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The functionality of most secreted proteins depends on their assembly into a defined quaternary structure. Despite this, it remains unclear how cells discriminate unassembled proteins en route to the native state from misfolded ones that need to be degraded. Here we show how chaperones can regulate and control assembly of heterodimeric proteins, using interleukin 23 (IL-23) as a model. We find that the IL-23 α-subunit remains partially unstructured until assembly with its β-subunit occurs and identify a major site of incomplete folding. Incomplete folding is recognized by different chaperones along the secretory pathway, realizing reliable assembly control by sequential checkpoints. Structural optimization of the chaperone recognition site allows it to bypass quality control checkpoints and provides a secretion-competent IL-23α subunit, which can still form functional heterodimeric IL-23. Thus, locally-restricted incomplete folding within single-domain proteins can be used to regulate and control their assembly., It is unclear how unassembled secretory pathway proteins are discriminated from misfolded ones. Here the authors combine biophysical and cellular experiments to study the folding of heterodimeric interleukin 23 and describe how ER chaperones recognize unassembled proteins and aid their assembly into protein complexes while preventing the premature degradation of unassembled units.

In many European countries and particularly in Germany, piritramide is the first choice opioid analgesic for the management of postoperative and posttraumatic pain.The aim of this study was to review the pharmacological properties of piritramide and to evaluate whether these result in any clinical advantages with respect to effectiveness, safety and side effect profile compared to other strong opioids.A systematic literature search was conducted in PubMed and Google Scholar and 27 articles published between 1961 and 2015 were retrieved and included in this review.Piritramide is a strong opioid that can only be administered parenterally. After intravenous injection it is effective after 17 min with pain relief lasting for up to 6 h. It is metabolized in the liver to inactive compounds, which is advantageous compared to morphine where active metabolites can accumulate in patients with renal failure. Piritramide is highly lipophilic resulting in a long context-sensitive half-life, making it unsuitable for continuous infusions. Studies further suggest that the side effect profile of piritramide is comparable to morphine.So far there is little evidence to support the widespread use of piritramide as first-line opioid analgesic for postoperative pain management in Germany. Especially lacking are in-depth studies about its mechanisms of action, receptor pharmacology, dose-response relationships and clinical dosing regimens. It is therefore questionable why piritramide is given priority.

Many patients under oral anticoagulation therapy need percutaneous or surgical interventions/operations. For vitamin K antagonists (VKA), there are recommendations regarding preoperative or postoperative administration. Management of the new oral anticoagulants (NOAC) was supposed to be easier - but some aspects must be considered. Due to the different pharmacokinetic profiles of substances such as dabigatran, rivaroxaban, apixaban, and edoxaban, different recommendations are given.Upon periprocedural management, thromboembolic risk has to be considered in patients treated with NOACs. NOACS have a pharmacokinetic advantage in terms of a rapid onset and rapid elimination via the liver and kidneys. Impaired renal function results in extended half-life of NOACs considerably.Surgical procedures under NOACS can be scheduled at the beginning of next dosing interval or omitted in low/minimal bleeding risk patients, so that only 2-3 NOAC doses are not administered. In patients with moderate and high risk of bleeding, there should be a NOAC break of 24-48 h prior to surgery in order to allow a corresponding decay of the active metabolite. In patients with low/intermediate risk for thromboembolism, no bridging is necessary if the "unprotected" time (NOAC break) is less than 4-5-(7) days. In patients at high risk of thromboembolism, individual consideration must be taken regarding bridging or extended NOAC break. Whether NOACs can be dispensed or bridging is necessary in these patients must be clarified in randomized trials for periprocedural management of NOACs patients.

Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used in patients with deep vein thrombosis (DVT), pulmonary embolism (PE) and atrial fibrillation (AF). However, there is insufficient data concerning the periinterventional, perioperative, and intensive care management of patients on NOACs. Therefore, the recommendations regarding this management rely on pharmacokinetics of the particular NOAC in combination with the individual patient's characteristics, bleeding risk of the planned intervention/surgery, and urgency of the procedure. This review summarizes evidence and recommendations regarding the optimal periinterventional/perioperative antithrombotic management of patients on NOACs.

Optimized dosage regimens of antibiotics have remained obscure since their introduction. During the last two decades pharmacokinetic(PK)-pharmacodynamic(PD) relationships, originally established in animal experiments, have been increasingly used in patients. The action of betalactams is believed to be governed by the time the plasma concentration is above the minimum inhibitory concentration (MIC). Aminoglycosides act as planned when the peak concentration is a multiple of the MIC and vancomycin seems to work best when the area under the plasma vs. time curve (AUC) to MIC has a certain ratio. Clinicians should be aware that these relationships can only be an indication in which direction dosing should go. Larger studies with sufficiently high numbers of patients and particularly severely sick patients are needed to prove the concepts. In times where all antibiotics can be measured with new technologies, the introduction of therapeutic drug monitoring (TDM) is suggested for ICUs (Intensive Care Unit). The idea of a central lab for TDM of antibiotics such as PEAK (Paul Ehrlich Antibiotika Konzentrationsmessung) is supported.

Die Glykosylierung von Biopharmazeutika erreicht einen immer höheren Stellenwert in der Biotechnologischen Industrie. Es ist einer der wichtigsten kritischen Qualitätsmerkmale für die Sicherheit und Wirksamkeit von Biopharmazeutika. Die Herstellung von rekombinanten Proteinen muss unter streng kontrollierten Bedingungen durchgeführt werden, damit die Produktqualität und Prozessstabilität gewährleistet werden kann. Hierfür wird eine Produktspezifikation erstellt, welche die genauen Akzeptanzkriterien der jeweiligen kritischen Prozessparameter beinhalten. Die kritischen Prozessparameter der Fermentation von rekombinanten Proteinen sind unter anderem pH, Temperatur, Zelldichte und Sauerstoff. Diese Prozessparameter können die Glykosylierung der rekombinanten Proteine stark beeinflussen, indem sich ihre N-Glykanstruktur oder der Gehalt an Sialinsäuren verändern. Insbesondere sind die Sialinsäuren von Bedeutung in Bezug auf die Halbwertszeit von rekombinanten Proteinen. Diese Masterarbeit beschreibt den Einfluss der kritischen Prozessparameter auf die N-Glykanstruktur des rekombinanten von Willebrand Faktor-Proteins, basierend auf einer Überprüfung der definierten Akzeptanzkriterien im Labormaßstab. Es konnte ein signifikanter Einfluss der Prozessparameter auf die N-Glykanstruktur und die Sialinsäuren ermittelt werden. Weiters wurde auch ein Einfluss der Prozessparameter auf die Produktqualität und Prozessstabilität ermittelt. The glycosylation of biopharmaceuticals is reaching a continuous importance in the biotechnology industry. It is one of the most critical quality attributes for the safety and efficacy of biopharmaceuticals. The production of recombinant proteins must be carried out under strictly controlled conditions to ensure product quality and process stability. For this purpose, a product specification is created, which contains the detailed acceptance criteria of each critical process parameter. The critical process parameters of the recombinant proteins in fermentation include pH, temperature, cell density and oxygen saturation. These process parameters can have strong influence on the glycosylation of recombinant proteins, indicated by change of the N-glycan structure or the amount of sialic acids. Especially the sialic acids are important with regards to the half-life of recombinant proteins. This thesis describes the effect of the critical process parameters on the N-glycan structure of recombinant von Willebrand factor protein, based on a review of the defined acceptance criteria at small scale. A significant influence of process parameters on the N-glycan structure and the sialic acids was seen. Furthermore an influence of the process parameters on product quality and process stability was identified. vorgelegt von: Ulrike Prem Masterarbeit Wien, FH Campus Wien 2015

Insulin degludec (IDeg) is a basal insulin with a stable, flat action profile and an even distribution of the blood glucose lowering effect over 24 hou rs. The terminal half-life of IDeg is about 25 hours, which reflects a mean prolongation by factor 2 compared to Insulin glargin (lGlar).This may enable for a more flexible daytime dosing versus up to now available basal insulins.Two open, randomized, treat-to-target studies enrolled patients with type 1 diabetes (n =493) or type 2 diabetes (n = 687). Both phase 3 studies compared a daytime flexible dosing of IDeg (IDeg-flex) with IDeg at the evening meal (IDeg-evening) and IDler at a fixed daytime. In the IDeg-flex-group dosing intervals were predefined with variations between 8 and 40 hours.In patients with type 1 diabetes IDeg-flex proved to be non-inferior with respect to reduction of HbA1C (-0.40%) versus IDeg-evening (-0.41%) and IGlar (-0.58%) after 26 weeks. In addition, nocturnal hypoglycemic events were reduced by 40% (p0.01) with IDeg-flex versus IGlar. In patients with type 2 diabetes reduction of HbA1C with ID)eg-flex (-1.28%) was non-inferior to IDeg-evening (-1.07%) and IGlar (-1.26%), respectively, whereas rates for hypoglycemia were comparable.Patients with diabetes mellitus are enabled to dose a basal insulin flexibly when needed (minimum interval of 8 hours after the last injection is necessary). Impacts of this treatment option on quality of life and adherence and outcomes should be examined in observational trials.

This paper provides a brief portrait of Botrychium simplex and starts by describing its biological characteristics and distribution in Germany. In the third part, a demographic study is presented reporting on long-term observations of the only presently known German population (Senne area, North Rhine-Westphalia). As with all moonworts, the spores of B. simplex germinate in the soil, and the gametophytes start developing only if they are infected by an arbuscular mycorrhizal symbiont. The sporophytes are mycotrophic as well. Sporophytes can remain dormant for one or more years without producing aboveground leaves. As a low growing plant and a weak competitor B. simplex is dependent on an open and low plant vegetation cover. The leaves are morphologically highly variable with the form of the sterile portion being particularly diversified. Of the several varieties distinguished in North America, var. tenebrosum occurs in Central Europe, in addition to the more common var. simplex. Botrychium simplex is a species inhabiting the north temperate to cool-temperate zone with a range that includes Europe, North America, India, and Japan. In Germany, localities from the past three centuries and 12 ordnance survey maps (German TK 25) are known. The majority of findings date back to the 19th century, only 5 have been reported for the 20th century. The dynamics of the population in the Senne area (North Rhine-Westphalia) were examined every year since 1994. At the time of its discovery (1993), the population appeared to be at an optimum stage and included three closely spaced sub-populations; in later years three more sub-populations were discovered. Only one sub-population produced leaves permanently (with the exception of one year). After just one year, a clear decrease in leaf number was registered, a trend that continued in subsequent years. Similar negative changes were found with regards to leaf length, the proportion of fertile leaves, and the number of sporangia formed per leaf. The sporophyte is very short-lived in species of subgenus Botrychium, which includes B. simplex; the half-life is short as well and amounts to a few years only. The decrease in population size observed in the Senne agrees very well with the one predicted assuming a 3-year half-life. Additional factors, which could have been involved in the decline, various biotic factors and possible impairments, indirectly or directly caused by human activities are discussed as well. It is likely that, in addition to a spore bank, gametophytes, sporophytic juveniles or older rhizomes exist in the soil, which could contribute to leaf formation in the future. Therefore, long lasting conservation elements and management regimes are proposed for the population in the Senne to achieve the possibility of a rejuvenation of the population or a restoration of the population from the spore bank.

After subcutaneous injection, IDeg self-associates to form multihexamer chains that slowly dissociate into monomers. This results in a duration of action of more than 42 hours as well as a smooth level action profile with low intra-individual variability. Pharmacokinetic studies foun IDeg to have a half-life of approximately 25 hours which is considerably longer than that from other current insulin formulations. Based on these properties, IDeg demonstrated low risk for nocturnal hypoglycaemic events in the clinical study program. Concurrently, phase 3 studies have provided evidence for a non-inferior glucose lowering effect when compared to other currently available basal insulin formulations. Moreover, the long duration of action suggests a flexible handling which could be better adapted to patients' needs in daily routine. This article gives an overview of the mechanism of action of IDeg and the latest results from phase 2 and phase 3 studies.

The aim of the perioperative management of anticoagulation in patients with long-term oral anticoagulation is to minimize bleeding complications of surgical interventions.We aimed to give a summary of current data and to give practical recommendations for colleagues practicing surgery.This article gives a narrative overview of available data from 31 publications between 2000 and 2013.Every perioperative decision on whether to continue oral anticoagulation is preceded by an assessment of the risk of bleeding and embolism. In cases with a low risk of bleeding, oral anticoagulation can usually be continued. In contrast, for larger interventions with a moderate to high risk of bleeding, a discontinuation of phenprocoumon with temporary bridging is required. In this case it is common practice to discontinue phenprocoumon 7-9 days preoperatively and administer heparin mostly in the form of low molecular weight heparin (LMWH) depending on the international normalized ratio (INR). In contrast perioperative management of direct oral anticoagulants (DOAC) is discussed controversially. Based on the pharmacokinetics of the DAOC, the recommendations are to minimize the anticoagulation-free interval to 2-4 half-lives (HWZ) preoperatively (1-5 days) and early postoperative restart. In this case no bridging is necessary. On the other hand, an early interruption of DOAC 5 days prior to surgery to a minimum of 2 days postoperatively is favored by some surgeons to assure an adequate perioperative hemostasis. Depending on the risk of thromboembolism, bridging is required. These recommendations are justified by limited clinical experience and the absence of antagonism.The perioperative management of coagulation is still a challenge. While there are consolidated decision aids for phenprocoumon, the approach under DOAC treatment is still controversial due to limited data.

According to international surveys, the appetite suppressant phentermine has frequently been seized although its approval has been withdrawn in Germany. Phentermine is an isomer of methamphetamine though is not optically active such as e. g. amphetamine. The drug acts as a potent substrate at the norepinephrine transporter simultaneously promoting its release; it has a weaker activity at the dopamine transporter whereas its activity towards the serotonin transporter is negligible. Overall, its pharmacological action is comparable to that of amphetamine albeit less strong. Due to its declining effect with time and its addiction potential it has been recommended that phentermine should be used for a few weeks only. Phentermine hydrochloride is a readily soluble salt; absorption of the resinate compound is considerably slower. The drug is not extensively biotransformed; p- and N-hydroxyphentermine are the primary metabolites also being excreted as glucuronide conjugates. Gas chromatographic techniques to identify and to quantify phentermine in biological specimens are applicable following derivatization; however, liquid chromatography coupled to mass spectrometry is currently preferred for analysis of urine, serum or hair. Short-term clinical studies having been performed in the 80s and 90s revealed no serious harmful side effects. However, there are case reports proposing that phentermine usage might be associated with severe health risks due to hypertension, vasoconstriction and vasculopathy; in some individuals, mental illness had been observed. Apart from the legal consequences following purchase of drugs that have been withdrawn its user will simultaneously run serious and unpredictable health risks.

Psychostimulants (methylphenidate and amphetamines) are the drugs of first choice in the pharmacological treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD).We summarize the pharmacological characteristics of amphetamines and compare them with methylphenidate, special emphasis being given to a comparison of effects and side effects of the two substances. Finally, we analyze the abuse and addiction risks.Publications were chosen based on a Medline analysis for controlled studies and meta-analyses published between 1980 and 2011; keywords were amphetamine, amphetamine salts, lisdexamphetamine, controlled studies, and metaanalyses.Amphetamines generally exhibit some pharmacologic similarities with methylphenidate. However, besides inhibiting dopamine reuptake amphetamines also cause the release of monoamines. Moreover, plasma half-life is significantly prolonged. The clinical efficacy and tolerability of amphetamines is comparable to methylphenidate. Amphetamines can therefore be used if the individual response to methylphenidate or tolerability is insufficient before switching to a nonstimulant substance, thus improving the total response rate to psychostimulant treatment. Because of the high abuse potential of amphetamines, especially in adults, the prodrug lisdexamphetamine (Vyvanse) could become an effective treatment alternative. Available study data suggest a combination of high clinical effect size with a beneficial pharmacokinetic profile and a reduced abuse risk.In addition to methylphenidate, amphetamines serve as important complements in the psychostimulant treatment of ADHD. Future studies should focus on a differential comparison of the two substances with regard to their effects on different core symptom constellations and the presence of various comorbidities.

Vitamin K antagonists are currently the most frequently used anticoagulants. However, practical limitations of their application, such as variability in dose response, a narrow therapeutic index and numerous drug and dietary interactions, have lead to development of new oral anticoagulants with better efficacy and safety profile. Recent advances included the development of orally active FXa inhibitors rivaroxaban and apixaban. Rivaroxaban received its marketing approval in September 2008. Apixaban has recently been approved for prevention of venous thromboembolism after total hip or knee replacement. This review describes the pharmacological properties of apixaban and discusses the latest findings from clinical trials.

Since the 90's, human erythropoietin is produced recombinantly and used clinically. There are various products from different suppliers, which differ primarily in their production but not in their half-life or effectiveness. 2001 genetically modified darbepoetin alpha was launched, which is characterized by an approximately three times longer half-life. A further extension of the half-life to 130 hours is achieved with the current continuous erythropoietin receptor activator (CERA), which therefore must be applied only once or twice a month. The indication for epoetin therapy is primarily for the symptomatic renal anemia and chemotherapy-associated anemia. Corrections of low hemoglobin levels in asymptomatic patients are not allowed. The generally recommended hemoglobin target range is 10-12 g/dl. Hb values13 g/dl should be avoided because they are associated with significant adverse effects and do not improve patient survival.

The aim of the study was to estimate the external radiation exposure emitted by the patient to his surroundings after discharge. Being in compliance with legal requirements is especially important when doing multiple therapies. To estimate the effective half-life to be used quite realistically, the individual effective half-lives for 41 patients with 52 therapies were calculated. From the resulting histogram the maximum value was determined to be 100 h. Substituting the physical half-life by this maximum effective half-life results in dose estimates, which are lower but still conservative. In addition, the analysis of dose related parameters for patients who underwent multiple therapies demonstrates that the parameters estimated for the first therapy cannot be transferred to the subsequent ones.

Decades after its registration, amiodarone is still regarded as the most effective antiarrhythmic drug available for the treatment of tachyarrhythmias. Amiodarone is classified as a class III antiarrhythmic drug. In addition to the prolongation of cardiac repolarization, its leading pharmacologic features are sodium and calcium channel block, nonselective β-adrenergic inhibition as well as high lipophilicity and a very long plasma half-life. In patients with paroxysmal atrial fibrillation, amiodarone is the most effective antiarrhythmic drug in maintaining sinus rhythm. Furthermore, it prevents ventricular arrhythmias, such as frequent ventricular extrasystoles or nonsustained runs of ventricular tachycardia, as well as sustained ventricular tachycardia and ventricular fibrillation. In patients with increased risk for sudden cardiac death, e.g., with severely depressed left ventricular function, amiodarone is a highly effective and safe antiarrhythmic drug. In addition, amiodarone has been shown to reduce the number of appropriate and inappropriate shocks in patients with an implantable cardioverter-defibrillator. During long-term amiodarone treatment, typical side effects including corneal microdeposits, blue-gray skin discoloration, photosensitivity, hypothyroidism, hyperthyroidism, peripheral neuropathy, optical neuritis and hepatotoxicity accrue. Upon cessation of medication, these are almost always reversible. Irreversible, severe adverse effects, such as pulmonary toxicity, are very rare under the currently used maintenance dose of 200 mg/day. With regard to its side effect profile, an adequate follow-up of patients including laboratory values, lung function tests, and visual acuity is necessary.

The development of neutralizing allo-antibodies against factor VIII (FVIII) or FVIII inhibitors is a severe complication in the treatment of haemophilia A. About 25% of the children with severe haemophilia A develop FVIII inhibitors. Here we report on a boy with severe haemophilia A and intron 22 inversion of the FVIII gene who was diagnosed at ten months of age. After 16 exposure days to FVIII (81 days after initial exposure) he developed a FVIII inhibitor (maximum: 9.76 BU/ml).We started immune tolerance induction (ITI) according to the Bonn protocol with high dose plasma derived FVIII concentrate (100 IU per kg body weight) twice daily. For additional inhibitor elimination treatment the patient received intravenous immunoglobulin (ivIg) at a dose of 1-2 g/kg body weight every 4 to 6 weeks. After start of treatment a rapid decline of the inhibitor level was observed, nevertheless low FVIII inhibitor levels persisted (5 BU/ml). Furthermore, the FVIII half-life was still accelerated. However, after every course of ivIg the inhibitor level declined and FVIII half-life was prolonged. Currently, the FVIII half-life is approaching normal values after more than seven months of ITI duration.Additional application of immunoglobulin is beneficial for immune tolerance induction.

More and more targeted radiotherapies (TRT) are carried out with pure beta-emitters such as 90Y. Normally fixed activities are administered without considering the individual biokinetics increasing the risk of under- or overdosing. In addition, it would be helpful to obtain additional data on dose-response relationships for further optimization of TRTs. Therefore, post-therapeutic dosimetry using quantitative imaging becomes more important. For an optimization of TRTs additional aspects such as the changing dose rate and radiobiological considerations need to be taken into account. This paper provides an overview on bremsstrahlung imaging modalities after therapies with pure beta-emitters. In addition, new dosimetric methods are described which consider dose rate and fractionation of treatment.

Amiodarone treatment affects thyroid status in about the half of patients. Amiodarone causes a wide spectrum of effects on the thyroid function including hypothyroidism and thyreotoxicosis. Amiodaron-induced thyroid dysfunction is the most reason for discontinuation of amiodaron therapy. In this report we describe amiodaron-induced thyroid dysfunction and the diagnostic and therapeutic challenges in such patients.

Dronedarone is a benzofuran derivative structurally similar to amiodarone but non-iodinated. The agent was systematically developed with the aim to maintain the antiarrhythmic potency of amiodarone while reducing the extracardiac side effects of the drug. Dronedarone is less lipophilic compared to the mother compound, which manifests in a substantial lower time to steady state (4-8 days compared to 1-3 weeks with amiodarone), and a more rapid elimination (half life 25-30 hours). Dronedarone has antiarrhythmic properties of all Vaughan-Williams classes. Among other channel blocking effects, It blocks sodium ion channels at higher stimulation frequency, prolongs the cardiac action potential, and has properties of a calcium channel blocker. Further, dronedarone has non-competitive antiadrenegic effects. No reverse use dependence has been documented at higher heart rate. These effects explain the antiarrhythmic and rate control properties of dronedarone in patients with atrial fibrillation.

The German Society of Nuclear Medicine (DGN) criticizes the methodological approach of the IQWiG for evaluation of PET and the conclusions, which represent the opposite point of view compared to the most other European countries and health companies in the USA: 1.) Real integration of experienced physicians into the interpretation of data and the evaluation of effectiveness should be used for best possible reporting instead of only formal hearing. 2.) Data of the National Oncologic PET Registry (NOPR) from the USA have shown, that PET has changed the therapeutic management in 38% of patients. 3.) The decision of the IQWiG to accept outcome data only for their benefit analyses, is controversial. Medical knowledge is generated by different methods, and an actual analysis of the scientific guidelines has shown that only 15 % out of all guidelines are based on the level of evidence demanded by the IQWiG. Health economics has created different assessment methods for the evaluation of a diagnostic procedure. The strategy chosen by the IQWiG overestimated the perspective of the population and undervalue the benefit for an individual patient. 4.) PET evaluates the effectiveness of a therapeutic procedure, but does not create an effective therapy. When the predictive value of PET is already implemented in a specific study design and the result of PET define a specific management, the trial evaluate the whole algorithm and PET is part of this algorithm only. When PET is implemented as test during chemotherapy or by the end of chemotherapy, the predictive value of PET will depend decisively on the effectiveness of the therapy: The better the therapy, the smaller the differences in survival detected by PET. 5.) The significance of an optimal staging by the integration of PET will increase. Rationale is the actual development of "titration" of chemotherapy intensity and radiation dose towards the lowest possible, just about effective dosage. 6.) The medical therapy of malignancies will be improved continuously. It is the claim of the health insurances to implement innovative therapeutic approaches in controlled clinical trials with tools of quality control. The monitoring committee is responsible for the safety of the patients. PET is part of the health care. Internationally accepted rules for clinical trials stipulate that any interim analyses of those trials are confidential as long as recruitment is active. The delay until evidence is documented by the published final analysis is methodologically accepted and not a characteristic of PET. 7.) Procedures in nuclear medicine without the use of PET-tracers with short half-life will increase the radiation exposure of the patients; the use of non-PET-tracers with longer half-life is in contravention of the German regulation of radiation protection.

Erectile dysfunction (ED) is often associated with increased cardiovascular risk. There is increasing evidence suggesting that dysfunction of the vascular endothelium with reduced bioavailability of nitric oxide (NO) may be the pathogenetic link between ED and cardiovascular disease. The crucial importance of the NO-guanylatecyclase-cGMP-phosphodiesterase pathway for penile erection is mirrored by the efficacy of phosphodiesterase-5 (PDE5) inhibitors in the treatment of ED. In contrast to other currently available PDE5 inhibitors with a half-life time of about 4 h Tadalafil has a half-life time of about 17.5 h resulting in erectile responsiveness for up to 36 h after 1 single dose. Most clinical experience has been reported with on-demand use of PDE-5 inhibitors, but meanwhile several studies were able to demonstrate that Tadalafil given daily in low (2.5 and 5 mg) doses is both highly effective and well-tolerated. In three randomized, double-blind, placebo-controlled multi-center trials, various validated measures of erectile function indicated that once daily Tadalafil at doses of 2.5, 5, and 10 mg was significantly superior to placebo.In another mono-center trial, once daily Tadalafil has shown significant efficacy even after failure of on-demand treatment. In a controlled cross-over study of on-demand versus daily Tadalafil treatment, 72% of the patients preferred once daily administration, mainly because of superior and longer efficacy allowing a more spontaneous sexual life. Interestingly in a pilot study of on-demand versus chronic administration of Tadalafil for 4 weeks, only regular dosing improved several markers of endothelial function.

Intoxications with medications are among the most frequent diagnoses in patients admitted to medical emergency departments and intensive care units. Due to their particular toxicity tricyclic antidepressants play an important role despite a decreasing incidence. Tricyclic antidepressant toxicity includes an inhibition of myocardial excitability, central (sedation, seizures) and peripheral anticholinergic signs, and arterial hypotension. Cardiac arrhythmia including ventricular tachycardia and fibrillation, sustained seizures and severe central anticholinergic symptoms such as agitation, delirium, and hyperthermia, are life threatening. Important treatment options include gastrointestinal decontamination with oral single-dose activated charcoal within 1-2 hours post ingestion, and antidotal therapy with boluses of sodium bicarbonate for cardiotoxicity. The selective serotonin reuptake inhibitors (SSRI) and the atypical antidepressants are far less toxic than tricyclics. They may lead to serotonin toxicity (serotonin syndrome).

The starting dose of a drug determines both onset of action and tolerability of the compound. In contrast to most drug therapies, which may immediately be started with regular maintenance doses, compounds undergoing substantial autoinduction (e.g. carbamazepine) must be administered at slowly increasing doses to compensate for an initially low clearance and to avoid toxicity. Gradual dose escalation is also necessary whenever a drug induces substantial counter-regulatory reflex activation or adaptation processes. In these cases administration of standard doses may lead to excessive adverse reactions (e.g. cardiac decompensation after initiation of beta-receptor antagonism). Also in these situations cautious dose titration is required. After long-term administration those drugs should be withdrawn only very carefully to avoid potentially life-threatening withdrawal syndromes like hypertensive emergencies after abrupt discontinuation of clonidine or rebound epilepsies after discontinuation of anticonvulsants.

We describe a 64-year old patient who was admitted comatose to the medical emergency department. After excluding relevant differential diagnoses and considering the clinical picture of a "sedative toxidrome" a presumable diagnosis of an intoxication with an unknown sedative substance was made. Phenobarbital was detected in the blood. Decontamination procedures and therapy in patients with phenobarbital intoxication are delineated and discussed.

The version 3 of the procedure guideline for radioiodine test is an update of the guideline previously published in 2003. The procedure guideline discusses the pros and cons of a single measurement or of repeated measurements of the iodine-131 uptake and their optimal timing. Different formulas are described when one, two or three values of the radioiodine kinetic are available. The probe with a sodium-iodine crystal, alternatively or additionally the gamma-camera using the ROI-technique are instrumentations for the measurement of iodine-131 uptake. A possible source of error is an inappropriate measurement (sonography) of the target volume. The patients' preparation includes the withdrawal of antithyroid drugs 2-3 days before radioiodine administration. The patient has to avoid iodine-containing medication and the possibility of additives of iodine in vitamin- and electrolyte-supplementation has to be considered.

Cyanobacterial toxins are substances produced by cyanobacteria or blue-green algae. They can occur in surface waters worldwide and have to be reliably removed when using affected surface waters as a drinking water source. Bank filtration has been used for 150 years for drinking water (pre-)treatment. It utilizes natural elimination processes like sorption and degradation in the sub-surface. Retention of cells on the sediment surface is the most prominent process for eliminating these primarily cell-bound toxins. Middle to coarse grained sands eliminated more than 99.9 % of intracellular toxins within the first 10 cm of flow path. Elimination of extracellular microcystin during underground passage is mainly due to biodegradation. Reversible adsorption processes do not reduce the total load but lead to longer contact times for extended biodegradation. Laboratory experiments showed that the sediment structure, i.e. high clay/silt and organic content, is crucial for maximum adsorption. However, redox conditions play an important role for degradation rates: under aerobic conditions half-lives of less than one day occurred frequently, whereas anoxic conditions resulted in lag phases of one day and more, as well as in half lives of more than 25 days. Field experiments showed that temperature is crucial for degradation velocity under natural conditions. Under optimal conditions 10 d residence time are sufficient to reduce microcystin concentrations to values below the WHO guidelines value for drinking water (1 microg/L). Under sub-optimal conditions a residence time of up to 90 days may be necessary.

Modern bone samples were experimentally degraded by incubation into water at increased temperature and examined in terms of their collagen content, the stable C and N isotopic ratios, and the molar C/N ratio. The same analyses were carried out with archaeological human bone of varying age (300 up to 8000 years). The experimentally degraded samples exhibited changes of the collagen's integrity, which influence the stable isotope ratios. In the case of the archaeological material, a correlation between stable delta13C- and delta15N-values and collagen content could be demonstrated. The molar C:N ratio was no suitable criterion for the assessment of the state of preservation of extractable collagen.

Die vorliegende Arbeit umfasste zwei Studien zum langfristigen Einfluss einer Hochproteinernährung sowie einer langfristigen Leucinsupplementierung der Diät auf den Proteinmetabolismus adulter Ratten als Tiermodell. Bisherige Isotopenmodelle zu den Auswirkungen einer hohen Proteinzufuhr finden zumeist über einen kurzen Zeitraum bei einmaliger oraler oder intravenöser Verabreichung des Tracers statt. Dadurch werden längerfristige Prozesse im Proteinstoffwechsel nicht ausreichend berücksichtigt. Die in vorliegender Studie angewandte Methode beruhte dagegen auf der alimentären Markierung des Tierkörpers durch die langfristige Verfütterung eines Gemischs 15N-markierter Aminosäuren an juvenile, wachsende Sprague-Dawley-Ratten. Nach Abschluss der Markierung konnte anhand des 15N-Eliminationsverlaufs die Austauschdynamik des Körperproteins in einzelnen Organen und Geweben der Tiere über einen langen Versuchszeitraum untersucht werden. Eine langfristig hohe alimentäre Proteinaufnahme von 26,6 % RP führte über einen Zeitraum von 41 Tagen gegenüber 9,9 % RP zu keiner zusätzlichen Akkumulation von Protein im Gesamtkörper. Im Verlauf des Versuchs wuchsen die Tiere beider Gruppen geringfügig, jedoch zeigte sich der Stickstoffansatz nahezu indifferent gegenüber der Behandlung. Der Überschuss an diätetischem Stickstoff wurde über erhöhte Harn- und Kotausscheidungen ausgeglichen. Eine exzessive Proteinaufnahme beschleunigte den Austausch von Körperstickstoff im Blutplasma, den Organen und Gewebefraktionen im Vergleich zur adäquaten Proteinversorgung. Dies könnte ein Hinweis auf einen erhöhten Proteinturnover und eine Verringerung der Rezyklierung des endogenen Stickstoffs körpereigener Aminosäuren im Gewebe sein. Die Höhe des Proteinaustauschs unterschied sich zwischen den analysierten Gewebefraktionen und nahm in der Reihenfolge Blutplasma > Leber > Verdauungstrakt > Nieren > Milz > Lunge > Herz > Gehirn > Skelettknochen > Haut > Skelettmuskulatur ab. Eine langfristig gesteigerte Leucinaufnahme von bis zu 2,76 % in der Diät führte über einen Zeitraum von 30 Tagen zu keiner Veränderung der Proteinmenge im Gesamtkörper im Vergleich zur Kontrollgruppe (0,46 % Leucin). Die Erhöhung der Leucinversorgung führte zu keiner signifikanten Steigerung des Proteinaustauschs im Plasma und den einzelnen Organen und Gewebefraktionen. Insgesamt zeigt sich in vorliegender Arbeit die breite homöostatische Kompensationsfähigkeit des Organismus angesichts eine langfristigen nutritiven Protein-Überernährung. Die einzelnen Organe und Gewebefraktionen reagierten auf eine langfristige Steigerung der Proteinversorgung durchwegs mit einer zunehmenden Erhöhung und Beschleunigung des Proteinaustauschs bei einem gleichzeitig unveränderten Gesamtbestand an Körperprotein. Mit zunehmender Proteinaufnahme (6,4 % vs. 9,9 % vs. 26,6 % RP) sank die Halbwertszeit des Austauschs im Proteinpool des Gesamtkörpers (40 vs. 34 vs. 22 Tage). Die Differenzierung im Austausch des markierten Stickstoffs im Vergleich zwischen den untersuchten Organen und Geweben ergibt sich möglicherweise langfristig aus den gewebsspezifisch unterschiedlichen Anteilen an mobilen und immobilen Proteinfraktionen. The present study consisted of two experiments considering the effects of a long-term high dietary protein intake and a chronic dietary leucine supplementation on protein metabolism in 15N-labeled rats a animal model. Previous 15N-tracer studies on the effects of excessive protein intakes are usually performed over short-time periods by giving a single oral dose of the tracer or by intravenous administration and so the impacts of a longer-term or chronic nutrient intake on human protein metabolism are difficult to judge. Therefore, the present study was based on an alimentary labeling technique, in which juvenile Sprague-Dawley rats were reared with a semisynthetic diet supplemented with a mixture of 15N-labeled amino acids for about 7 weeks. After labeling the body homogeneously, the dynamics of protein exchange could be determined for the long term by plotting curves of 15N-clearances in single organs and tissues of the adult animals. A long-term high dietary protein intake of 26.6 % crude protein did not stimulate accumulation of protein mass in the whole-body compared to an intake of 9.9 % crude protein over a period of 41 days. During the experimental period body weight of animals in both groups increased marginally, but nitrogen retention remained constant irrespective of the dietary protein level. The surplus of dietary nitrogen was compensated by increased renal and fecal nitrogen excretions. A high protein intake accelerated the exchange rate of body protein compared to an adequate protein intake in plasma, organs and tissues. This finding possibly indicates a higher rate of body protein turnover and a lower degree of recycling of endogenous amino acids in single tissues. Total levels of protein exchanges were different in comparison between all analyzed organs and tissue fractions and decreased as follows: blood plasma > liver > digestive tract > kidney > spleen > lung > heart > brain > skeletal bones > skin > skeletal muscle. Whole-body protein content was not affected by a chronic increased leucine intake as far as 2.76 % leucine for 30 days compared to the control group (0.46 %). In this case, the increased leucine content did not significantly stimulate the levels of protein exchange in plasma, organs and tissues. To sum up, the present study demonstrates the ability of nitrogen homeostasis to counterregulate a long-term high protein diet. Rates of protein exchange were more pronounced and accelerated in all organs and tissues of rats ingesting a high protein diet compared to an adequate protein intake, while tissue nitrogen was fairly well maintained. In the light of increasing protein intakes (6.4 % vs. 9.9 % vs. 26.6 % crude protein) half-lifes of protein exchange in the whole-body protein pool decreased simultaneously (40 d vs. 34 d vs. 22 d). For the long-term, dissimilar quantities of exchanged nitrogen in comparison between single organs and tissues could be a consequence of different proportions of tissue-specific mobile and immobile protein fractions.

Das Proteasom spielt eine zentrale Rolle beim Proteinabbau und der Antigen-Generierung für die adaptive Immunantwort. Vertebraten exprimieren zwei Typen des proteolytischen 20S-Kernkomplexes: das konstitutive c20S (mit den aktiven Untereinheiten beta 1, 2, 5) und das Immunoproteasom i20S (mit den Immunountereinheiten LMP2, MECL-1, LMP7). Die i20S-Expression wird durch Interferon_gamma (IFNg) induziert, was die Antigen-Präsentation auf MHC Klasse I und die Immunantwort gegen infizierte bzw. maligne entartete Zellen durch cytotoxische T-Zellen steigert. Proteasomen werden über komplexe, bisher unvollständig verstandene Biogenese-Prozesse formiert. Die initialen Schritte der humanen 20S-Formation wurden in dieser Arbeit untersucht und eine Methode zur Isolation früher Assemblierungsintermediate (EPIs) etabliert. Die 20S-Biogenese bedarf der Assistenz von Hilfsfaktoren wie dem Proteasom-Maturierungsprotein POMP. Diese Komponente von Precursorkomplexen stellt das erste Substrat gereifter c20S dar. In dieser Arbeit konnte erstmalig gezeigt werden, dass POMP ebenfalls die i20S-Formation vermittelt und sich die Biogenese von c20S und i20S hinsichtlich der Maturierungskinetik unterscheidet. POMP wird durch IFNg induziert und interagiert mit der Immunountereinheit LMP7. Dieses molekulare Zusammenspiel bewirkt eine schnellere Maturierung von i20S- im Vergleich zu c20S- Precursorkomplexen, wodurch POMP einem schnelleren Abbau unterliegt. Die forcierte i20S-Biogenese ist eine intrinsische Eigenschaft und unabhängig von weiteren, IFNg-induzierten Faktoren. Nur die LMP7_E2-Variante vermittelt die schnelle Degradation von POMP, während das nicht funktionelle LMP7_E1 mit einer anderen Prosequenz nicht in i20S-Vorläufer inkorporiert wird. Somit führt die alleinige LMP7_E1-Expression in IFNg-stimulierten Carcinom-Zellen zu einer i20S-Defizienz, was eine mögliche Immunevasions-Strategie darstellt. Weiterhin besitzen beide 20S-Typen unterschiedliche Halbwertszeiten: i20S sind, unabhängig von weiteren IFNg-induzierten Proteinen, signifikant instabiler als c20S. Somit werden i20S sowohl schneller formiert als auch zügiger wieder abgebaut als c20S, womit sie typische Eigenschaften cytokin-regulierter Proteine aufweisen. Die i20S-Formation ist also eine transiente Antwort und stellt ein effizientes Instrument zur schnellen Reaktion auf immunologische Herausforderungen wie z.B. eine Infektion dar. Nach einer wirksamen Immunantwort erlaubt die geringere i20S-Stabilität eine schnelle Rückkehr zur standardmäßigen c20S-Expression. The proteasome plays a crucial role in protein degradation and antigen generation for the adaptive immune response. Vertebrates express two types of the proteolytic 20S core complex: the constitutive proteasome c20S (with the active subunits beta 1, 2 and 5) and the immunoproteasome i20S (with the immunosubunits LMP2, MECL-1 and LMP7). Interferon_gamma (IFNg) induces the i20S expression, that supports a more efficient MHC class I antigen presentation and an effective immune response against infected or malignant cells by cytotoxic T-cells. Proteasomes are formed by a complex and not well understood biogenesis program. The initial steps in the human 20S formation have been analyzed in this thesis and a method for the isolation of ´early proteasome assembly intermediates´ (EPIs) has been established. The 20S biogenesis requires the assistance of accessory factors like the proteasome maturation protein POMP. This component of precursor complexes becomes the first substrate of the matured c20S. The described experiments demonstrate for the first time that POMP mediates the i20S formation and that biogenesis of c20S and i20S differ in their maturation kinetics. POMP is induced by IFNg and interacts with the immunosubunit LMP7. This molecular interplay provokes a faster maturation of i20S compared to c20S precursor complexes, whereby POMP becomes subject to a faster degradation. The accelerated i20S biogenesis is an intrinsic characteristic and independent of additional IFNg-induced factors. Exclusively the LMP7_E2 variant causes the rapid degradation of POMP, whereas the non-functional LMP7_E1 bearing another prosequence is not incorporated into i20S precursor complexes. Thus, LMP7_E1 expression in IFNg-stimulated carcinoma cells leads to a i20S deficiency pointing out a possible immune evasion strategy. In addition, both 20S types display different half-life values: i20S are, independent of other IFNg-induced proteins, significantly less stable than c20S. Thus, i20S are not only faster assembled, but also more quickly decomposed compared to c20S, showing typical attributes of proteins regulated by cytokines. Consequently, i20S formation is a transient response and represents an efficient instrument for a rapid adjustment to varying immunological challenges like an infection. Once the immune response has been effective, the lower stability of i20S permits an expeditious return to the standard c20S expression.

Contrary to the situation in "classical" clinical pharmacology, non-steady state phenomena play a fundamental role for clinical pharmacology in anesthesia. Their understanding is of tantamount importance for the safe and efficient application of drugs relevant to anesthesia. Concepts like optimised target-controlled infusion (TCI), effect compartment targeting and the small margin of error tolerable during maintained spontaneous ventilation, force the anesthesiologist to acquire a firm understanding of the difference between the concentration time course at the effect side vs. time course of the plasma concentration. The underlying concepts, their application for the rational use of muscle relaxants, propofol with TCI systems, volatile anaesthetics and opioids will be discussed.

Bioavailability and bioequivalence studies are essential in the clinical development of medicinal products and the optimization of pharmaceutical forms. Bioavailability means the rate and extent to which the active substance or active moiety is absorbed from a pharmaceutical form and becomes available at the site of action. In practice, drug concentration-time courses are measured in the systemic circulation, and the area under the curve (AUC) as well as the observed maximum concentration (C(max)) are determined. Products are considered bioequivalent if their bioavailabilities after administration of the same molar doses are similar to such a degree that their effects, with respect to both efficacy and safety, will be essentially the same and thus, there are no relevant differences in terms of AUC and C(max). In 2002 a revised version of the 'Note for Guidance on the Investigation of Bioavailability and Bioequivalence' came into effect (CPMP/EWP/QWP/1401/98). Relevant changes in comparison to the previous version are: request for GLP-compliant bioanalytical measurements; for long half-life drugs a truncated AUC is acceptable; acceptance criteria for bioequivalence assessment and requirements for a waiver of bioequivalence studies were further specified. In this context the Biopharmaceutics Classification System (BCS) seems appropriate to decide whether in special cases of rapidly dissolving solid oral dosage forms a biowaiver may be granted or not. Products not considered critical in this matter are medicinal products for which the formulation does not affect the rate and extent of absorption, i. e. bioavailability, of the active moiety. Highly soluble (and highly permeable) drugs (BCS class I) are such candidates. Comprehensive state-of-the-art guidance on the design, conduct and analysis of bioavailability and bioequivalence studies is given in the current European guideline.

Guidelines are an important instrument for improving the quality of medical care. In 2001, the German STD Society (DSTDG) published guidelines for syphilis diagnostics and treatment. For two reasons, these guidelines had to be reviewed urgently: Firstly, there is an obvious "renaissance" of syphilis among men having sex with men, which is complicated by a frequent comorbidity with HIV infection. Secondly, the standard drug for syphilis treatment in Germany, clemizole penicillin, has no longer been available since July 2003. In this article, the new German guidelines for syphilis treatment 2004, published by the DSTDG, are compared with other syphilis guidelines, which are valid for the European countries, i.e., the CDC, UK, Russian, and European guidelines 2002.

The detection rate of liver lesions using ultrasonography is 53-77%, rendering this method inferior to CT and MRI. Despite well-known limitations, development of stable second-generation contrast agents in conjunction with new techniques of contrast display has led to increased diagnostic accuracy. Characterization of focal liver lesions with ultrasound contrast agents follows known features of iodine- and gadolinium-containing contrast agents, but compared to CT and MRI sensitive visualization of intratumoral vessels takes place in real time. In addition to very high diagnostic accuracy in differentiating benign from malignant lesions, detectability of tumors of nonhepatocellular origin is increased significantly and direct assessment of treatment success with minimally invasive tumor ablative interventions in the liver is possible. The active principle of ultrasound contrast agents, examination technique as well as distinguishing features and appearance of various, frequently observed focal liver lesions are illustrated by cases from our department.

Melagatran is a direct inhibitor of thrombin and-like its oral prodrug ximelagatran-a newly developed dipetide with high antithrombotic efficacy. They present a linear dose-response, a short plasma half-life and the therapeutic range may be advantageous compared with classic anticoagulants such as heparins or vitamin K antagonists. The results of clinical studies for prevention and treatment of thromboembolic complications are encouraging. The use of melagatran and ximelagatran will gain significance in the perioperative management, thus being of particular importance for anaesthesiology and critical care medicine in the near future.