Katharina Wenzel-Seifert

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Ziel der Studie war es zu überprüfen, ob die Verordnung „potenziell inadäquater Wirkstoffe“ (PIW) mit einem erhöhten Risiko für unerwünschte Arzneimittelwirkungen (UAW) einhergeht. Methodik: 304 stationäre gerontopsychiatrische Patienten wurden in die Studie eingeschlossen. Anhand der klinischen Daten und Verlaufsdokumentationen wurden Hinweise auf...

Introduction: Although antidepressant-induced sexual dysfunction is very common it is rarely reported spontaneously by the patients or enquired by the attending physicians. In this review the risk of antidepressants for causing sexual dysfunction (SD), the therapy and prophylaxis of this SD will be evaluated. Method: For assembling the substance-sp...

This contribution evaluates the prevalence, medication use as well as age and sex distribution in inpatients with hyperkinetic disorders at the KinderAGATE hospitals for 2009-2012. The age, sex, leading diagnosis, prescribed medication, and dosage of each patient were recorded anonymously twice a year. They provide an outstanding epidemiological ba...

Fragestellung: Die vorliegende Auswertung untersucht Prävalenz, Medikation sowie Alters- und Geschlechterverteilung bei Patienten mit hyperkinetischen Störungen in den KinderAGATE Kliniken 2009–2012. Methodik: Zweimal im Jahr an den sog. «Stichtagen» wurden anonymisiert von jedem Patienten Alter, Geschlecht, Hauptdiagnose, Medikation und zugehörige...

Background Delirogenic potential of medications, especially anticholinergic properties, may give rise to adverse drug reactions (ADRs) in old aged patients. Objectives of the study were to assess a risk scale for rating of delirogenic properties of drugs and compare theoretical risks with observed side effects in old aged psychiatric inpatients. Me...

Atomoxetine, methylphenidate, amfetamine, dexamfetamine and lisdexamfetamine, which are approved for therapy of attention deficit/hyperactivity disorder (ADHD), elevate the concentration of dopamine and norepinephrine in the synaptic cleft. Thereby, adverse symptoms of an increased activity of the sympathetic nervous system such as insomnia, restle...

Introduction: The main objective of this study was to investigate the influence of the use of multiple medications and other risk factors on citalopram plasma concentrations. Methods: A retrospective cohort study with a naturalistic population of 957 patients for whom routine therapeutic drug monitoring (TDM) of citalopram had been requested bet...

Diagnosis of late-life depression is given when depressive symptoms emerge in persons older than 65 years. Great care is needed when elderly patients receive psychopharmacotherapy due to altered pharmacokinetic status. As a consequence, age is considered to have a significant effect on serum concentrations of antidepressant drugs. The magnitudes of...

Desirable and undesirable effects of a drug are related to its concentration at various sites of actions. For many psychotropic drugs, it has been shown that drug concentration in brain correlates with concentration in blood. The latter is also an available estimate of clearance and bioavailability. Its monitoring enables identifi cation of multipl...

Introduction: Due to a dose-dependent risk for QTc prolongations, torsade de pointes tachyarrhythmia and sudden death age-dependet maximal daily doses of citalopram are recommended. Concomitant drugs which prolong QTc or inhibit the metabolism of citalopram may increase the risk for adverse events. The aim of this study was to further analyse the i...

In comparison to cardiovascular adverse events, particularly orthostatic hypotension, psychotropic drug induced cardiotoxic side effects, e.g. cardiac conduction disorders, arrhythmias, myocarditis and cardiomyopathies are rare, but they can lead to sudden cardiac death. These effects can be explained by the mode of action of the drugs. Orthostatic...

Objective: The present analysis evaluates the prevalence and medication use in inpatients with depression during childhood and adolescence at the KinderAGATE hospitals in 2010. Also discussed are age and sex distribution. Method: Since 2009 the following information has been recorded anonymously twice a year from each patient at the participating h...

Tricyclic antidepressants (TCA) have varying degrees of affinity to peripheral and central muscarinic cholinergic receptors. Typical and common peripheral anticholinergic adverse events (ADR) are dry mouth, blurred vision, constipation, urinary retention, tachycardia, increase of intraocular pressure, and tachycardia. Central side effects include i...

Objective: The present analysis evaluates the prevalence and medication use in inpatients with depression during childhood and adolescence at the KinderAGATE hospitals in 2010. Also discussed are age and sex distribution. Method: Since 2009 the following information has been recorded anonymously twice a year from each patient at the participatin...

The human g 1 -adrenoceptor ( g 1 AR) exists in several isoforms and activates adenylyl cyclase (AC) via G s -proteins. The Arg389-isoform of the g 1 AR ( g 1 AR-R389) expressed in CHW cells is much more efficient than the Gly389 isoform of the g 1 AR ( g 1 AR-G389) at stabilizing the ternary complex and activating AC (Mason et al. 1999). The g 1 A...

Many psychotropic drugs can delay cardiac repolarization and thereby prolong the rate-corrected QT interval (QTc). A prolonged QTc often arouses concern in clinical practice, as it can be followed, in rare cases, by the life-threatening polymorphic ventricular tachyarrhythmia called torsade de pointes (TdP). We searched PubMed for pertinent literat...

Psychisch Erkrankte haben ein besonders hohes Risiko, an einem metabolischen Syndrom zu erkranken, u. a. wegen der oft mit einer medikamentösen Therapie verbundenen Gewichtszunahme. Welche substanzspezifischen Unterschiede Sie bei den am häufigsten verordneten Psychopharmaka, den Antidepressiva und Antipsychotika, beachten müssen, erfahren Sie im n...

Selective serotonin-reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants and are generally well tolerated. Specifi cally, less cardiovascular toxicity has been reported in comparison with tricyclic antidepressants. However, an increasing number of case reports and reviews of pharmacovigilance and toxicology databases describ...

According to the two-state model of G-protein-coupled receptor (GPCR) activation, GPCRs isomerize from an inactive (R) state to an active (R*) state. In the R* state, GPCRs activate G-proteins. Agonist-independent R/R* isomerization is referred to as constitutive activity and results in an increase in basal G-protein activity, i.e. GDP/GTP exchange...

The human beta(1)-adrenoceptor (beta(1)AR) exists in several isoforms and activates adenylyl cyclase (AC) via G(s)-proteins. The Arg389-isoform of the beta(1)AR (beta(1)AR-R389) expressed in CHW cells is much more efficient than the Gly389 isoform of the beta(1)AR (beta(1)AR-G389) at stabilizing the ternary complex and activating AC (Mason et al. 1...

Species isoforms of histamine H2-, H3-, and H4-receptors differ in their pharmacological properties. The study aim was to dissect differences between the human H1R (hH1R) and guinea pig H1R (ghH1R). We coexpressed hH1R and gpH1R with regulators of G-protein signaling in Sf9 insect cells and analyzed the GTPase activity of Gq-proteins. Small H1R ago...

The formyl peptide receptor (FPR) is expressed in neutrophils, couples to Gi-proteins and activates phospholipase C, chemotaxis and cytotoxic cell functions. FPR isoforms 26, 98, and G6 differ from each other in amino acids 101, 192 and 346 (FPR-26: V101, N192, E346; FPR-98: L101, N192, A346; FPR-G6: V101, K192, A346), but the functional significan...

Xanthine nucleotide-selective small GTP-binding proteins with an Asp/Asn mutation are valuable for the analysis of individual GTP-binding proteins in complex systems. Similar applications can be devised for heterotrimeric G-proteins. However, Asp/Asn mutants of Gαo, Gα11, and Gα16 were inactive. An additional Gln/Leu mutation in the catalytic site,...

The human formyl peptide receptor (FPR) is N-glycosylated and activates phagocytes via G(i)-proteins. The FPR expressed with G(i)alpha(2)beta(1)gamma(2) in Sf9 insect cells exhibits high constitutive activity as assessed by strong inhibitory effects of an inverse agonist and Na(+) on basal guanosine 5(')-O-(3-thiotriphosphate) (GTPgammaS) binding....

The human beta1-adrenoceptor (beta1AR) exists in several isoforms and activates adenylyl cyclase (AC) via Gs-proteins. The Arg389-isoform of the beta1AR (beta1AR-R389) expressed in CHW cells is much more efficient than the Gly389 isoform of the beta1AR (beta1AR-G389) at stabilizing the ternary complex and activating AC (Mason et al. 1999). The beta...

The G-protein G(i)alpha can activate adenylyl cyclase (AC), but the relevance of this AC activation is unknown. We used receptor-G protein co-expression and receptor-G protein fusion proteins to investigate G(i)alpha(2) regulation of AC in Sf9 cells. G(i)alpha(2) was fused to the beta(2)-adrenoceptor (beta(2)AR), a preferentially G(s)-coupled recep...

The aim of this review is to provide a systematic overview on constitutively active G-protein-coupled receptors (GPCRs), a rapidly evolving area in signal transduction research. We will discuss mechanisms, pharmacological tools and methodological approaches to analyze constitutive activity. The two-state model defines constitutive activity as the a...

The G-protein Giα can activate adenylyl cyclase (AC), but the relevance of this AC activation is unknown. We used receptor-G protein co-expression and receptor-G protein fusion proteins to investigate Giα2 regulation of AC in Sf9 cells. Giα2 was fused to the β2-adrenoceptor (β2AR), a preferentially Gs-coupled receptor, or the formyl peptide recepto...

The human beta1-adrenoceptor (beta1AR) and beta2-adrenoceptor (beta2AR) couple to Gs-proteins to activate adenylyl cyclase (AC). There are differences in desensitization between the beta2AR and the originally cloned Gly389-beta1AR, but with respect to ternary complex formation, constitutive activity, and AC activation the picture is unclear. To lea...

The human β1-adrenoceptor (β1AR) and β2-adrenoceptor (β2AR) couple to Gs-proteins to activate adenylyl cyclase (AC). There are differences in desensitization between the β2AR and the originally cloned Gly389-β1AR, but with respect to ternary complex formation, constitutive activity, and AC activation the picture is unclear. To learn more about the...

The human histamine H2-receptor (hH2R) couples to Gs-proteins to activate adenylyl cyclase and to Gq-proteins to activate phospholipase C, but phospholipase C activation has not consistently been observed. The aim of this study was to compare coupling of hH2R to insect and mammalian Gs- and Gq-proteins in Spodoptera frugiperda (Sf9) cells. Interact...

Fusion proteins allow for the analysis of receptor/G protein coupling under defined conditions. The beta(2)-adrenoceptor (beta(2)AR) fused to the long splice variant of G(salpha) (G(salphaL)) exhibits a higher apparent constitutive activity than the beta(2)-adrenoceptor fused to the short splice variant of G(salpha) (G(salphaS)). Experimentally, th...

The formyl peptide receptor (FPR) is a prototypical chemoattractant receptor expressed in neutrophils. It is well known that the FPR couples to Gi proteins to activate phospholipase C, chemotaxis, and cytotoxic cell functions, but the in vivo role of the FPR in man has remained elusive. Recently, F110S and C126W mutations of the FPR have been assoc...

It is unknown why the potencies and efficacies of long-chained guanidine-type histamine H2-receptor (H2R) agonists are lower at the H2R of human neutrophils than at the H2R of the guinea pig atrium. To elucidate these differences, we analyzed fusion proteins of the human H2R (hH2R) and guinea pig H2R (gpH2R), respectively, and the short splice vari...

The olfactory G protein G(alphaolf) differs from the short splice variant of G(salpha) (G(salphaS)) in 80 amino acids, but little is known about biochemical differences between G(alphaolf) and G(salphaS). We addressed this question by analyzing fusion proteins of the beta2-adrenoceptor (beta2AR) and G(alphaolf) and G(salphaS), respectively, using S...

The olfactory G protein Gαolf differs from the short splice variant of Gsα (GsαS) in 80 amino acids, but little is known about biochemical differences between Gαolf and GsαS. We addressed this question by analyzing fusion proteins of the β2-adrenoceptor (β2AR) and Gαolf and GsαS, respectively, using Sf9 insect cells as expression system. The fusion...

The interaction of an agonist-bound G-protein-coupled receptor (GPCR) with its cognate G-protein initiates a sequence of experimentally quantifiable changes in both the GPCR and G-protein. These include the release of GDP from G(alpha), the formation of a ternary complex between the nucleotide-free G-protein and the GPCR, which has a high affinity...

Neutrophils express receptors for the chemoattractants N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) complement C5a, leukotriene B4 (LTB4) and platelet-activating factor (PAF). The aim of this study was to analyze the constitutive activity of chemoattractant receptors by studying binding of guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) t...

The “professional phagocytes”, that is, neutrophils, basophils, eosinophils, monocytes, and macrophages, play key roles in host defense against invading bacteria (Rossi, 1986, Seifert and Schultz, 1991). The importance of phagocytes in host defense is highlighted by chronic granulomatous disease in which certain components of the superoxide anion (...

The β2-adrenoceptor (β2AR) couples to the G-protein G(s) to activate adenylyl cyclase. Intriguingly, several studies have demonstrated that the β2AR can also interact with G-proteins of the G(i)- and G(q)-family. To assess the efficiency of β2AR interaction with various G-protein α-subunits (G(xα)), we expressed fusion proteins of the β2AR with the...

The β2-adrenoceptor (β2AR) couples to the G-protein Gs to activate adenylyl cyclase. Intriguingly, several studies have demonstrated that the β2AR can also interact with G-proteins of the Gi- and Gq-family. To assess the efficiency of β2AR interaction with various G-protein α-subunits (Gxα), we expressed fusion proteins of the β2AR with the long (G...

The human formyl peptide receptor (FPR) is a prototypical G(i) protein-coupled receptor, but little is known about quantitative aspects of FPR-G(i) protein coupling. To address this issue, we fused the FPR to G(i)alpha(1), G(i)alpha(2), and G(i)alpha(3) and expressed the fusion proteins in Sf9 insect cells. Fusion of a receptor to Galpha ensures a...

The aim of our study was to examine the effects of different purine nucleotides [GTP, ITP, and xanthosine 5'-triphosphate (XTP)] on receptor/G protein coupling. As a model system, we used a fusion protein of the beta(2)-adrenergic receptor and the alpha subunit of the G protein G(s). GTP was more potent and efficient than ITP and XTP at inhibiting...

The efficiency of interactions between G-protein-coupled receptors (GPCRs) and heterotrimeric guanine nucleotide-binding proteins (G proteins) is greatly influenced by the absolute and relative densities of these proteins in the plasma membrane. The study of these interactions has been facilitated by the use of GPCR–Gα fusion proteins, which are fo...

Reconstitution of high-affinity agonist binding at the beta2-adrenoceptor (beta2AR) expressed in Sf9 insect cells requires a large excess of the stimulatory G-protein of adenylyl cyclase, Gsalpha, relative to receptor [R. Seifert, T. W. Lee, V. T. Lam & B. K. Kobilka, (1998) Eur. J. Biochem. 255, 369-382]. In a fusion protein of the beta2AR and Gsa...

The beta2-adrenoceptor (beta2AR) activates the G-protein Gsalpha to stimulate adenylate cyclase (AC). Fusion of the beta2AR C-terminus to the N-terminus of Gsalpha (producing beta2ARGsalpha) markedly increases the efficiency of receptor/G-protein coupling compared with the non-fused state. This increase in coupling efficiency can be attributed to t...

The formyl peptide receptor (FPR) couples to pertussis toxin (PTX)-sensitive Gi-proteins to activate chemotaxis and exocytosis in neutrophils. PTX reduces not only formyl peptide-stimulated but also agonist-independent (“basal”) Gi-protein activity, suggesting that the FPR is constitutively active. We aimed at identifying an inverse FPR agonist,i.e...

The beta2-adrenoreceptor (beta2AR) couples to the G-protein Gs to mediate adenylyl cyclase activation. The splice variants of Gs alpha differ by a 15-amino acid insert between the Ras-like domain and the alpha-helical domain. The long splice variant of Gs alpha (Gs alphaL) binds GDP with lower affinity than the short splice variant (Gs alphaS), but...

The β2-adrenoreceptor (β2AR) couples to the G-protein Gs to mediate adenylyl cyclase activation. The splice variants of Gsα differ by a 15-amino acid insert between the Ras-like domain and the α-helical domain. The long splice variant of Gsα (GsαL) binds GDP with lower affinity than the short splice variant (GsαS), but the impact of this difference...

In human neutrophils, the chemotactic peptide, N-formyl-L-methionyl-L-leucyl-L-phenalalanine (fMLP), the Ca(2+)-ATPase inhibitor, thapsigargin, and the lectins, concanavalin A (Con A) and mistletoe lectin I (ML I), stimulate the entry of Ca2+ and Na+ with subsequent activation of exocytosis and superoxide anion (O2-) formation. We studied the role...

Mistletoe lectin I (ML I) from Viscum album inhibits cell growth and induces apoptosis (programmed cell death) in several cell types. Because increases in cytosolic Ca2+ concentration ([Ca2+]i) constitute a signal for the induction of apoptosis, we studied the effects of ML I on basal [Ca2+]i, receptor-mediated rises in [Ca2+]i and cell viability,...

The mannose-specific lectin, concanavalin A (ConA), activates Ca2+ entry in human neutrophils by an as yet poorly defined mechanism. The question of whether the sugar specificity of lectins influences signal transduction is unresolved too. Therefore, we studied the effects of ConA in comparison to those of the beta-galactoside-specific lectin, mist...

The Ca2+-ATPase inhibitor thapsigargin (TG) activates bivalent-cation early in human neutrophils via depletion of intracellular Ca2+ stores bu little is known about the underlying mechanism and the functional role of TG-induced cation entry. We studied the effects of TG on univalent- and bivalent cation entry, lysozyme release and superoxide-anion...

1. HL-60 human leukemia cells are a widely employed model system for the analysis of signal transduction processes mediated via regulatory heterotrimeric guanine nucleotide-binding proteins (G-proteins). HL-60 promyelocytes are pluripotent and can be differentiated into neutrophilic or monocytic cells. 2. HL-60 cells express formyl peptide-, comple...

The wasp venom, mastoparan (MP), activates reconstituted pertussis toxin (PTX)-sensitive G-proteins in a receptor-independent manner. We studied the effects of MP and its analogue, mastoparan 7 (MP 7), on G-protein activation in HL-60 cells and a reconstituted system and on nucleoside diphosphate kinase (NDPK)-catalysed GTP formation. MP activated...

Cyclosporin A (CsA) has been reported to inhibit phorbol myristate acetate (PMA)-induced superoxide anion (O2−) formation in human neutrophils and murine macrophages. We found that CsA inhibited O2− formation in HL-60 cells induced by PMA (30nM) and dibutyrate (200 nM) with a half-maximal effect at 1 and 0.75 ωM, respectively. One possible targetof...

The role of protein kinase C (PKC) isoenzymes in the regulation of cell functions is largely unknown. We studied the effects of 2-(1H-indol-3-yl)-3- [1-(3-dimethylaminopropyl)-1H-indol-3-yl]-maleinimide (Gö 6850), a selective inhibitor of c- and n-PKC isoenzymes, and 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo[2 ,3- a]pyrrolo[3...

Unlabelled: Inhibition of Na+/D-glucose transport by oleic acid was investigated in renal brush-border membrane vesicles (BBMV). Lipid physical parameters were determined by spectrofluorometry. cis-Unsaturated C16-C22 long-chain fatty acids (LCFA) as oleic acid reduced nonzero limiting anisotropy r infinity with DPH and 12-AS as probes and decreas...

Synthetic lipopeptides activate superoxide-anion (O2-) formation in human neutrophils in a pertussis-toxin (PTX)-sensitive manner, suggesting the involvement of G-proteins of the Gi family in the signal-transduction pathway. We compared G-protein activation by lipopeptides and the chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLP) in...

The macrolide, FK-506, is a potent and effective inhibitor of lymphocyte activation. We studied the effects of FK-506 on human neutrophil activation induced by chemoattractants and by various substances which circumvent receptor stimulation. After preincubation for 5 min at 37 degrees C, FK-506 (1 microM) inhibited N-formyl-L-methionyl-L-leucyl-L-p...

The cyclic undecapeptide, cyclosporin (Cs) H, is a potent inhibitor of FMLP-induced superoxide anion (O2-) formation in human neutrophils. We studied the effects of CsH in comparison with those of N-t-butoxycarbonyl-L-phenylalanyl-L-leucyl-L-phenylalanyl-L-leucyl-L- phenylalanine (BocPLPLP), a well known formyl peptide receptor antagonist, and of o...

The chemoattractants, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMet-Leu-Phe), complement C5a and platelet-activating factor (PAF), induce beta-glucuronidase release and aggregation and an increase in cytosolic Ca2+ [Ca2+]i in human neutrophils. We studied the roles of cAMP and cGMP in neutrophil avtivation, using their cell-permeant analogues...

Cyclosporin (Cs)A but not CsH inhibits activation of human lymphocytes. We studied the effects of CsA, CsD, and CsH on human neutrophil activation induced by chemoattractants and by various substances that circumvent receptor stimulation. CsH inhibited superoxide (O2-) formation induced by the chemotactic peptide, FMLP (30 nM), with a half-maximal...

The first patient had total parathyroidectomy (PTX) with autografting 2 years before. She developed disabling soft-tissue calcifications following kidney transplantation. After reduction of the autograft--a complete removal was not possible--the subcutaneous calcifications regressed. In the second patient, fulminant necrotizing vascular calcinosis...

Undifferentiated and differentiated HL-60 leukemic cells possess nucleotide receptors which functionally couple to phospholipase C via pertussis toxin-sensitive guanine nucleotide-binding proteins (G-proteins). We investigated the role of extracellular nucleotides in the regulation of beta-glucuronidase release in HL-60 cells. In dibutyryl cyclic A...

A 76-year-old woman with multiple allergic reactions was treated 17 times by haemodialysis. Symptoms of anaphylactoid reactions of increasing severity led to final death due to cardiorespiratory arrest. Anaphylactoid reactions appeared 5—30 min after the start of dialysis and lasted for 15—20 min. They first occurred on the 7th dialysis and consist...