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In recent years, software-assisted imaging systems, such as computed tomography, have contributed to the improvement of noninvasive options for the diagnostics of coronary heart disease (CHD). In addition, the possibilities of individual morphological and functional atherosclerotic plaque evaluation could be further refined, e.g. by the use of optical coherence tomography or the quantitative flow ratio (QFR). Due to the development of robotic-assisted catheter systems, it has been possible to make coronary interventions more precise and with less radiation exposure for the examiner. It is to be expected that in the future even better algorithms will be developed by the analysis of very large amounts of data. These will enable a more exact, dynamic and personalized prediction of, e.g. treatment success or individual risk profiles, in order to positively and sustainably influence the treatment of patients with cardiovascular diseases.Softwaregestützte Bildgebungsverfahren, wie die koronare Computertomographie, haben in den letzten Jahren dazu beigetragen, die nicht-invasiven Optionen zur Diagnostik bei koronarer Herzkrankheit (KHK) zu verbessern. Zudem konnten z. B. durch die Anwendung der optischen Kohärenztomographie oder der quantitativen Flussreserve (QFR) die Möglichkeiten der individuellen morphologischen wie auch der funktionellen atheroklerotischen Plaqueevaluation weiter verfeinert werden. Durch die Entwicklung von roboterassistierten Kathetersystemen ist es zudem gelungen, Koronarinterventionen präzise und weniger strahlungsintensiv für den Untersucher zu gestalten. Es ist zu erwarten, dass zukünftig durch die Analyse sehr großer Datenmengen noch bessere Algorithmen entwickelt werden, die eine genaue, dynamische und personalisierte Voraussage von z. B. Therapieerfolgen erlauben oder individuelle Risikoprofile erstellen, um die Behandlung von Patienten mit kardiovaskulären Erkrankungen nachhaltig positiv zu beeinflussen.

Die Bifurkationsbehandlung stellt eine alltagliche interventionelle Herausforderung hinsichtlich Strategie und Technik dar. Deshalb ist die Einhaltung einfacher Regeln der Grundstein fur einen langanhaltenden Prozedurerfolg. Entscheidend fur die Auswahl der richtigen Strategie ist eine ausreichende Beurteilung der Bifurkationslasion hinsichtlich Seitastrelevanz, Gefasdiameter und Abgangswinkel des Seitasts. Die Evaluierung einer Bifurkationsstenose kann unter Beachtung der bekannten Limitationen durch die fraktionelle Flussreserve (FFR) erleichtert werden. Bildgebende Verfahren konnen die Strategie einer Bifurkationsbehandlung mitbeeinflussen.

Die Prognose von Patienten mit eingeschrankter linksventrikularer Funktion und interventionsbedurftiger koronarer Herzerkrankung ist deutlich eingeschrankt. Fruhe Studien zum Vergleich medikamentoser mit operativer Therapie haben nachgewiesen, dass gerade diese Hochrisikopatienten von einer kompletten Revaskularisierung profitieren. Die Datenlage ist deutlich dunner fur den Vergleich zwischen den beiden Revaskularisationsmethoden PCI und Bypassoperation. Dies liegt vor allen daran, dass in den meisten Studien eine eingeschrankte linksventrikulare Funktion als Ausschlusskriterium definiert ist. Dementsprechend mussen hier Ergebnisse aus anderen Patientenkollektiven extrapoliert werden. Komplexe Koronaranatomien mit multiplen Stenosen und hoher Wahrscheinlichkeit groser Stentlangen sollten demnach genauso wie Diabetiker eher chirurgisch versorgt werden. Die PCI kann bei geringerer Stenosekomplexitat eine wertvolle und weniger invasive Alternative sein. Um eine moglichst optimale Behandlung fur diese haufig schwerkranken Patienten zu gewahrleisten, sollte eine individuelle Therapiefestlegung durch das Heart Team erfolgen.

To evaluate the awareness and knowledge of the German population regarding diseases in general, a survey of 1446 people aged 60 years or older was conducted in 14 German towns. The focus was on heart valve diseases with special emphasis on aortic valve stenosis (AS). While cancer was the disease that respondents were most concerned about (25.2%), only 3.3% were concerned about heart valve diseases. In this respect, the knowledge was broadly limited: only 7.4% of participants claimed to have some familiarity with heart valve diseases and only 12.5% could correctly describe the symptoms of AS. Even so, 35.0% of the participants could correctly name the number of human heart valves, 71.6% knew at least one therapy option for AS and 30.6% were familiar with transcatheter aortic valve implantation (TAVI). After providing a brief clarification of the prevalence, symptoms and course of AS, 45.6% of respondents were more concerned about the condition, 15.7% wanted to know more about the symptoms of AS and 4.7% even recognized the typical symptoms in themselves. Most of the participants would like to seek more information preferably in discussion with a specialist physician (77.2%), with their general practitioner (43.2%) or using the internet (29.7%). Despite its high prevalence, high morbidity and mortality, the vast majority of the German population were neither concerned nor fully aware of treatment options for AS. There is a strong case for public awareness campaigns that provide better knowledge of AS, and support check-ups that enable timely treatment and the avoidance of unnecessary hospitalization and death.

Die perioperative Myokardischamie ist bei gefaschirurgischen Eingriffen haufig und prognostisch relevant. Myokardiale Biomarker konnen die perioperative Risikostratifizierung zusatzlich zu etablierten Risikoscores verbessern. Basierend auf einer selektiven Literaturrecherche unter Berucksichtigung von in PubMed gelisteten Originalpublikationen und Metaanalysen aus den Jahren 2000–2013 zur Ursache, Diagnose und Therapie von periprozeduraler Myokardischamie sowie von Leitlinien nationaler und internationaler Fachgesellschaften wird eine Ubersicht uber aktuelle Arbeiten zur Validitat von Biomarkern zur Abschatzung des perioperativen Myokardischamierisikos gegeben. Die wissenschaftliche Literatur zur perioperativen Myokardischamie besteht im Wesentlichen aus monozentrischen, retrospektiven Untersuchungen. Es existieren nur wenige prospektiv randomisierte Studien oder strukturierte Reviews. Die Inzidenz der perioperativen Myokardischamie liegt zwischen 11 und 47 %. In den letzten Jahrzehnten wurde eine Vielzahl verschiedener Scores zur individuellen Risikostratifizierung entwickelt. Biomarker, insbesondere die kardialen Troponine, stellen jedoch teilweise die einzige Moglichkeit zur periprozeduralen Ischamiediagnostik dar. Durch die hohe Sensitivitat der neueren Troponinassays ist die Erkennung von geringem myokardialen Zelluntergang und somit eine schnellere Diagnosestellung und Behandlung moglich. Die perioperative Myokardischamie muss unbedingt erkannt und behandelt werden, um die langfristig begleitende Morbiditat und Mortalitat zu verringern. Die hochsensitive Troponinbestimmung bietet hierbei eine mogliche Schlusselrolle in der adaquaten Patientenversorgung.

Bifurcation lesions are a therapeutic challenge in the interventional treatment of coronary artery disease. Thus, consideration of anatomical aspects and selection of the most appropriate strategy for an individual bifurcation have an impact on the interventional outcome. Accordingly, assessment of the type of bifurcation stenosis, including the relevance of the side branches, vessel diameter and the angle between the two branches are critical for the optimal choice of interventional strategy. The fractional flow reserve (FFR) is a parameter that provides a measure of the severity of coronary stenosis and despite some limitations, FFR can be applied to bifurcation lesions. In addition, intravascular imaging tools, such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT) can be used to determine anatomical configurations.

Zusammenfassung Nach viertagiger Applikation von Parachlorphenylalanin (PCPA) (PCPA-methyl-ester ˙ HCl 100 mg/kg tagl., i. p.) konnte bei weiblichen Ratten eine Hypersexualitat ausgelost werden, die durch Kombination von PCPA mit Testosteron (Testosterononanthat 1,4 mg/kg tagl., i. m.) erheblich gesteigert wurde. Als Ursache wird der Ausfall der inhibitorischen Wirkung des Serotonins auf die hypothalamisch-hypophysaren Regulationszentren diskutiert. Gestutzt wird diese Auffassung durch den Nachweis einer Anreicherung von 14C-markiertem PCPA in den die Sexualitat beeinflussenden Arealen des Gehirns. Summary Female rats treated with parachlorophenylalanine (PCPA) (PCPA-methyl-ester ˙ HCl 100 mg/kg P. D., i. p.) for four days, exhibited hypersexuality which was potentiated by combination of PCPA and testosterone (testosterone enanthate 1,4 mg/kg P. D., i. m.). This effect can be explained by loss of the inhibitory function of serotonin on the hypothalamo-hypophysial system. This interpretation is supported by the findings, that 14C labeled PCPA is accumulated in those centres of brain influencing sexuality. Resume L'administration de la parachlorphenylalanine (PCPA) (Methylester de la PCPA 100 mg/kg par jour, i. p.) aux rats femelles provoque une hypersexualite qui est augmentee par la combinaison de PCPA et de testosterone (Enanthate de la testosterone 1,4 mg/kg par jour, i. m.). Ces manifestations suggerent comme mode d'action une suppression de l'inhibition de la serotonine sur les centres hypothalamo-hypophysaires. Cette interpretation est affirmee par la preuve d'une accumulation de la PCPA marquee au 14C dans les centres du cerveau influant sur la sexualite. Fur wertvolle technische Mitarbeit danken wir K. Wilp und B. Remki.

Zusammenfassung Der Plasmalogengehalt im Hoden- und Nebenhodengewebe von Ratten nach einer durch p-Chlorphenylalanin induzierten hypersexuellen Phase wurde histochemisch, fluoreszenzmikroskopisch und quantitativ-chemisch untersucht. Der dabei auftretende Plasmalogenabfall konnte histochemisch erfast und durch quantitativ-chemische Bestimmungen statistisch gesichert werden. Als Ursache wird die extrem gesteigerte Gewebsaktivitat und der damit verbundene erhohte O2-Verbrauch in diesen Organen diskutiert. Es kann daher angenommen werden, das die im Spermaplasma vorhandene Fruktose fur die Energiebereitstellung nicht ausreicht, so das durch Oxydation von Plasmalogenfettsauren dieses Defizit gedeckt werden kann. Resume Le content des plasmalogenes dans le testicule et dans l'epididyme des rats est examine par la microscopie fluorescente et par des methodes histochimiques et chimiques pendant une phase hypersexuelle provoquee par la parachlorphenylalanine. Une diminution des plasmalogenes est demontree par des methodes histochimiques qui est affirmee statistiquement par des methodes chimiques. La cause pour la diminution des plasmalogenes dans ces organes peut etre l'activite du tissu extremement intensifiee et la consommation d'oxygene augmentee. Il est suppose que le fructose du plasma du sperme est insuffisant pour l'approvisionnement en energie. Le deficit peut etre comble par l'oxydation des acids grasses des plasmalogenes.

2-Deoxy-d-glucose (2-DG) is a glucose analogue that has been proposed for cancer therapy due to its cytostatic properties. Its effect on the proliferation of smooth muscle cells and endothelial cells has not been fully clarified. The aims of this study were to investigate the effects of 2-DG on the proliferation of porcine aortic endothelial cells (PAEC) and porcine smooth muscle cells (PSMC), to establish an overview of its dose-dependent inhibitory capacity and to examine whether the short-term incubation of cells with 2-DG has an impact on cell proliferation in culture. Our results showed a dose-dependent significant inhibitory effect on proliferation, which was more pronounced in PSMC than in PAEC. Even after short-term incubation of cells with 2-DG, relevant inhibition of proliferation was documented. The clinical application of 2-DG might be a promising concept by inhibiting cells that show a potentially rapid proliferation in response to non-malignant stimuli, such as smooth muscle cells after intracoronary stenting.

Aortic valve stenosis (AS) is the most common acquired valve disease in the industrialized countries. Most patients--especially young and low-risk patients--can be safely and effectively operated with aortic valve replacement. Due to increasing life expectancy, however, the number of elderly patients with AS and various concomitant diseases will increase in the coming decades. For those elderly high-risk patients, transfemoral or transapical aortic valve implantation (TAVI) has evolved as a valuable alternative to conventional surgery. The TAVI approach has been shown to be superior to standard medical treatment in these high-risk patients. All patients considered for TAVI should be discussed in a consensus conference consisting of cardiac surgeons and cardiologists (heart team). Furthermore, for successful treatment with transcatheter techniques, sophisticated pre-interventional imaging is required to screen patients. Available data on TAVI from randomized trials and large-scale registries demonstrate that this method is very promising.

Coronary artery disease (CAD) is a leading cause of morbidity and mortality in western countries and is of significant socio-economic importance due to its increasing prevalence. Until percutaneous coronary interventions (PCI) were established, CAD could only be treated by surgical revascularization or pharmacological therapy. In-stent restenosis remains a major problem after stent implantation. However, the use of new materials and stent coatings have led to a significant reduction in in-stent restenosis. Thus, surgical revascularization and PCI are currently of equal value for the treatment of CAD. The decision-making for PCI or surgical revascularization depends on various factors such as number of diseased vessels, complexity of the coronary stenoses, concomitant diseases, and the patient's general condition. The therapeutic regime of every patient should be adjusted to the recommendations of the European and German Society for Cardiology, while controversial and complex cases should be discussed in an interdisciplinary case conference ("heart team").

Due to increasing life expectancy in the coming decades the number of elderly patients with aortic valve stenosis (AS) and various concomitant diseases will increase. Conventional surgical aortic valve replacement represents the treatment of choice in patients with severe and symptomatic AS. Transfemoral and transapical aortic valve implantation (T-AVI) has evolved as a standard procedure for patients with severe AS who are technically inoperable or at very high risk for surgical valve replacement. The T-AVI approach has been shown to be superior to the standard medical treatment in these high-risk patients. All patients to be considered for T-AVI should be discussed in a consensus conference consisting of cardiac surgeons and cardiologists (heart team).

Coronary artery disease (CAD) is a leading cause of morbidity and mortality in western countries and is of significant socio-economic importance due to its increasing prevalence. Until percutaneous coronary interventions (PCI) were established, CAD could only be treated by surgical revascularization or pharmacological therapy. In-stent restenosis remains a major problem after stent implantation. However, the use of new materials and stent coatings have led to a significant reduction in in-stent restenosis. Thus, surgical revascularization and PCI are currently of equal value for the treatment of CAD. The decision-making for PCI or surgical revascularization depends on various factors such as number of diseased vessels, complexity of the coronary stenoses, concomitant diseases, and the patient's general condition. The therapeutic regime of every patient should be adjusted to the recommendations of the European and German Society for Cardiology, while controversial and complex cases should be discussed in an interdisciplinary case conference ("heart team").

Little is known about the impact of early invasive treatment in patients following out-of-hospital cardiac arrest (OHCA). The present study investigated the clinical characteristics and long-term prognosis of 1254 patients with suspected acute coronary syndrome, including 65 with OHCA who underwent successful cardiopulmonary resuscitation (CPR) and 1189 patients who did not require CRP. All patients underwent immediate coronary angiography even if clear signs of myocardial infarction (MI) were absent. The incidence of ST-elevation and non-ST-elevation MI did not differ between the two groups. Cardiac biomarkers were significantly higher in CPR patients despite a shorter period from symptom onset to admission. The 6-month mortality rate was 29% in the CPR group and 4% in the non-CPR group, with > 90% of fatalities occurring ≤ 3 weeks after admission. In summary, early invasive treatment leads to a considerably reduced mortality and improved prognosis in patients after OHCA.

Tako-Tsubo cardiomyopathy (TTC), also referred to as stress cardiomyopathy (SCM), was first described in the 1990s and is characterized by transient left ventricular dysfunction. Its incidence represents 1-2% of all acute coronary syndromes (ACS). In most cases extreme emotional or physical stress precedes this syndrome. The majority of patients affected are postmenopausal women. Since its first description, various hypotheses regarding the pathophysiology of TTC have been discussed. From a historical perspective, coronary vasospasm has often been proposed as a possible cause of this disorder. However, reviews from numerous registries were able to demonstrate that coronary vasospasm plays only a minor role in the pathogenesis of TTC. Several groups showed disturbances in myocardial microcirculation and energy metabolism in the acute phase of TTC. Nevertheless, with regard to the data currently available, it cannot be differentiated whether these changes are the cause or rather the result of TTC. However, recent concepts include an excessive catecholamine overload and morphological changes which are unequivocally documented in TTC. The relation between elevated catecholamine levels and myocardial dysfunction analogous to TTC could be confirmed in animal experiments.In summary, it can be assumed that TTC is caused by an excessive cardiotoxic release of catecholamines. Ventricular dysfunction can be explained by increased numbers of β-adrenergic receptors in the apex, leading to greater vulnerability to catecholamine overload. Individual anatomical differences in the sympathoadrenergic system and distribution from β-adrenergic receptors are presumably responsible for the interindividual occurrence of wall motion abnormalities in TTC.

Tako-Tsubo cardiomyopathy (TTC) is a heart syndrome associated with transient contractile dysfunction. It is also referred to as "broken heart syndrome" or "transient left ventricular apical ballooning." Leading symptom is a sudden onset of chest pain, often accompanied by dyspnoea. Clinical features include new electrocardiographic changes (ST-Segment elevations, T wave inversions), moderate elevation of the cardiac enzymes and transient wall motion abnormalities in absence of significant coronary artery obstruction. Although causal treatment has not been established, TTC has a favourable prognosis with a low mortality and a complete recovery of the contractile function in nearly all cases. Although several mechanisms have been proposed, the pathophysiology is not yet fully understood. However, emotional and physical stress followed by excessive release of catecholamines might play a pivotal role in the development of TTC.

During recent years, the treatment of pulmonary diseases could be significantly improved due to the introduction of modern retrometabolism-based corticosteroids with improved therapeutic ratio. It is the goal of all inhaled corticosteroids to produce long lasting therapeutic effects at the pulmonary target site and to minimize systemic side effects by rapid clearance of the absorbed drug and low oral bioavailability. The development of PK/PD models allows predictions of drug effects based on the administered dose. For example, the cumulative suppression of endogenous cortisol release (CCS) as one of the major systemic side effects of inhaled corticosteroid therapy can be described with an integrated Emax based PK/PD model. In order to assess the predictive power of this model, a study was conducted to compare the PK/PD-based predictions with CCS data obtained from actual clinical trials for flunisolide, fluticasone propionate, budesonide and triamcinolone acetonide. CCS was predicted for different single doses from different inhaler devices for each drug and a good correlation was observed. Thus, the presented PK/PD model proved to be a valid tool for predicting CCS of inhaled corticosteroids. By fully understanding the underlying mechanisms it will be possible to further improve their therapeutic index.

The suppression of endogenous cortisol release is one of the major systemic side effects of inhaled corticosteroids in the treatment of asthma. The circadian rhythm of the endogenous cortisol release and the resulting plasma concentrations as well as the release suppression during corticosteroid therapy could previously be described with an integrated PK/PD model. Based on this model, a PK/PD approach was developed to quantify and predict the cumulative cortisol suppression (CCS) as a surrogate marker for the systemic activity of inhaled corticosteroid therapy. The presented method was applied to predict CCS after single doses and during short-term multiple dosing of the inhaled corticosteroids flunisolide (FLU), fluticasone propionate (FP), and triamcinolone acetonide (TCA), and after oral methylprednisolone as systemic reference therapy. Drug-specific PK and PD parameters were obtained from previous single-dose studies and extrapolated to the multiple-dose situation. For single dosing, a similar CCS within the range of 16-21% was predicted for FP 250 micrograms, FLU 500 micrograms, and TCA 1000 micrograms. For multiple dosing, a respective CCS of 28-33% was calculated for FLU 500 micrograms bid, FP 250 micrograms, bid, and TCA 1000 micrograms bid. Higher cortisol suppression compared to these single and multiple dosing regimens of the inhaled corticosteroids was predicted after oral doses of only 1 mg and 2 mg methylprednisolone, respectively. The predictive power of the approach was evaluated by comparing the PK/PD-based simulations with data reported previously in clinical studies. The predicted CCS values were in good correlation with the clinically observed results. Hence, the presented PK/PD approach allows valid predictions of CCS for single and short-term multiple dosing of inhaled corticosteroids and facilitates comparisons between different dosing regimens and steroids.

Lymphocytopenia is a sensitive surrogate marker for the immunological effects of corticosteroids. This pharmacokinetic/pharmacodynamic (PK/PD) study investigated whether the circadian variation of blood lymphocytes observed after placebo is secondary to the circadian rhythm of endogenous cortisol, and developed based on this relationship an improved PK/PD model for a more sensitive description of the effect of low-dose corticosteroid therapy on blood lymphocytes considering the net activity of the exogenous corticosteroid budesonide and endogenous cortisol.In an open, parallel study design, 3 mg oral budesonide or placebo were given at 8.00 a.m., 4.00 p.m. and midnight to two groups of 12 volunteers. Lymphocyte counts and serum concentrations of budesonide and cortisol were monitored for 24 hours. A mechanism-based PK/PD model which considered the non-linear protein binding of cortisol and the budesonide-induced cortisol suppression was employed to relate changes in blood lymphocytes to free cortisol levels after placebo and to the net activity of free budesonide and free endogenous cortisol after active treatment.The circadian rhythm of blood lymphocytes observed after placebo could inversely be related to the circadian rhythm of serum cortisol. After budesonide administration, lymphocyte counts could accurately be linked to the net activity of budesonide and endogenous cortisol. The resulting EC50 values for the effect of budesonide on cortisol, budesonide on lymphocytes and cortisol on lymphocytes were 0.063 +/- 0.034, 0.22 +/- 0.13 and 26.3 +/- 15.0 ng/ml (placebo group 15.4 +/- 3.4 ng/ml), respectively.The presented mechanism-based PK/PD model suggests that blood lymphocytes are under physiological control of cortisol. It further indicates that endogenous and exogenous corticosteroids and their pharmacological interaction need to be considered for modeling the effects of low doses of exogenous corticosteroids on the immune system.

Corticosteroids are used for the treatment of a variety of different diseases both locally and systemically. Most therapeutic effects result from glucocorticoid receptor-mediated events, and there seems to be no substance-specific difference in the post-receptor reaction cascade. Therefore, the extent and duration of glucocorticoid effects depend only on the availability of the respective steroid at the receptor site and its affinity to the receptor. This makes glucocorticoids an ideal candidate for PK/PD modelling. Availability at the receptor site is governed by pharmacokinetic parameters such as bioavailability, clearance, protein binding, and volume of distribution. The receptor affinity can easily be measured in vitro. A suitable indirect-response PK/PD model is presented that allows description of the receptor-mediated drug effects such as endogenous cortisol suppression as a function of time. Furthermore, this model allows prediction of the systemic activity of newly developed corticosteroids based on their pharmacokinetics and their respective receptor-binding affinity. The model can also be applied in order to study systemic steroid effects after topical administration or to investigate the effect of the time of dosing on cortisol suppression. Comparison of predictions based on this model and results from large clinical studies are in excellent agreement. Corticosteroids may represent an ideal class of drugs for the successful use of PK/PD modelling during drug development allowing to save time and expenses.

The pharmacokinetics and pharmacodynamics of cloprednol after oral administration in doses of 2.5 to 15 mg to healthy volunteers were determined. The half-life of cloprednol ranged from 1.8 h to 2.7 h, the oral clearance (CL/F) was determined to be 15-22 l/h. Since cloprednol shows nonlinear plasma protein binding, the plasma concentrations were converted to their free, unbound concentrations for the PK/PD-analysis. Due to this nonlinearity, the half-life of free, unbound cloprednol was shorter than that of the total drug. For the assessment of pharmacodynamics, differential white blood cell counts were obtained over 24 hours. An integrated pharmacokinetic-pharmacodynamic (PK/PD) approach using a modified Emax-model was applied to link unbound corticosteroid concentrations to the effect on lymphocytes and granulocytes. The E50 value for unbound cloprednol ranged from 3.6 to 4.7 ng/ml and 1.2 to 4.6 ng/ml for granulocytes and lymphocytes, respectively. The PK/PD model allowed a good prediction of the observed effects and was consistent with reported values for glucocorticoid receptor binding affinities for cloprednol.

A problem in the evaluation of pharmacokinetic interactions between prednisolone and cortisol is that both steroids bind to cortisol binding globulin (CBG) and albumin. The binding of both steroids to CBG is saturable in the therapeutic concentration range. General drug binding equations were applied to two drugs and two binding sites and two implicit cubic equations were derived. These equations cannot be solved algebraically. However, the free concentration can be calculated using spreadsheet programs on a personal computer. A spreadsheet for these equations was developed using EXCEL 5.0 and its SOLVER option. Free concentrations of prednisolone and cortisol were determined as a function of total concentrations of both ligands. The simulations show that the protein binding of cortisol remains relatively constant in the physiological range but changes when exogenous corticosteroid is present. However, the degree of protein binding of exogenous corticosteroids that bind to CBG depends on the cortisol concentration which competes for binding sites. At the same time, the exogenous corticosteroid suppresses the release of endogenous cortisol. The presented approach is able to take all of these pharmacokinetic and pharmacodynamic interactions into account leading to a more accurate estimation of active free corticosteroid concentrations.

The pharmacokinetics and pharmacodynamics of deflazacort after oral administration (30 mg) to healthy volunteers were determined and compared with those of 20 mg of methylprednisolone and 25 mg of prednisolone.Methylprednisolone, prednisolone and the active metabolite of deflazacort, 21-desacetyldeflazacort, were measured in plasma using HPLC. For the assessment of pharmacodynamics, differential white blood cell counts were obtained over 24 hours. An integrated pharmacokinetic-pharmacodynamic (PK-PD) model was applied to link corticosteroid concentrations to the effect on lymphocytes and granulocytes.Deflazacort is an inactive prodrug which is converted rapidly to the active metabolite 21-desacetyldeflazacort. Maximum concentrations of 21-desacetyldeflazacort averaged 116 ng/ml and were observed after 1.3 h. The average area under the curve was 280 ng/ml.h, and the terminal half-life was 1.3 h. 21-Desacetyldeflazacort was cleared significantly faster than both methylprednisolone and prednisolone. The PK-PD-model was suitable to describe time course and magnitude of the observed effects. The results were consistent with reported values for glucocorticoid receptor binding affinities for the investigated compounds.Due to the short pharmacokinetic half-life of its active metabolite, pharmacodynamic effects of deflazacort are of shorter duration than those of methylprednisolone and prednisolone. The PK-PD model allows good prediction of pharmacodynamic effects based on pharmacokinetic and receptor binding data.

The clinical pharmacokinetics and pharmacokinetic/dynamic properties of the beta-adrenergic drugs fenoterol, salbutamol and terbutaline are reviewed. Sulfate conjugates are the main metabolites in man. The protein binding of these derivatives is rather weak with most pronounced binding observed e.g. fenoterol (40%). Disposition after parenteral administration shows a multi-exponential behavior for all the substances with linear but also stereo-selective pharmacokinetics. After parenteral administration, the drugs are mainly eliminated by renal processes while after oral administration a pronounced metabolic clearance (high first pass effect) is responsible for a low bioavailability, especially for fenoterol (2%). The total clearance for fenoterol is about twice that of salbutamol and terbutaline. Seven to 15% of the delivered aerosol reach typically the systemic circulation. In patients with respiratory disorders, pulmonary absorption is however highly dependent on the disease state. Pharmacokinetics in children do not significantly differ from adults when expressed per kg body weight. Patients with renal failure but not asthmatics show changed pharmacokinetic profiles. Only insignificant interactions with other drugs have been found. Pharmacokinetic/dynamic modeling approaches indicated that fenoterol is 25 times more active at the site of action than salbutamol and terbutaline, but all three drugs show similar bronchopulmonary selectivities. When the overall clinical activity, determined by pharmacokinetic and dynamic properties is compared, the activity gap is reduced: fenoterol (8) greater than salbutamol (2) greater than terbutaline (1). Differences in the first pass effect even inverse the pattern after oral administration. PK/PD modeling quantified the pulmonary effect after inhalation and suggested that the higher incidence of side effects for fenoterol might be linked to an overdosing problem. The application of PK/PD principles may improve the clinical usage and therapy of beta-2-adrenergic drugs.

The pharmacokinetics and pharmacodynamics of prednisolone were investigated according to four different routes of administration: 20 and 40 mg prednisolone orally in the morning, 20 mg prednisolone orally in the evening and 40 mg prednisolone intravenously in form of prednisolone phosphate in the morning. The plasma levels of prednisolone were followed using HPLC. To study the pharmacodynamics of prednisolone, glucose levels and various blood cell parameters such as erythrocytes, leukocytes, segmented neutrophilic granulocytes, eosinophils, basophils, monocytes and lymphocytes were followed. To summarize the data, the area under the effect-time-curve (AUCE) was calculated by the trapezoidal rule. The results show that the pharmacokinetics of prednisolone is dose-dependent (non-linear) and time-dependent. Prednisolone concentrations in plasma after a 20 mg and 40 mg dose are very similar, indicating that the pharmacokinetics of prednisolone are non-linear and dose-dependent with a higher clearance for higher concentrations. The comparison of 20 mg administered in the morning with the same dose given in the evening shows that the pharmacokinetics of prednisolone after oral administration of equal doses changes during the day with higher concentrations in the morning than in the evening. Furthermore, the results of the present study confirm the presence of pharmacodynamic corticosteroid effects on blood cell count and blood glucose. No statistically significant differences were observed for the four different treatments. In summary, it can be concluded that due to the complex pharmacokinetics of prednisolone, it is difficult to make accurate predictions of the expected effect-time relationships.

Pulmonary and cardiac effects of the beta 2-adrenergic drug fenoterol were studied in 27 asthmatic patients using an integrated pharmacokinetic/dynamic (PK/PD) approach. Airway resistance (Rf), intrathoracic gas volume (IGV), heart rate, and plasma levels were monitored after placebo, injection (12.5 and 25 micrograms), nasal instillation (400 micrograms), inhalation (200 and 400 micrograms), and infusion (200 micrograms/180 min with or without loading dose). The pharmacokinetics were best described by an open three-compartment model with a terminal half-life of 200 min (gamma = 0.23 +/- 0.08 L/hr), a volume of distribution at steady state of 1.9 +/- 0.8 L/kg, and a clearance of 0.86 +/- 0.32 L/hr/kg, with 14 and 9% absorbed after nasal and pulmonary administration, respectively. For the noninhalation regimens, a PK/PD correlation linked the concentration in the shallow pharmacokinetic compartment to the investigated effects via an Emax relationship, resulting in three to five times higher EC50 values (concentration necessary to achieve half-maximal effect) for the heart rate than for the beta 2-mediated effects on IGV and Rf. In contrast, pulmonary effects after inhalation could not be incorporated into the correlation, indicating that these effects are induced locally after inhalation. Intrapatient variability for EC50 and Emax was approximately 90%.

The pharmacokinetics and pharmacodynamics of methylprednisolone were investigated after intravenous administration of methylprednisolone phosphate to healthy subjects at seven different doses (16 to 1000 mg). Forty different pharmacodynamic parameters were followed for 1 week. The pharmacodynamic data were analyzed as a function of time as well as cumulative effects in form of the areas under the effect-time curves. Statistically significant dose-dependent effects of methylprednisolone were observed for 15 pharmacodynamic parameters. Highly significant (P less than or equal to 0.0001) effects were increases in glucose levels, number of white blood cells, and segmented granulocytes as well as a decrease in the number of lymphocytes. For these pharmacodynamic effects an integrated pharmacokinetic/pharmacodynamic model was derived that translates the methylprednisolone plasma concentration-time profiles into effect-time profiles. This model allows prediction of pharmacodynamic effects for any single dose in the range studied at any time point.

Die Synthese des 7-(Butin-(3′)-yl)-theophyllins-3H wird beschrieben. Ganztierautoradiographische Untersuchungen an Wistar-Ratten ergaben eine Anreicherung der Substanz im liquor cerebrospinalis, sowie im Glaskorper des Auges und den Zwischenwirbelscheiben. Bei einer histologischen Analyse der Niere zeigte sich in den tubuli contorti I und II Abschnitten eine vakuolige Auflockerung mit teilweiser Zerstorung der gesamten Zelle. Studies of [3H]-7-(3-Butynyl)theophylline by Whole-Body Autoradiography The synthesis of [3H]-7-(3-butynyl)-theophylline is described. Whole-body autoradiography of Wistar rats after application of the compound shows a cumulation of radioactivity in the cerebrospinal fluid, in the vitreous body of the eye and in the intervertebral discs. Histologic analysis of the kidney showed a vacuolic structure and partial destruction of the cells in convoluted tubules I and II.

In in-beam (p, p′) experiments, electron and γ-spectra were measured in the electron energy range of 500-1840 keV for102Pd and104Pd, and 600–1580 keV for106Pd. The conversion coefficients of all transitions in this range were obtained with accuracies of about 20%, in some favourable cases 10%.

Um die Identifizierung von Phenylathylamin-Abkommlingen durch die Kernresonanzspektroskopie zu ermoglichen, wurde von 20 derartigen Substanzen das Spektrum aufgenommen und die fur sie charakteristischen Signale angegeben.

Die Glomera carotica von 12 Kaninchen wurden nach viertagiger Applikation von Reserpin (2 mg/kg KG; i.p.) (I), Parachlorphenylalanin-methylester-hydrochlorid (PCPA; 100 mg/kg KG; i.p.) (II) und physiologischer NaCl-Losung (III) mit der Falckschen Fluoreszenzmethode aufgearbeitet und cytospektrofluorometrisch (Mikrospektrograph Leitz) ausgewertet. An Hand der Fluoreszenzspektren der spezifischen Glomuszellen (Typ I) lies sich eine Depletion der Catecholamine und des Serotonins verfolgen: hiernach senkt PCPA vor allem das Serotonin, Reserpin hingegen die Catechol- und Indolamine in etwa gleichem Umfang. Durch Zerlegung einiger Gesamtspektren in die Anteile fur Catecholamine und das Serotonin mit Hilfe eines Iterationsverfahrens der nichtlinearen Regression konnte gezeigt werden, das nur eine geringfugige Beeinflussung der Catecholamin-Peakhohe durch das Serotonin vorliegt. Uber die Messung der Peakhohe im Catecholaminbereich der Gesamtspektren konnte daher die Reduktion der Catecholamine auf 64±22% durch PCPA und auf 13±4% durch Reserpin statistisch gesichert werden. Die Befunde werden im Zusammenhang mit den moglichen Wirkungsmechanismen der applizierten Substanzen diskutiert. Eine ausfuhrliche tabellarische Zusammenstellung der bisherigen Angaben uber Gehalt und Zusammensetzung der biogenen Amine des Glomus caroticum erganzt diese Diskussion.

Topochemisch konnten im Kaninchenthymus Ketosteroide nachgewiesen werden, fur deren Vorhandensein die chemische Analyse von Thymuslipidextrakten Hinweise ergeben hatte. Die Darstellung der Ketosteroide erfolgte mit der NAHD-Reaktion (Camber, 1949). Diese Befunde durften als spezifisch gelten, da eine Verfalschung durch freie Gewebsaldehyde, Plasmalogene (Gomori, 1952) und Corticosteroide (Khanolkar et al., 1958) ausgeschlossen wurde.

Durch Neutronenaktivierungsanalyse wird nachgewiesen, das bei der Eatte von symptomlos vertragenem metallischem Quecksilber, oral zugefuhrt, ein geringer Anteil resorbiert wird, welcher zu einer Erhohung der Queeksilberwerte in Blut und Niere auf reichlich das 10fache der Norm fuhrt.

Der Lipidgehalt des schlachtfrischen Kalbsthymus betragt 4,1 %. Davon sind 1 – 3 % Kohlenwasserstoffe, 66– 69 % Neutrallipide und 22,5 – 24 % Phospholipoide. In der letzgenannten Fraktion konnten nachgewiesen werden: Phosphatidylcholin, Phosphatidylathanolamin, Sphingomyclin, Phosphatidylinositid. Die Hauptkomponenten sind: Phosphatidylcholin (0,56%), Phosphatidylathanolamin (0,27 %) und Sphingomyelin (0,12 %). Ihre Analyse erfolgte nach DC an Kieselgel/Magnesiumsilikat durch eine kolorimetrische Phosphorbestimmung. Investigations of the Phospholipids of Calf Thymus The thymus of freshly slaughtered calves was found to contain 4,1 % of lipids, of which 1 – 3 % consisted of hydrocarbons, 66 – 69 % of neutral lipids and 22,5 – 24 % of phospholipids. In the latter fraction were identified: phosphatidyl choline, phosphatidyl ethanolamine, sphingomyelin, phosphatidyl serine and phosphatidyl inositol. The main components are: phosphatidyl choline (0,56 %), phosphatidyl ethanolamine (0,27 %) and sphingomyelin (0,12 %). Their analysis was done by Kieselgel/magnesium silicate thinlayer chromatography using the colorimetric determination of phosphorus.

Nachdem durch die NAHD-Reaktion (Camber, 1949) Ketosteroide in den granulierten Zellen des Kaninchenthymus dargestellt werden konnten (Mollmann et al., 1973), wurde der Ketosteroidgehalt des Thymus an Hand des zahlenmasigen Verhaltens der Camber-positiven Zellen in der Postnatalzeit (1.–30. Tag), nach Glucocorticoidapplikation sowie nach Metopirongabe uberpruft. Die bei der Geburt nur vereinzelt auftretenden granulierten Zellen vermehrten sich stetig bis zu einem Maximum am 9. postnatalen Tag, um daraufhin wieder abzunehmen. Ein Vergleich dieser Befunde mit dem relativen Thymusgwicht ergab eine nahezu gegensinnige Korrelation. Nach Verabreichung von Glucocorticoiden von Geburt an zeigten die Thymi von Kaninchen, die nicht am Wasting-Syndrom verstarben, eine deutliche Zunahme der Camber-positiven Zellen, wiederum gegenlaufig zum relativen Thymusgewicht. Hingegen fuhrte die mehrtagige Applikation von Metopiron zu keinen Veranderungen der Zahl und des Aussehens dieser Zellen.

Die organspezifischen Strukturen im Glomus caroticum und Nebennierenmark zeigen unter verschiedenen experimentellen Bedingungen ein unterschiedliches Bild. So last sich unter anderem durch Modifizierung der Fixationsmedien (Glutaraldehyd, Osmiumsaure in Kombination mit verschiedenen Puffern) eine optimale Differenzierung der zellularen Strukturelemente von Glomuszellen erreichen. An den osmiophilen Vesikeln fallt eine starke Variabilitat ihres Erscheinungsbildes auf. Feinstrukturelle Unterschiede werden in Elektronendichte des Vesikelinhaltes, Grose und Ausbildung des Hofes sowie in Aufbau und Verlauf der Membran deutlich. Auf Grund dieser Kriterien lassen sich im wesentlichen 4 Haupttypen der Granula von seltener vorkommenden Sonderformen abgrenzen.

Der Einflus von p-Chlorphenylalanin-methylester-hydrochlorid (PCPA) und Reserpin auf die biogenen Amine des Glomus caroticum von Kaninchen wurde ultrastrukturell und fluoreszenzmikroskopisch untersucht. Die elektronenmikroskopische Analyse ergab keine eindeutigen Kriterien fur arzneimittelinduzierte Veranderungen. Fluoreszenzmikroskopisch lies sich nach Applikation von Reserpin eine ausgepragte Senkung des Catecholamin- und Indolamin-Gehaltes und nach PCPA eine Abnahme des Serotonins erkennen.