Prostacyclin Group Research Articles

Inhibition of hepatic metastasis from a human pancreatic adenocarcinoma (RWP-2) in the nude mouse by prostacyclin, forskolin, and ketoconazole

Metastasis is a multistep phenomenon in which platelets appear to play an important role. This study examined several compounds for their effects on experimental hepatic metastasis and on human pancreatic tumor cell-platelet interactions. Prostacyclin (PGI2) and forskolin (stimulators of platelet adenylate cyclase) and ketoconazole (inhibitor of lipoxygenese and thromboxane synthetase) were used in order to investigate their effects on hepatic metastases from a human pancreatic tumor cell (RWP-2) in the nude mouse. The tumor cells were injected intrasplenically and the animals were divided into control, prostacyclin (PGI2 200 micrograms), forskolin (150 micrograms), and ketoconazole (180 micrograms) groups. All three drugs were administered intraperitoneally 30 minutes before and 24 hours after the tumor cell injections. Statistically significant differences were observed between control and treated groups in tumor surface area (P less than 0.001), percentage of liver surface area occupied by tumor (P less than 0.001), and number of tumor colonies (P less than 0.004 for prostacyclin, P less than 0.005 for forskolin, and P less than 0.001 for ketoconazole). These agents also strongly inhibited RWP-2-induced platelet aggregation in human platelet-rich plasma.

Epoprostenol (Prostacyclin) in Unstable Angina

The purpose of this randomized, double-blind multicenter trial was to investigate the potential therapeutic effect of epoprostenol (prostacyclin, PGI2) in patients with unstable angina, as compared with placebo, and to investigate the safety of this agent. Of the 184 patients enrolled, 28 did not fit the study criteria; of the remaining 156 patients, 30 received prostacyclin in an open-label fashion. In the double-blind portion of the study, 63 patients each received prostacyclin or placebo. The drug or its vehicle was infused intravenously up to 5 ng/kg/min dose for 72 hours with a tapering off period for the last 12 hours. Both treatment groups from the double-blind portion were comparable in regard to the demographic data, length of infusion, and total dose received. There were no significant differences between the placebo and prostacyclin group in the following clinical endpoints: levels of cardiac enzymes throughout hospitalization period (with the exception of lower SGOT level in the prostacyclin group at day 2), and severity of angina (throughout the study), and at the end of the study (day 30). The number of patients who had congestive heart failure, new myocardial infarction, balloon pump insertion, coronary artery bypass grafting, or percutaneous coronary angioplasty was similar in both groups. Similar results in regard to the efficacy endpoints were also apparent in the prostacyclin group that was treated under open-label fashion. There was also no difference in the New York Heart Association (NYHA) functional status at the end of the double-blind study.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral Blood Flow and Metabolism during Cardiopulmonary Bypass with Special Reference to Effects of Hypotension Induced by Prostacyclin

Cerebral blood flow and metabolism of oxygen, glucose, and lactate were studied in 43 patients undergoing aortocoronary bypass. Twenty-five patients received prostacyclin infusion, 50 ng per kilogram of body weight per minute, during cardiopulmonary bypass (CPB), and 18 patients served as a control group. Regional cerebral blood flow (CBF) was studied by intraarterially injected xenon 133 and a single scintillation detector. Oxygen tension, carbon dioxide tension, oxygen saturation, glucose, and lactate were measured in arterial and cerebral venous blood. Mean arterial blood pressure decreased during hypothermia and prostacyclin infusion to less than 30 mm Hg. The regional CBF was, on average, 22 (standard deviation [SD] 4) ml/100 gm/min before CPB. It increased in the control group during hypothermia to 34 (SD 12) ml/100 gm/min, but decreased in the prostacyclin group to 15 (SD 5) ml/100 gm/min. It increased during rewarming in the prostacyclin group. After CPB, regional CBF was about 40 ml/100 gm/min in both groups. The cerebral arteriovenous oxygen pressure difference decreased more in the control group than in the prostacyclin group during hypothermia. The cerebral metabolic rate of oxygen decreased in both groups from approximately 2 ml/100 gm/min to about 1 ml/100 gm/ min during hypothermia, increased again during rewarming, and after CPB was at the levels measured before bypass in both groups. There was no difference between the groups in regard to glucose and lactate metabolism.

A prospective, randomized study of the effects of prostacyclin on platelets and blood loss during coronary bypass operations

A randomized, double-blind study was designed to evaluate the therapeutic effect and safety of prostacyclin (epoprostenol) in patients undergoing cardiopulmonary bypass. One hundred patients having isolated coronary bypass grafting received 300 units/kg of heparin and then either prostacyclin (12.5 ng/kg/min from heparinization until cardiopulmonary bypass, 25 ng/kg/min during bypass) or buffer/diluent in a similar manner. Standardized anesthetic, perfusion, and surgical techniques were used. Drug and placebo groups were similar in demographic data and bypass times, and there were no deaths. Activated coagulation time and platelet count were significantly higher during cardiopulmonary bypass in patients receiving prostacyclin. Platelet count remained significantly higher 24 hours after bypass in the active drug group. Immediately after operation, there was significantly less prolongation of bleeding time (1.3 versus 2.9 minutes; p = 0.009) in the patients receiving prostacyclin. Blood loss was significantly reduced during the first 4 hours postoperatively in the prostacyclin group (261 +/- 159 versus 347 +/- 197 ml; p = 0.02). There was no significant difference between the groups when total blood loss was compared (710 +/- 351 versus 869 +/- 498 ml; p = 0.07). Patients receiving prostacyclin required an average of 257 ml less blood transfused in the intensive care unit (p = 0.02). We conclude that the clinical impact of prostacyclin in patients undergoing coronary artery operations was demonstrable, but small. Prostacyclin may provide clinical benefits in patients undergoing cardiopulmonary bypass when there are contraindications to or other difficulties with blood transfusion. With prostacyclin, reduced heparin dose is possible and therefore reduced protamine requirement would offer a potential benefit of less cardiovascular depression immediately after bypass. However, the advantages offered by prostacyclin are not sufficient to recommend its routine use during cardiopulmonary bypass.

Somatosensory evoked potentials and cerebral metabolism during cardiopulmonary bypass with special reference to hypotension induced by prostacyclin infusion

Somatosensory evoked potentials and cerebral metabolism were studied during cardiopulmonary bypass in 41 patients undergoing coronary bypass. Twenty-two patients received prostacyclin 50 ng/kg/min during cardiopulmonary bypass for platelet protection and 19 patients served as controls. Mean arterial blood pressure in the prostacyclin group was below 30 mm Hg during the first 30 minutes of bypass, but it remained above 50 mm Hg in the control group. Central conduction time, a measure of the electrical conduction time in the central nervous system, was prolonged in both groups during bypass up to 30 minutes of rewarming. The prolongation was greater in the control group early during bypass. At 20 minutes of cardiopulmonary bypass, central conduction time was increased by 81% (standard deviation 38) of the prebypass value in the control group and by 44% (standard deviation 17) in the prostacyclin group (p less than 0.001). Arteriovenous oxygen difference across the brain was greater in the prostacyclin group early during bypass. It was 36 ml/L (standard deviation 9) in the control group and 60 ml/L (standard deviation 18) in the prostacyclin group (p less than 0.001) at 10 minutes of bypass. There was no difference between the groups in regard to glucose and lactate. We conclude that cardiopulmonary bypass with hypothermia prolongs central conduction time. The hypotension induced by prostacyclin (50 ng/kg/min) did not further impair conduction in the central nervous system.

Effects of cardiopulmonary bypass and prostacyclin on plasma catecholamines, angiotensin II and arginine-vasopressin.

Infusion of prostacyclin during cardiopulmonary bypass (CPB) reduces platelet activation, diminishes postoperative blood loss and decreases arterial blood pressure. In spite of continuous prostacyclin infusion, there is a delayed gradual rise in arterial pressure and resistance from low initial levels. We measured epinephrine (E), norepinephrine (NE), serotonin (5-HT), angiotensin II (ATII) and arginine-vasopressin (AVP) in plasma and carried out hemodynamic studies in 19 patients operated for coronary vascular disease. Eight patients served as a control group and were subjected to routine CPB. Eleven patients received prostacyclin 50 ng/kg/min during CPB. E and NE increased four- to sixfold during CPB from about 0.5 ng/ml (P less than 0.001). There was no difference between the groups. During CPB AVP increased sixfold from about 20 pg/ml in both groups (P less than 0.001), decreased early after CPB and increased again to high levels 3 h after CPB. The combined action of E, NE and AVP is of likely importance for the rise in systemic vascular resistance and/or need of vasodilation during CPB in the control group. ATII did not increase in the control group, but increased fourfold to about 20 pg/ml (P less than 0.01) during CPB in the prostacyclin group. The addition of AT II to E, NE and AVP seems responsible for the gradual return of arterial pressure and resistance during prostacyclin infusion. Postoperative hypertension and/or need of vasodilation 3 h after CPB was associated with high AVP levels in both groups. Hypotension caused by prostacyclin infusion did not increase E, NE or AVP above levels produced by CPB and moderate hypotension alone.

Effects of Prostacyclin Infusion on Platelet Activation and Postoperative Blood Loss in Coronary Bypass

The effects of infusion of prostacyclin were studied in 41 patients undergoing aortocoro-nary bypass. Twenty-three patients received heparin (2 mg per kilogram of body weight) and prostacyclin (50 ng per kilogram per minute) during cardiopulmonary bypass (CPB). Eighteen patients received heparin (3 mg per kilogram). One hour after CPB, the platelet count was 98 ± 16% of the value obtained before CPB in the prostacyclin group and 73 ± 18% in the control group ( p < 0.001). The plasma level of platelet factor 4 rose only initially during CPB in the prostacyclin group, but increased continuously in the control group; at 90 minutes of CPB it was 92 ± 35 ng per milliliter and 376 ± 119 ng per milliliter, respectively ( p < 0.001). Beta-throm-boglobulin showed a similar pattern. Postoperative chest drainage was 386 ± 87 ml in the prostacyclin group and 596 ± 342 ml in the control group ( p < 0.05). Blood transfused during and five days after operation was 1,359 ± 751 ml in the prostacyclin group and 2,047 ± 915 ml in the control group ( p < 0.05).

Prostacyclin infusion during extracorporeal circulation for coronary bypass

The effects of prostacyclin on whole blood platelet count, blood coagulation factors, and postoperative bleeding were investigated in 20 patients undergoing aorta-coronary bypass. Eleven patients received heparin 2 mg/kg and prostacyclin 50 ng/kg/min during cardiopulmonary bypass (CPB). Nine patients received only heparin 3 mg/kg. CPB was by roller pump and bubble oxygenator primed with Ringer's acetate. Hypothermia to 28 degrees C was induced. In the control group, platelet count, corrected for hemodilution, was 70% +/- 15% (mean +/- SD) of pre-CPB value after 30 minutes of bypass and remained at this level 1 hour after CPB. In the prostacyclin group, the platelet count after 30 minutes was 85% +/- 17%, after 120 minutes 111% +/- 20%, and 1 hour after CPB 92% +/- 17%. There was a significant difference between the groups (p less than 0.05) from 60 minutes of CPB up to 1 hour after CPB. Prostacyclin allowed reduction of the heparin dosage while retaining anticoagulation as measured by activated coagulation time (ACT), fibrinopeptide A, and fibrinogen determinations. The ACT was more than 900 seconds in the prostacyclin group after 30 minutes of CPB, as compared to 523 +/- 118 seconds (p less than 0.05) in the control group. This difference diminished later during CPB. In the prostacyclin group, arterial blood pressure was 30 mm Hg or less during the first hour of CPB and the systemic vascular resistance was half of that in the control group. All patients survived. There were no clinical signs of neurologic damage. Postoperative bleeding was 352 +/- 61 ml in the prostacyclin group and 550 +/- 338 ml (NS) in the control group.

Effects of prostacyclin during cardiopulmonary bypass in man.

Effects of prostacyclin infusion were studied in adult patients operated on for acquired heart disease during the period November 1979-June 1980. In group A. 10 patients received prostacyclin 50 ng × kg b.w.−1 x min−1 for the first 30 min of cardiopulmonary bypass (CPB). Twelve patients served as controls. In group B, 14 patients received prostacyclin 100 ng × kg b.w.−1 x min−1 throughout CPB apart from the last 5-20 min. Nine patients served as controls. CPB was by roller pump and bubble oxygenator primed with a crystalloid solution. Hypothermia to 25-28°C was induced. All patients were given heparin 3 mg/kg b.w. before cannulation + 50-75 mg added to the pump prime.There were 3 deaths in the control groups and 1 death in the prostacyclin groups. One control and 2 prostacyclin patients were re-operated on for bleeding. There was no difference between control and prostacyclin patients in regard to intra- or postoperative bleeding. One prostacyclin patient operated on for calcific aortic stenosis suffered ...