Disposition of oral and intravenous pravastatin in MRP2-deficient TR- rats.

The aim of this study was to characterize the role of the efflux transporter Mrp2 (Abcc2) in the pharmacokinetics of orally and intravenously administered pravastatin in rats. Eight Mrp2-deficient TR- rats and eight wild-type rats were given an oral dose of 20 mg/kg pravastatin. Four TR- animals and four wild-type animals were studied after intravenous administration of pravastatin (5 mg/kg). The TR(-) rats showed a 6.1-fold higher mean area under the plasma concentration-time curve (AUC) of pravastatin (p < 0.001) after oral administration and a 4.7-fold higher AUC (p < 0.01) after intravenous administration of pravastatin as compared with the wild-type animals. The mean systemic (total) clearance of pravastatin was 4.6-fold higher (39.2 versus 8.50 l/h/kg, p < 0.001) and the mean V 4.3-fold higher (14.1 versus 3.29 l/kg, p < 0.01) in the wild-type rats. The mean renal clearance of pravastatin in the TR(-) rats was 16.5-fold increased as compared with the wild-type animals (0.695 versus 0.042 l/h/kg, p < 0.05). The increased systemic exposure to oral pravastatin in the TR- rats was associated with a greater inhibitory effect on 3-hydroxy-3-methylglutaryl CoA reductase, as shown by smaller lathosterol to cholesterol concentration ratios. These results suggest that the reduced biliary pravastatin excretion in the Mrp2-deficient TR- rats is partly compensated for by increased urinary excretion of pravastatin. Furthermore, intestinal Mrp2 does not appear to play a major role in the oral absorption of pravastatin in normal rats.     

Pharmacogenetic screening and therapeutic drugs.

BACKGROUND: Pharmacogenetics is the science of the influence of heredity on pharmacological response. ISSUES: The cost of severe adverse drug reactions in individuals has been estimated in the US alone to be in excess of US$4 billion. It has been argued that in a significant proportion of cases, the efficacy and toxicity profiles of drug therapy would be substantially improved in individuals if characteristics due to genetic variation were taken into account. Methods are now available, which make screening for susceptibility feasible. CONCLUSIONS: There are several therapeutic areas in which screening may give rise to significant improvements in outcome with cost-benefits to both the individual and the community. However, there is currently a lack of data on which cost-benefit analysis can be based. The challenge is to provide this information for new drugs, and for drugs with established therapeutic roles.     

Dyspepsie und Helicobacter-pylori-Infektion bei Besch?ftigten eines gro?en Industrieunternehmens Ergebnisse der prospektiven BASF-Helicobacter-pylori-Vorsorgeaktion

Zusammenfassung Hintergrund: Die Assoziation zwischen Helicobacter-pylori-(H.-pylori-)Infektion und Dyspepsie wird kontrovers diskutiert. Im Rahmen der BASF-H.-pylori-Vorsorgeaktion wurde u. a. die Prävalenz von Dyspepsie bei arbeitsfähigen Personen ermittelt sowie der Zusammenhang mit der H.-pylori-Infektion und der Erfolg einer Eradikationstherapie untersucht. Probanden und Methodik: 6 132 Beschäftigte der BASF wurden untersucht und im Rahmen einer standardisierten Anamnese u. a. zu dyspeptischen Beschwerden befragt. Diese wurden entsprechend der führenden Symptomatik den Dyspepsiesubtypen vom Ulkustyp, Dysmotilitätstyp, Refluxtyp und unspezifischen Typ zugeordnet. Bei allen Beschäftigten wurde die Seroprävalenz (IgG-ELISA) der H.-pylori-Infektion bestimmt. Allen H.-pylori-positiven Personen mit Dyspepsie wurde weitere Diagnostik in Form einer Ösophagogastroduodenoskopie und einer Sonographie des Abdomens bei Fachärzten empfohlen und eine H.-pylori-Eradikationstherapie (Italian-Triple-Therapie) angeboten. In einer Untergruppe endoskopisch untersuchter Beschäftigter mit peptischer Ulkuskrankheit (PUD, n = 37) bzw. Non-Ulcer-Dyspepsie (NUD; n = 39) wurde der prognostische Wert der im Western Blot ermittelten Antikörper gegen CagA und VacA untersucht. Ergebnisse: 1 255 der 6 143 Beschäftigten (20,4%) berichteten über Dyspepsie. 492 Personen mit Dyspepsie (39,2%) waren gleichzeitig H.-pylori-positiv. Bei Personen ohne dyspeptische Symptome betrug die H.-pylori-Prävalenz 35,8%. Personen mit unterschiedlichen Dyspepsiesubtypen unterschieden sich nicht hinsichtlich der H.-pylori-Prävalenz. Personen, die häufige und intensive dyspeptische Beschwerden angaben, waren allerdings signifikant häufiger H.-pylori-positiv (OR 2,09, CI 1,43-3,05). Die Seroprävalenz von CagA und VacA bei Personen mit PUD unterschied sich nicht signifikant von derjenigen bei Personen mit NUD. 458 H.-pylori-positiven Personen wurde die Eradikation empfohlen. 330 Personen (72,1%) folgten der Empfehlung. 128 (27,9%) ließen sich nicht behandeln. An der Nachkontrolle nach 12 Monaten nahmen 402 Personen (87,8%) teil, davon waren 300 behandelt, 102 nicht. Der serologisch analysierte Eradikationserfolg lag bei 81,5%. 42,8% der erfolgreich behandelten Personen berichteten über Besserung ihrer Beschwerden, 33,2% über Beschwerdefreiheit. Bei den nicht behandelten Personen war dies nur in 16,7% bzw. in 37,3% der Fall. Vermehrte Refluxbeschwerden traten nach erfolgreicher Eradikation nicht auf. Schlussfolgerung: Wir konnten keinen generellen Zusammenhang zwischen Dyspepsie und H.-pylori-Infektion in einem großen Kollektiv arbeitsfähiger Personen erkennen. Häufige und intensive dyspeptische Symptome scheinen allerdings ein prädikativer Faktor für die H.-pylori-Seropositivität zu sein. Die serologisch bestimmbaren Virulenzfaktoren tragen nicht zur Unterscheidung PUD oder NUD bei. Die Eradikationstherapie führte nach 1 Jahr zwar häufiger zur Besserung, aber nicht häufiger zu Beschwerdefreiheit bei Beschäftigten mit dyspeptischen Beschwerden im Vergleich zu unbehandelten Personen. Abstract Background: The role of Helicobacter pylori (H. pylori) infection in dyspepsia is controversial. In the course of a health initiative within a large industrial corporation, we investigated the prevalence of both dyspepsia and positive H. pylori serology and the outcome of eradication therapy in symptomatic H. pylori positive employees. Test Persons and Methods: H. pylori serology (IgG ELISA) was determined in 6,143 employees of BASF AG Ludwigshafen/Germany who were also asked to complete a standardized health history administered by a physician. Peptic ulcer disease (PUD) and dyspepsia subgroups were defined based on past medical history and symptom profiles using the criteria of Heading. Upper GI endoscopy, abdominal ultrasound and eradication therapy (Italian Triple Therapy) was recommended for symptomatic H. pylori positive individuals. The prognostic value of antibodies against CagA and VacA was evaluated in 37 and 39 employees with PUD and non-ulcer dyspepsia (NUD) confirmed by endoscopy, respectively. Results: Of 6,143 employees, 1,255 (20.4%) were classified as dyspeptic, 492 (39.2%) of whom were H. pylori positive. The seroprevalence of H. pylori in asymptomatic employees was 35.8%. There were no significant differences in H. pylori seroprevalence among dyspepsia subgroups (reflux only, dysmotility only, reflux/dysmotility, ulcer-like and non-specific). However, individuals reporting severe dyspeptic symptoms were significantly more likely to be H. pylori positive (OR 2.09, CI 1.43-3.05). The seroprevalence of CagA and VacA was not significantly different among employees with NUD compared to referents or among employees with NUD compared to those with PUD. 330 (72%) of 458 employees with dyspepsia received eradication therapy, 128 persons refused therapy. Based on a 12-month follow-up of 402 individuals (300 of whom had received therapy), eradication success was 81.5% as judged by serology. Of the successfully treated employees, 33.2% reported a total absence and 42.8% reported a decrease in symptoms. Among the employees who refused therapy, the corresponding percentages were 37.3% and 16.7%, respectively. An increase in reflux complaints was not observed among treated employees. Conclusion: In a large active employee population, at most a very weak association was observed between the prevalence of H. pylori seropositivity and dyspepsia. Frequent and severe dyspeptic symptoms were associated with an increased rate of H. pylori seropositivity. The analysis of the virulence factors is not particularly helpful in discriminating PUD or NUD. Eradication of H. pylori infection leads to a decrease in dyspeptic symptoms after 12 months, but not more often to their complete absence compared to untreated individuals.     

Initial lithium augmentation improves the antidepressant effects of standard TCA treatment in non-resistant depressed patients

The hypothesis was tested that an initial lithium-tricyclic antidepressant (TCA) combination has a better antidepressant effect than standard TCA treatment in non-refractory depression at the beginning of an episode. Twenty bipolar melancholic type depressed inpatients under lithium-TCA treatment were compared with 20 patients with the same diagnosis and TCA-placebo treatment for 5 weeks under double-blind conditions. All patients were male. Initial lithium-TCA treatment reduced depressive symptoms significantly more than antidepressant treatment with TCA and placebo after 5 weeks, but not in weeks 1 or 2. It can be concluded that lithium augmentation of TCA treatment should be started even at the beginning of antidepressant TCA treatment to provide a better treatment response in those patients who will profit from long-term lithium prophylaxis, e.g. bipolar patients with melancholic type depression.     

Valproic acid induced encephalopathy--19 new cases in Germany from 1994 to 2003--a side effect associated to VPA-therapy not only in young children.

Valproic acid (VPA) is a broad-spectrum antiepileptic drug and is usually well-tolerated. Rare serious complications may occur in some patients, including haemorrhagic pancreatitis, bone marrow suppression, VPA-induced hepatotoxicity and VPA-induced encephalopathy. The typical signs of VPA-induced encephalopathy are impaired consciousness, sometimes marked EEG background slowing, increased seizure frequency, with or without hyperammonemia. There is still no proof of causative effect of VPA in patients with encephalopathy, but only of an association with an assumed causal relation. We report 19 patients with VPA-associated encephalopathy in Germany from the years 1994 to 2003, none of whom had been published previously.     

Measurement of acceleration: a new method of monitoring neuromuscular function

A new method for monitoring neuromuscular function based on measurement of acceleration is presented. The rationale behind the method is Newton's second law, stating that the acceleration is directly proportional to the force. For measurement of acceleration, a piezo-electric ceramic wafer was used. When this piezo electrode was fixed to the thumb, an electrical signal proportional to the acceleration was produced whenever the thumb moved in response to nerve stimulation. The electrical signal was registered and analysed in a Myograph 2000 neuromuscular transmission monitor. In 35 patients anaesthetized with halothane, train-of-four ratios measured with the accelerometer (ACT-TOF) were compared with simultaneous mechanical train-of-four ratios (FDT-TOF). Control ACT-TOF ratios were significantly higher than control FDT-TOF ratios: 116 +/- 12 and 98 +/- 4 (mean +/- s.d.), respectively. In five patients not given any relaxant during the anaesthetic procedure (20-60 min), both responses were remarkably constant. In 30 patients given vecuronium, a close linear relationship was found during recovery between ACT-TOF and FDT-TOF ratios. It is concluded that the method fulfils the basic requirements for a simple and reliable clinical monitoring tool.