Elucidation of Neu-P11 metabolism in urine of volunteers by liquid chromatography-tandem mass spectrometry.

The novel melatonin agonist Neu-P11 is used in treatment of physiological insomnia. In animal studies Neu-P11 showed sleep-promoting effects. In a phase 1 study Neu-P11 was administered to cohorts of healthy young male volunteers in an ascending single dose study. Up to now the metabolism of this new drug in humans has not been investigated. The first aim of this study was to identify possible metabolites in pooled urine samples of the first collecting period (0-8 h) of volunteers with the highest Neu-P11 oral dosage (200 mg). The objective of the second part of the study was to estimate the concentrations of the main metabolites of Neu-P11 - in this urine sample. The analyte Neu-P11 and metabolites were separated from human urine using dilution and precipitation with acetonitrile. Samples were analyzed for formation of both phase I and phase II metabolites using LC-MS/MS in precursor ion mode, product ion mode, neutral loss mode and the multi-reaction monitoring mode (MRM). Urine samples were analyzed before and after addition of beta-glucuronidase and sulfatase. In the pooled urine sample eight metabolites could be proved. The parent drug, the sulfated demethylated Neu-P11, the sulfated 6OH-Neu-P11 and the di-oxygenated product gave the highest signals in these urine samples and probably had the highest concentration. But quantification without reference substances is not possible. So in the second part of the study the urine samples were additionally analyzed with UV-detection for a better estimation of the metabolite concentrations. The concentration of the sulfated metabolites was more than ten times higher than the concentration of the unchanged drug in urine. Other metabolites were not measurable with UV-detection. The di-oxygenated Neu-P11 and an additional mono-oxygenated Neu-P11 showed relatively high signals in MS/MS. Probably the other metabolites, namely glucuronides, unconjugated demethylated Neu-P11 and unconjugated 6OH-Neu-P11, were formed at a lesser extent.

Simultaneous determination of drugs in human autopsy material using phase-optimized liquid chromatography.

In legal medicine in many cases drugs are detected in autopsy material without connection to the cause of death, and until now no further investigations have taken place. In our study more than 50 drugs were measured directly in several compartments. The deceased had received continual therapeutic treatment, treatment during an operation or an unsuccessful emergency therapy. Liquid-liquid extraction and an LC-MS/MS method were developed for the determination of these drug concentrations. When measuring many transitions in a biological matrix, two problems should be excluded: ion suppression and too few measurement points per peak. A relatively short operation time and sufficient separation were achieved by column, eluent and gradient optimization with POPLC (phase-optimized liquid chromatography). Various autopsy materials from about 170 cases were investigated. In particular, in nine cases with four or more simultaneously determined drugs, their distribution in the compartments is very interesting for pharmacokinetic examinations. The distribution patterns of the drugs in the compartments of one individual deceased were compared. This meant that the great differences between subjects that are normally encountered these studies could be excluded. Measurements of drug concentrations in human autopsy material deepens knowledge of the respective drugs' pharmacokinetics.

[Dietary supplements--evaluation of patient inquiries at a drug information service]. / Nahrungsergänzungsmittel--Evaluation der Patientenanfragen an einen Arzneimittelberatungsdienst.

BACKGROUND: Dietary supplements are a product group of foods, which are meant to supplement the general nutrition with micronutrients and other substances. They are widely used in Germany. We evaluated the frequency of their use and of information requirements concerning dietary supplements in patients who contacted the independent drug information service at TU Dresden. PATIENTS AND METHODS: All inquiries from 2008 to 2010 were evaluated regarding information requirement about dietary supplements, the kind of products used and characteristics of patients using supplements. Sociodemographic characteristics, kind and number of drugs and dietary supplements as well as underlying diseases were recorded from the inquiring patients. RESULTS: 23.3 % of persons looking for advice used dietary supplements. The most frequently used product groups included vitamins and minerals (52.5 %) as well as plant extracts (14.0 %). Information requirements were especially high for plant extracts and for products containing glucosamine/chondroitin and lutein/zeaxanthin. Users of dietary supplements were exposed to a higher number of different products than non-users. CONCLUSIONS: Information requirements were primarily detected for products without clearly proven benefits or for supplements which are advertised to relieve certain diseases or symptoms although the product characteristics do not support such utilization. The frequency of use of dietary supplements among patients which already receive multiple medications substantiates the necessity to include dietary supplements in assessments of drug interactions and to scrutinize indications for supplement use.

[Benefits and risks of current pharmacotherapy in the treatment of type 2 diabetes]. / Nutzen und Risiken der modernen Pharmakotherapie des Typ-2-Diabetes.

The development of new drugs for the treatment of type 2 diabetes (T2DM) and metabolic disorders is currently one of the most innovative areas of drug development. However, a considerable number of newly developed drugs have either not reached the market and were stopped late in development or have been withdrawn after initial approval soon after market authorization due to serious safety concerns. How can drug safety problems be anticipated and, even more important, how can adverse events definitely caused by a drug be differentiated from incidences of naturally occurring diseases? This review article will provide an update about the state of the art treatment of type 2 diabetes and reflect on the newest available study evidence on glitazones, incretin mimetics (GLP-1 agonists and DPP-4 inhibitors), SGLT-2 inhibitors (gliflocines) and pan-PPAR agonists (glitazars). Furthermore, new and still experimental approaches for the treatment of T2DM, such as bardoxolone, salsalate and anakinra will be briefly reviewed.

[Immunoglobulins in PID, SID and neurological autoimmune disease]. / Anwendung von Immunglobulinen bei primären und sekundären Immundefekten und neurologischen Autoimmunerkrankungen.

Human immunoglobulins (IG, mostly IgG) are used as replacement therapy in patients with inherited primary immunodeficiencies, and in patients with secondary immuno-deficiencies often observed in multiple myeloma or chronic lymphocytic leukemia. Ig are also approved as immunomodulatory therapy in neurological autoimmune diseases (NAID) such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). 16 different Ig preparations for intravenous and subcutaneous use are at the moment available in Germany. The SIGNS study (Assessment of immunoglobulins in a long-term non-interventional study) investigates the clinical use of these drugs under clinical practice conditions. In this non-interventional prospective open-label cohort study, 550 patients with new or maintenance Ig therapy are observed with respect to drug utilization, effectiveness, (i. e. number of infections in PID and SID, functionality in NAID), tolerability, quality of life and costs in approximately 50 sites throughout Germany (neurologists, pediatricians, oncologists, other) for at least two years. This largest study of its kind is expected to contribute to optimization of Ig therapy in the postmarketing setting.

Tobacco use among medical students in Europe: results of a multicentre study using the Global Health Professions Student Survey.

OBJECTIVE: To examine smoking prevalence, knowledge and attitudes, and tobacco cessation training among university students attending European medical schools using the Global Health Professional Students Survey approach. METHODS: A cross-country, cross-sectional study was performed among 12 medical schools in four countries in Europe (Germany, Italy, Poland and Spain). The survey was performed during the second semester of the third year of study from March to May 2009. RESULTS: In total, 2249 subjects entered the study (overall response rate 92%). The overall prevalence of smoking among medical students was 29.3% (95% confidence interval 28.1-34.7), with percentages ranging from 28% in Germany to 31.3% in Italy. This study found that more than two-thirds of medical students believe that health professionals are role models for patients, with different beliefs in Poland (89.6%) and Germany (77.7%) vs Italy and Spain (57.2% and 54.4%, respectively) (P < 0.001). Smoking cessation training at medical school was only reported by 16.5% of students (lowest proportion in Italy, 3.5%) (P < 0.001). In terms of smoking cessation methods, the vast majority (89.8%) of medical students were aware of nicotine patches and gum (highest prevalence in Spain, 96.3%), and 24.4% were aware of the use of antidepressants (highest prevalence in Germany, 33.6%). CONCLUSION: This European survey found that the prevalence of smoking was higher among medical students than the general population. There is a strong need to provide medical students with training in smoking cessation techniques.

Distribution of metoprolol in human autopsy material.

In forensic medicine autopsy material is primarily investigated to find out the cause of death. But the results of corresponding toxicology measurements often involve more information. With screening methods drugs were detected not being related to the cause of death. Liquid/liquid extraction and LC/MS/MS methods were used for the determination of drug concentrations. In seven cases metoprolol could be determined in different autopsy materials. In all cases the dosage of the drug was unknown. In cases with oral application probably the patients took a normal customary continuous dosage. Intoxication with metoprolol could be excluded in all cases. The concentrations of metoprolol in blood were all in the therapeutic range. The time between oral intake and death was unknown. Therefore and because of the low number of cases statistic calculations were not meaningful and an individual case study was necessary. In three cases the highest concentration of metoprolol was found in the liver. Probably, metoprolol was taken shortly before the person died. In the other cases the highest concentration of metoprolol was found in urine. This means the elimination process of the drug predominated at the time of death. In all cases the concentrations of metoprolol were similar in the compartments heart blood, venous blood and brain. In this study it was possible to measure the distribution of metoprolol in human directly in several compartments. Measurement of drug concentrations in human autopsy material deepen the knowledge of its pharmacokinetics.

Distribution of metoprolol, tramadol, and midazolam in human autopsy material.

In this study it was possible to measure the distribution of metoprolol, tramadol, and midazolam in human directly in several compartments. In the legal medicine autopsy material is normally investigated to find out the cause of death. But the results of corresponding toxicology measurements often involve more information. With screening methods drugs were detected without connection to the cause of death. The deceased had either a continual therapeutic treatment, a treatment during an operation, or an unsuccessful urgent therapy. A liquid/liquid extraction and a LC/MS/MS method were developed for the determination of the drug concentrations. Different autopsy materials of about 120 cases were investigated. Most frequently the drugs metoprolol, tramadol, and midazolam could be proved and determined simultaneously. Metoprolol was found in seven cases, tramadol in seven cases and midazolam in thirteen cases. The dosage of the drugs was unknown. Therefore and because of the low number of cases statistic calculations were not meaningful and an individual case study was necessary. In all cases with oral metoprolol application the patients probably took a normal customary continuous dosage. The concentrations of tramadol in blood were in the toxic range in three cases. The distribution of tramadol in the compartments was independent of the dosage. The time between oral intake of metoprolol or tramadol and death was unknown. With the distribution pattern of metoprolol in the compartments it was possible to estimate the duration between drug intake and death. In most cases midazolam was given intravenously during an operation or an unsuccessful urgent therapy. Sometimes the time between dosage and death was documented. The duration between application of the drug and death played the crucial role for the distribution of midazolam in the compartments. Measurements of drug concentrations in human autopsy material deepen the knowledge of the respective drugs' pharmacokinetics.

[Urinary bladder tuberculosis and bacillus calmette-guérin instillation: reduced efficacy of bisoprolol in hypertension]. / Tuberkulose durch Bacillus-Calmette-Guérin-Instillation bei Blasenkarzinom und Hypertonie.

HISTORY AND ADMISSION FINDINGS: A 71-year-old patient with a superficial carcinoma of the urinary bladder and high risk of recurrence was treated with intravesical instillation of Bacillus Calmette-Guérin (BCG) after transurethral resection. As a complication of the catheterization during BCG-instillation therapy the patient suffered from tuberculosis. The patient received a tuberculosis triple-therapy including rifampicin 600 mg once daily, isoniazid 300 mg once daily and ethambutol 400 mg thrice daily. The existing arterial hypertension had successfully been controlled by 3.75 mg bisoprolol medication once daily for the last 15  years. An increase of blood pressure and cardiac arrhythmia were seen after combining the ß (1)-receptor blocker treatment with the triple-therapy. INVESTIGATIONS AND DIAGNOSIS: The blood pressure was 160 / 90 mmHg. The heart rate reflected a value of 98  beats per minute. In the resting ECG monotopic ventricular extrasystoles could be diagnosed. TREATMENT AND COURSE: The dosage of bisoprolol was changed to 3.75 mg in the morning and additional 1.875 mg in the evening. Due to this increase of dosage the blood pressure could be controlled sufficiently. CONCLUSION: Rifampicin is one of the best known potent enzyme inducing drugs. It strongly induces the expression of cytochrome P450 3A4 in the liver. The enzyme induction enhance the hepatic bisoprolol metabolism, hence the metabolic clearance of the drug increased. The maximal plasma level of bisoprolol decrease and in our use the arterial hypertension could not be treated sufficiently. It is well known that half the dose of bisoprolol undergoes oxidative metabolism in the liver and the rest eliminated unchanged in the kidney. A dosage adjustment of bisoprolol is necessary if the clinical status of the patient requires treatment with the antituberculosis drug rifampicin.

[Urinary bladder tuberculosis and Bacillus Calmette-Guérin instillation: reduced efficacy of bisoprolol in hypertension]. / Tuberkulose durch Bacillus-Calmette-Guérin-Instillation bei Blasenkarzinom und Hypertonie: Verminderte Bisoprolol-Wirkung durch Rifampicin.

HISTORY AND ADMISSION FINDINGS: A 71-year-old patient with a superficial carcinoma of the urinary bladder and high risk of recurrence was treated with intravesical instillation of Bacillus Calmette-Guérin (BCG) after transurethral resection. As a complication of the catheterization during BCG-instillation therapy the patient suffered from tuberculosis. The patient received a tuberculosis triple-therapy including rifampicin 600 mg once daily, isoniazid 300 mg once daily and ethambutol 400 mg thrice daily. The existing arterial hypertension had successfully been controlled by 3.75 mg bisoprolol medication once daily for the last 15 years. An increase of blood pressure and cardiac arrhythmia were seen after combining the ß1-receptor blocker treatment with the triple-therapy. INVESTIGATIONS AND DIAGNOSIS: The blood pressure was 160/90 mm Hg. The heart rate reflected a value of 98 beats per minute. In the resting ECG monotopic ventricular extrasystoles could be diagnosed. TREATMENT AND COURSE: The dosage of bisoprolol was changed to 3.75 mg in the morning and additional 1.875 mg in the evening. Due to this increase of dosage the blood pressure could be controlled sufficiently. CONCLUSION: Rifampicin is one of the best known potent enzyme inducing drugs. It strongly induces the expression of cytochrome P450 3A4 in the liver. The enzyme induction enhance the hepatic bisoprolol metabolism, hence the metabolic clearance of the drug increased. The maximal plasma level of bisoprolol decrease and in our use the arterial hypertension could not be treated sufficiently. It is well known that half the dose of bisoprolol undergoes oxidative metabolism in the liver and the rest eliminated unchanged in the kidney. A dosage adjustment of bisoprolol is necessary if the clinical status of the patient requires treatment with the antituberculosis drug rifampicin.