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Epistaxis is a symptom with many causes, often multifactorial and a frequent cause of consultation in acute medicine.The goal of this study is to analyse the diagnostics used for and therapy of epistaxis, complications and the predictive benefit of laboratory tests.In this retrospective clinical analysis reports of 720 patients with epistaxis in the period from January 2005 to December 2015 were evaluated. The causes and the therapy of the epistaxis relapses were analysed.Male patients were predominant. Patients with relapses of epistaxis were significantly more likely to be older than 70 years, with higher multimorbidity and more often had used a combination of blood thinning medications. Posterior bleeding was the most found location and was associated with a longer hospitalization. In laboratory tests most patients with coumarins were shown to have inadequate INR (international normalized ratio) control. The prevalence of nicotine consumption was clearly increased compared to the total population. The most used therapy was nasal tamponade. The most complication was anemia with need of blood transfusion.High age and posterior bleeding source seem to raise the necessity of inpatient therapy. In most cases tamponade is sufficient for treatment. Initial laboratory tests are of limited use to estimate risk of recurrence, but is necessary for patients taking coumarins to determine INR control.

Epistaxis hat multifaktorielle Ursachen und ist häufiger Konsultationsgrund der Akutmedizin. Untersucht wurden Diagnostik und Therapie sowie Komplikationen. Es wurden 720 Datensätze stationär behandelter Patienten vom 01.01.05 bis 31.12.15 evaluiert. Prädisposition des männlichen Geschlechts. Rezidivpatienten waren signifikant älter als 70 Jahre, multimorbider und es bestand häufiger eine Kombination blutverdünnender Medikamente. Posteriore Blutungen traten am häufigsten auf. Es zeigte sich ein hoher Anteil von INR-Entgleisungen unter Einnahme von Cumarinen. Deutlich erhöhte Prävalenz des Nikotinkonsums im Vergleich zur Gesamtbevölkerung. Häufigste Therapieform war die Nasentamponade, häufigste Komplikation war Transfusionspflichtigkeit. Bei hohem Alter und posteriorer Blutungsquelle scheint Hospitalisierung häufiger notwendig. Die Tamponade stellt eine suffiziente Therapieform dar. Das Aufnahmelabor ist zum Ausschluss von INR-Entgleisungen notwendig., Epistaxis is often multifactorial and a frequent cause of consultion in acute medicine. Diagnostic investigation, therapy and complications were analysed. The data of 720 clinical treated patients from 01.01.2005 to 31.12.2015 were evaluated. Male patients were predominant. Patients with relapses were significant more often older than 70 years, with higher multimorbidity and had more often a combination of blood dilutive medication. Posterior bleeding was the most found location. Most patients with coumarins shown a lapse of INR. The prevalence of nicotine consumption was clearly raised in comparison to the total population. Most used therapy was nasal tamponade. Most occurred complication was need of blood transfusion. High age and posterior bleeding source seems to raise the necessity of inpatient therapy. In most cases tamponade is a successive therapy. Laboratory tests are necessary for patients with coumarins for elimination of INR lapses.

Vitamin K antagonists (VKA) are used for the prophylaxis and treatment of thrombotic and thromboembolic events. Most important indications are venous thrombosis and pulmonary embolism, atrial fibrillation, and mechanical heart-valve replacement. Hence they are from high relevance for the neurologist and his daily praxis in cardio-neurological routine. Here, we give an overview about VKA with focus on mode of action, indications and efficacy, practical aspects of treatment, side effects, and monitoring.

Chronic venous disease (CVD) affects at least 15-25 % of the general population incurring not only high morbidity but also considerable economical burden. The mainstay of modern treatment of CVD are endovenous therapeutic procedures and compression therapy. As far as the pathogenesis of CVD is being gradually unraveled the interest in drugs able to impact the process is growing. Here we have presented an overview of a majority of oral preparations used so far to treat CVD including venous leg ulcers. After several decades of clinical use a few flavonoid preparations, in the first place micronized purified flavonoid fraction, collected enough evidence to recommend them as a short-term adjunct treatment of CVD. However, other compounds are also promising in this regards. Yet, we need more larger and longer-term clinical trials to more precisely define effects, cost-effectiveness and, above all, capacity for prophylactic application of the drugs. Learning more about basis of CVD will help design new drugs directed at specific aspects of the disease process.

Pseudotumor cerebri is an idiopathic increase in intracranial pressure, which commonly affects obese women of fertile age. The diagnostic criteria according to the guidelines of the German Society for Neurology are increased cerebrospinal fluid (CSF) pressure, symptoms of increased CSF pressure, normal results of CSF examination, no relevant medication and a lack of structural and vascular lesions in magnetic resonance imaging (MRI).This article presents the case of a 39-year-old male patient who presented at hospital with visual obscuration and recently occurred double vision. Except for a recently diagnosed thrombosis of the left jugular vein of unknown origin, there was nothing else of note in the medical history. Biomicroscopic examination showed papilledema with hemorrhages and cotton wool spots. The CSF opening pressure was initially 50 cmH2O. During therapy by lumbar puncture (three times), oral carbonic anhydrase inhibitors and loop diuretics, the abducens nerve palsy and papilledema receded. Anticoagulation therapy (initially with coumarin derivatives, then with low molecular weight heparins) was unsuccessful in eliminating the thrombosis of the jugular vein. Surgical intervention was not recommended by the vascular surgeons.This case report demonstrates the unusual combination of (idiopathic) intracranial hypertension and thrombosis of the jugular vein, which occurred spontaneously and without any detectable coagulation disorders.

We report the case of a 28-year old woman with extensive red-black colored lesions of the skin on the left thigh, which appeared without trauma. The disease arrived during longterm coumarin therapy because of a deep vein thrombosis and an antiphospholipid syndrome. After consideration of the differential diagnoses and due to the typical clinical picture we made the diagnosis of coumarin necrosis. We review the clinical and therapeutic features for this rare complication.

Im Rahmen dieser Arbeit konnte eine effiziente Eintopfsynthese verschiedener Isoxazolin-Aminosäureesterderivate entwickelt werden. Durch Kombination der Michael-Addition eines chelatisierten TFA-Glycinester-Enolats an ein Nitroalken mit einer in situ Nitriloxid-Trans-formation und einer anschließenden 1,3-dipolaren Cycloaddition konnte der Aufbau neuer heterocyclischer Strukturen aus einfachen Vorstufen in nur einem Schritt ermöglicht werden. Das für die Cycloaddition benötigte Dipolarophil wurde sowohl über das Nukleophil als auch über das Nitroalken eingeführt. Im zweiten Teil wurden Fluoreszenz-Labels auf 7 Dialkyl-Aminocumarin-Basis für das biomolekulare Imaging synthetisiert und spektroskopisch charakterisiert. Eines dieser Labels fand zudem Anwendung als false fluorescent neurotransmitter in der Exozytose-Visualisierung von Adrenalin in Chromaffinzellen (Kooperation Prof. J. Rettig, Uniklinik Homburg). Des Weiteren wurden verschiedene Labels in bioorthogonalen Reaktionen zum Fluoreszenzmarkieren von Aminosäuren und Peptiden eingesetzt. Hierbei gelang neben der Markierung des N-Terminus, des C-Terminus und einer Aminosäure-Seitenkette auch die Markierung des Aminosäurerückgrates. Within the scope of this thesis a straightforward approach towards isoxazoline amino acid esters was developed. The synthesis of these new structures was described by a combination of a Michael addition with chelated glycine ester enolates to nitroalkenes, in situ nitrile oxide transformation and 1,3 dipolar cycloaddition. The dipolarophile required for the cycloaddition was introduced either via the nitroalkene or via the chelated enolate. Therefore, different types of heterocyclic amino acids could be obtained in a simple one-pot protocol. The second part of the thesis deals with the synthesis and the spectroscopic characterization of fluorescence dyes based on 7-(dialkylamino)coumarins. These labels allow the in-vestigation of cellular processes or target identification. One label acted also as false fluorescent neurotransmitter in the adrenalin exocytosis of chromaffin cells (in cooperation with Prof. J. Rettig, Uniklinik Homburg). Furthermore, some coumarins were attached to amino acids and peptides by bioorthogonal reactions for the biomolecular imaging. In these reactions, the labels were fixed to the C-terminus, N-terminus and an amino acid sidechain. Even the amino acid backbone was labeled.

Die Verwendung von Phototriggern (caged Verbindungen) hat sich als äußerst nützliche Methode erwiesen, um zelluläre Prozesse in situ zu untersuchen. Bei den caged Verbindungen handelt es sich um photolabile inaktive Derivate von Biomolekülen, aus denen durch Bestrahlung mit Licht die natürliche, biologisch aktive Substanz schnell lokal freigesetzt werden kann. Im Rahmen dieser Arbeit wurden neue effiziente photoaktivierbare Schutzgruppen für Carbonylfunktionen mit hoher Wasserlöslichkeit entwickelt und erprobt. Dafür wurden Syntheseverfahren für substituierte 4-(1,2-Dihydroxyethyl)cumarine erarbeitet, die zum Schutz von Verbindungen mit Carbonylfunktionen verwendet wurden. Die erhaltenen caged Carbonylverbindungen, chemisch Cumarinyl-substituierte 1,3-Dioxolane, wurden vollständig photophysikalisch und photochemisch charakterisiert. Die als optimal befundene Schutzgruppe leitet sich von 8-[Bis(carboxymethyl)aminomethyl]-6-brom-4-(1,2-dihydroxyethyl)-7-hydroxycumarin ab. Der neuartige Chromophor zeichnet sich durch eine sehr gute Wasserlöslichkeit in wässrigen Pufferlösungen, einen hohen Extinktionskoeffizienten im ultravioletten und sichtbaren Bereich des Lichts, sowie eine effiziente Photolysierbarkeit aus. Es wurden erstmals caged Verbindungen von den Biomolekülen Bourgeonal und Progesteron sowie dessen Derivat Progesteron-3-O-(carboxymethyl)oxim (Progesteron-3-CMO) synthetisiert, und es wurde die Anwendbarkeit der neu entwickelten photolabilen Carbonyl- Schutzgruppen bei der Untersuchung der Chemotaxis menschlicher Spermien gezeigt. Schließlich wurden auf der Basis eines Progesteron-3-CMO-Peptid- Derivates Werkzeuge zur Identifizierung der Rezeptorbindungsstelle für Progesteron an menschlichen Spermien entwickelt., The application of phototriggers (caged compounds) has proven to be a very useful method for in situ studies of cellular processes. Caged compounds are photolabile inactive derivates of biologically active molecules which can release rapidly the active biomolecule by irradiation with light. In this thesis new efficient and highly water soluble photoactivatable protecting groups for carbonyl functions were developed and tested. For this, the syntheses of substituted 4-(1,2-dihydroxyethyl)coumarins were developed and the compounds were used for the protection of carbonyl compounds. The obtained cumarinyl-substituted 1,3-dioxolanes have been completely characterized regarding their photophysical and photochemical properties. The optimal protection group found is derived from 8-[bis(carboxymethyl)aminomethyl]-6-bromo-4-(1,2-dihydroxyethyl)-7-hydroxycoumarin. It combines very good water solubility in aqueous buffers, high extinction coefficients in the ultraviolet and visible range of light, and efficient photoreactivity. For the first time, caged compounds of the biomolecules bourgeonal and progesterone and its derivative progesterone-3-O-(carboxymethyl) oxime (progesterone-3-CMO) were synthesized. Furthermore the applicability of the newly developed photolabile carbonyl protecting groups in the study of chemotaxis of human sperm was demonstrated. Finally, on the basis of a progesterone-3 CMO-peptide derivative tools to identify the receptor binding site for progesterone on human sperm were developed.

In contrast to heparins and oral anticoagulants, anti IIa inhibitors (thrombin inhibitors) are able to directly inhibit the protease activity of thrombin and can thereby precisely control the blood coagulation process. Direct thrombin inhibitors are either biosimilars (r-hirudin) or synthetically produced substances (bivalirudin, argatroban, dabigatran). In 1997 r-hirudin was introduced into clinical practice, however due to its narrow therapeutic range and the necessity of drug monitoring it has not gained widespread clinical use by now. Since 2004 and 2005 the synthetic thrombin inhibitors bivalirudin and argatroban, respectively, are available. With dabigatran the first oral synthetic thrombin inhibitor followed in 2008. These four drugs can inhibit even clot bound thrombin and show low plasma protein binding. They differ in respect to route and duration of application as well as elimination from the body, thereby offering a precise inhibition of blood coagulation adjusted to the individual case and without danger of HIT II. These advantages shall be used and advanced by the development of further direct thrombin inhibitors.

A survey is given on pharmacology and indications for the treatment with vitamin K antagonists. The therapeutic handling and self control by the patient is described.

There is little consensus on the optimal perioperative management for most patients on oral anticoagulation with vitamin K antagonists. Bridging therapy is not recommended for the majority of patients on oral anticoagulation as most are at low risk for perioperative stroke. Though most clinicians choose an aggressive perioperative strategy for patients with high thromboembolic risk (e.g., mechanical mitral valve replacement) by withholding warfarin perioperatively and the use of full-dose heparin, prophylactic dose heparin is given for lower risk cagegories (e.g., bileaflet aortic valve replacement and atrial fibrillation). The amount of increase in postoperative major bleeding when full-dose anticoagulation is administered soon after surgery is the factor in the decision with the least available data. The optimal method for returning the International Normalized Ratio (INR) to the desired range preoperatively depends upon its degree of initial elevation and whether or not clinically significant bleeding is present. Rapid reversal of excessive anticoagulation should be undertaken in patients with serious bleeding at any degree of anticoagulation. Vitamin K therapy is an effective treatment for INR prolongation in patients with vitamin K-associated coagulopathy; coagulation factor replacement is required, in addition, in patients with major bleeding or with an indication for immediate correction of their INR. Patients receiving prothrombin complex concentrate have a more rapid and more complete reversal of their anticoagulation as compared with fresh frozen plasma.

It has long been a standard procedure to replace coumarin by heparin if a patient using this oral anticoagulant had to undergo dental surgery. The Quick-Value had then to exceed a certain limit before surgery could be safely performed. Today this procedure has changed in that a switch to heparin is only made for invasive and large area surgery. Simple dental extractions, small biopsies and periodontal treatments are performed under continuous oral anticoagulation and local hemostyptic measures are applied. It has been shown that the likelihood of postoperative bleeding complications after adequate local hemostasis during dental surgery is much lower than is the risk of thrombosis or embolic complication following cessation of anticoagulant medication before surgery.

Painful pink or magenta colored skin lesions characterized by a clear line of demarcation between the affected area and surrounding tissue appearing under therapy with coumarins may be a sign for evolving coumarin-necrosis. Immediate treatment with a protein C preparation in patients with protein C deficiency can prevent necrosis.

In pregnancy, thromboembolic complications are six times more frequent than in nonpregnant women. Maternal age, idiopathic or secondary thrombosis in the patients history, the mode of delivery, bed rest and / or obesity as well as the thrombophilic defects are considerable factors for an increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE). Compared to unfractionated heparins (UFHs) prophylactic treatment relies mainly on low molecular weight heparins (LMWHs) which safety is now well established in pregnant women. In view of their multiple side effects oral anticoagulants such as cumarine or aspirin are contraindicated or of subordinate importance. The procedures to exclude DVT follow the usual diagnostic algorithms considering maximum radiation protection in case of further apparative diagnostics. Although there are reported good experiences with LMWHs in the treatment of DVT, UFHs are still the preferred drugs in this clinical condition. Insufficient heparin treatment or impending postthrombotic complications may be reasons for additional therapies like thrombolysis or operative thrombectomy.

Patients on anticoagulants of the vitamin K antagonist type may sometimes be scheduled for invasive procedures or surgical operations. In order to minimize the risk of thromboembolism caused by the interruption of chronic anticoagulation for the procedure, temporary administration of anticoagulants with shorter half-lives is required (so-called bridging anticoagulation). The present review outlines the spectrum of risks during this period regarding both thromboembolism and major bleeding. Low molecular weight heparins may be considered the medication of choice for bridging anticoagulation, mainly for practical reasons. Since they require no coagulation monitoring or dose adjustment, outpatient treatment is feasible. Such heparins are not labelled for the indication of bridging anticoagulation. However, based on recent studies of large patient cohorts, evidence of their efficacy and safety is significantly more solid than for unfractionated heparin. A simple dosing scheme for low molecular weight heparins is given here and all requirements are discussed for safe guidance through episodes of bridging anticoagulation.

A 71-year-old patient suddenly developed a painful, bizarre livid erythema on the right foot. Based upon the clinical and histological presentation, cholesterol emboli were diagnosed. These cholesterol emboli were induced by therapy with phenprocoumon (a coumarin derivative), which had been initiated 5 months previously. Arterial emboli may rarely occur during anticoagulation and have to be included in the differential diagnosis.

Free-selling rodenticides contain highly potent and long-acting coumarins that may cause severe and prolonged coagulopathies.A 46-year-old male was admitted after accidental ingestion of a rodenticide with spontaneous hematomas and a nonmeasurable prothrombin time (International Normalized Ratio [INR]). He had a prolonged coagulopathy and required high doses of vitamin K(1) to normalize the prothrombin time. A dose reduction of vitamin K(1) was followed by a new rise in the INR.In cases of coagulopathy and suspicion of an intoxication with anticoagulants, an ingestion of rodenticides containing highly potent coumarins should be taken into account. Intoxications with these "superwarfarins" require high doses of vitamin K(1) given for several weeks.

Patients with non-rheumatic atrial fibrillation (AF) have an increased risk for ischemic stroke. The presence of risk factors such as a history of ischemic stroke, transient ischemic attack, diabetes mellitus, arterial hypertension or advanced age allows the classification of patients with AF in three groups with high, moderate, and low stroke risk. High-risk patients should receive oral anticoagulants, low-risk patients aspirin, and moderate-risk patients one of both antithrombotic agents. However, primary stroke prevention studies suggest that many high-risk patients are not anticoagulated, whereas low risk patients receive anticoagulants instead of aspirin. Our retrospective analysis of prospectively collected data examined the antithrombotic therapy of patients with first-ever stroke and known non-valvular AF and compared the results with the recommendations of the Atrial Fibrillation Investigators (AFI) and the Stroke Prevention in Atrial Fibrillation (SPAF) study. Contraindications against anticoagulation were taken into consideration. High-risk patients received in 36% an appropriate antithrombotic therapy according to the AFI-guidelines, and in 28% according to the SPAF-guidelines. About one quarter of low-risk patients were anticoagulated unnecessarily. Our study confirms that many patients with AF and high stroke risk do not get the appropriate antithrombotic therapy, while some patients with low-risk are anticoagulated without cause.

During the first generalised epileptic attack, a patient suffered a humerus fracture which necessitated an operation. This patient also had a history of spontaneous lung emboli and an elevated anti-cardiolipin plasma level for which coumarin was prescribed but was stopped preoperatively. After induction of general anaesthesia for a total shoulder arthroplasty, the patient became hypotensive and the bispectral index recorded perioperatively dropped to 0. Postoperatively, the patient developed signs of a unilateral borderzone cerebral infarct in the area of the medial cerebral artery. The possible pathomechanisms involved are discussed. In cases of known cerebral pathology intraoperative hypotension should be avoided by at all costs. Patients with increased anti-cardiolipin antibody levels and who suffer from epileptic attacks have an increased risk of thromboembolic events.

The most effective and safest option for the prevention of atrial fibrillation and its sequelae--cardiovascular morbidity and mortality, stroke)--is primary prophylaxis. Here, the management of arterial hypertension--the most common cause underlying atrial fibrillation--is of considerable importance. In addition to blood pressure reduction, substances with an action of the autonomic nervous system and the renin-angiotensin-aldosterone system (ACE-inhibitors, AT1 antagonists, beta blockers) have a positive effect on the remodeling, so-called, of the atrial myocytes, and thus on the occurrence of atrial fibrillation with its associated stroke risk. For patients with elevated blood pressure, therefore, the therapeutic strategy should, in the individual case, give consideration to the possibility of exerting a positive effect on atrial fibrillation.

Deep venous thrombosis and pulmonary embolism are considered to be two variants of one disease--'venous thromboembolism'. Pathogenesis, therapy and prognosis of these both entities are very similar and therefore the term 'venous thromboembolism' has been used in recent literature. The cornerstone of therapy is anticoagulation and initially consists of heparin for at least five days. Because of pharmacokinetic advantages low molecular weight heparins are the therapy of choice. They are as efficient and save as unfractionated heparins and allow weight-adapted dosing with daily subcutaneous injections in most patients. Low molecular weight heparins do not require regularly laboratory monitoring with few exceptions, e.g. renal failure. Therefore outpatient treatment of deep venous thrombosis is possible in most patients. Although there are promising data about outpatient treatment of pulmonary embolism, this is still being studied and can not be recommended outside clinical trials. Introduction of coumarin therapy for venous thromboembolism should be started on day 1 of diagnosis, keeping the total duration of heparin therapy at no more than five days and therefore minimizing the incidence of heparin-induced thrombocytopenia. Evidence from multiple studies indicates that effective coumarin therapy in venous thromboembolism is usually reflected by an INR of 2.0 to 3.0. In patients with massive and hemodynamically relevant thromboembolism alternative therapeutic approaches such as thrombolytic therapy, thrombectomy or insertion of intravenous filters may be useful. Adequately fit compression stockings can reduce the risk of post-thrombotic syndrome after deep venous thrombosis.

For haemostatic and circulatory reasons pregnancy is associated with an about 6-fold relative increase of thrombotic risk which is further raised by additional risk factors, such as history of thrombosis or acquired and hereditary thrombophilia, respectively. Recently, the thrombophilias have been revealed as risk factors for severe preeclampsia, abruptio placentae, fetal growth retardation, abortion and still birth as well. Thus, there are several situations in which the question for the need of antithrombotic medication is raised in a pregnant woman, either for therapy of acute thromboembolism or for prophylaxis of thrombosis and obstetrical complications, respectively. While acute thromboembolism has to be treated in every case, indication for prophylaxis has to be weighed in the light of the individual risk profile of the pregnant woman and the potential side effects and inconvenience of the medication. The first part of this article deals with the pregnancy related problems of coumarins, heparins and aspirin and demonstrates that the low molecular weight heparins are the anticoagulants of choice for most indications in pregnancy. The second part of this overview shows in which specific situations and how the antithrombotic medications mentioned above are used in pregnancy.

The diagnosis of neuropsychiatric lupus erythematosus (NPSLE) can be difficult and has to be differentiated from neurologic complications that result from hypertension, drugs, infection, uremia, and metabolic changes.There is no single test which is diagnostic. Therefore, the clinical presentation, serologic tests and neuroimaging techniques have to be combined to support the diagnosis of cerebral lupus. Magnetic resonance imaging (MRI) is routinely used with a sensitivity of 50-87%. However, the abnormalities such as white matter lesions or brain atrophy are nonspecific and were also found in asymptomatic patients (16-52%). A negative MRI result does not exclude a diagnosis of cerebral lupus. Antibodies against phospholipids are an important immunoserologic marker due to the close association with thromboembolic events. Echocardiography and cerebrospinal fluid examination should be added to rule out cardiac embolic disease and CNS infection. Functional brain imaging techniques such as single-photon emission computed tomography, positron emission tomography, magnetization transfer imaging or magnetic resonance spectroscopy may be helpful especially in patients with unconspicuous MRI, but the findings are not SLE-specific.The treatment of cerebral lupus is empiric, due to a lack of randomized studies. Inflammatory brain lesions are treated with corticosteroids and immunosuppressive drugs (e. g., cyclophosphamide). Anticoagulant therapy with coumarins (at a target INR of 3.0-3.5) is recommended in cases of thrombotic events associated with antiphospholipid antibodies. However, no studies exist on patients with arterial thrombosis, including strokes, supporting this target INR.

During the acute phase of the disease the aim of conservative treatment of DVT is relief of symptoms as well as prevention of thrombus progression and pulmonary embolism. In the chronic phase treatment should prevent recurrence and post-thrombotic syndrome. Besides general measures such as compression therapy, elevation of the leg and mobilisation anticoagulation therapy with heparin and coumarin has been proved to be successful. Even though not more effective or safer low-molecular weight heparin has recently replaced unfractionated heparin in the initial treatment of DVT mainly because of its more convenient use allowing modern ambulatory and outdoor treatment. Doses depend on the kind of heparin used. In the secondary prevention therapy with coumarins, an INR of 2-3 is generally accepted whereas the duration of oral anticoagulant therapy is under discussion. Compression therapy is recommended for at least 2 years, in case of post-thrombotic syndrome life-long therapy is necessary. When comparing the effectiveness of DVT-treatment today with the results in the preanticoagulant era, the modern treatment is more effective, safe and cost-effective; it also guarantees more quality of life, but the long-term results have to be improved.

An important consideration for the utilisation of in vitro culture models for studies on drug metabolism as an alternative to animal testing is the maintenance of a defined degree of cell differentiation. Thus, in vitro conditions reflecting as near as possible the in vivo situation of the cells within the whole organ are required. A bioreactor was developed for the cultivation of liver cells which allows the reorganisation of hepatocytes and non-parenchymal cells of the liver in coculture to form three-dimensional, tissue-like structures including extracellular matrix components produced by the cells. In this study, the vitality and metabolic activity of isolated rat hepatocytes was investigated over a two week culture period in bioreactors. The results show that after a reorganisation phase, the cells preserve specific functions, such as protein and urea synthesis capacity and specific cytochrome P450 activities during the culture period, with maximal values during the first week. Possible applications of the model in pharmaceutical industry are studies on metabolite patterns, enzyme induction, drug-drug-interactions, first pass effects and long-term toxicity of drugs.

Prospective, randomized placebo-controlled double-blind study to prove the efficacy of Coumarin/Troxerutine (Venalot Depot) for protection of salivary glands during a head and neck irradiation.Forty-eight radiotherapy patients (60 Gy) with head and neck cancer were included in this trial. During radiotherapy the salivary glands were located in the core irradiation field. Primary efficacy parameters were sialometry, quantitative salivary gland scintigraphy and clinical evaluation of early effects of radiotherapy (RTOG-score, Table 1). All data were collected at 6 assessments: 1 week pre-radiation (U1), at start (U2), half time (U3) and end (U4) of irradiation, 8 days (U5) and 28 days (U6) after the end of irradiation (Figure 1).Twenty-three patients (11 verum, 12 placebo) completed the study with all assessments. Sialometrically, all patients were severely (half of radiotherapy) or completely (end of radiotherapy) xerostomatic (Figure 2). In a global efficacy measure according to O'Brien combining scintigraphy and RTOG there was a tendency for a higher efficacy of verum compared to placebo (p = 0.068). After start of irradiation therapy, the RTOG-score showed continuously and significantly lower early radiation effects under verum than under placebo (U3 vs U6: p0.05, area under curve: p = 0.032; Table 2, Figure 3). The scintigraphically determined excretion fraction was slightly less impaired in the verum group compared to the placebo treatment (p = 0.12. Figure 4). There was no difference in drug safety between placebo and verum for adverse events, changes in the activity of liver enzymes and for global impression of tolerability.The results give support for an advantageous effect of Venalot Depot in the treatment of radiogenic sialadenitis and mucositis. In even a small number of evaluable patients, early clinical effects of irradiation (RTOG-score) were less pronounced in the active treatment group than in the placebo group, but the sample size was too low to prove statistically also the benefit of coumarin/troxerutine with the scintigraphic method. Sialometry seems not suitable for the assessment of early radiation effects.