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PubMed1988

Nonlinear intestinal first-pass metabolism of salicylamide in dogs after portacaval transposition.

The dose-dependent first-pass metabolism and pharmacokinetics of salicylamide (SAM) were studied at four dose levels in dogs before and after portacaval transposition. Four minutes after each p.o. dose, a tracer dose of [14C]SAM was given i.v. to determine clearance and bioavailability. Over the dosage range studied pretransposition, 5 to 40 mg/kg, bioavailability increased from 0.24 +/- 0.14 (mean +/- S.D.) to 0.76 +/- 0.20 (P less than .05). Clearance decreased from 3.4 +/- 1.0 to 0.6 +/- 0.11 liter/min (P less than .01) and half-life increased from 5.0 +/- 1.2 to 23.5 +/- 6.1 min (P less than .01). Over the dosage range studied post-transposition, 1.5 to 20 mg/kg, bioavailability increased from 0.31 +/- 0.09 to 0.99 +/- 0.08. Clearance and half-life had the same values and showed the same dose-dependence as in the normal dogs. The amount of SAM removed by the intestine during first-pass remained constant at about 1 mg/kg over the dose range given to the post-transposition animals. Therefore, although more easily saturable than the liver, the intestine plays an important role in first-pass metabolism of low p.o. doses of SAM. In contrast to previous results in the normal dog, the p.o. coadministration of sodium sulfate did not reduce the bioavailability of SAM in transposed dogs. This indicates that the nonlinear intestinal first-pass metabolism of SAM is not due to the depletion of the cosubstrate precursor, inorganic sulfate.

Administration, Oral↗
PubMed1987

[Musical systolic murmur produced by oscillation of the systolic anterior motion of the mitral apparatus: relation to the genesis of Still's murmur].

The genesis of a musical systolic murmur produced by systolic anterior motion (SAM) of the mitral apparatus was investigated in four patients using phonocardiography and echocardiography. Two patients (Case 1 and 3) had hypertrophic cardiomyopathy (one, the obstructive type; the other, the nonobstructive type) and the remaining two (Case 2 and 4) had redundant chordae tendineae. 1. In every patient, regular oscillation of the SAM was observed, coinciding in time with the musical systolic murmur, which was simultaneously recorded. The fundamental frequency of the musical systolic murmur was recorded as integrally multiplied numbers of the SAM. Such regular oscillation was not observed in the echograms of other cardiac structures. In a patient with hypertrophic obstructive cardiomyopathy (Case 1), both the amplitude and oscillation of the SAM were increased by amyl nitrite inhalation, and were decreased by angiotensin II infusion. Correspondingly, the intensity of the musical murmur showed similar reaction. No findings suggestive of mitral valve prolapse or mitral regurgitation were found in any patients. Therefore, the oscillation of the SAM produced by blood ejected from the left ventricle was considered the source of the musical systolic murmur in these patients. 2. Two patients with redundant chordae tendineae had no clinical abnormalities except for chordal redundancy; therefore, the musical murmur in these cases was considered to be functional. Particularly, one of them was compatible in character with the so-called Still's murmur. In conclusion, the regular oscillation of the SAM may be the source of the musical systolic murmur, and they must be taken into consideration as part of the genesis of Still's murmur.

Adolescent↗
PubMed1987

Enhancement of macrophage and monocyte cytotoxicity by the surface active material of lung lining fluid.

The surface active material (SAM) of alveolar lining fluid has been shown to have immunologic activity. We studied the effect of SAM on monocyte-macrophage cytotoxicity against a tumor cell line. Alveolar macrophages were studied from 15 subjects without cancer. Tumor growth, as assessed by tritiated thymidine incorporation, was significantly inhibited by the macrophages alone (tumor alone median 39,401 cpm, macrophages plus tumor median 12,153 cpm, P less than 0.01). Tumor cytotoxicity was enhanced by preincubating the macrophages with lipopolysaccharide (median 37 cpm, P less than 0.01) or coincubating the tumor cells and macrophages with SAM (median 5474 cpm, P less than 0.01). Similar results were seen when using blood adherent mononuclear cells. There was increasing cytotoxicity for the adherent mononuclear cells with increasing amounts of SAM. When the various phospholipids of SAM were studied, it was found that phosphatidylcholine, sphingomyelin, and phosphatidyl glycerol all enhanced adherent mononuclear cell cytotoxicity, whereas phosphatidylinositol inhibited adherent mononuclear cell cytotoxicity. These studies suggest that SAM may have important immunoregulatory function for the alveolar macrophage.

Cell Line↗
PubMed1979

[Echocardiographic diagnosis of obstructive myocardiopathies: study of the systolic anterior motion of the mitral valve and septal hypertrophy as compared with the hemodynamic and mechanographic findings. Evolution under medical treatment].

Characteristic echocardiographic features of hypertrophic obstructive cardiomyopathy were recorded in 24 patients, all of whom had asymmetric septal hypertrophy and systolic anterior motion of the mitral valve (SAM) at rest or after pharmacodynamic stimulation. The relationship between outflow tract obstruction and SAM was assessed by comparison with data obtained at cardiac catheterisation and external mechanography: SAM seems to be a non-specific phenomenon and may be recorded in cases of hypertrophic cardiomyopathy without obstruction during pharmacodynamic stimulation. In forms with obstruction, SAM and the severity of obstruction increase with the degree of spetal hypertrophy. The increased contractility of the left ventricular posterior wall appears to be an important factor in the mechanism of SAM which can be prevented by betablockade in moderate or labile forms. When SAM is permanent, whatever the gradient recorded, it is a sign of anatomical deformation of the left ventricle and may be an additional indication for cardiac surgery.

Adrenergic beta-Antagonists↗
PubMed1984

Dose-dependent bioavailability and metabolism of salicylamide in dogs.

The dose-dependent first-pass metabolism and pharmacokinetics of salicylamide (SAM) were studied at four dose levels in six dogs. Four minutes after each oral dose, a tracer dose of [14C]SAM was given i.v. to determine clearance and bioavailability. Over the dosage range studied, 5 to 40 mg/kg, bioavailability increased from 0.24 +/- 0.14 (mean +/- S.D.) to 0.76 +/- 0.20 (P less than .05). Clearance decreased from 3.4 +/- 1.0 to 0.60 +/- 0.11 liters/min (P less than .01) and half-life increased from 5.0 +/- 1.2 to 23.5 +/- 6.1 min (P less than .01). Measurement of SAM clearance to individual metabolites indicated that the sulfoconjugation and not the glucuronidation pathway was responsible for the dose-dependent effects observed. These effects occurred even at doses not expected to have caused significant depletion of body stores of inorganic sulfate; the plasma concentration of inorganic sulfate decreased by only a maximum of 13 and 26% after the 5- and 10-mg/kg SAM doses, respectively. When [14C]SAM was given alone in tracer amounts, clearance values greatly exceeded cardiac output. This suggests that SAM undergoes sulfation in organs other than the liver and intestinal wall.

Animals↗
PubMed1982

[Swine alveolar macrophages: description and functional analysis].

Swine alveolar macrophages (SAM) were characterized according to several properties: this spherical cell is able to adhere in vitro to plastic and glass substrata. Its size varies from 10 to 20 mu; on the cytochemistry level, up to 85% SAM appear to be peroxidase-negative, whereas they are all esterase-positive. The SAM phagocytic capacities were investigated by using three different substrata: zymosan, chicken red blood cells and Listeria monocytogenes. SAM were also characterized by their "accessory" function in mitogen-induced lymphocyte proliferation: under our experimental conditions SAM were not shown to be able to inhibit PHA-induced blood lymphocyte proliferation, as was shown for some other animal species. Finally, in an antibody-dependent cell-mediated cytotoxicity test (ADCC), SAM were shown to be inactive although swine blood monocytes were cytotoxic.

Animals↗
PubMed1983

Intestinal absorption of S-adenosyl-L-methionine in humans.

S-adenosyl-L-methionine (SAM) has proven to be fairly stable in gastric and duodenal juices as well as in bile. It was, therefore, administered orally to six healthy subjects. No increase in SAM levels was observed in the systemic blood. SAM was then directly injected into a jejunal loop of nine patients undergoing cholecystectomy. SAM concentrations increased significantly in venous mesenteric and systemic blood. Infusions of methionine directly into the jejunum by the same method used for SAM did not induce any increase in SAM concentrations in the mesenteric or systemic blood.

Female↗
PubMed1993

Isolation of the complementary DNA encoding a mouse heparin-binding growth factor receptor with the use of a unique kinase insert sequence.

With the use of reverse transcriptase-polymerase chain reaction techniques focused on a unique kinase insert sequence, the complementary DNA for a mouse tyrosine kinase receptor gene, designated sam3, was isolated from a mouse brain complementary DNA library as a member of the heparin-binding growth factor receptor family or fibroblast growth factor receptor family. The kinase insert region was selected as the probe synthesized by polymerase chain reaction techniques because it composes a unique structure in this receptor family. The sam3 protein, 800 amino acids long, has high homology to mouse K-sam/bek (67%) and N-sam/flg (63%), which we also cloned as the mouse counterparts of human K-sam/bek and N-sam/flg genes, other members of this family. The sam3 protein also has high homology to human FGFR3 (92%) and chicken cek2 (80%) proteins. The sam3 protein is most likely to be a mouse counterpart of human FGFR3 and chicken cek2 proteins. mRNAs of K-sam/bek, N-sam/flg, and sam3/FGFR3 genes were detected in mouse embryo through some adult tissues. The relative amounts of these mRNAs were different depending on the organs examined. Thus, these gene products may have different biological functions in organ development including the central nervous system.

Amino Acid Sequence↗
PubMed1996

Left ventricular outflow tract obstruction in hypertrophic cardiomyopathy: presurgical and postsurgical evaluation by computed tomography magnetic resonance imaging.

Along with hypertrophy of the left ventricle (LV), hypertrophic cardiomyopathy (HC) is characterized by LV outflow tract (LVOT) obstruction, partly from systolic anterior motion (SAM) of the anterior mitral leaflet; if obstruction is significant, excision of excess subaortic septal myocardium may be indicated. In this study, the ability of computed tomography magnetic resonance imaging (Cine MRI) to provide information about LVOT obstruction was assessed in a series of 37 HC cases undergoing evaluation, including echocardiography (0 to 14 days before), for possible septal myectomy; in 4 cases, Cine MRI was used postsurgically (5 to 25 months after). Blinded to echocardiography results, 3 reviewers analyzed by consensus the Cine-MRI LVOT-long-axis image-loops for SAM grade (none, mild, severe) and "aorta:LVOT signal ratio" (intensity in descending aorta/intensity in LVOT at maximum systolic-flow disturbance). Resting LVOT flow velocities were separately determined using Doppler analysis, permitting differentiation between insignificant (< 30 mm Hg) and significant (< or = 30 mm Hg) gradients. With echocardiography, significant resting obstruction was found in 62% of cases, including 92% treated surgically. A significant association between SAM grade and obstruction was found; all cases with a SAM grade of none had insignificant ([-] predictive value: 100%) and most with a severe grade had significant ([+] predictive value: 78%) obstruction. Signal ratio in the absence of a significant gradient was significantly lower than in its presence; a significant linear relationship between aorta:LVOT signal ratio and resting gradient was found: LVOT gradient = ([2.9] x [signal ratio]) + 22.8. SAM grade did not contribute significantly in obstruction categorization when signal ratio was known. In all cases studied after surgery, SAM grade had decreased from severe to insignificant levels and aorta:LVOT signal ratio had been significantly reduced. Insights into the dynamic nature of the LVOT in HC patients can be provided by Cine MRI, either during their evaluation for surgery or after their septal myectomy.

Cardiomyopathy, Hypertrophic↗
PubMed1997

Prevention of amyloid-like deposition by a selective prolyl endopeptidase inhibitor, Y-29794, in senescence-accelerated mouse.

Our study was performed to assess the hypothesis that prolyl endopeptidase (PEP) would be functionally involved in the senescence-accelerated amyloid formation and that long-term inhibition of prolyl endopeptidase would suppress the progression of A beta-like deposition in the hippocampus of the senescence-accelerated mouse (SAM). Granular structures of A beta-LI were observed in the hippocampus and around cerebral microvessels of the SAM after immunohistochemical staining with specific anti-A beta antibody. Repeated treatment of the SAM with Y-29794 (1, 10, 20 mg/kg, p.o.), a specific inhibitor of prolyl endopeptidase, significantly reduced the number and density of A beta-positive granular structures in the hippocampus of the SAM, after digital image analysis with NIH Image software. Furthermore, the characteristic biphasic distribution of the digitized density of the granules was significantly modulated after the treatment with Y-29794. These results suggest that chronic treatment of the SAM with Y-29794, a nonpeptide inhibitor of prolyl endopeptidase, prevents the progression of A beta-like deposition in the hippocampus of the SAM.

Aging↗
PubMed1996

Rapid in vitro tests of surfactant film formation: advantages of the Exerowa black film method.

Based on our research, the natural configuration of surfactant from birth through adulthood takes the form of intraalveolar bubbles. Thus, bubble film analysis would seem to be the specific in vitro testing method for lung surfactant. In the present study we report a battery of five in vitro tests for assessing structural and functional properties of surfactant bubbles and bubble films from hydrophobic extracts, namely, the therapeutic surfactants Survanta (SU) and Infasurf (IN) (full strength and diluted to 3 mg phospholipid/mL) and from aqueous extracts from rabbit lung lavage at 3 mg phospholipid/mL (SAM). Each substrate was assessed by: 1) Shake test: stable bubbles from SU, IN, and SAM (50/50, v/v in 95% ethanol) covered the peripheral surfaces, indicating positive response; bubble production by IN and SAM always exceeded SU; 2) Click test: bubble clicking began immediately in all preparations except for undiluted SU, in which the onset of clicking was delayed more than 40 sec; 3) Pattle's stability test: diameters of SU, IN, and SAM bubbles were unchanged for more than 20 min in aerated solution, indicating stable very low surface tension; 4) bubble generation by gas dispersion from a single capillary: full-strength concentration of SU and IN produced relatively large bubbles-bubble rate (number/min) and size were comparable; all SU bubbles rupture in < 25 min, whereas IN bubbles were stable for > 30 min; and 5) Exerowa black film method: in contrast with each of the preceding methods for studying intact bubbles, the Exerowa method focuses on the contact between bubble films and permits direct observation of film formation and determination of film structure. Stable black films were formed spontaneously by both IN (full strength and diluted) and SAM. Conversely, SU (full strength) formed no black films but stable rheological films. Diluted SU films ruptured in 50% of trials. Since methods 1, 2, and 3 were nondiscriminatory and method 4 produced unphysiologically large bubbles for most mammals, we concluded that the black film method of Exerowa is the most discriminating of the tests studied here. It provides a unique visual record of foam film formation and stability and clearly defines differences relative to both the nature and concentration of the preparations.

Animals↗
PubMed1984

An evaluation of two-dimensional echocardiography in the diagnosis of hypertrophic cardiomyopathy.

Various anatomical and functional features of hypertrophic cardiomyopathy are analyzed in view of the data provided by two-dimensional echocardiography. Measurement of septal thickness is crucial, and is best done by a combination of M-Mode and 2-D echo. Two types of systolic anterior movement of the mitral valve (SAM) are observed and are related to the degree of subvalvular gradient. The specificity of these patterns of SAM is analyzed. The functional anatomy of the mitral valve in relation to the presence and degree of mitral regurgitation shows that although the presence and type of SAM are important, there are other causes of mitral regurgitation in hypertrophic cardiomyopathy unrelated to SAM. We emphasize the fact the 2-D echo cannot "diagnose" hypertrophic cardiomyopathy except when cardiac hypertrophy plus SAM involving the body of the mitral valve is seen; in the remaining cases, 2-D echo confirms/suggests the clinical diagnosis.

Cardiomyopathy, Hypertrophic↗
PubMed2004

Determination of the heterogeneous association constants of metal ions to omega-mercaptoalkanoic acids by using double-layer capacity measurements.

The binding of metal ions to ligands in homogeneous solutions and that to the same ligands anchored to metallic surfaces through self-assembled monolayers (SAMs) are expected to differ primarily due to the difference in the degree of freedom of the ligands and the surface potential. We studied the heterogeneous binding of CdII ions to omega-mercaptoalkanoic-acid SAMs on Au. This was accomplished by adding metal ions at a constant pH and following the changes in the double-layer capacity. A mathematical treatment, which is based on calculating the electrochemical-potential differences at the double layer-solution interface, has been developed. Our approach follows that proposed by White et al. and Kakiuchi, who used the acid-base equilibrium at the monolayer-electrolyte interface as a means of calculating the pK of ionizable SAMs. Experimentally, SAMs of omega-mercaptoalkanoic acids, HS(CH2)nCO2H, with different chain lengths (i.e., n=2, 5, and 10) in 0.1 M sodium perchlorate were assembled on Au surfaces and studied. The capacity was measured first in the absence of CdII at different pH values, and then at a constant pH while increasing the concentration of CdII in the solution. We found that the interfacial capacity decreased as the concentration (of either protons or CdII) increased. The results matched the model fairly well, which allowed the extraction of the thermodynamic equilibrium constant that is established at the monolayer-electrolyte interface. The suggested mathematical treatment of this model system is simple and yet very useful for estimating the heterogeneous association constants of metal ions by SAMs.

Journal Article↗
PubMed1997

Effects of S-adenosyl-L-methionine on hepatic and renal oxidative stress in an experimental model of acute biliary obstruction in rats.

We used an animal model of extrahepatic biliary obstruction of 7 days' duration to study the production of thiobarbituric acid reactive substances (TBARS), total glutathione (TG), reduced glutathione (GSH), and oxidized glutathione (GSSG), and the enzymatic activities of GSH-peroxidase, GSSG-reductase, and GSH-transferase. Four groups of six rats each were treated with saline, drug solvent, S-adenosyl-L-methionine (SAM) 5 mg/kg/d, subcutaneously, or SAM 10 mg/kg/d, subcutaneously. Extrahepatic biliary obstruction increased TBARS. SAM had the dose-dependent effects of inhibiting TBARS production and increasing TG content, mainly as a result of the increase in GSH. The activity of GSH-peroxidase and GSH-transferase was also significantly increased. In renal tissue these effects were statistically significant only in animals given the higher dose of SAM. In liver we found a reduction in biochemical values indicative of liver damage. We conclude that effect of SAM on hepatorenal function is strongly influenced by the drug's ability to reestablish equilibrium after oxidative tissue stress.

Animals↗
PubMed1995

Contact activation of the plasma coagulation cascade. I. Procoagulant surface chemistry and energy.

Contact activation of the intrinsic pathway of porcine blood plasma coagulation is shown to be a steep exponential-like function of procoagulant surface energy, with low activation observed for poorly water-wettable surfaces and very high activation for fully water-wettable surfaces. Test procoagulants studied were a system of oxidized polystyrene films with varying wettability (surface energy) and glass discs bearing close-packed self-assembled silane monolayers (SAMs) with well-defined chemistry consisting of 12 different terminating chemical functionalities. A monotonic trend of increasing coagulation activation with increasing water wettability was observed for the oxidized polystyrene system whereas results with SAM procoagulants suggested a level of chemical specificity over and above the surface energy trend. In particular, it was noted that coagulation activation by SAMs terminated with--CO2H was much higher than anticipated based on surface wettability whereas--NH3(+)-terminated SAMs exhibited very low procoagulant activity. SAMs terminated in--(CH2)2(CF2)7CF3 behaved as anticipated based on surface energy with very low procoagulant activity and did not exhibit special properties sometimes attributed to perfluorinated compounds. Quantitative ranking of the inherent coagulation activation properties of procoagulant surfaces was obtained by application of a straightforward phenomenological model expressed in a closed-form mathematical equation relating coagulation time to procoagulant surface area. Fit of the model with a single adjustable parameter to experimental measurements of porcine platelet-poor plasma coagulation time was very good, implying that assertions and simplifications of the model adequately simulated reality. Two important propositions of the model were that (1) the number of putative "activating sites" scaled linearly with procoagulant surface area, and (2) contact activation of the plasma coagulation cascade was catalytic in the sense that these activating sites were not consumed or "poisoned" by irreversible or slowly reversible protein adsorption during coagulation. An extension of the coagulation model proposed that procoagulant activation properties scale exponentially with the surface density of polar (acid-base) sites, which, in turn, was related to procoagulant wettability.

Animals↗
PubMed2003

Deposition of complement protein C3b on mixed self-assembled monolayers carrying surface hydroxyl and methyl groups studied by surface plasmon resonance.

Since complement activation is recognized as a common response of the host defense system when an artificial medical device is applied to a patient, great effort has been devoted to studies on the interaction of the complement system with artificial materials. However, some uncertainties remain, partially because of the lack of well characterized surfaces and suitable analytic methods for study of the surface phenomena that occur on artificial materials under physiologic conditions. In this study, we employed self-assembled monolayers (SAMs) and the surface plasmon resonance (SPR) technique to study interactions of the serum complement with well characterized surfaces. Self-assembled monolayers carrying various concentrations of hydroxyl groups were prepared using 11-mercapto-1-undecanol (C11-OH) and one of n-nonanethiol, n-dodecanethiol, and n-hexadecanethiol. The amount of NHS deposition on the SAMs increased with increasing C11-OH content of the SAMs, and the amount of anti-C3b antibody immobilization formed on the NHS deposition layers increased with increasing C11-OH content of the SAMs. These results clearly demonstrate that a large amount of C3b, produced through the activation of the complement system, binds covalently to and is adsorbed by hydroxyl-group-rich surfaces. The combination of SAMs and the SPR technique is suitable for studying the interaction of the complement system with solid surfaces, and the results should give basic information needed for a rational design of biocompatible surfaces on synthetic materials.

Autoantibodies↗
PubMed2003

Protein adsorption on mixtures of hydroxyl- and methyl-terminated alkanethiols self-assembled monolayers.

The effect of surface composition and wettability on the adsorption of human serum albumin (HSA) was studied. Self-assembled monolayers (SAMs) containing mixtures of longer chain methyl- and shorter chain hydroxyl-terminated alkanethiols on gold were used to produce a range of surfaces with different wettabilities and exposed functional groups. Different SAMs were characterized by X-ray photoelectron spectroscopy, water contact angles, and Fourier transform infrared reflection absorption spectroscopy (IRAS). HSA adsorption onto the different SAMs was evaluated by contact angle measurements (wetting tension determinations), radiolabeling of proteins, and IRAS. Concerning HSA adsorption, all the techniques demonstrated higher HSA adsorption on more hydrophobic surfaces. The wetting tension measurements and IRAS suggested a gradual decrease of the HSA adsorption with increases of surface hydrophilicity. Radiolabeled albumin measurements also demonstrated a significant decrease of HSA adsorption on the pure hydroxyl-terminated SAMs. However, no significant differences were detected between mixed and pure methyl-terminated SAMs. Studies of HSA exchangeability with human fibrinogen have suggested that an ideal percentage of hydroxyl groups on the surface may increase albumin affinity without fibrinogen adsorption.

Adsorption↗
PubMed2003

Investigation of elasto-mechanical properties of alginate microcapsules by scanning acoustic microscopy.

High-frequency scanning acoustic microscopy (SAM) was used for investigation of acoustic impedance and 3D-surface topography of full alginate microspheres that act as model of artificial biological cells. Elasto-mechanical properties of the investigated specimens have been characterized by acoustic impedance. Mean surface impedance of microspheres (diameter: 300 microm) was measured with SAM at 900 MHz with a spatial resolution of 1.5 microm. The sensitivity and reproducibility of SAM had to be increased considerable to receive and quantify signals in the very low impedance region. The multilayer analysis method was used to get quantitative data of acoustic impedance with SAM at a microscopic level. 3D images show details of structure and surface topography. As a reference, bulk measurements were performed on full alginate cylinders. The acoustical impedance and the mechanical stiffness c(11) were obtained from mass density and longitudinal ultrasound velocity at 6 MHz. The impedances received with both methods are in close agreement. The results demonstrate the SAM as a powerful tool for characterizing mechano-elastical parameters as well as surface structure and topography of microspheres with high spatial resolution.

Acoustics↗