 for three or five days every four weeks and the preliminary antitumor activity noted indicate that further disease-directed studies of docetaxel and 5-FU are warranted in patients with relevant solid malignancies.

Phase I and pharmacokinetic study of paclitaxel in combination with biricodar, a novel agent that reverses multidrug resistance conferred by overexpression of both MDR1 and MRP.

PURPOSE: To evaluate the feasibility of administering biricodar (VX-710; Incel, Vertex Pharmaceuticals Inc, Cambridge, MA), an agent that modulates multidrug resistance (MDR) conferred by overexpression of both the multidrug resistance gene product (MDR1) P-glycoprotein and the MDR-associated protein (MRP) in vitro, in combination with paclitaxel. The study also sought to determine the maximum-tolerated dose (MTD) of paclitaxel that could be administered with biologically relevant concentrations of VX-710 and characterize the toxicologic and pharmacologic profiles of the VX-710/ paclitaxel regimen. PATIENTS AND METHODS: Patients with solid malignancies were initially treated with VX-710 as a 24-hour infusion at doses that ranged from 10 to 120 mg/m2 per hour. After a 2-day washout period, patients were re-treated with VX-710 on an identical dose schedule followed 8 hours later by paclitaxel as a 3-hour infusion at doses that ranged from 20 to 80 mg/m2. The pharmacokinetics of both VX-710 and paclitaxel were studied during treatment with VX-710 alone and VX-710 and paclitaxel. Thereafter, patients received VX-710 and paclitaxel every 3 weeks. RESULTS: VX-710 alone produced minimal toxicity. The toxicologic profile of the VX-710/paclitaxel regimen was similar to that reported with paclitaxel alone; neutropenia that was noncumulative was the principal dose-limiting toxicity (DLT). The MTD levels of VX-710/ paclitaxel were 120 mg/m2 per hour and 60 mg/m2, respectively, in heavily pretreated patients and 120/60 to 80 mg/m2 per hour in less heavily pretreated patients. At these dose levels, VX-710 steady-state plasma concentrations (Css) ranged from 2.68 to 4.89 microg/mL, which exceeded optimal VX-710 concentrations required for MDR reversal in vitro. The pharmacokinetics of VX-710 were dose independent and not influenced by paclitaxel. In contrast, VX-710 reduced paclitaxel clearance. At the two highest dose levels, which consisted of VX-710 120 mg/m2 per hour and paclitaxel 60 and 80 mg/m2, pertinent pharacokinetic determinants of paclitaxel effect were similar to those achieved with paclitaxel as a 3-hour infusion at doses of 135 and 175 mg/m2, respectively. CONCLUSION: VX-710 alone is associated with minimal toxicity. In combination with paclitaxel, biologically relevant VX-710 plasma concentrations are achieved and sustained for 24 hours, which simulates optimal pharmacologic conditions required for MDR reversal in vitro. The acceptable toxicity profile of the VX-710/ paclitaxel combination and the demonstration that optimal pharmacologic conditions for MDR reversal are achievable support a rationale for further trials of VX710/paclitaxel in patients with malignancies that are associated with de novo or acquired resistance to paclitaxel caused by overexpression of MDR1 and/or MRP.

Phase I trial of paclitaxel and gemcitabine administered every two weeks in patients with refractory solid tumors.

PURPOSE: Paclitaxel and gemcitabine possess broad spectra of clinical activity, distinct mechanisms of cytotoxicity, and are differentially affected by mutations in cell-cycle regulatory proteins, such as bcl-2. This phase I trial was designed to identify the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of paclitaxel and gemcitabine when both drugs were given together on a once-every-two-week schedule in patients with solid tumors. PATIENTS AND METHODS: A total of 37 patients were treated at nine different dose levels ranging from paclitaxel 75-175 mg/m2 administered over three hours followed by gemcitabinc 1500-3500 mg/m2 administered over 30-60 minutes. Both drugs were administered on day 1 of a 14-day cycle. Dose escalation was performed in a stepwise manner in which the dose of one drug was escalated while the dose of the other drug was kept constant. RESULTS: Dose limiting toxicity (DLT) was observed at dose level 9: paclitaxel 175 mg/m2 and gemcitabine 3500 mg/m2 in the form of grade 4 neutropenia lasting for > or = 5 days (one patient) and grade 3 elevation of alanine aminotransferase (AST/SGPT) (one patient). An analysis of delivered dose intensity (DI) over the first three cycles revealed that higher dosages of both drugs were delivered at dose level 7, paclitaxel 150 mg/m2 and gemcitabine 3000 mg/m2 dose level, than at the MTD, dose level 8, paclitaxel 150 mg/m2 and gemcitabine 3500 mg/m2. Partial responses were confirmed in two patients with transitional cell carcinoma (one of the bladder, one of the renal pelvis) and in one patient with adenocarcinoma of unknown primary. CONCLUSIONS: Paclitaxel and gemcitabine is a promising drug combination that can be administered safely and repetitively on an every-other-week schedule. Using this drug administration schedule, the recommended phase II dose is paclitaxel 150 mg/m2 and gemcitabine 3000 mg/m2.

Phase I and pharmacokinetic study of the water-soluble dolastatin 15 analog LU103793 in patients with advanced solid malignancies.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic profile of the dolastatin 15 analog LU103793 when administered daily for 5 days every 3 weeks. PATIENTS AND METHODS: Fifty-six courses of LU103793 at doses of 0.5 to 3.0 mg/m2 were administered to 26 patients with advanced solid malignancies. Pharmacokinetic studies were performed on days 1 and 5 of course one. Pharmacokinetic variables were related to the principal toxicities. RESULTS: Neutropenia, peripheral edema, and liver function test abnormalities were dose-limiting at doses greater than 2.5 mg/m2 per day. Four of six patients developed DLT at 3.0 mg/m2 per day, whereas two of 12 patients treated at 2.5 mg/m2 per day developed DLT. Pharmacokinetic parameters were independent of dose and similar on days 1 and 5. Volume of distribution at steady-state (Vss) was 7.6 +/- 2.0 L/m2, clearance 0.49 +/- 0.18 L/h/m2, and elimination half-life (t1/2) 12.3 +/- 3.8 hours. Peak concentrations (Cmax) on day 1 related to mean percentage decrement in neutrophils (sigmoid maximum effect (Emax) model). Patients who experienced dose-limiting neutropenia had significantly higher Cmax values than patients who did not, whereas nonhematologic DLTs were more related to dose. CONCLUSION: The recommended dose for phase II evaluations of LU103793 daily for 5 days every 3 weeks is 2.5 mg/m2 per day. The lack of prohibitive cardiovascular effects and the generally acceptable toxicity profile support the rationale for performing disease-directed evaluations of LU103793 on the schedule evaluated in this study.

Docetaxel in combination with fluorouracil: study design and preliminary results.

The relatively recent introduction of a new class of chemotherapeutic agents--the taxoids--has raised hope of improved survival for patients with advanced or metastatic cancer. Following encouraging preclinical results of taxoid combinations, this phase I, nonrandomized trial was designed to evaluate a 1-hour intravenous infusion of docetaxel (Taxotere) on day 1 combined with fluorouracil (5-FU) as a daily intravenous bolus for 5 consecutive days. To date, 27 patients with advanced solid neoplasms have received 86 courses of docetaxel/5-FU at the following dose levels: 25/100, 35/150, 50/200, 60/200, and 60/300 mg/m2. Preliminary results showed no unexpected toxicities, and the principal toxicity was neutropenia of short duration. A treatment regimen of 60 mg/m2 docetaxel on day 1 and 300 mg/m2 of 5-FU given for 5 days, with a single course length of 28 days, is projected as the maximum tolerated dose.

Diagnosis of heparin-induced thrombocytopenia in the vascular surgery patient.

BACKGROUND: Recent studies have shown that patients with heparin-induced thrombocytopenia (HIT) form immunoglobulin G (IgG) and/or IgM antibodies directed against a complex of platelet factor 4 (PF4) and heparin. This recognition has resulted in the development of enzyme-linked immunosorbent assays (ELISAs) that use the heparin/PF4 complex as the antigen. This study describes the use of a standardized ELISA to assess antibody formation in five patients suspected of having HIT. METHODS: Five patients received heparin for treatment of arterial or venous thrombotic disorders. All patients had the ELISA performed to detect IgG or IgM antibodies directed against heparin-PF4, as well as the 14C serotonin release assay, when HIT was clinically suspected. RESULTS: HIT was diagnosed in four patients and ruled out in a fifth by using the ELISA. All patients had a 40% decrease in platelet count that returned to normal after heparin cessation. Only one of the four patients who tested positive by ELISA for IgG antibodies also tested positive by the 14C serotonin release assay. Treatment was significantly altered by the ELISA results in all five patients. CONCLUSIONS: It is likely that the ELISA is more sensitive in the diagnosis of HIT than the more traditional aggregation tests, and it may emerge as a new gold standard. Prospective studies in which serial laboratory testing is combined with measurement of clinical outcomes are needed and will eventually provide a greater understanding of the full spectrum of HIT and the clinical settings that precipitate thrombosis in the vascular surgery patient.

Extramedullary myeloid cell tumors in myelodysplastic-syndromes: not a true indication of impending acute myeloid leukemia.

The purpose of this report is to record a patient with myelodysplastic syndrome (MDS) associated acute myelogenous leukemia (AML) and leukemia cutis who had blast expression of the neural cell adhesion molecule (NCAM) and to review the world literature on prognostic implications of extramedullary myeloid cell tumors (granulocytic sarcoma, myeloblastoma, chloroma and leukemia cutis) in MDS and MDS associated AML. Case report and world literature from January 1965-January 1994 for all cases of MDS-associated extramedullary myeloid cell tumors (EMT) is reviewed, and the first patient with EMT, MDS associated AML and blast expression of NCAM is described. There have been 46 cases of MDS associated EMT previously reported. 32 cases occurred in the absence of AML. AML developed in 47% of these patients at a mean of 38 weeks from initial EMT. Of the patients not developing AML, median survival from initial EMT was 11 weeks. Nine patients received chemotherapy at the time of EMT and had a median survival of 36 weeks. The median survival for patients receiving conservative therapy for EMT was 48 weeks. Patients (n = 15) with EMT and MDS associated AML had a poor outcome regardless of therapy with a median survival of 11 weeks. Unlike other forms of isolated EMT, MDS associated EMT is not always a forerunner of AML. Premature induction therapy for MDS associated EMT does not appear to prolong survival. EMT in the setting of MDS associated AML is associated with a poor prognosis despite aggressive chemotherapy. Blast expression of NCAM may prove to be a risk factor for EMT in MDS associated AML.

Acquired von Willebrand's disease: a rare manifestation of postpartum thyroiditis.

This report describes the diagnosis of acquired type I von Willebrand disease in a 30-year-old woman (G5P5) who presented with complaints of excessive bleeding in the postpartum period. The patient's additional complaints of fatigue, depression, and inability to lose weight resulted in laboratory testing that indicated hypothyroidism due to thyroiditis. Clinical symptoms and laboratory tests for von Willebrand disease and hypothyroidism normalized with L-thyroxine replacement. Thyroiditis resulting in symptomatic hypothyroidism occurs in 2-4 per cent of postpartum women. The possibility of underlying hypothyroidism should be considered for those patients, especially if they are parous women, who appear to have an acquired bleeding disorder suggestive of von Willebrand disease.

Effect of experimental cardiopulmonary bypass on systemic and transcardiac thromboxane B2 levels.

Systemic and cardiac metabolism of thromboxane was studied in a canine model (n = 13) of standard cardiopulmonary bypass and surgical cardioplegia. Sterile techniques were applied and no donor blood was used. Systemic samples (thoracic aorta) and transcardiac gradients (coronary sinus - aortic root) were obtained (1) 5 minutes after cannulation, (2) 20 minutes after the onset of partial bypass, (3) 5 seconds after the first administration of cardioplegic solution (CP-1), and (4) 5 seconds after the second administration of cardioplegic solution (CP-2). Cardioplegic doses were administered 30 minutes apart and consisted of 500 ml of hypothermic (8 degrees C), hyperkalemic (25 mEq potassium chloride) solution infused into the aortic root at 60 to 70 mm Hg. Thromboxane B2 was determined by a double-antibody radioimmunoassay (picograms per milliliter +/- standard error of the mean). Onset of partial bypass was followed by a significant rise in systemic arterial thromboxane B2 levels: after cannulation, 115 +/- 21 pg/ml; after the onset of partial bypass, 596 +/- 141 pg/ml; p less than 0.01). Significant transcardiac thromboxane B2 gradients were found during the first and second cardioplegic washouts (CP-1: aortic root 73 +/- 12 pg/ml, coronary sinus 306 +/- 86 pg/ml, p less than 0.01; CP-2: aortic root 65 +/- 11 pg/ml, coronary sinus 355 +/- 98 pg/ml, p less than 0.01). Transcardiac gradients of 6-keto-prostaglandin F1 alpha and thromboxane B2 were obtained at CP-1 and CP-2. Gradients of 6-keto-prostaglandin F1 alpha were not different from thromboxane B2 gradients during CP-1 but were significantly higher than thromboxane B2 gradients during CP-2. In a subgroup of five dogs, transcardiac thromboxane B2, lactate, and platelet gradients were measured simultaneously. Cardiac thromboxane B2 generation was found only in the presence of cardiac lactate production. Transcardiac platelet gradients were significantly higher at CP-1 (13,900 +/- 3,000/mm3) than at CP-2 (4,000 +/- 1,230/mm3) (p less than 0.05), whereas thromboxane B2 gradients were similar at CP-1 and CP-2. Our study demonstrates that thromboxane B2 is released into the coronary circulation during surgical cardioplegic arrest with anaerobiosis.