A dialysis patient with fatigue and ascites.
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Ascites↗
Biomedical subjects
W Kramer
Publications and source records attributed to W Kramer.
Bile acid derived HMG-CoA reductase inhibitors.
The target organ for HMG-CoA reductase inhibitors to decrease cholesterol biosynthesis in hypercholesterolemic patients is the liver. Since bile acids undergo an enterohepatic circulation showing a strict organotropism for the liver and the small intestine, the structural elements of an inhibitor for HMG-CoA reductase were combined with those for specific molecular recognition of a bile acid molecule for selective uptake by hepatocytes. Either, the HMG-CoA reductase inhibitors HR 780 and mevinolin were covalently attached to 3 xi-(omega-aminoalkoxy)-7 alpha, 12 alpha-dihydroxy-5 beta-cholan-24-oic acids to obtain bile acid prodrugs, or the side chain of bile acids at C-17 was replaced by 3,5-dihydroxy-heptanoic acid--a structural element essential for inhibition of HMG-CoA reductase--to obtain hybrid bile acid: HMG-CoA reductase inhibitors. The prodrugs could, as expected, not inhibit rat liver HMG-CoA reductase to a significant extent, whereas the hybrid inhibitors showed a stereospecific inhibition of HMG-CoA reductase from rat liver microsomes with an IC50-value of 0.7 microM for the most potent compound S 2467 and 6 microM for its diastereomere S 2468. Uptake measurements with isolated rat hepatocytes and ileal brush-border membrane vesicles from rabbit small intestine revealed a specific interaction of both classes of bile acid-derived HMG-CoA reductase inhibitors with the hepatocyte and ileocyte bile acid uptake systems. Photoaffinity labeling studies using 3-azi- or 7-azi-derivatives of taurocholate with freshly isolated rat hepatocytes or rabbit ileal brush-border membrane vesicles revealed a specific interaction of bile acid derived HMG-CoA reductase inhibitors with the respective putative bile acid transporters in the liver and the ileum demonstrating the bile acid character of these derivatives, both for the prodrugs and the hybrids. Cholesterol biosynthesis in Hep G2 cells was inhibited by the bile acid prodrugs with IC50-values in the range of 68 nM to 600 nM compared to 13 nM for HR 780 and 130 nM for mevinolin. Among the hybrid inhibitors, S 2467 was the most active compound with an IC50-value of 16 microM compared to 55 microM for its diastereomere S 2468. Preliminary in vivo experiments showed an inhibition of hepatic cholesterol biosynthesis after oral dosage only with prodrugs such as S 3554, whereas the hybrid molecules were inactive after oral application.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Synthesis and biological activity of bile acid-derived HMG-CoA reductase inhibitors. The role of 21-methyl in recognition of HMG-CoA reductase and the ileal bile acid transport system.
To increase hepatoselectivity of HMG-CoA reductase inhibitors by using the specific bile acid transport systems, deoxycholic acid-derived inhibitors 9 and 11 have been synthesized, on the basis of the concept of combining in one molecule structural requirements for specific inhibition of the HMG-CoA reductase and specific recognition by the ileal bile acid transport system. The 1-methyl-3-carboxylpropyl subunit of deoxycholic acid was replaced by the 3,5-dihydroxyheptanoic acid lactone of lovastatin, and position 12-OH was esterified with 2-methylbutyric acid. Compounds 9 and 11 were evaluated for their inhibitory activity on rat liver HMG-CoA reductase, cholesterol biosynthesis in HEP G2 cells, and [3H]taurocholate uptake in rabbit brush border membrane vesicles and compared with methyl derivatives 8 and 10. The steroidal 21-CH3 group affects both activity on HMG-CoA reductase and recognition by the ileal bile acid transport system.
Androstanols↗
[Medical-social aspects of repatriation flights].
The increase of journeys abroad has led to a continual rise of international flights repatriating ill or injured persons. These repatriations flights are carried out by rescue organisations such as the German Air Rescue Organisation. A survey of the patients transported has been made in respect with the patient collective. The following factors were taken into accounts: the severity of condition with regulation aids of the NACA (National Advisory Committee for Aeronautics), used by the American Army. Together with medical and social indications an additional parameter had be considered. A questionnaire is available to access the social indications. A neutral observer is recommended to protect the interest of the patient, insurance company and the rescue organisation.
Adolescent↗
Platelet adhesion to collagen in individuals lacking glycoprotein IV.
The Naka isoantigen is expressed on glycoprotein (GP) IV (CD36), a platelet membrane GP that has been identified as having a role in platelet interactions with collagen and thrombospondin and in binding Plasmodium falciparum-infected erythrocytes to endothelial cells and melanoma cells. We have studied normal platelets and Naka- platelets from two Japanese donors that have 1% of GPIV by concentration-dependent antibody binding and flow cytometry. We studied the adherence of normal and Naka- platelets to types I, III, and IV collagen in static and to type I collagen in flowing systems at high shear force. We have also studied aggregation of normal and Naka- platelets to type I collagen. Naka- platelets showed normal or increased aggregation to type I collagen and normal adhesion to types I, III, and IV collagen in the presence of Mg++ or EDTA. Platelet aggregation and adhesion were inhibited by the anti-alpha 2 beta 1 antibody 176D7 to the same extent in Naka- as in normal platelets. We also studied endogenous thrombospondin surface expression and found that thrombin-stimulated Naka- platelets expressed the same amount of thrombospondin as did normal platelets. From our studies with Naka- platelets, we cannot identify a definitive role for GPIV in platelet aggregation, in adhesion to types I, III, and IV collagen, or in endogenous thrombospondin binding to platelets.
Antigens, CD↗
Differential interaction of glimepiride and glibenclamide with the beta-cell sulfonylurea receptor. I. Binding characteristics.
Glimepiride is a novel sulfonylurea drug for treatment of non-insulin-dependent diabetes mellitus with higher blood sugar lowering efficacy in diabetic patients than glibenclamide raising the question whether this characteristics is in line with different binding of glimepiride and glibenclamide to the beta-cell sulfonylurea receptor. Scatchard plot analysis of [3H]sulfonylurea binding to membranes isolated from rat beta-cell tumors and (RINm5F) insulinoma cells and to RINm5F cells demonstrated that glimepiride has a 2.5-3-fold lower affinity than glibenclamide. This corresponded well to the 8-9-fold higher koff and 2.5-3-fold higher kon rates of glimepiride compared to glibenclamide as revealed by the dissociation and association kinetics of [3H]sulfonylurea binding and the Kd values calculated thereof. In agreement, the concentrations required for half-maximal displacement of [3H]sulfonylurea bound to beta-cell membranes were significantly higher for glimepiride compared to glibenclamide. However, the binding affinity of glimepiride measured by both equilibrium binding and kinetic binding studies upon solubilization of beta-cell tumor membranes and RINm5F cell membranes increased up to the value for glibenclamide. This was primarily based on a drastic decrease of the dissociation rate constant of glimepiride whereas the kinetics of glibenclamide binding remained largely unaffected upon solubilization. These data suggest that the Kd value alone is not sufficient for characterization of a sulfonylurea drug, since the kinetic binding parameters may also determine its acute blood sugar lowering efficacy.
ATP-Binding Cassette Transporters↗
Differential interaction of glimepiride and glibenclamide with the beta-cell sulfonylurea receptor. II. Photoaffinity labeling of a 65 kDa protein by [3H]glimepiride.
Glimepiride is a novel sulfonylurea for the treatment of type II-diabetic patients exhibiting different receptor binding kinetics to beta-cell membranes with 8-9-fold higher koff rate and 2.5-3-fold higher kon rate compared to glibenclamide (see accompanying paper (Müller, G. et al. (1994) Biochim. Biophys. Acta 1191, 267-277)). To elucidate the molecular basis for this differential behaviour of glimepiride and glibenclamide, direct photoaffinity labeling studies using beta-cell tumor membranes were performed. [3H]Glimepiride was specifically incorporated into a membrane polypeptide of M(r) = 65,000 under conditions, which led to predominant labeling of a 140 kDa protein by [3H]glibenclamide (Kramer, W. et al. (1988) FEBS Lett. 229, 355-359). Labeling of the 140 kDa protein by [3H]glibenclamide was inhibited by unlabeled glimepiride and, vice versa, glibenclamide inhibited labeling of the 65 kDa protein by [3H]glimepiride. The 65 kDa protein was also specifically photolabeled by the sulfonylurea [125I]35623, whereas an 4-azidobenzoyl derivative of glibenclamide, N3-[3H]33055, exclusively labeled a 33 kDa protein. Competitive Scatchard analysis of [3H]glimepiride-binding and [3H]glibenclamide-binding to RINm5F cell membranes using glibenclamide and glimepiride, respectively, as heterologous displacing compounds yielded non-linear plots. These findings may be explained by cooperative interactions between the 140 and 65 kDa sulfonylurea-binding proteins. The possibility that sulfonylureas of different structure have different access to the 140 and 65 kDa receptor proteins due to the beta-cell membrane barrier was investigated by photoaffinity labeling of solubilized beta-cell membrane proteins. Interestingly, solubilization of beta-cell tumor membranes led to a shift of specific [3H]glibenclamide binding from the 140 kDa to the 65 kDa binding protein, exclusively, and to an increased labeling of the 65 kDa protein by [3H]glimepiride. The labeling of a unique protein is in agreement with similar Kd values measured for both sulfonylureas upon solubilization of beta-cell tumor and RINm5F cell membranes (see accompanying paper). Furthermore, competitive Scatchard plots of [3H]glimepiride binding to solubilized RINm5F cell membrane proteins in the presence of glibenclamide and vice versa approximate linearity suggesting loss of cooperativity between the 140 kDa glibenclamide-binding and 65 kDa glimepiride-binding proteins upon solubilization. The physiological significance of the differential interaction of glimepiride and glibenclamide with different binding proteins was also substantiated by photoaffinity labeling of RINm5F cells leading to labeling of a 140 kDa protein by [3H]glibenclamide and of a 65 kDa protein by [3H]glimepiride.(ABSTRACT TRUNCATED AT 400 WORDS)
ATP-Binding Cassette Transporters↗
Intestinal absorption of peptides by coupling to bile acids.
Poor intestinal absorption of peptides greatly limits their use as drugs for the treatment of chronic diseases. Since bile acids are efficiently absorbed by an active, Na(+)-dependent transport system in the ileum of mammals, model peptides of different chain length were attached to the 3-position of modified 3 beta-(omega-amino-alkoxy)-7 alpha, 12 alpha-dihydroxy-5 beta-cholan-24-oic acid. These peptide-bile acid conjugates inhibited Na(+)-dependent [3H]taurocholate uptake into brush-border membrane vesicles isolated from rabbit ileum in a concentration-dependent manner. Furthermore, photoaffinity labeling of the bile acid-binding proteins of M(r) 93,000 and 14,000, identified as the protein components of the ileal Na(+)-dependent bile acid transport system in rabbit ileum (Kramer, W., Girbig, F., Gutjahr, U., Kowalewski, S., Jouvenal, K., Müller, G., Tripier, D., and Wess, G. (1993) J. Biol. Chem. 268, 18035-18046) by the photoreactive taurocholate analogue, (3,3-azo-7 alpha, 12 alpha-dihydroxy-5 beta [7 beta, -12 beta-3H]cholan-24-oyl)-2-aminoethanesulfonic acid, was inhibited by the peptide-bile acid conjugates. In contrast, the parent peptides and amino acids neither had a significant effect on [3H]taurocholate uptake by ileal brush-border membrane vesicles nor on photoaffinity labeling of the ileal bile acid-binding membrane proteins. The inhibitory effect of peptide-bile acid conjugates on [3H]taurocholate transport and photoaffinity labeling of the bile acid-binding proteins in rabbit ileal vesicles decreased with increasing chain length of the attached peptide radical. By in vivo ileum perfusion in anesthetized rats an intestinal absorption of the bile acid conjugate S3744 of the fluorescent oxaprolylpeptide 4-nitrobenzo-2-oxa-1,3-diazol-beta-Ala-Phe-5-Opr-Gly (S1037) and secretion of the intact compound into bile could be demonstrated, whereas the parent peptide S1037 or its t-butylester S4404 were not absorbed. The intestinal absorption of S3744 showed a similar temperature dependence as [3H]taurocholate absorption and was inhibited by the presence of taurocholate indicating a carrier-mediated uptake of S3744 via the ileal bile acid transporter. In conclusion, these results indicate that oligopeptides can be made enterally absorable by coupling to modified bile acid molecules making use of the specific intestinal absorption pathway for bile acids. This finding may be of great importance for the design and development of orally active peptide drugs.
Amino Acid Sequence↗
Specific inhibitors of ileal bile acid transport.
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Animals↗
Nimodipine in the management of preeclampsia: maternal and fetal effects.
OBJECTIVE: Our purpose was to determine the effects of orally administered nimodipine on selected maternal and fetal parameters in patients with preeclampsia. STUDY DESIGN: Ten consecutive patients were given 30 mg of nimodipine orally every 4 hours from admission until 24 hours after delivery. Maternal and fetal cerebral blood velocity, umbilical artery blood velocity, fetal heart rate variability, maternal blood pressure and heart rate, and transplacental passage of the drug were studied. All 10 patients were delivered within 24 hours of the first dose of nimodipine. RESULTS: There was an acute and significant reduction in the pulsatility index in the smaller diameter maternal cerebral arteries (ophthalmic and central retinal) and in the fetal middle cerebral artery. The umbilical artery systolic/diastolic ratio was also significantly reduced. Maternal blood pressure was controlled without the need for other antihypertensive medication, and although there was an increase in heart rate after administration of the drug, it was well tolerated. Nimodipine reached significant maternal and fetal levels within 2 hours. CONCLUSIONS: Nimodipine is rapidly absorbed after oral administration and has significant maternal and fetal cerebral vasodilator activity. It is an effective, easily administered antihypertensive agent when used in patients with preeclampsia.
Adult↗
Behavior of different suture materials in the urinary bladder of the rabbit with special reference to wound healing, epithelization and crystallization.
Five urinary bladder incisions were performed in 16 rabbits and the defects closed by plain catgut 4-0, chromic catgut 4-0, polypropylene 4-0, polyglactin 910 4-0 and polyglactin 910 8-0 in the form of an all-layer suture, thereby obtaining a total of 80 suture sites. The running sutures in 8 animals were reviewed by light microscopy after 1, 2, 7 and 15 weeks, and in 8 additional animals after 3 days, 1, 2, 7 and 15 weeks by scanning electron microscopy. Moreover, we analyzed and compared the autopsy findings on gross inspection, the urinary sediments and urinary cultures of the individual animals. Scanning electron-microscopic evaluations showed that epithelization of the intraluminal suture portions can be accomplished after 3 days already. Reduced suture strength and rapid absorption of the suture material prevent later postoperative incrustations. Light-microscopic inspection of the segments of the bladder wall bearing this suture material suggests that a minor inflammatory tissue response around the suture material--with polyglactin 910 8-0 in particular--is more likely to enhance regeneration of the tunica muscularis and to prevent formation of cysts than seen with a long-standing highly inflammatory tissue response around the suture site of catgut threads. In the animal experiment, the polyglactin 910 suture has shown sufficient firmness and proved to be superior to any other suture material as regards the reaction to foreign bodies and inclination to incrustation.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Diastolic dysfunction of the left ventricle in dialysis patients.
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Diastole↗
[Malignant lymphoma of the small intestine as a cause of small intestine perforation].
The malignant non-Hodgkin-lymphoma is the main cause of spontaneous extraduodenal small intestine perforation. This rare incidence occurs as a consequence of an enteropathic associated affection manifested extranodally, mostly in the higher part of the jejunum. The diagnosis is made after a spontaneous perforation. The risk of a recurrent perforation is high. In a female patient we made the diagnosis not before resecting the small intestine.
Aged↗
Intestinal bile acid absorption. Na(+)-dependent bile acid transport activity in rabbit small intestine correlates with the coexpression of an integral 93-kDa and a peripheral 14-kDa bile acid-binding membrane protein along the duodenum-ileum axis.
The anatomical localization of the Na+/bile acid cotransport system from rabbit small intestine was determined using brush border membrane vesicles prepared from eight different segments of the small intestine. Na(+)-dependent transport activity for bile acids, both for [3H]taurocholate and [3H]cholate, was found in the distal segment 8 only representing the terminal 12% of the small intestine. In contrast, the Na(+)-dependent D-glucose transporter and the H(+)-dependent oligopeptide transporter were found over the whole length of rabbit small intestine in all segments. Photoaffinity labeling with 7,7-azo- and 3,3-azo-derivatives of taurocholate with subsequent fluorographic detection of labeled polypeptides after one- and two-dimensional gel electrophoresis showed that an integral membrane polypeptide of M(r) 87,000 is present in the entire small intestine, whereas an integral membrane protein of M(r) 93,000 together with a peripheral membrane protein of M(r) 14,000 are exclusively expressed in the distal small intestine correlating with Na(+)-dependent bile acid transport activity. Photoaffinity labeling with the cationic bile acid derivative 1-(7,7-azo-3 alpha,12 alpha-dihydroxy-5 beta[3 beta-3H]cholan-24-oyl)-1,2- diaminoethane hydrochloride and 7,7-azo-3 alpha,12 beta-dihydroxy-5 beta[12 alpha-3H]cholan-24-oic acid did not result in a specific labeling of the above mentioned proteins, demonstrating their specificity for physiological bile acids. Photoaffinity labeling of the 93- and 14-kDa bile acid-binding proteins was strongly Na(+)-dependent. Significant labeling of the 93- and 14-kDa proteins occurred only in the presence of Na+ ions with maximal labeling above 100 mM [Na+] showing a parallel [Na+] dependence to transport activity. Inactivation of Na(+)-dependent [3H]taurocholate uptake by treatment of ileal brush border membrane vesicles with 4-nitrobenzo-2-oxa-1,3-diazol chloride led to a parallel decrease in the extent of photoaffinity labeling of both the 93- and 14-kDa protein. Sequence analysis of the membrane-bound 14-kDa bile acid-binding protein surprisingly revealed its identity with gastrotropin, a hydrophobic ligand-binding protein exclusively found in the cytosol from ileocytes and thought to be involved in the intracellular transport of bile acids from the brush border membrane to the basolateral pole of the ileocyte. In conclusion, the present studies suggest that both an integral 93- and a peripheral 14-kDa membrane protein, identified as gastrotropin, and both exclusively expressed in the terminal ileum, are essential components of the Na+/bile acid cotransport system in rabbit terminal ileum.
Affinity Labels↗
Interaction of the orally active dianionic cephalosporin cefixime with the uptake system for oligopeptides and alpha-amino-beta-lactam antibiotics in rabbit small intestine.
The uptake of two orally active beta-lactam antibiotics of different chemical structure, the zwitterionic alpha-aminocephalosporin cephalexin and the dianionic carboxymethoxyimino-cephalosporin cefixime, by brush border membrane vesicles obtained from rabbit small intestine and their molecular interaction with the H+/oligopeptide transport system were investigated. The uptake of both compounds was stimulated by an inwardly directed H(+)-gradient with a profound pH-maximum for cephalexin at pH 6outside and pH 7.4inside whereas cefixime uptake was maximal below pH 5outside. Modification of histidyl residues of membrane proteins led to a complete loss of pH dependence of transport of both cephalosporins. The uptake of cephalexin was competitively inhibited by cefixime and dipeptides and vice versa that of cefixime by cephalexin and dipeptides. The uptake of cefixime was trans-stimulated by cephalexin and glycyl-L-proline whereas cephalexin uptake could only be trans-stimulated by glycyl-L-proline, not by cefixime. Photoaffinity labeling with [3H]benzylpenicillin as a direct photoaffinity probe of the H+/oligopeptide transport system demonstrated a direct molecular interaction of both cephalexin and cefixime with this transporter in the pH range of 5-8. Thermal pretreatment of membrane vesicles inhibited the cephalexin transport system temperature-dependently, whereas cefixime uptake was not inhibited, but stimulated. Taken together we conclude that dianionic cephalosporins like cefixime bind to the transport system shared by oligopeptides and alpha-amino-beta-lactam antibiotics. Their transport across the enterocyte brush border membrane, however, may occur to a significant extent by a different transport system.
Animals↗
Effects of acetate on left ventricular function in hemodialysis patients.
Two approaches were chosen to assess the controversially debated influence of acetate on the heart in dialysis patients: (1) To separate acetate effects from influences of dialysis, acetate was infused in 12 chronic dialysis patients with normal systolic function on a dialysis-free day, and left ventricular (LV) function was assessed by LV pressure/volume loops. Hyperacetatemia (3-5 mmol/l) resulted in a decrease in LV preload (LV end-diastolic pressure decreased from 16 +/- 3 to 10 +/- 4 mm Hg, p < 0.01) but had no influence on LV contractility. (2) In 8 dialysis patients without cardiac disease, isovolemic acetate or bicarbonate dialysis was performed. During both procedures, there were comparable changes in serum electrolytes as well as in echocardiographic parameters. LV contractility measured by velocity of circumferential fiber shortening increased during acetate and bicarbonate dialysis (1.47 +/- 0.22 to 1.77 +/- 0.29, p < 0.01; 1.47 +/- 0.21 to 1.70 +/- 0.22 circ/s, p < 0.01). It is concluded that mild hyperacetatemia does not influence LV contractility and that dialysis-induced changes in serum electrolytes are responsible for the increase in LV contractility during dialysis. However, the pronounced acetate effect on LV preload implies considerable therapeutic implications.
Acetates↗
Follow-up of cardiac changes induced by anemia compensation in normotensive hemodialysis patients with left-ventricular hypertrophy.
28 anemic [hematocrit (Hct) < 25%] and normotensive patients on maintenance hemodialysis with uremia-associated left-ventricular (LV) hypertrophy were treated with recombinant human erythropoietin. Before correction of anemia, after 4 months at a target Hct of 35% and 16 months (Hct still 35%) patients were assessed by echocardiography and physical stress testing. Partial correction of anemia resulted in a decrease in the LV end-diastolic diameter from 52.6 +/- 3.4 SD mm to 49.6 +/- 3.4 mm at 4 months (p < 0.01) and 47.9 +/- 2.9 mm at 16 months (p < 0.001). Concomitantly there was a slight decrease of LV end-systolic diameter (30.4 +/- 3.1 vs. 32.6 +/- 3.5 mm, p < 0.05) and LV posterior wall thickness (12.1 +/- 0.9 vs. 12.8 +/- 0.8 mm, p < 0.05) at 16 months. The calculated LV muscle mass index was reduced from 199 +/- 35 g/m2 to 173 +/- 34 g/m2 at 4 months (p < 0.01) and 160 +/- 28 g/m2 at 16 months (p < 0.001). Heart rate at rest was reduced significantly from 80 +/- 12 to 73 +/- 11 min (p < 0.01) at 4 and 16 months. LV ejection fraction, thickness of LV septum and blood pressure did not change. Partial correction of anemia led to an increase of maximal physical stress tolerance from 1.4 +/- 0.4 to 1.85 +/- 0.5 W/kg b.w. at 4 months (p < 0.01), which was maintained at 16 months.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Options in dialysis therapy: significance of cardiovascular findings.
Most patients receiving renal replacement therapy have cardiovascular disease. The most frequent conditions are left ventricular hypertrophy and coronary artery disease. Hemodialysis is associated with a characteristic spectrum of acute complications (such as hypotension, sudden death) that can be explained by typical dialysis-induced effects on the heart. With continuous ambulatory peritoneal dialysis (CAPD) some of those cardiovascular complications are ameliorated due to slow ultra-filtration and absence of an arteriovenous fistula. It is concluded that CAPD might be the preferable option in patients with cardiovascular disease when hemodialysis can only be performed in a standardized and often aggressive manner. However, achievement of medically-defined goals appears to be more important than technique in dialysis therapy.
Cardiovascular Diseases↗