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1.
A. Goll H. Glossmann R. Mannhold 《Naunyn-Schmiedeberg's archives of pharmacology》1986,334(3):303-312
Summary Partially purified plasma membranes were prepared from cat ventricle. The purification factors for the calcium channel ligands (+)-3H-PN 200-110, 3H-nimodipine (1,4-dihydropyridines) and (–)-3-H-desmethoxyverapamil (a phenylalkylamine) were 3.1-, 3.4- and 2.9-fold, respectively, whilst -adrenoceptors labelled with (–)-3H-dihydroalprenolol were purified 3.0-fold.(+)-3H-PN 200-110 bound to 930±140 fmol/mg of membrane protein with a dissociation constant of 70 pmol/l at 25°C. Under the same conditions 3H-nimodipine bound to 490±24 fmol/mg of sites with a K
D of 120 pmol/l. (–)-3-H-desmethoxyverapamil bound to 530±55 fmol/mg of sites with a K
D of 2.47 nmol/l.Twelve 1,4-dihydropyridines were evaluated for binding inhibition constants (K
i) with (+)-3H-PN 200-110 and 13 phenylalkylamines with (–)-3-H-desmethoxyverapamil in radioligand binding assays. Of the twelve 1,4-dihydropyridines evaluated (±)-nitrendipine was the most potent with a K
i-value of 280 pmol/l, nifedipine had a K
i-value of 500 pmol/l and the weakest drug tested, (±)-Bay b4328, had a K
i-value of 14.3 nmol/l. The EC50-values of the same 1,4-dihydropyridines to inhibit the electrically driven cat papillary muscle were 77- to 3,450-fold higher and little correlation existed between K
i and EC50-values.Thirteen phenylakylamines were tested for their potency to inhibit (–)-3-H-desmethoxyverapamil binding. The most potent phenylalkylamine with respect to negative inotropy was (±)-D 595 with an EC50-value of 794 nmol/l, the least potent substance was (±)-Sz 45 with an EC50-value of 39.8 mol/l. The binding inhibition constants for the phenylalkylamines were 13-to 322-fold lower than the values for negative inotropy, but a significant positive correlation between the K
i and EC50-values (n=12, r=0.84) was observed. The absolute differences may reflect the state-dependent binding of phenylalkylamines to the channel.QSAR analysis revealed nearly identical correlations between physicochemical substituent properties on the one hand and binding affinities or functional potency on the other hand. In both cases the electronic properties (F-constant) of ring substituents mainly determine the variance in potency. 相似文献
2.
Fabian F Moebius Raphael J Reiter Markus Hanner Hartmut Glossmann 《British journal of pharmacology》1997,121(1):1-6
- The sigma-drug binding site of guinea-pig liver is carried by a protein which shares significant amino acid sequence similarities with the yeast sterol C8–C7 isomerase (ERG2 protein). Pharmacologically - but not structurally - the sigma1-site is also related to the emopamil binding protein, the mammalian sterol C8–C7 isomerase. We therefore investigated if sterol C8–C7 isomerase inhibitors are high affinity ligands for the (+)-[3H]-pentazocine labelled sigma1-binding site.
- Among the compounds which bound with high affinity to native hepatic and cerebral as well as to yeast expressed sigma1-binding sites were the agricultural fungicide fenpropimorph (Ki 0.005 nM), the antihypocholesterinaemic drugs triparanol (Ki 7.0 nM), AY-9944 (Ki 0.46 nM) and MDL28,815 (Ki 0.16 nM), the enantiomers of the ovulation inducer clomiphene (Ki 5.5 and 12 nM, respectively) and the antioestrogene tamoxifen (Ki 26 nM).
- Except for tamoxifen these affinities are essentially identical with those for the [3H]-ifenprodil labelled sterol C8–C7 isomerase of S. cerevisiae. This demonstrates that sigma1-binding protein and yeast isomerase are not only structurally but also pharmacologically related. Because of its affiliations with yeast and mammalian sterol isomerases we propose that the sigma1-binding site is localized on a sterol isomerase related protein, involved in postsqualene sterol biosynthesis.
3.
Jan Petter Arnestad M.D. Anders Bengtsson M.D. Ph.D. Jan-Peter Bengtson M.D. Ph.D. Larsolof Hafstrom M.D. Ph.D. Heinz Redl Ph.D. Günther Schlag M.D. 《World journal of surgery》1995,19(6):861-866
Fourteen patients with liver tumor malignancy and sixteen patients with malignant melanoma localized to one limb were studied regarding leukocyte activation with the release of polymorphonuclear neutrophilic (PMN) elastase and of neopterin and formation of cytokines (TNF- and Il-6) during the surgical treatment. Patients undergoing liver resection (n=10), abdominal hysterectomy (n=10), or hip replacement surgery (n=10) served as control groups. Isolated hyperthermic liver perfusion was performed with cytostatic-containing perfusate (melphalan and cisplatinum). Patients with recurrent malignant melanoma confined to one limb underwent isolated hyperthermic limb perfusion with cytostatic-containing perfusate (melphalan). Blood samples for determination of PMN elastase, neopterin, TNF-, and IL-6 were drawn from the patients preoperatively, 1 minute before the start of the perfusion, 60 and 120 minutes after the start of the perfusion, and 24 hours postoperatively. Samples from the perfusate were drawn 60 minutes after the start of the perfusion. High concentrations of plasma PMN clastase were found both in patients undergoing liver and limb perfusion and in patients undergoing liver resection surgery. Elevated concentrations of Il-6 were found in the patients undergoing liver perfusion and in patients undergoing liver resection. In none of the patients were there increased concentrations of neopterin or TNF-. The perfusate contained high concentrations of PMN elastase, neopterin, and IL-6. This study also demonstrated that major surgery leads to elevated concentrations of PMN elastase and IL-6. An increase of PMN elastase and IL-6 was seen in response to perfusion and to surgical trauma.
Resumen Catorce pacientes con tumores malignos del hígado y 16 pacientes con melanoma maligno localizado en una extremidad fueron estudiados en relación con la activación de leucocitos con liberación de elastasa de PMN y de neopterina y la formación de citocinas (FNT- e IL-6) en el curso del tratamiento quirúrgico. Pacientes sometidos a resección del hígado (n=10), histerectomía abdominal (n=10) y reemplazo de cadera (n=10) sirvieron como grupos control. Se realizó perfusión hipertérmica aislada del hígado con perfusato citostácico (melfalán y cisplatino). Los pacientes con melanoma maligno recurrente confinado a una extremidad fueron sometidos a perfusión hipertérmica aislada de la extremidad con perfusato citostácico (melfalán). Se tomaron muestras de sangre para determinación preoperatoria de elastasa de PMN, neopterina, FNT- e IL-6, un minuto antes de comenzar la perfusión, 60 y 120 minutos después del comienzo de la perfusión y 24 horas después de la operación. Se tomaron muestras del perfusato a los 60 minutos luego del comienzo de la perfusión. Se encontraron altas concentraciones de elastasa de PMN tanto en los pacientes sometidos a perfusión hepática o de la extremidad, como en los pacientes sometidos a resección hepática. Se encontraron concentraciones elevadas de IL-6 en los pacientes sometidos a perfusión hepática y en los pacientes sometidos a resección del hígado. En ningún paciente se encontraron concentraciones aumentadas de neopterina o de FNT-. El perfusato contenía altas concentraciones de elastasa de PMN, neopterina e IL-6. Se encontró un aumento en la elastasa de PMN y en la IL-6 en respuesta a la perfusión y al trauma quirúrgico.
Résumé Quatorze patients ayant une tumeur maligne du foie et 16 patients ayant un mélanome malin localisé à une extrémité ont été étudiés en ce qui concerne l'activation des leucocytes associée à un relargage d'élastase PMN et de néoptérine ainsi que la formation de cytokinines (TNF- et IL-6) pendant le traitement chirurgical. Trente patients avant eu soit une résection hépatique (n=10), soit une hystérectomie abdominale (n=10) ou une prothèse de hanche (n=10) ont servi de témoins. On a perfusé le foie avec un perfusât de cytostatiques (mélphalane et cis-platine). Les patients ayant un mélanome malin d'une extrémité ont eu une perfusion isolée hyperthermique avec une perfusion de cytostatique (mélphanane). Des échantillons du sang ont été retirés pour déterminer les taux d'élastase PMN, de la néoptérine, du TNF-, et de l'IL-6 en préopératoire, une minute avant le début de la perfusion, 60 et 120 minutes après le début de la perfusion, et 24 heures postopératoirement. Des échantillons ont été retirés 60 minutes après le début de la perfusion. Des concentration élevées d'élastase PMN ont été retrouvées à la fois chez les patients ayant une perfusion hépatique et de l'extrémité et chez les patients ayant eu une résection du foie. Des concentration élevées en IL-6 ont été retrouvées chez le patient ayant une perfusion du foie et chez le patient ayant une résection hépatique. Les concentrations en néoptérine et en TNF- n'étaient pas élevées. Le liquide de perfusion contenait des concentrations élevées en élastase PMN, néoptérine et en IL-6. Cette étude démontre aussi que la chirurgie majeure est associée avec des concentrations élevées en PMN elastase et IL-6. Une augmentation en PMN-élastase et en IL-6 a été retrouvée en réponse à la perfusion et au traumatisme chirurgical.相似文献
4.
Summary Binding sites for iodohydroxybenzylpindolol with characteristics of a 2-adrenergic receptor have been identified in a crude membrane fraction from guinea-pig lung. The binding sites could be solubilized by treatment of the membrane fraction with digitonin. Upon solubilization receptors retain their 2-adrenergic type as indicated by the rank order of potencies of agonists in binding-inhibition experiments. The solubilized receptors demonstrate a marked increase in affinity for agonists compared with particulate receptors whereas antagonist affinity remains unchanged. Solubilized receptors are insensitive to divalent cations (Mg2+, Mn2+, Ca2+) which increase the potency of agonists for particulate receptors. The effects of Mg2+ can be reversed by Gpp(NH)p in particulate preparations; Gpp(NH)p is ineffective for the solubilized preparation. These experiments establish that -adrenergic receptors can be solubilized even from crude mammalian membrane preparations. They also show that the mammalian -adrenergic receptor in situ is under constraints with respect to agonist affinity and is modulated by divalent cations and guanyl nucleotides in the intact membrane.with technical assistance of L. Braun and C. KonradThis report is part of a dissertation to be presented by J. K. to the Fachbereich Humanmedizin, Justus Liebig-Universität Giessen, in partial fulfillment of the requirements for a Doctor of Medical Science degree 相似文献
5.
Ulrich Schwabe Volker Lenschow Dieter Ukena David R. Ferry Hartmut Glossmann 《Naunyn-Schmiedeberg's archives of pharmacology》1982,321(1):84-87
Summary N6-p-Hydroxyphenylisopropyladenosine (HPIA) has been labelled with carrier-free Na[125I] to very high specific activity (2,175 Ci/mmol) and used as an agonist ligand to characterize Ri adenosine receptors in rat cerebral cortex membranes. The binding is saturable, reversible, stereospecific and dependent on protein concentration. The specific binding at 37°C was of high affinity with an equilibrium dissociation constant KD of 0.48 nmol/l and was saturable with 0.23 pmol of [125I]HPIA per mg of protein. The rate constant of association, k1, was 3.25×108 l mol–1 min–1 and that of dissociation, k2, 0.0110 min–1 yielding a t1/2 of 63 min. In competition experiments the (–)isomer of N6-phenylisopropyladenosine (PIA) was 16-fold more potent than the (+)isomer in competing for the binding sites. Specific binding was most effectively displaced by N6-cyclohexyladenosine (CHA, ki=0.26 nmol/l), (–)PIA (ki=0.33 nmol/l) and HPIA (ki=0.52 nmol/l), whereas 5-N-ethylcarboxamidoadenosine (NECA, ki-1.42 nmol/l) was less effective. The methylxanthines 3-isobutyl-1-methylxanthine (IBMX), theophylline and caffeine which have been classified as adenosine antagonists had ki values between 5–34 mol/l. Binding of [125I]HPIA was regulated by guanine nucleotides and divalent cations. The results indicate that [125I]HPIA labels Ri adenosine receptors in rat brain membranes. 相似文献
6.
R. Hornung P. Presek H. Glossmann 《Naunyn-Schmiedeberg's archives of pharmacology》1979,308(3):223-230
Summary Tritiated prazosin was used to characterize high affinity binding sites with characteristics similar to
1 adrenoceptors in rat brain membranes. These sites were compared with
2 adrenoceptors labeled with tritiated clonidine. The prazosin sites had an association constant of 2 nM–1 and bound the ligand optimal around pH 7.0. The density of the sites was 300 fmoles per mg of protein; the half time of dissociation of prazosin was 7 min at 30° C. The order or potencies of agonists, determined from binding-inhibition experiments with labeled prazosin, was: naphazoline > clonidine > adrenaline > noradrenaline > phenylephrine >
-methylnoradrenaline > dophamine. The order of potencies of antagonists was: prazosin > phenoxybenzamine > phentolamine > clozapine > yohimbine. Sodium ions and divalent cations as well as guanyl nucleotides have little or no effect on the binding of the labeled antagonist. This is in contrast to the binding of the labeled agonist clonidine (Glossmann and Presek, 1979a, 1979b). Labeled prazosin may be a useful tool to characterize
1 adrenoceptors.This is part of the thesis of R. H. to be presented to the Fachbereich Humanmedizin, Justus Liebig-Universität Giessen, in partial fulfillment of the requirements for a Doctor of Medical Science degreee 相似文献
7.
A Josting C Rudolph M Mapara J-P Glossmann M Sienawski M Sieber H H Kirchner B D?rken D K Hossfeld J Kisro B Metzner W E Berdel V Diehl A Engert 《Annals of oncology》2005,16(1):116-123
BACKGROUND: We designed a dose- and time-intensified high-dose sequential chemotherapy regimen for patients with relapsed and refractory Hodgkin lymphoma (HD). PATIENTS AND METHODS: Eligibility criteria included age 18-65 years, histologically proven primary progressive (PD) or relapsed HD. Treatment consisted of two cycles DHAP (dexamethasone, high-dose cytarabine, cisplatinum); patients with chemosensitive disease received cyclophosphamide followed by peripheral blood stem cell harvest; methotrexate plus vincristine, etoposide and BEAM plus peripheral blood stem cell transplantation (PBSCT). RESULTS: A total of 102 patients (median age 34 years, range 18-64) were enrolled. The response rate was 80% (72% complete response, 8% partial response). With a median follow-up of 30 months (range 3-61 months), freedom from second failure (FF2F) and overall survival (OS) were 59% and 78% for all patients, respectively. FF2F and OS for patients with early relapse were 62% and 81%, for late relapse 65% and 81%; for PD 41% and 48%, and for multiple relapse 39% and 48%, respectively. In multivariate analysis response after DHAP (P <0.0001) and duration of first remission (PD and multiple relapse versus early and late relapse; P=0.0127) were prognostic factors for FF2F. Response after DHAP (P <0.0081), duration of first remission (P=0.0017) and anemia (P=0.019) were significant for OS. CONCLUSION: Based on the promising results of this study, a prospective randomized European intergroup study was started comparing this intensified regimen with two courses of DHAP followed by BEAM (HD-R2 protocol). 相似文献
8.
Jan-Peter van Wieringen Jan Booij Vladimir Shalgunov Philip Elsinga Martin C. Michel 《Naunyn-Schmiedeberg's archives of pharmacology》2013,386(2):135-154
Dopamine D2 receptors, similar to other G-protein-coupled receptors, exist in a high- and low-affinity state for agonists. Based upon a review of the methods for detecting D2 receptor agonist high-affinity states, we discuss alterations of such states in animal models of disease and the implications of such alterations for their labelling with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) tracers. The classic approach of detecting agonist high-affinity states compares agonist competition for antagonist radioligands, in most cases using [3H]-spiperone as the radioligand; alternative approaches and radioligands have been proposed, but their claimed advantages have not been substantiated by other investigators. In view of the advantages and disadvantages of various techniques, we critically have reviewed reported findings on the detection of D2 receptor agonist high-affinity states in a variety of animal models. These data are compared to the less numerous findings from human in vivo studies based on PET and SPECT tracers; they are interpreted in light of the finding that D2 receptor agonist high-affinity states under control conditions may differ between rodent and human brain. The potential advantages of agonist ligands in studies of pathophysiology and as diagnostics are being discussed. 相似文献
9.
Economic evaluation of chronic lymphocytic leukemia from a hospital management perspective
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10.
Theodor Baars Ursula Neumann Mona Jinawy Stefanie Hendricks Jan-Peter Sowa Julia K?lsch Mona Riemenschneider Guido Gerken Raimund Erbel Dominik Heider Ali Canbay 《Medicine》2016,95(6)
Detection of high-risk subjects in acute myocardial infarction (AMI) by noninvasive means would reduce the need for intracardiac catheterization and associated complications. Liver enzymes are associated with cardiovascular disease risk. A potential predictive value for liver serum markers for the severity of stenosis in AMI was analyzed.Patients with AMI undergoing percutaneous coronary intervention (PCI; n = 437) were retrospectively evaluated. Minimal lumen diameter (MLD) and percent stenosis diameter (SD) were determined from quantitative coronary angiography. Patients were classified according to the severity of stenosis (SD ≥ 50%, n = 357; SD < 50%, n = 80). Routine heart and liver parameters were associated with SD using random forests (RF). A prediction model (M10) was developed based on parameter importance analysis in RF.Age, alkaline phosphatase (AP), aspartate aminotransferase (AST), and MLD differed significantly between SD ≥ 50 and SD < 50. Age, AST, alanine aminotransferase (ALT), and troponin correlated significantly with SD, whereas MLD correlated inversely with SD. M10 (age, BMI, AP, AST, ALT, gamma-glutamyltransferase, creatinine, troponin) reached an AUC of 69.7% (CI 63.8–75.5%, P < 0.0001).Routine liver parameters are associated with SD in AMI. A small set of noninvasively determined parameters can identify SD in AMI, and might avoid unnecessary coronary angiography in patients with low risk. The model can be accessed via http://stenosis.heiderlab.de. 相似文献