Accurate and cost-effective evaluation of breast masses in males

OBJECTIVE: The primary objective was to evaluate the effect of 7 days treatment with nimesulide on bleeding time. Blood coagulation, von Willebrand factor and platelet aggregation ex vivo were investigated as a secondary objective. METHOD: A randomised, double-blind, placebo-controlled, parallel group, single centre study performed on 20 healthy male volunteers who received either placebo or nimesulide 100 mg twice daily for 7 days. Bleeding time, platelet count and platelet aggregation, thromboplastin time (prothrombin time), activated partial thromboplastin time, fibrinogen, Factor VIII:C, vWF:Ag, vWF:RCof and platelet-rich plasma aggregation following stimulation with adenosine 5'-diphosphate, collagen, arachidonic acid, ristocetin, thrombin and thrombin receptor-activating peptide were measured at baseline (day 0), and then 3 h after the first (day 1) and last (day 7) treatment. RESULTS: The bleeding times for all subjects remained within the normal range throughout the study period, with no significant differences between the two treatment groups. There were no significant changes from baseline in platelet aggregation studies or in any of the other haemostasis tests, with no significant differences between the two groups. No clinically significant adverse events were reported or observed. CONCLUSIONS: Daily administration of 200 mg nimesulide for 7 days neither prolongs bleeding time nor modifies any of the other haemostasis variables measured. The lack of interactions with important haemostatic mechanisms suggests that nimesulide may also be used in patients with bleeding problems. This expectation has still to be confirmed by clinical experience.     

Pre-operative aspirin decreases platelet aggregation and increases post-operative blood loss--a prospective, randomised, placebo controlled, double-blind clinical trial in 100 patients with chronic stable angina

Aspirin has an established benefit in reducing the incidence of coronary events and vein graft occlusion. We have now assessed the risk of pre-operative aspirin in a prospective, randomised, double-blind clinical trial in 100 patients scheduled for elective coronary artery surgery. Any prescribed aspirin and non-steroidal anti-inflammatory drugs were discontinued 2 weeks pre-operatively and these were replaced by a randomly assigned tablet of either aspirin 300 mg daily or placebo taken until the day of surgery. Patient compliance was confirmed by serum and urinary salicylate analysis. The two groups were similar in demographic characteristics, bypass time, number of grafts placed and number of internal mammary arteries used. All patients survived to be discharged home (see Table). Aspirin decreases platelet aggregation to arachidonic acid and to collagen both pre- and post-operatively. The benefit of pre-operative aspirin has to be balanced against the risk of increasing post-operative blood loss, re-exploration for excessive bleeding and transfusion requirements.     

Treatment of osteoarthritis with aspartame

OBJECTIVE: The binding of sweet-tasting compounds in a human (Mcg) Bence-Jones dimer has been characterized by x-ray crystallography. Aspartame binding in this immunoglobulin fragment is remarkable. Unexpected pain relief noted by A.B.E., a crystallographer with diagnosed osteoarthritis, suggested that the accommodation of aspartame in the active site of the dimer may represent surrogate binding by other proteins, with analgesia as the outcome. METHODS: X-ray analysis of the complex of aspartame and the Bence-Jones dimer was conducted with crystalline Mcg protein and pure aspartame. A single-blind (n = 1) study to confirm analgesia was completed by administration of aspartame to A.B.E. A controlled double-blind trial was performed in patients with x-ray-documented osteoarthritis. Pain and performance changes were evaluated with use of two doses of placebo and two doses of aspartame. Effects on bleeding time were then evaluated by determination of template bleeding times in 34 normal volunteers. Finally, antipyretic effects were studied in Sprague-Dawley rats given intramuscular turpentine injections. RESULTS: Aspartame binding in the Bence-Jones dimer was verified by x-ray crystallography. Improvements in performance and pain relief were observed in A.B.E. at p < 0.001. Decreased pain and improved performance were also observed in patients with osteoarthritis (p < 0.001). Mild antihemostatic responses were observed in bleeding times after aspartame treatment. Modified template bleeding times increased at p < 0.01. Aspartame blocked the turpentine-mediated febrile responses in the treated rats (p < 0.01). CONCLUSIONS: L-Aspartyl-L-phenylalanine methyl ester is biologically active and appears to relieve pain, induce mild antithrombotic effects in humans, and decrease fever in animals.     

A double-blind randomized comparison of combined aspirin and ticlopidine therapy versus aspirin or ticlopidine alone on experimental arterial thrombogenesis in humans

No randomized study comparing the effect of combined ticlopidine and aspirin therapy versus each drug alone in reducing poststenting thrombotic complications has been performed. To compare these three antiplatelet regimens versus placebo, we conducted a double-blind randomized study using an ex vivo model of thrombosis. Sixteen healthy male volunteers were assigned to receive for 8 days the following four regimens separated by a 1-month period: aspirin 325 mg/d, ticlopidine 500 mg/d, aspirin 325 mg/d + ticlopidine 500 mg/d, and placebo. At the end of each treatment period, native nonanticoagulated blood was drawn directly from an antecubital vein over collagen- or tissue factor (TF)-coated coverslips positioned in a parallel-plate perfusion chamber at an arterial wall shear rate (2, 600 s-1 ) for 3 minutes. Thrombus, which formed on collagen in volunteers treated by placebo, were rich in platelets and poor in fibrin. As compared with placebo, aspirin and ticlopidine alone reduced platelet thrombus formation by only 29% and 15%, respectively (P > .2). In contrast, platelet thrombus formation was blocked by more than 90% in volunteers treated by aspirin + ticlopidine (P < .01 v placebo or each treatment alone). Furthermore, the effect of the drug combination therapy was significantly larger than the sum of the two active treatments (P < .05). Thrombus, which formed on TF-coated coverslips in volunteers treated by placebo, were rich in fibrin and platelets. Neither of the three antiplatelet treatments significantly inhibited fibrin deposition and platelet thrombus formation on this surface (P > .2). Thus, the present study shows that combined aspirin and ticlopidine therapy dramatically potentiates the antithrombotic effect of each drug alone, but that the antithrombotic effect of the combined treatment depends on the nature of the thrombogenic surface.     

A comparison of antrafenine and aspirin on platelet aggregation and frusemide-induced diuresis

The effects of antrafenine were compared with aspirin and placebo on platelet aggregation and on the diuretic action of frusemide in normal volunteers. Aspirin significantly reduced platelet aggregation at 3 and 6 hr after administration, but antrafenine only at 3 hr. Only aspirin significantly reduced the increase in urine sodium and potassium produced by frusemide.     

Impairment of memory following discrete thalamic infarction

Thirteen healthy men (age range 24-59 years) received three single doses (30, 75, and 150 mg/day) of aspirin for seven days, followed by a wash-out period of three weeks, in a randomized order. The arachidonic acid metabolite 12-L-5,8,10-heptadecatrienoic acid (12-HHT) was taken as a measure of platelet cyclooxygenase activity. There was a large inter-individual variation in 12-HHT production prior to and during aspirin treatment. After one week of treatment the mean reduction was 69, 72 and 83% for the doses 30, 75 and 150 mg/day respectively. When the degree of cyclooxygenase inhibition was expressed per microgram aspirin administered per kg bw, a positive correlation was established to the activity before medication. It was found that doses exceeding 1500 micrograms per kg bw is required to achieve a predictable reduction in cyclooxygenase activity. Thus, by determining the pre-treatment cyclooxygenase activity in an individual it should be possible to adjust the enzyme activity to any desired level below 40% of its initial value. 150 mg aspirin/day for one week had a stimulating effect on the platelet basal production of 12-HHT when measured three weeks after the cessation of treatment. This rebound phenomenon was also observed up to six weeks after a single dose of 600 or 1200 mg of aspirin.     

Red-wine polyphenols and inhibition of platelet aggregation: possible mechanisms, and potential use in health promotion and disease prevention

Correction of uremic platelet serotonin (5-HT) storage pool deficiency is one of the very early hemostatic effects of erythropoietin (Epo) therapy. In this work, platelet 5-HT with relation to primary hemostasis was studied in 15 hemodialysis patients treated with Epo for 8 months. Moreover, effects of ketanserin, a blocker of platelet and vascular smooth muscle cell 5-HT2A receptors, in these patients were followed. The parameters studied were compared with relevant values in healthy controls and in hemodialysis patients not treated with Epo, and remeasured in the long-term Epo patients after a 14-day oral ketanserin trial. Platelet 5-HT content in the eighth month of Epo therapy was not different from the one in untreated patients. Ristocetin- and collagen-induced platelet aggregation were enhanced in comparison with both control groups, as opposed to unaltered response to ADP and arachidonic acid. Fibrinogen concentration was lower than in the untreated group. An inverse correlation between ADP-induced platelet aggregation and the skin bleeding time (r=-0.536, p<0.05) and a positive one between the former and platelet 5-HT (r=0.644, p<0.01) were found. Platelet count correlated positively with both platelet 5-HT (r=0.823, p<0.0002) and ADP-induced platelet aggregation (r=0.596, p<0.02). Ketanserin produced a decrease in ristocetin-induced platelet aggregation, fibrinogen, and prolongation of the bleeding time. The first two of the changes correlated positively with their pre-ketanserin values (r=0.923, p<0.00001 and r=0.839, p< 0.0001, respectively). Post-ketanserin, positive correlations between depressed ristocetin- and arachidonic acid-induced platelet aggregation (r=0.760, p<0.005), and between collagen- and corresponding values of arachidonic acid- (r=0.622, p<0.02), ADP-induced platelet aggregation (r=0.396, p<0.01), and platelet 5-HT (r=0.654, p<0.05) were found. Efficient hemostasis in hemodialysis patients on protracted Epo therapy is, in part, dependent on enhanced platelet aggregability. Correction of platelet 5-HT storage pool deficiency is not evident in this stage but 5-HT still influences complex mechanisms of primary hemostasis. Ketanserin is of anticoagulant value in these patients but its effects must be weighted against possible exacerbation of the anemia.     

Laparoscopic pull-through procedure for Hirschsprung''s disease

BACKGROUND: We investigated the suitability of two commercially available in-vitro bleeding tests (IVBT), the PFA-100 and the Hepcon HMS, to predict blood loss following operations with extracorporeal circulation (ECC) and compared them with conventional coagulation studies. METHODS: In 40 patients subjected to elective open heart surgery with ECC a blood sample was taken before and after ECC to measure platelet count, prothrombin time, aPTT, D-dimers, fibrinogen, and PFA-100 and Hepcon HMS data. The postoperative blood loss was recorded hourly until removal of drains. RESULTS: A significant correlation was found between total blood loss (250-1750 ml) and the preoperative PFA-100 (r = 0.41, p = 0.022), the preoperative platelet count (r = -0.42, p = 0.007), the preoperative D-dimer concentration in the plasma (r = 0.41, p = 0.01), and duration of ECC (r = 0.35, p = 0.044). There was no significant correlation between blood loss and the Hepcon HMS system. CONCLUSIONS: Although a significant correlation was found between blood loss and the PFA-100 IVBT, the practical value of these tests in the clinical situation is limited due to a great variability in individual results.     

Effects of clopidogrel, aspirin and combined therapy in a porcine ex vivo model of high-shear induced stent thrombosis

AIMS: Use of ticlopidine in coronary stenting is limited by delayed onset of action. We studied the effects of clopidogrel, a rapidly acting analog of ticlopidine alone, and in combination with aspirin, in inhibiting stent thrombosis. METHODS: Unpolished nitinol stents were deployed in a porcine ex vivo arteriovenous shunt and exposed to flowing arterial blood at a shear rate of approximately 1500. s-1. Stent thrombus, platelet aggregation and bleeding times were measured at baseline and after treatment. RESULTS: Intravenous clopidogrel produced a rapid (within 30 min) and dose-dependent inhibition of stent thrombosis, with 87% reduction at a dose of 10 mg.kg-1 (P < 0.001). Aspirin alone (10 mg.kg-1) was minimally effective (20% inhibition P > 0.05) in inhibiting stent thrombosis. Combined treatment with clopidogrel and aspirin produced 95-98% inhibition of stent thrombosis, even at low doses of clopidogrel (2.5-5.0 mg.kg-1) (P < 0.0001). At effective doses both clopidogrel and combined therapy produced significant prolongation of bleeding time (P < 0.05) and inhibition of platelet aggregation (P < 0.05). CONCLUSION: Clopidogrel, either alone or combined with aspirin, may have a potential role in preventing stent thrombosis in high-risk clinical situations.     

Pharmacodynamic efficacy, clinical safety, and outcomes after prolonged platelet Glycoprotein IIb/IIIa receptor blockade with oral xemilofiban: results of a multicenter, placebo-controlled, randomized trial

BACKGROUND: Parenteral administration of platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor blockers can reduce ischemic complications of coronary angioplasty. Orally active GP IIb/IIIa blockers may allow more sustained receptor antagonism with the potential for long-term secondary prevention. The pharmacodynamic efficacy, clinical safety, and outcomes after prolonged receptor blockade with an orally active GP IIb/IIIa antagonist are not known. The Oral Glycoprotein IIb/IIIa Receptor Blockade to Inhibit Thrombosis (ORBIT) Trial is a multicenter, placebo-controlled, randomized trial of xemilofiban, an oral platelet GP IIb/IIIa blocking agent, administered to patients after percutaneous coronary intervention. METHODS AND RESULTS: After successful elective percutaneous coronary intervention, 549 patients were randomized to receive either placebo or xemilofiban in a dose of 15 or 20 mg. Stented patients randomized to placebo also received ticlopidine 250 mg orally BID for 4 weeks. Patients who received abciximab during the coronary intervention and who were randomized to receive xemilofiban were administered a reduced dosage (10 mg TID for 2 weeks) followed by the randomized maintenance dose of 15 or 20 mg BID for 2 more weeks. All patients received 325 mg aspirin PO QD. Ex vivo platelet aggregation in response to 20 micromol/L ADP and 4 microg/mL collagen was measured over time after the initial dose of study drug and at days 14 and 28 of long-term therapy in 230 patients. All patients were followed clinically for 90 days. Xemilofiban inhibited platelet aggregation to both ADP and collagen with peak levels of inhibition that were similar at 14 and 28 days of long-term oral therapy. Plasma levels of xemilofiban correlated with the degree of platelet inhibition. Peak platelet inhibition on day 1 correlated with the subsequent occurrence of insignificant or mild bleeding events. Although this study was not powered to evaluate differences in clinical outcomes, a trend (P=0.04) was observed for reduction of cardiovascular events at 3 months in patients not treated with abciximab who received the highest dose (20 mg) of xemilofiban studied. CONCLUSIONS: Xemilofiban inhibited platelet aggregation and was well tolerated during 28 days of long-term oral therapy. The observed trend in reduction of cardiovascular events in follow-up awaits confirmation in the larger-scale phase III study (EXCITE trial) currently in progress.     

Aspirin related gastrointestinal bleeders have an exaggerated bleeding time response due to aspirin use

BACKGROUND: Gastrointestinal bleeding is related to non-steroidal anti-inflammatory drug (NSAID) use, especially aspirin, but only a small subset of users bleed. AIM: To look for risk factors or mechanisms whereby aspirin may promote gastrointestinal bleeding. PATIENTS: Sixty one patients with previous aspirin related upper gastrointestinal bleeding and 61 matched controls. METHODS: Patients and controls were given 375 mg of aspirin and sequential skin bleeding time and blood aspirin levels were measured. Additional studies included platelet lumiaggregation, von Willebrand factor, Factor VIII, and coagulation studies. RESULTS: Baseline skin bleeding time was similar in bleeders and controls, but bleeders had a more prolonged skin bleeding time after aspirin use. Hyper-response was more frequent in bleeders (30% v 9.3%; p < 0.01) and was associated with more than one previous separate bleeding event and a lower packed cell volume during the preceding bleeding episode. No differences were found in other factors studied. Logistic regression analysis identified prolonged skin bleeding time after aspirin use as an independent factor contributing to aspirin related gastrointestinal bleeding (RR = 5.4; 95% CI: 1.8 to 17.1). CONCLUSIONS: 30% of patients with a history of aspirin related gastrointestinal bleeding have an exaggerated prolongation of skin bleeding time in response to aspirin, which may be a risk factor for bleeding. This intrinsic defect or to subclinical von Willebrand disease or different aspirin metabolism.     

Integrilin prevents prolonged bleeding times after cardiopulmonary bypass

BACKGROUND: Cardiopulmonary bypass reduces platelet number and function, increases postoperative bleeding time, and is the major, unsolved cause of nonsurgical bleeding after open heart operations. Temporary inhibition of platelet function during cardiopulmonary bypass (platelet anesthesia) protects platelets and reduces postoperative bleeding time and bleeding. METHODS: Integrilin, a short-acting, reversible platelet glycoprotein IIb/IIIa inhibitor was studied in 28 baboons that had 60 minutes of normothermic cardiopulmonary bypass using peripheral cannulas. A control group, two groups that received different doses of Integrilin, and a group that received a combination of Integrilin and low-dose Iloprost were studied. Blood samples for platelet count, aggregation to adenosine diphosphate, beta-thromboglobulin, prothrombin fragment F1.2, thrombin-antithrombin complex, and fibrinopeptide A were obtained at seven time points. Template bleeding times were measured before and at five intervals after cardiopulmonary bypass. RESULTS: Both doses of Integrilin and the combination of Integrilin and Iloprost significantly protected platelet number, inhibited the response to adenosine diphosphate, and reduced postoperative bleeding times, but they did not reduce beta-thromboglobulin release except in the high-dose Integrilin group. Thrombin formation and activity were qualitatively, but not significantly, reduced in all treatment groups. Bleeding times were not significantly different from baseline at the time protamine was given in the combination group and 60 minutes after protamine administration in all treatment groups. CONCLUSIONS: Integrilin alone or in combination with Iloprost significantly reduces platelet activation during cardiopulmonary bypass and produces normal or near-normal bleeding times at the time protamine is given.     

Short-chain fatty acids in the treatment of radiation proctitis: a randomized, double-blind, placebo-controlled, cross-over pilot trial

PURPOSE: Treatment of chronic radiation proctitis remains unsatisfactory. Short-chain fatty acids are the preferred energy source for the colonic epithelium. We aimed to determine for the first time whether topical butyric acid enemas relieve symptoms and improve the macroscopic and microscopic findings in chronic radiation proctitis. METHODS: A randomized, double-blind, placebo-controlled, cross-over pilot trial compared patients given two weeks of butyric acid enemas (40 mmol) twice per day with those given placebo, with a one-week washout period; 15 patients were randomized and 12 completed both arms of the trial. A total symptom score combined six symptom items per week (rectal pain, episodes of rectal bleeding, amount of blood passed, days with diarrhea, number of stools, and urgency). Symptom, endoscopic, and histologic scores were obtained at the beginning of the study and again at the last week of each treatment arm. RESULTS: Total symptom score at baseline (median, 5.5) improved for those patients receiving active treatment (median, 3.5), but compared with placebo (median, 4.5), the change was not significant. Endoscopic appearances were largely unaltered by active treatment. Histology was abnormal in 82 percent of patients receiving placebo compared with 55 percent of those given butyric acid enemas (P = not significant). CONCLUSION: Butyric acid enemas do not appear to be superior to placebo in the treatment of chronic radiation proctitis.     

Studies on the influence of glucose infusion on parameters of hemostasis

In continuation of previous in vitro experiments the influence of glucose infusions on the following haemostatic functions was investigated: bleeding time, platelet count, platelet aggregation, release reaction, fibrinogen concentration, partial thromboplastin time. Five volunteers with normal metabolism a glucose infusion (100 g) was given for two hrs. Before, 1, 2, 3, 4 and 5 hrs after the beginning of the infusion blood sugar, insulin level and haemostatic parameters were determined. Apart from an increase in the glucose and insulin level, a prolonged bleeding time, increased platelet count, inhibition of platelet aggregation and release reaction occurred. Simultaneously, fibrinogen concentration increased and partial thromboplastin time shortened. The possible causes of these changes in haemostasis during glucose supply are discussed.     

Clopidogrel inhibition of stent, graft, and vascular thrombogenesis with antithrombotic enhancement by aspirin in nonhuman primates

BACKGROUND: A recent study showed that clopidogrel reduces thrombo-occlusive complications in patients with symptomatic atherosclerosis more effectively than aspirin. METHODS AND RESULTS: The effects of clopidogrel and aspirin have been compared, singly and in combination, for measurements of 111In-labeled platelets and 125I-labeled fibrin deposition in baboon models of arterial thrombosis and related to platelet aggregation and expression of activation epitopes induced by ADP, collagen, and thrombin receptor agonist peptide (TRAP) and to template bleeding times (BTs). Low-dose oral clopidogrel (0.2 mg. kg-1. d-1) produced cumulative (1) intermediate decreases in 111In-platelet and 125I-fibrin deposition for segments of prosthetic vascular graft, deployed endovascular metallic stents, and endarterectomized aorta (P<0.009 in all cases); (2) elimination of ADP-induced platelet aggregation (P<0.001); (3) modest inhibition of collagen-induced platelet aggregation (P<0.01); (4) no reduction in TRAP-induced platelet aggregation; and (5) minimal prolongation of BTs (P=0.03). High-dose oral clopidogrel (>/=2 mg/kg) produced the same effects within 3 hours. The effects of clopidogrel dissipated over 5 to 6 days. Aspirin 10 mg. kg-1. d-1 alone did not decrease 111In-platelet and 125I-fibrin deposition on segments of vascular graft but detectably decreased 111In-platelet and 125I-fibrin accumulation on stents (P<0.01), minimally inhibited ADP- and collagen-induced platelet aggregation (P<0.05 in both cases), and minimally prolonged BTs (P=0.004). Within 3 hours of aspirin administration, the antithrombotic effects of acute high-dose or chronic low-dose clopidogrel were substantially enhanced, and BTs were modestly prolonged without inhibiting platelet aggregation induced by TRAP (P<0.001 in all cases compared with clopidogrel alone). CONCLUSIONS: Clopidogrel produces irreversible, dose-dependent, intermediate reduction in thrombosis that is substantially enhanced by the addition of aspirin. The effects of combining aspirin and clopidogrel need to be evaluated in patients at risk of vascular thrombosis.     

Elevation of liver enzymes in multiple dose trials during placebo treatment: are they predictable?

The present study examined the increase in transaminases, especially in ALT in young healthy males during placebo treatment in phase I multiple dose trials. The primary objective was to investigate whether volunteers showing increasing ALT levels also present characteristic patterns of demographic data, laboratory parameters, and vital signs. The secondary objective was to determine whether there is a possibility to predict increases of ALT during a trial by analyzing demographic data and baseline levels of routine safety laboratory parameters and vital signs. In a meta-analysis of 13 placebo-controlled multiple dose phase I studies, volunteers showing elevations of ALT during placebo treatment were compared with those presenting no clinically significant changes of ALT levels. Demographic data as well as routine safety laboratory values and vital signs measured at screening and on the first day of the in-house stay were subject to the analysis. Using Wilcoxon's rank sum test, significant differences between ALT-susceptibles and ALT-nonsusceptibles were found for baseline values (mean values of screening and the first day of the in-house stay) of ALT, gamma GT, AST/ALT, and AST/ gamma GT. Differences found for the screening values of the heart rate were statistically rather than clinically significant. Cut-off values were found for baseline levels of ALT and AST/ALT ratio. Their use resulted in a sensitivity of 73% and a specificity of 74% with regard to predictability of ALT levels increasing during the trial.     

Lewis and secretor gene dosages affect CA19-9 and DU-PAN-2 serum levels in normal individuals and colorectal cancer patients

It is unknown whether the addition of aspirin might increase both the efficacy and the potency of clopidogrel, a potent and selective ADP blocker. For that purpose, the efficacy of clopidogrel (1-20 mg/kg, p.o.) administered orally to rabbits alone or in combination with aspirin (0.1-10 mg/kg, p.o.) was determined in several experimental models. A potent synergistic effect of the clopidogrel/aspirin association was demonstrated with regard to collagen-induced platelet aggregation measured ex vivo. Similarly, aspirin potentiated the antithrombotic activity of clopidogrel measured with regard to experimental thrombosis induced by a silk thread or on stents placed in an arteriovenous shunt, thrombus formation following electrical stimulation of the rabbit carotid artery and with regard to 111In-labeled platelet deposition on a stent implanted in an arteriovenous shunt or on the subendothelium following air drying injury of the rabbit carotid artery. A similar potentiating effect of aspirin was obtained with regard to myointimal proliferation (restenosis) in the femoral arteries of atherosclerotic rabbits which occurred as a consequence of stent placement. The clopidogrel/aspirin combination showed only additive-type effects on bleeding time prolongation induced by ear transection in the rabbit, therefore showing that combined inhibition of cyclooxygenase and ADP's effects provide a marked enhanced antithrombotic efficacy. Such a combination may provide substantial protection against platelet aggregation leading to thrombotic occlusion at sites of endothelial injuries and coronary artery stenosis in humans.     

In vivo and in vitro studies of the inhibitory effect of propofol on human platelet aggregation

BACKGROUND: The inhibitory effects of propofol on platelet aggregation are controversial because the fat emulsion used as the solvent for propofol may affect platelet function. The effects of propofol on platelet intracellular calcium ion concentration and on aggregation were investigated. METHODS: Platelet aggregation was measured in 10 patients who received an intravenous infusion of propofol. Intralipos, the propofol solvent, was infused in 10 healthy volunteers and platelet aggregation were measured. The in vitro effects of propofol and Intralipos on platelets were also investigated. The inhibitory effects of various concentrations of propofol were studied. The effects of propofol on the changes in intracellular calcium level using a fluorescent dye, fura-2, were also observed. Template bleeding time was measured to determine the effect of propofol in clinical use. RESULTS: Platelet aggregation was significantly inhibited by infusion of propofol, although bleeding time was not prolonged. Intralipos did not inhibit platelets either in vivo or in vitro. Propofol significantly inhibited platelet aggregation in vitro and at 5.81 +/- 2.73 microg/ml but not at 2.08 +/- 1.14 microg/ml. The increase of intracellular calcium concentration was inhibited both in influx and discharge of calcium. CONCLUSIONS: Propofol inhibited platelet aggregation both in vivo and in vitro. Inhibition of platelet aggregation appeared to be caused by propofol itself and not by the fat emulsion. This inhibitory effect was also supported by the suppressed influx and discharge of calcium. No change in the bleeding time suggests that this inhibitory effect does not impair hemostasis clinically.     

Randomised comparison of subcutaneous heparin, intravenous heparin, and aspirin in unstable angina. Studio Epoorine Sottocutanea nell'Angina Instobile (SESAIR) Refrattorie Group

Intravenous heparin has been used in the control of myocardial ischaemia in patients with unstable angina. We set out to assess the efficacy of subcutaneous heparin in reducing myocardial ischaemia in patients with unstable angina. 343 of 399 patients with unstable angina were monitored for 24 h and 108 were refractory to conventional antianginal treatment and were entered into a randomised multicentre trial. 37 patients were assigned to heparin infusion (partial thromboplastin time 1.5-2 times baseline), 35 to subcutaneous heparin (adjusted dose with partial thromboplastin time 1.5-2 times baseline), and 36 to aspirin (325 mg daily). All had additional conventional antianginal therapy. After the run-in patients were monitored for 3 days. The primary endpoint was reduced myocardial ischaemia assessed by the number of anginal attacks, silent ischaemic episodes, and duration of ischaemia per day. At 1 week and 1 month we accounted for anginal attacks and other clinical events (myocardial infarction, revascularisation procedures, and death). Aspirin did not significantly affect the incidence of myocardial ischaemia. On the first 3 days, infused and subcutaneous heparin significantly decreased the frequency of angina (on average by 91% and 86%, respectively), episodes of silent ischaemia (by 56% and 46%), and the overall duration of ischaemia (66% and 61%) versus run-in day and aspirin (p < 0.001 for all variables). The favourable effects of heparin therapy remained evident during follow-up. Only minor bleeding complications occurred. Subcutaneous heparin is effective in the control of myocardial ischaemia in patients with unstable angina.