The pharmacodynamics of i.v. and subcutaneous (s.c.) tinzaparin sodium compared with heparin in healthy volunteers were studied. A randomized, open-label, five-treatment, five-period-crossover study ...with a Latin square design was performed in 30 healthy men to estimate tinzaparin pharmacodynamics (anti-Xa and anti-IIa activities) after single-dose i.v. and s.c. administration, to evaluate absolute bioavailability, to determine the effect of a preservative (benzyl alcohol), to evaluate the dose-activity relationship, and to compare tinzaparin with unfractionated heparin. Treatments were (1) heparin 5,000 units s.c., (2) tinzaparin 4,500 anti-Xa IU without preservative s.c., (3) tinzaparin 4,500 anti-Xa IU without preservative i.v., (4) tinzaparin 12,250 anti-Xa IU with preservative s.c., and (5) tinzaparin 4,500 anti-Xa IU with preservative s.c. Blood samples for the measurement of anti-Xa and anti-IIa activities were drawn over 24 hours. Anti-Xa and anti-IIa activities were determined by chromogenic methods; data were analyzed by using a noncompartmental approach. The clearance of tinzaparin based on anti-Xa activity ranged from 1.14 to 2.04 L/hr. The volume of distribution was 3.1-5.0 L, suggesting that the molecular entities responsible for anti-Xa and anti-IIa activities are confined to the intravascular space. Mean peak anti-Xa activity occurred three to four hours after s.c. injection, independent of the dose. The mean half-life of anti-Xa activity after s.c. injection ranged from 3.41 to 4.13 hours and was independent of the dose. The mean absolute bioavailability of s.c. tinzaparin was 86.7%. Intersubject pharmacodynamic variability was low for tinzaparin compared with heparin. Benzyl alcohol did not affect tinzaparin pharmacodynamics. A clear dose-activity relationship was seen for the two fixed doses of tinzaparin (12,250 and 4,500 IU). Single doses of tinzaparin were safe and well tolerated after administration by either route. The anti-Xa profile of tinzaparin supports the pharmacodynamic superiority of low-molecular-weight heparins over standard i.v. heparin administration. This pharmacodynamic study in healthy volunteers indicates that s.c. tinzaparin sodium was well absorbed; the presence of a preservative, benzyl alcohol, did not affect the activity of tinzaparin; and tinzaparin activity is dose-related.
The covalent structures of two, novel, neutrophile, leucocyte-derived, strongly basic proteins of porcine and human origin have been determined by microsequencing in combination with time-of-flight ...plasma desorption mass spectrometry. The porcine protein primary structure of 219 amino acid residues was shown to contain 6 cysteine residues, 2 putative carbohydrate sites and 14% basic residues. The human protein contained 221 amino acid residues of which 8 were cysteine, 4 putative carbohydrate sites and 12% basic. A 47% direct sequence similarity to human neutrophile elastase was found, but due to mutations of two of the three amino acids in the catalytic triad, proteolytic activity is absent. Modelling and alignment studies unveil a close relationship of both proteins to the serine protease family, the greatest similarity being to those serine proteases present in granules from peripheral blood cells. Both proteins have been shown to be chemotactically active for monocytes and fibroblasts in vitro.
Since detailed knowledge about velocity fields downstream of heart valve prostheses obtained from in vitro studies has not been followed up by similar detailed studies in vivo a pig model for acute ...velocity field studies downstream of aortic valve prostheses was established. Two mechanical and two bioprosthetic valves were studied and a dynamic three dimensional visualisation of velocity fields one diameter downstream performed under different haemodynamic conditions in a total of 22 pigs. The Ionescu-Shiley pericardial valve had velocity fields very similar to the normal native porcine aortic valve. The Edwards-Carpentier porcine valve caused a jet type flow, and the valve design of the St Jude Medical and Björk-Shiley Monostrut valves was reflected in the velocity profile. Normalised (mean(SEM systolic Reynolds normal stresses in the total cross sectional area were: native porcine 15(1.5) Nm-2; St Jude Medical 24(3.4) Nm-2; Björk-Shiley Monostrut 25(1.6) Nm-2; Edwards-Carpentier Supra-annular 51(6.6) Nm-2; Ionescu-Shiley Pericardial 19(2.0) Nm-2. Reynolds normal stresses were higher in areas of rapidly changing or constantly high velocity gradients.
Since data on velocity fields in the ascending aorta downstream of normal aortic valves in pigs have not yet been obtained velocity profiles were visualised using a hot film anemometer needle probe ...before and after total cardiopulmonary bypass and cold cardioplegic arrest. Furthermore, measurements were made during increased heart rate and cardiac output. A dynamic three dimensional visualisation of velocity fields showed a skewed clockwise rotating velocity profile, developing from peak systole and continuing throughout the systolic deceleration phase. This pattern was consistent regardless of the haemodynamic state. Heart rate was increased to 180 beats.min-1 and cardiac output by a maximum of 91%. It is concluded that the pig model is valuable for haemodynamic studies in the ascending aorta before and after cold cardioplegic arrest and that the velocity profiles found in this study are important basic data for velocity field studies downstream of artificial heart valves implanted in the aortic position.
To study the local distribution of blood velocities in the abdominal aorta and trifurcation, hot-film anemometry was used for point blood velocity measurements in the entire cross-sectional area in ...the abdominal aorta and abdominal aortic trifurcation in pigs weighing 90 kg. The geometry was visualized by use of a casting procedure. General hemodynamic and geometric parameters in the abdominal aorta were comparable to values found in humans. The porcine trifurcation differed somewhat from the human bifurcation. The velocity measurements in the abdominal aorta showed consistently skewed velocity profiles with the highest velocities at the anterior vessel wall. No signs of developed turbulence were found. Velocity measurements in the external iliac vessels showed high velocities at the flow divider, and low velocities with signs of retrograde flow during part of diastole at the lateral vessel wall.
A line probe assay (GenoType MTBC) was evaluated for species differentiation within the Mycobacterium tuberculosis complex (MTBC). We included 387 MTBC isolates, 43 IS6110 low-copy MTBC isolates, 28 ...clinical specimens with varying microscopy grade, and 30 isolates of non-tuberculous mycobacteria. The assay was 100% specific and identified all 387 isolates and 98% of all IS6110 low-copy strains in concordance with the gold standard. The 2% discrepancy was caused by 1 isolate showing a faint restriction fragment length polymorphism (RFLP) pattern. The assay could provide specifies identification in 13 of 19 (68%) microscopy-positive specimens and 0 of 9 microscopy-negative specimens. To our surprise, the probe for M. africanum subtype I reacted with M. pinnipedii. This cross-reaction has not previously been reported. The assay was rapid, easy to perform and directly applicable in highly smear-positive specimens. We predict that the assay will enable enhanced surveillance of species-specific treatment outcome, which may change treatment regimens.
Because late valve-related complications such as hemolysis and thromboembolic events are considered related to flow disturbances caused by the inserted valve, velocity fields downstream of aortic ...valve prostheses were studied in pigs. Acute hemodynamic evaluation of size 25-mm porcine and pericardial aortic valve prostheses 1 diameter downstream of the valve ring was performed using dynamic three-dimensional visualization of velocity profiles and spatial distribution of turbulence. Point blood velocity signals obtained with a 1-mm hot-film anemometer needle probe were used to compute Reynolds normal stresses (RNS) by calculation of the turbulent velocity energy of the axial velocity component in the systole. The porcine valves caused a skewed velocity and turbulence profile revealing mean spatial systolic RNS at 70 nm-2 +/- 35 nm-2 (+/- SD). The spatial maximum RNS was 275 +/- 139 nm-2. Corresponding values for the pericardial valves were 20 +/- 11 nm-2 and 72 +/- 46 nm-2. The pericardial valves revealed plug-shaped velocity profiles and turbulent profiles with slightly higher RNS values at the stent posts. From a hemodynamic point of view, these acute studies indicate superiority of the pericardial valves compared to the porcine valves. The turbulent stresses found in this study are of a magnitude that may cause blood corpuscular and endothelial damage.
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