Joseph E. Devine

Response to exogenous cholecystokinin of six human gastrointestinal cancers xenografted in nude mice

Gastrointestinal hormones regulate growth of cancers as well as normal tissues. We investigated whether long-term cholecystokinin (CCK) administration might affect growth or metabolism of human tumors xenografted in nude mice. In each experiment, approximately 20 nude mice bearing subcutaneous xenografts of the particular cancer line being studied were used. Half received CCK and half received saline solution intraperitoneally twice daily for 14 days. Tumor volume and body weight were measured every 3 days. If the tumors produced marker substances, these were measured in nude mouse serum and also in the xenografts. Tumor growth was significantly retarded by CCK in two of the six cancers studied. In each case, DNA, RNA, and protein reflected tumor volumes. In one of these tumors (SLU 077), serum carcinoembryonic antigen (CEA) levels paralleled the tumor volumes. In another tumor (SLU 132), serum CEA levels and tumor immunolabeling for CEA and pancreatic oncofetal antigen increased in response to CCK administration, whereas tumor volumes did not. These findings suggest that exogenous highdose CCK altered the growth and metabolism in two of six human cancers studied.

Intraoperative Myocardial Protection: A Comparison of Blood and Asanguineous Cardioplegia

Cardiac arrest was achieved in 84 patients using asanguineous cardioplegia and in 97 patients using cold blood potassium cardioplegia. The patient groups were similar in age, sex ratio, and preoperative risk factors. Other than the cardioplegic solution used, the conduct of each operation was identical. There were no differences in mean total pump time (118 minutes for the asanguineous cardioplegia group versus 117 minutes for the cold blood cardioplegia group) or cross-clamp time (73.5 versus 70 minutes, respectively). However, the blood cardioplegia group had a greater number of distal anastomoses per patient (3.9 versus 3.7; p less than 0.05). Myocardial protection was assessed clinically and by serial electrocardiograms. Cellular integrity was determined by release of the myocardial isoenzyme of serum creatine kinase (CK-MB). Cellular morphology was studied in 6 randomly selected patients in each group by electron microscopic examination of left ventricular myocardial samples obtained before and after bypass. Three patients given blood cardioplegia and 5 given asanguineous cardioplegia required intraaortic balloon counterpulsation at termination of bypass. There were no ultrastructural changes in either group. Electrocardiographic changes (Minnesota code) occurred in 12 of 84 patients receiving asanguineous cardioplegia versus 12 of 97 patients receiving cold blood potassium cardioplegia. To maintain a satisfactory cardiac index (greater than 2.0 L/min/m2), 38 of 84 patients given asanguineous cardioplegia versus 25 of 97 patients given blood cardioplegia required inotropic support up to 24 hours postoperatively (p less than 0.05). Infarct size determined from CK-MB release was significantly greater (p less than 0.05) in patients given asanguineous cardioplegia (36.27 gm-equivalents) than in those given blood cardioplegia (26.7 gm-equivalents).(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitation of CK-MB release: diagnostic utility in coronary artery bypass grafting.

The quantitative release of creatine kinase (CK-MB) into the circulation of 97 patients receiving between three and five distal aorto-coronary bypass grafts was used to quantitate the minimal operative myocardial injury and to determine the diagnostic utility of this measurement in the detection of perioperative myocardial infarction. Independently read electrocardiography (ECG) was used to define infarction. The +/- SD confidence range for traumatized heart tissue based on 88 patients without infarction was 0-40.5 g equivalents. Six patients with perioperative myocardial infarction had values significantly above this range. Three patients with indeterminate ECG both released CK-MB significantly above the reference range and were clearly abnormal from a clinical standpoint.

Diltiazem as an Adjunct to Cold Blood Potassium Cardioplegia: A Clinical Assessment of Dose and Prospective Randomization

Diltiazem was evaluated as an adjunct to cold blood potassium cardioplegia in 63 patients undergoing elective coronary artery bypass grafting. The dual-phase study compared incrementally increasing doses (50, 100, and 150 micrograms/kg) of diltiazem using a single-blind, randomized schedule with an equivalent volume of placebo added to each of three infusions of cold (10 degrees C +/- 2 degrees C) blood containing potassium chloride at 25 mEq/L for the initial infusion (400 ml) and at 12 mEq/L for the next two infusions (300 ml each). Observations included a number of operative variables, creatine kinase (CK)-MB curves, two-dimensional echocardiography, and pulsed Doppler sonography before operation and on postoperative days 1 and 5. Pulmonary artery thermistor catheter responses were observed for 16 hours postoperatively, as were left ventricular micromanometer-tipped catheter responses in 7 patients. As the dose of diltiazem was increased, there was increasing time to atrioventricular node refunction (23.6 to 62.0 minutes). Diltiazem at 100 micrograms/kg (D-100) resulted in a significantly lower peak CK-MB activity than its placebo. Peak - dp/dt increased in treated patients and decreased in patients given the placebo. The cardiac index in D-100 patients was greater on the first postoperative day than preoperatively. The stroke index returned to the control level by the fifth postoperative day in D-50 and D-100 patients only, and it remained depressed in placebo patients. Although few benefits were realized from the addition of diltiazem to cold blood potassium cardioplegia, there was dose-related prolongation of the atrioventricular node recovery time, which required cardiac pacing and thus was associated with its attendant risks.

Effect of chronically administered somatostatin on the nude mouse

We investigated the impact of chronically administered synthetic cyclic somatostatin-14 on the nude mouse. Four groups of seven animals each received intraperitoneal injections twice daily for 14 days with diluent or 5, 50, or 500 mcg/kg somatostatin in hydrolyzed gelatin. Overall health and body weight were unaffected by this treatment. Among the seven organs examined at necropsy, kidney alone showed a dose-related gain in weight with increasing somatostatin dose. Renal RNA content also increased in response to somatostatin treatment, but liver DNA content and small bowel DNA content and protein content decreased. This work indicates that somatostatin affects metabolism of gastrointestinal tissues and provides evidence that renal growth can be regulated by somatostatin. Whether similar effects occur at a physiological somatostatin level is unknown, but the current findings suggest new therapeutic possibilities for this hormone.

Drug-protein binding interferences caused by the plasticizer TBEP

Tris (2-butoxyethyl) phosphate (TBEP) is a plasticizer used in the rubber stoppers of evacuated blood collection tubes which disrupts the binding of basic drugs to the carrier protein alpha-1-acid glycoprotein (AAG). When blood drawn for therapeutic monitoring is exposed to TBEP, drug-protein binding is disrupted leading to increased free drug which is taken into red blood cells, resulting in decreased serum drug levels. Units of donor blood were spiked with quinidine or lidocaine and then exposed under various conditions to stoppers with and without TBEP. Total drug levels were determined by enzyme immunoassay as were free drug levels after equilibrium dialysis. AAG levels were determined by rate nephelometry. TBEP lowered quinidine levels by 11% at 8.20 mumol/L and by 32% at 4.38 mumol/L; lidocaine levels were reduced by 10% at 32.39 mumol/L and by 18% at 12.74 mumol/L. Exposure to TBEP increased free lidocaine from 66.7% to 80.0% of total lidocaine in the serum. The TBEP effect is diminished when the AAG level is low.

Effect of chronically administered cholecystokinin on the nude mouse

The nude mouse has been used to evaluate the effect of cholecystokinin (CCK) on xenografted tissues, but little is known about long-term actions of cholecystokinin on native organs in this animal. We investigated the impact of chronically administered synthetic cholecystokinin octapeptide on the nude mouse. Six groups of eight animals each received intraperitoneal injections twice daily for 14 days with diluent or a 4-log range of cholecystokinin. Overall health, behavior, and body weight were unaffected by this treatment. Among the seven organs examined at necropsy, pancreas alone showed a dose-related increase in weight. Pancreatic DNA content decreased with increasing dosages of CCK-8, while RNA content exhibited a biphasic response to CCK-8. The only histological abnormality occurred in the pancreas and was confined to the higher doses. These data indicate for the first time the action of CCK on the non-tumor-bearing nude mouse. Unlike other animal models, the nude mouse responds to cholecystokinin administration with pancreatic hypoplasia and hypertrophy, which is accompanied by pancreatitis at higher doses.