Viscoelasticity and red blood cell aggregation in patients with coronary heart disease.

Viscoelastic parameters were evaluated in 169 consecutive male patients with clinical signs of coronary heart disease. The patients were classified according to the extent of coronary artery stenosis. Levels of blood viscosity, erythrocyte aggregation, and plasma viscosity were elevated in patients with extensive coronary vessel disease. However, the differences between the several groups were not statistically significant. The increase of hemorheologic parameters was mainly due to high hematocrit, fibrinogen, and cholesterol concentrations. There was a significant correlation between plasma fibrinogen values and plasma viscosity levels. Blood viscosity and erythrocyte aggregation can be described by multiple linear regression as a function of the sum of log hematocrit, fibrinogen, cholesterol, and alpha 2-macroglobulin.

Reference ranges of viscoelasticity of human blood.

From 204 presumably healthy volunteers 113 (56 women, 57 men) were accepted as reference population for viscoelastic parameters of blood by medical history, physical examination and more than 20 laboratory controls. To avoid bias through processing or calculating, the reference ranges of human whole blood viscoelasticity were given at their native packed cell volumes (see figure 2). The ranges of normal plasma viscosity were determined as 1.16 to 1.41 mPas with the median of 1.31 mPas. The rheological parameters tested are independent of age and gender.

Haemodilution therapy in ischaemic stroke: plasma concentrations and plasma viscosity during long-term infusion of dextran 40 or hydroxyethyl starch 200/0.5.

In 21 patients with ischaemic strokes we have monitored plasma viscosity, total plasma concentration, numeric average molecular weight (Mn), and weight average molecular weight (Mw) of Dextran 40 (dextran) and hydroxyethylstarch 200/0.5 (HES) during 10 days of treatment (days 1-4, 2 X 500 ml; days 5-10, 1 X 500 ml). Plasma concentrations of dextran increased during the first 4 days (8.3 mg X ml-1 on the first day to 18.0 mg X ml-1 on the fifth day), reached an apparent steady state of 17.2 mg X ml-1 during the next 6 days, and declined subsequently with a half-time (t1/2) of 4.03 days. After ten days treatment Mn and Mw were shifted towards higher values. Plasma viscosity increased from 1.26 mPas to 1.69 mPas on Day 10 (p less than 0.01) and was linearly correlated with the total plasma concentration of dextran (p less than 0.001; r = 0.88). Total plasma concentrations of HES averaged 11.7 mg X ml-1 on Day 1 and 12.4 mg X ml-1 on Day 5. The molecular weight distribution did not change during the infusions but decreased in comparison with the administered solution. Plasma viscosity fell from 1.40 mPas to 1.30 mPas at Day 10 (p less than 0.05) and was not related to the concentration of HES. The haemodiluting effect, as indicated by a decrease of the haematocrit, was 22% and 16.8% for dextran and HES respectively. These data suggest several advantages of HES compared with dextran in haemodilution therapy of ischaemic stroke.

The influence of I.V. application of pentoxifylline on the viscoelasticity of blood in patients with peripheral vascular disorders.

Viscoelastic parameters of blood from 9 patients with vascular disorders before and at different time intervals after POF infusion were investigated. There was a significant decrease in both parameters up to 1h after the end of POF application. Parallel measurements of hematocrit, density of whole blood and plasma, and particle volume distribution of RBC's would suggest that this drug reduces the enhanced aggregation tendency of RBC present in most pathological conditions.

Disposition and antiarrhythmic effect of lorcainide.

The disposition and the antiarrhythmic effect of lorcainide (R 15,889) were investigated in 11 patients with ventricular premature beats (VPB) after a single intravenous dose of 100 mg or 2 mg/kg and after multiple intravenous and oral dosing. Pharmacokinetic parameters were computed according to the two-compartment open model. The half-life of the initial phase, t 1/2 (alpha), was calculated as 0.3 +/- 0.1 hr (mean +/- SD) and the terminal half-life, t 1/2 (beta), varied independently of the dose and route of administration between 5.8 and 12.5 hr (7.8 +/- 2.5 hr). After the single intravenous dose total plasma clearance (Cl) ranged from 570 to 1670 ml/min (988 +/- 425 ml/min) while after multiple dosing Cl decreased to 666 +/- 27 ml/min. Comparison of the area under the curves during steady state (ss) indicated a complete bioavailability of multiple oral doses. After the single intravenous dose, VPB were diminished or reduced for about 4 hr if the plasma concentrations exceeded 120 to 150 ng/ml. During ss-therapy plasma levels fluctuated between 200 and 550 ng/ml with an effective prevention of arrhythmias. Thus, the new drug demonstrates a therapeutic range of approximately 150 to 400 ng/ml and oral therapy seems to be effective with 100 mg t. i. d.

Pharmacokinetics of lorcainide in man: a new antiarrhythmic agent.

A gas liquid chromatographic assay was developed to measure in plasma and urine concentrations of the new antiarrhythmic drug lorcainide, its dealkylated metabolite and an added internal standard of similar structure. The limit of sensitivity was 10ng/ml plasma. In 5 healthy volunteers and in 6 patients with ventricular premature beats (VPB) the pharmacokinetics were determined after a single intravenous dose of 100mg. In 4 of the patients with VPB, the disposition was also evaluated under steady-state conditions following oral administration of 100mg twice daily. In 4 of the healthy volunteers, the bioavailability of a single 100mg(n = 2) and 150mg (n = 2) oral dose was determined. In an additional crossover experiment, bioavailability of a single oral dose of 100 and 200mg was also measured in 2 patients with VPB. Less than 2% of the intravenous dose could be recovered as unchanged lorcainide in the urine, indicating extensive metabolism. The drug was bound to plasma proteins to the extent of 85.0 +/- 5.0% (mean +/- SD) in healthy subjects and 83.3 +/- 2.9% in patients with VPB. Since the plasma levels declined biexponentially after an intravenous dose, data were analysed according to a 2-compartment open model. The elimination half-life (t1/2beta) of 5.1 +/- 0.6h (healthy subjects) was somewhat longer (p = 0.02) in patients with VPB (7.6 +/- 2.2h), but total plasma or blood clearance were very similar; the latter approaching a normal liver blood flow of 1.5L/min. The apparent distribution volumes Vdbeta (8.6 +/- 2.4L/kg vs 10.7 +/- 4.2L/kg) and Vdss (6.4 +/- 2.4L/kg vs 8.8 +/- 3.4L/kg) showed no statistically significant difference between the healthy subjects and patients. After oral doses, high and saturable first--pass hepatic metabolism seems to exist. The crossover experiments in 4 subjects indicated bioavailability of about 1 to 4.5% after a single 100mg dose, between 7 and 20% after a 150mg dose, and between 35 and 65% after a 200mg dose. In contrast, 3 of 4 patients with VPB on oral maintenance therapy exhibited bioavailability of 100%. This indicates that lorcainide belongs to the group of drugs exhibiting non-linear elimination kinetics.

Quantitative nuclear angiocardiography in valvular heart disease.

A noninvasive method of quantitative nuclear angiocardiography was developed using a camera system and a computer. The investigation, which can be performed on an out-patient basis within 10-15 min, includes the following steps: injection of 10 mCi 99mTc-labelled human serum albumin into a femoral vein, and external recording of the passage of the bolus through the central circulation by a sequence of scintigraphic frames taken during diastole. From time--activity curves over the right ventricle, the pulmonary artery and the left ventricle, peak-to-peak times and mean circulation times were calculated. The method was applied to 424 patients with valvular heart disease proven by heart catherization. The following results were obtained: (1) The method proved to be highly sensitive in stating whether there was a hemodynamically significant valvular disease or not. But differential diagnosis concerning the different forms of valvular disease was not possible. (2) The prolongation of the circulation times correlated with the hemodynamic severity of the disease. (3) The circulation times were directly related to the cardiac index, the enddiastolic volume of the left ventricle and the pressures in the pulmonary vascular system. (4) The method could be used to evaluate the effect of surgery and for follow-up after operation. Quantitative nuclear cardiography may help to fill the gap between the nonquantitative, rather unspecific and the specific but invasive methods of cardiologic investigation.

[Coronary disease. I. A correlative study on hemodynamics and contactility in 110 patients]. / Zur koronaren Herzkrankheit I.: Eine korrelative Studie über Hämodynamik und Kontraktilität an 110 Patienten

Hemodynamics measures and indices of myocardial contractility were determined in 110 patients with coronary heart disease. In comparison to a normal group (n=20) right heart pressures (right ventricle, arteria pulmonalis) were increased in coronary heart disease by 48-71%. Systolic aortic pressure was increased by 20-22%. Left ventricular enddiastolic pressure was consideraibly increased by 130%, dependent on the severity degree of coronary artery disease. Cardiac output and cardiac index were decreased at comparable heart rate by 20-33%, dependent on an effective decrease of stroke volume. Isovolumic indices of myocardial contractility (dp/dtmax, t-dp/dtmax, dpmax/IP) WERE REDUCED IN CORONARY HEART DISEASE PARALLEl to the severity degree of coronary artery stenosis. All the hemodynamic chances were most pronounced in a group with left ventricular aneurysm. The results demonstrate that myocardial performance in coronary heart disease is characterized by decreases of pump function and contractility in correlation with the severity degree of coronary artery stenosis.

[Coronary disease. II. Analysis of diastolic pressure-volume correlations and left ventricular elasticity in 110 patients]. / Zur koronaren Herzkrankheit II.: Eine Analyse diastolischer Druck-Volumen-Beziehungen und linksventrikulärer Dehnbarkeit an 110 Patienten

Left ventricular pressure-volume relationships as well as diastolic compliance were determined in 110 patients with coronary heart disease during routine right and left heart catheterization, coronary angiography and ventriculography. 1. Enddiastolic and endystolic volume of the left ventricle were increased in severe coronary heart disease dependent on the degree of coronary stenosis; left ventricular ejection fraction was consecutively reduced. 2. Left ventricular enddiastolic pressure, diastolic pressure difference and diastolic rate of pressure rise were increased in corrleation with coronary artery stenosis. In contrast, last diastolic volume inflow into the left ventricle was nearly the same in all groups. Left ventricular stiffness, expressed as dP/dV, was significantly increased dependent on the severity degree of coronary artery disease. 3. Diastolic pressure-volume relationships revealed greater steepness in coronary artery disease, significantly dependent, on the corresponding severity degree. 4. Hemodynamic measures (stroke volume, cardiac index, ejection fraction) were decreased parallel to the increased left ventricular wall stiffness. The results demonstrated decreased left ventricular compliance in coronary heart disease. There was a striking correlation between the severity degree of coronary heart disease and the decrease of left ventricular compliance. Validity and limitations of the techniques of estimating left ventricular compliance from diastolic pressures and volumes as well as the effects of a decrease of left ventricular compliance on cardiac mechanics are discussed.