Erik Myhre

Prevention of arterial thromboembolism with acetylsalicylic acid: A controlled clinical study in patients with aortic ball valves

Prevention of arterial thromboembolism with acetylsalicylic acid (ASA) was studied in 148 patients with single Starr-Edwards aortic ball-valve prostheses. These patients are suitable for such a study because they have a high incidence of arterial emboli derived mainly from thrombi formed on the valves. They were given either 1 Gm. of ASA daily or placebo in combination with anticoagulants, and were observed for 2 years. Only two emboli occurred in patients receiving ASA, none of them severe. In the placebo group 12 thromboembolic episodes were diagnosed in 10 patients, and three with cerebral emboli died; in one a subdural hematoma unrelated to the embolus was found. In addition, one fatal and the one nonfatal intracranial bleeding occurred in each group, whereas gastrointestinal complications were seen more frequently in patients taking ASA. It is concluded that ASA combined with anticoagulants offered a significantly better protection against arterial thromboembolism than did anticoagulant therapy alone.

The effects of nifedipine, a calcium antagonist, on platelet function

Platelet function was studied before and 1 hour after ingestion of 20 mg nifedipine, a new calcium antagonist, in 20 patients with coronary heart disease. Platelet counts remained unchanged. Platelet adhesiveness, measured as retention in glass bead columns with Hellems method for native blood, did not drop significantly eigher when 0.9 or 3.6 ml of blood was used. Platelet aggregation, which is dependent on extracellular calcium, was induced in citrated platelet-rich plasma. The mean maximal rate of primary aggregation, initiated with three different concentrations of adenosine diphosphate, was reduced by 20% to 26%. The rate of irreversible collagen-induced aggregation was on average 23% lower after nifedipine. The mean bleeding time was 36 seconds, or 12%, longer after ingestion of the drug. The moderate, but significant reduction of platelet aggregation and prolongation of the bleeding time by nifedipine may be mediated through inhibition of calcium transport across the platelet membrane.

Reproducibility of cardiac stroke volume estimated by Doppler echocardiography

Doppler echocardiography was used to measure cardiac stroke volume in 10 patients with coronary artery disease who were treated with cardioactive drugs. Stroke volume estimates were determined at the aortic orifice by multiplying area by systolic velocity integral measured both from the suprasternal and the apical approach. Recordings were done independently by 2 experienced observers on the same day and repeated once after 1 to 21 days. Analysis of variance showed that no systematic differences were introduced by the 2 observers and Doppler approaches or by measuring on different days. The coefficient of variation between any pair of measurements in each patient was 9%. This variability is probably a result of the method or spontaneous fluctuations of the stroke volume and not of the varying recording conditions. The ultrasonic method detects day-to-day changes of cardiac stroke volume larger than 20% with a probability greater than 0.95.

Serum lactic dehydrogenase activity in patients with prosthetic heart valves: a parameter of intravascular hemolysis.

Abstract Intravascular hemolysis is a common complication following insertion of prosthetic heart valves. Most authors have studied this hemolysis by the use of less reliable methods, such as serum haptoglobin and plasma heme determinations, because measurements of the erythrocyte survival are too laborious and time-consuming for routine clinical work. Increased serum lactic dehydrogenase activity (LDH) has been observed by several authors in patients with heart valve prostheses. This was an expected finding since erythrocytes have a high content of this enzyme. Therefore, we determined red cell survival in 21 patients with different LDH levels after insertion of ball-valve prostheses, and in 12 patients with unoperated aortic-valvular disease. A very close correlation was demonstrated between the LDH level and the half-life of 51 Cr-labelled erythrocytes. We proposed that LDH determination was the most simple method available for evaluation of the degree of hemolysis in such patients. The practical approach and limitations in using LDH as a parameter of intravascular hemolysis was discussed.

Effects of a selective thromboxane synthetase inhibitor, dazoxiben, and of acetylsalicylic acid on myocardial ischemia in patients with coronary artery disease

Thromboxane A2 (TxA2) may aggravate myocardial ischemia by inducing vasoconstriction and platelet aggregation in small coronary vessels, whereas prostacyclin (PGI2) counteracts these effects. Acetylsalicylic acid (ASA) inhibits the formation of TxA2 as well as PGI2, whereas dazoxiben, a thromboxane synthetase inhibitor, reduces TxA2 formation selectively. In 25 patients with coronary artery disease, 2 identical atrial pacing stress tests were performed: before and after the administration of dazoxiben (200 mg) in 15 patients and before and after ASA (250 mg) in 10. The ischemic response, quantified by coronary sinus and aortic lactate levels and by ST depression, was significantly reduced after administration of dazoxiben (p less than 0.02) but not after ASA. Heart rate at rest, myocardial extraction of free fatty acids and the arteriovenous oxygen difference was unaffected by medication. Both drugs reduced TxB2 levels to the same extent, whereas collagen-induced aggregation was more reduced after ASA than after dazoxiben. The effect of dazoxiben on ischemia was probably a result of inhibited TxA2 and preserved PGI2 production, which increased blood flow to ischemic regions.

Clinical Pharmacokinetics of Methyldopa

SummaryAbsorption of methyldopa from the gastrointestinal tract is incomplete and variable; bio-availability after oral administration is about 25% (range 8 to 62%). The average lime to reach maximum plasma concentration (tmax) [chemically determined] is 2 hours, when the maximum plasma concentration of active drug accounts for 50% of the radioactivity, the remainder representing various metabolites.Physicochemical determination of methyldopa shows that bi-phasic elimination occurs after both intravenous and oral administration, the half-life of the α-phase being 0.21 hours (range 0.16 to 0.26 hours) and of the β-phase 1.28 hours (range 1.02 to 1.69 hours) in normal subjects. Methyldopa is less than 15% protein bound, whereas the primary metabolite, which most probably is the O-sulphate, is about 50% protein bound.The apparent volume of distribution in the central compartment is about 0.23L/kg (range 0.19 to 0.32L/kg), and the total volume of distribution (calculated as Vdarea) is about 0.60L/kg (range 0.41 to 0.72L/kg) in healthy volunteers.Acid-labile conjugates are formed after oral administration. These acid-labile conjugates, in particular the O-sulphate, are probably formed in the intestinal cells, since they are detected in very small amounts after intravenous administration. Additionally, there is a rapid formation of partly unidentified metabolites after both intravenous and oral administration. After intravenous administration the quantitatively most prominent metabolites are methyldopamine and the glucuronide of dihydroxyphenylacetone, but traces of 5 or 6 other metabolites have also been found and identified. These metabolites are probably formed in the liver, but the complete metabolic pattern is still unknown.The renal clearance of methyldopa (95ml/min/m2) is more than 50% higher than the endogenous creatinine clearance. Renal excretion of some metabolites is slower.Extrarenal elimination accounts for about 50% of the total body clearance of the drug. Renal excretion is very low in patients with renal failure, resulting in accumulation of both active drug and, in particular, its metabolites. There is a marked accumulation of unidentified metabolites in renal failure patients, which possibly explains the strong and prolonged hypotensive action of methyldopa in these patients.

Effects of dipyridamole and acetylsalicylic acid on platelet functions in patients with aortic ball-valve prostheses

The effects of dipyridamole and ASA on platelet functions were studied in patients with aortic ball-valve prostheses. Before ingestion, platelet adhesiveness was markedly reduced and platelet survival time slightly, but insignificantly shortened. ASA prolonged the bleeding time, reduced collagen-induced platelet aggregation, and inhibited secondary aggregation initiated by adrenalin. Similar effects were obtained with 2 Gm. of ASA alone as with 1 Gm. daily in combination with 225 mg. of dipyridamole. Platelet adhesiveness remained low. Depyridamole alone, 375 mg. daily, did not influence any of these parameters. The mean platelet half-life was prolonged from 3.52 to 3.72 days by each drug and to 4 days by the combined treatment. None of the differences was, however, statistically significant. A clinical study with ASA has been started in a larger series of patients to evaluate the effect on arterial thromboembolism.

Pharmacokinetics of methyldopa in healthy man

SummaryThe pharmacokinetics of 2-14C-L-α-methyldopa have been investigated in five healthy volunteers following intravenous and oral administration. In the intravenous study a bi-phasic plasma concentration curve was found both for chemically determined α-methyldopa and for radioactivity. The plasma level of radioactivity differed significantly from chemically determined drug, a pattern which was also found in urine. This suggests the presence of unidentified metabolite(s). The difference between plasma disappearance and urine recovery of α-methyldopa and radioactivity during the first 4 h after injection suggests distribution to an extravascular compartment. Plasma half-lives of total radioactivity and of unchanged drug were calculated. In three subjects, pharmacokinetic parameters for a two-compartment open body model were calculated from urine and plasma data. Urinary recovery of radioactivity was almost complete within 48 h after intravenous administration. After oral administration, however, only about 40 per cent of the radioactive dose was recovered in the urine, and it contained approximately equal amounts of unconjugated methyldopa, acid-labile conjugated methyldopa and unidentified metabolite(s). The acid-labile conjugate was found only after oral administration, which supports the theory of a mucosal conjugation process. The lack of acid-labile conjugated drug either in the plasma or urine after intravenous injection indicates that there is no enterohepatic circulation of this drug.

Platelet functions in patients with aortic ball valves

Platelet functions were studied in normal subjects and patients with single Staff-Edwards aortic ball valves of series 1200 and 2300. The most pronounced changes were found in platelet adhesiveness, measured with Hellems modified method. The mean percentage of adhesive platelets was reduced from 71.8 in normal subjects to 50.9 in patients with valve type 1200 and to 27.2 in those with type 2300. An inverse correlation was found between platelet adhesiveness and the degree of intravascular hemolysis, as reflected by serum LDH levels. The mean bleeding time was significantly prolonged in patients with valve 2300, and the individual values correlated inversely to the adhesiveness. The mean values of platelet counts, or irreversible aggregation induced by collagen or epinephrine, and of platelet survival were all moderately-but significantly-reduced as compared to normal. The most important mechanism behind the disturbed platelet reactivity is probably mechanical damage of the platelets by the valve, whereas refractoriness of platelets toward ADP liberated from red cells as well as consumption of adhesive platelets by thrombus formation is thought to have limited influence on platelet behavior. Platelet function was altered to the same extent in patients with a history of arterial thromboembolic complications as in those without. The disturbed platelet reactivity may predispose to bleeding, but may also offer some protection against arterial thromboembolism.

Effects of verapamil on left ventricular relaxation and filling dynamics in coronary artery disease: A study by pulsed Doppler echocardiography

The effect of verapamil on left ventricular diastolic function in coronary artery disease was assessed by Doppler echocardiography of transmitral flow velocities in 20 patients. At baseline, isovolumic relaxation time was prolonged compared with that in 18 age-matched normal subjects (95 +/- 13 msec versus 74 +/- 12 msec, p less than 0.001), but decreased to 80 +/- 14 msec (p less than 0.001) after treatment. The ratio between early and atrial-induced transmitral velocities (E/A-ratio) at baseline was lower in patients than in normal subjects (1.1 +/- 0.2 versus 1.4 +/- 0.3, p = 0.01), as was the filling fraction of the first third of diastole (43% +/- 5% versus 50% +/- 4%, p less than 0.001). Verapamil treatment increased the E/A-ratio to 1.3 +/- 0.4 (p less than 0.001) and filling fraction to 45% +/- 4% (p = 0.055) because of increased early filling. No change in systolic performance or heart rate was observed. Thus, coronary artery disease was associated with retarded relaxation and impairment of early filling. However, verapamil treatment enhanced relaxation and induced a filling shift toward early diastole, which indicated improved diastolic performance. The changes probably reflected reduced myocardial ischemia.