Pathological Gambling (PG) is an impulse control disorder with lifetime prevalence of 1-3%. Available treatments are limited by uncertain classification and complexity of implicated neurotransmitter systems. Dopamine (DA), a key neurotransmitter implicated in addictive behavior and reward is elevated in response to gambling and psychostimulants. Based on previous research, it was hypothesized that the D2 blocker, haloperidol (HAL), will enhance slot machine reinforcement in PG but not in Healthy Controls (HC). If this increase reflects preferential stimulation of D1 receptors and group differences in D1 sensitivity, D1-D2 blocker (fluphenazine, FLU) should offset increase in reinforcement seen with HAL in PG subjects. In line with DA's implicated role in 'wanting' vs. 'liking' of the addictive reinforcer, the results suggest that DA release mediated partial D1 activation under FLU led to clear differentiation between groups with increased 'wanting' seen in controls but not in gamblers. DA's role in 'liking' however remains elusive.

Pathological Gambling (PG) is an impulse control disorder with lifetime prevalence of 1-3%. Available treatments are limited by uncertain classification and complexity of implicated neurotransmitter systems. Dopamine (DA), a key neurotransmitter implicated in addictive behavior and reward is elevated in response to gambling and psychostimulants. Based on previous research, it was hypothesized that the D2 blocker, haloperidol (HAL), will enhance slot machine reinforcement in PG but not in Healthy Controls (HC). If this increase reflects preferential stimulation of D1 receptors and group differences in D1 sensitivity, D1-D2 blocker (fluphenazine, FLU) should offset increase in reinforcement seen with HAL in PG subjects. In line with DA's implicated role in 'wanting' vs. 'liking' of the addictive reinforcer, the results suggest that DA release mediated partial D1 activation under FLU led to clear differentiation between groups with increased 'wanting' seen in controls but not in gamblers. DA's role in 'liking' however remains elusive.

Univ., Diss.--Erlangen, 2004.

Zsfassung in dt. Sprache. - Würzburg, Univ., Diss., 2008

Zugl.: Berlin, Freie Universiẗat, Diss., 2009. / Auch als Online-Ressource: http://www.diss.fu-berlin.de/diss/receive/FUDISS_thesis_000000012680.

München, Techn. Univ., Diss., 2004.

Universiẗat, Diss., 2003--Bonn. / Erscheinungsjahr an der Haupttitelstelle: 2003.

Within this thesis are described synthetic approaches towards the phomactins which are novel platelet activating factor antagonists. The synthesis of known alcohol 162 is described, the two key intermediates being aldehyde 160 and vinyl iodide 161. The key step of the synthesis of aldehyde 160 is a [2,3]-Wittig-Still rearrangement of stannane 159 which introduces the hindered C1-C2 bond present in the phomactins. The vinyl iodide 161 is made in four steps from 4-pentyn-1-ol. Addition of the vinyl ytterbium species derived from the vinyl iodide to aldehyde 160 gave secondary alcohol 162. Subsequent transformations furnished the bisprotected macrocyclic sulfone 174 in four steps from alcohol 162 to give the C2 SEM protected macrocycle. Elaboration of the macrocycle to ketoaldehyde 206 was made possible by the TPAP oxidation/rearrangement reaction. Reduction with DIBAL-Hgave diol 175. Attempts at removing the sulfone appendage proved difficult so the diol was protected as the bis-acetate to attempt a selective epoxidation of the D3,4 olefin in the presence of the D1,15 olefin. Although this looked promising with the formation of the mono-epoxide 213, the inefficiency of removing the SEM group at C2 prior to the epoxidation meant the route was not viable. Removing both protecting groups from macrocycle 174 was possible with refluxing TBAF and after incorporating the epoxide of the D3,4 olefin, the macrocycle was elaborated to the benzyl ether 217. Applying the TPAP oxidation/DIBAL-H reduction sequence furnished advanced intermediate 179 which has the full carbon skeleton found in phomactin A and also had oxygen functionality at all the required positions.

Lithium ist noch immer der Goldstandard in der Behandlung der bipolaren Störung und kommt auch in der Behandlung der unipolaren Depression zur Anwendung. Die therapeutische Breite von Lithium ist jedoch gering. Bei zu hohen Spiegeln kann es zu schweren Nebenwirkungen bis hin zu Intoxikationen mit letalem Verlauf kommen. Mit zunehmendem Lebensalter nimmt die renale Lithiumclearance ab. Hinzu kommen somatische Komorbiditäten, welche die renale Lithiumcelarance ebenfalls beeinträchtigen können. Darüber hinaus gibt es eine Vielzahl von Arzneimitteln, welche ebenfalls Einfluss auf den Lithiumspiegel nehmen können. Zu diesen zählen Diuretika, ACE-Hemmer und AT1-Rezeptor-Antagonisten sowie nicht-steroidale Antirheumatika, welche den am häufigsten rezeptierten Medikamente gehören. In einer retrospektiven naturalistischen Studie wurde der Einfluss einer Komedikation aus einem Schleifen- (Furosemid/Torasemid), Thiazid- (HCT) oder kaliumsparenden Diuretikum (Amilorid, Spironolacton, Triamteren), einem ACE-Inhibitor (Captopril, Enalapril, Lisinopril, Ramipril) oder AT1-Rezeptor-Antagonisten (Candesartan, Losartan, Irbesartan, Olmesartan, Valsartan) oder einem nicht-steroidalen Antirheumatikum (Acetylsalicylsäure, Diclofenac, Ibuprofen) auf den dosisbezogenen Lithiumspiegel untersucht. Als Stichprobe dienten 501 Lithiumpatienten, welche stationär im Zentrum für Psychische Gesundheit der Universitätsklinik Würzburg behandelt worden waren (01/2008 – 12/2015). 92 Patienten (18,4 %) nahmen nur eines der aufgeführten Medikamente ein, während 76 (15,1 %) eine Kombination von bis zu 5 Medikamenten erhielten – somit beinhaltete die Komedikation von 33,5 % der Patienten mindestens eines der aufgeführten Medikamente. Als Kontrollgruppe diente eine Stichprobe von 333 Lithiumpatienten ohne entsprechende Komedikation. Altersintrinsische Faktoren (p < 0,001; R2=0,289), die GFR (p < 0,001; R2=0,377) sowie das Geschlecht (p < 0,001; R2=0,406) scheinen den größten Einfluss auf den Lithiumspiegel zu nehmen (ca. 41 %), während für die Komedikation ein geringerer Effekt anzunehmen ist (ca. 4%). Die Ergebnisse sprechen für ein signifikantes Interaktionspotential von Diclofenac und Ibuprofen (p = 0,001). Es ergeben sich auch Hinweise auf ein relevantes Interaktionspotential von Hydrochlorothiazid (p = 0,020). Patienten, welche Acetylsalicylsäure (p < 0,001) oder Allopurinol (p = 0,003) erhalten, scheinen ein Risikokollektiv für erhöhte Lithiumspiegel darzustellen. Die dosisbezogenen Lithiumspiegel der Stichproben mit Einnahme eines ACE-Hemmers/AT1-Rezeptor-Antagonisten und eines Schleifendiuretikums unterschieden sich dagegen nicht signifikant von denen der Kontrollstichprobe ohne Komedikation. Es ist zudem davon auszugehen, dass eine Kombination mehrerer Pharmaka mit Interaktionspotential (p < 0,001) ein höheres Risiko für erhöhte dosisbezogene Lithiumspiegel birgt als eine Monotherapie (p = 0,026) und die Indikation einer solchen sollte daher kritisch geprüft werden. Eine zusätzliche Analyse von 32 Fällen von supratherapeutischen Lithiumserumkonzentrationen von ≥ 1,3 mmol/l (1,3–4,1mmol/l) legt nahe, dass sich ein Großteil von Lithiumintoxikationen durch regelmäßige Spiegelkontrollen und Dosisanpassungen unter Berücksichtigung von Komedikation, Alter und Komorbiditäten sowie Psychoedukation der Patienten vermeiden ließen. / Lithium is still the gold standard in treating bipolar disorder and is indicated in the treatment of unipolar depression as well. Lithium has a narrow therapeutic range. Elevated lithium levels can lead to severe adverse effects and lethal intoxications. With increasing age, lithium clearance decreases. Somatic comorbidities can decrease lithium clearance as well. Moreover, there is a large number of drugs, which can affect lithium clearance. Among those are diuretics, ACE-inhibitors/AT1-receptor-antagonists and non-steroidal anti-inflammatory drugs. All of them belong to the most frequently prescribed drug. Retrospective data of lithium serum levels was analysed in 501 inpatients, who had been treated in the Department of Psychiatry, Psychosomatics and Psychotherapy of the University Hospital of Würzburg (01/2008–12/2015). We wanted to investigate whether comedication of loop diuretics (Furosemide/Torasemide), thiaziddiuretics (Hydrochlorothizide) or potassium-sparing diuretics (Amiloride, Spironolactone, Triamterene), ACE-inhibitor (Captopril, Enalapril, Lisinopril, Ramipril) or AT1-receptor-antagonists (Candesartan, Losartan, Irbesartan, Olmesartan, Valsartan) or non-steroidal anti-inflammatory drugs (Acetylsalicylic acid, Diclofenac, Ibuprofen)affect the serum concentration of lithium. 92 inpatients (18.4 %) received one of the mentioned drugs, whereas 76 inpatients (15.1 %) received a combination of up to 5 drugs – thus a total of 33.5 % of the patients were treated with at least one potentially interacting drug. The control sample consisted of 333 inpatients whithout comedication of any interacting drug. Age intrinsic factors (p < 0.001; R2=0,289), gfr (p < 0.001; R2=0,377), and sex (p < 0.001; R2=0,406) had the greatest impact on serum lithium concentration (41%) whereas the effect of comedication was lower (4%). There is evidence that Diclofenac and Ibuprofen have a significant effect on dose related lithium concentration (p = 0.001). Possibly hydrochlorothiazide does so, too (p = 0.020). Moreover patients receiving Acetylsalicylic acid (p < 0.001) and Allopurinol (p = 0.003) are at higher risk for elevates lithium concentrations. Dose related lithium levels of the samples receiving an ACE-inhibitor/AT1-receptor-antagonist or loop diuretic did not significantly differ from the control sample without interacting comedication. A combination of potentially interacting drugs (p < 0.001) seems to be more critical than taking only one of the investigated drugs (p = 0.026) and thus the indication should be critically considered. An additional analysis of 32 cases with elevated lithium concentrations ≥ 1.3 mmol/l (1.3–4.1mmol/l) indicates, that most lithium intoxications could be avoided by regular measurements of lithium serum concentration and adaption of lithium dosage in regard of comedication, age and comorbidity if indicated and by patients´ psychoeducation.

A great deal of research has shown decrements in force and power following static stretching. There has been little research investigating the acute effects of static stretching of the antagonist on the expression of strength and power. The purpose of this study was to investigate the effects of static stretching of the antagonist muscles on a variety of strength and power measures. Sixteen active males were tested for vertical jump height and isokinetic torque production in a slow knee extension (KES) at 60°/s and a fast knee extension (KEF) at 300°/s. Electromyography was taken during knee extension tests for the vastus lateralis and the biceps femoris muscles. Participants performed these tests in a randomized counterbalanced order with and without prior antagonist stretching. All variables for stretching and non-stretching treatments were compared using paired t tests at an alpha of .05. Paired samples t tests revealed a significant (p = .034) difference between stretch KEF and non-stretch KEF conditions. There was no significant (p > .05) difference between KES stretch and non-stretch conditions. Vertical jump height was significantly (p = .011) higher for the stretching treatment than the non-stretching treatment. Vertical jump power was also significantly higher (p = .005) in the stretch versus the non-stretch condition. Paired samples t test indicated no significant (p > .05) difference between testing conditions for electromyography, represented as a percentage of maximal voluntary contraction (MVC). These results suggest that stretching the antagonist hamstrings prior to high speed isokinetic knee extension increases torque production. It also demonstrated that stretching the hip flexors and dorsi flexors may enhance jump height and power. Practitioners may use this information to acutely enhance strength and power performances.