Pharmacokinetics of terodiline and a major metabolite in dogs with a correlation to a pharmacodynamic effect

The pharmacokinetics and pharmacodynamics of the anticholinergic and calcium antagonistic drug terodiline, N-tert-butyl-1-methyl-3,3-diphenylpropylamine, have been studied in beagle dogs. The bioavailability was about 25% (0.15 and 0.5 mg/kg), the terminal half-life 3 hr, the systemic clearance 40 ml/min..kg, the volume of distribution (V beta) about 7 l/kg and the unbound fraction in serum 0.14. p-Hydroxyterodiline and p-hydroxy-m-methoxyterodiline were quantitated and constituted 15-40% and 25%, respectively, of the amount excreted in urine (about 60% of the dose) and were the main metabolites, as in man. The dog was used as an experimental model to study the chronotropic effect. An increased heart rate was observed after acute administration of high doses of terodiline as well as after p-hydroxyterodiline. A 20% increase in heart rate was observed at a mean serum concentration of 1086 and 1010 micrograms/l following intravenous injection of terodiline or p-hydroxyterodiline, respectively. The corresponding unbound concentrations were 150 and 474 micrograms/l. The potency ratios of terodiline/p-hydroxyterodiline was 0.9 +/- 0.2 (based on total concentrations) and 3.2 +/- 0.8 (based on unbound concentrations). The estimated potency of parent drug and main metabolite and the fact that p-hydroxyterodiline constitutes 10-20% of the terodiline steady-state level in man, indicate that the contribution of the metabolite to the chronotropic effect observed in clinical studies is minor.     

Synthesis and alpha-adrenolytic activities of 2-(1,4-benzodioxan-2-yl- methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives

The synthesis of the title compounds starting from 2-Chlormethylbenzdioxan and Tetrahydroisochinolines is presented. Their actions on the platelet aggregation and the inhibition of alpha-adrenoceptors at the isolated rabbit aorta and the vas deferens of the guinea pig were investigated.     

18F-FDG PET for detecting myocardial viability: validation of 3D data acquisition.

(18)F-FDG PET is an important diagnostic tool for detecting myocardial viability in patients with coronary artery disease. In combination with perfusion scanning, (18)F-FDG PET allows differentiation between reversibly and irreversibly damaged myocardium and selection of patients likely to benefit from revascularization. Viability PET is usually performed in two-dimensional (2D) mode. Taking into account the rising number of three-dimensional (3D)-only scanners, a validation of 3D acquisition is required. METHODS: Twenty-one patients with coronary artery disease referred for (18)F-FDG PET underwent an imaging protocol of nongated 2D (2D-NG) and gated 2D (2D-G) acquisitions for 15 min each, followed by 3D gated acquisitions for 10 min (3D-10) and 5 min (3D-5), using an ECAT Exact HR+ scanner. Results were analyzed using a 20-segment polar map in terms of activity concentration (Bq/mL), viability (50% uptake threshold), regional activity distribution, visual assessment of viability based on a 3-point rating scale, and left ventricular ejection fraction. RESULTS: Activity concentration measured in each segment with 2D-G, 3D-10, and 3D-5 showed a good linear correlation with 2D-NG. Quantitative viability assessment with 3D-5 gave a sensitivity of 84% and a specificity of 98%, compared with 2D-NG. No differences in regional activity distribution and visual viability assessment were found between the various protocols. Left ventricular ejection fractions obtained with 3D-10 and 3D-5 showed a good linear correlation with those measured with 2D-G. CONCLUSION: An ECG-gated 3D imaging protocol gave results comparable to those of 2D acquisition with regard to absolute and regional myocardial activity distribution, left ventricular function, and visual viability assessment. Sensitivity for viability assessment with a 50% uptake threshold was significantly less with 3D, but specificity was maintained. This protocol delivers a clinical performance nearly equivalent to that of 2D acquisition.     

Nationales Reanimationsregister

Within the scope of the symposium “Rescue Medicine in Germany” (held at the Reisensburg near Ulm in 2002), the need for a standardized data acquisition set for prehospital cardiac arrest patients was identified. Therefore, the working group “Emergency Medicine” of the German Society of Anesthesiology and Intensive Care Medicine (DGAI) created a nationwide data acquisition system for primary medical care in prehospital cardiac arrest patients treated with cardiopulmonary resuscitation procedures. The system is in full accordance with the “Utstein style.” Integration of this data acquisition system, for example into the “Dortmund protocol,” is providing a standardized data web base of all acquired prehospital data analyze and to compare processing and structural quality. As additional modules for this nationwide data web base system, an inhospital module “further clinical treatment” and a “long-term follow-up” module are currently in the developmental process.     

Ziegenpeter

Ohne Zusammenfassung     

Tissue engineering of bone for mandibular augmentation in immunocompetent minipigs: preliminary study.

Large mandibular defects caused by trauma, infection or resection of a tumour are still a major problem for plastic and maxillofacial surgeons. The modern concept of tissue engineering combines the osteoinductive effects of osteogenic cells with a suitable scaffold structure to promote differentiation of osteoblasts and optimal matrix production. Critical size mandibular bone defects were therefore made to investigate the osteogenic potential of periosteal cells and a bioabsorbable polymer fleece (Ethisorb 510) in minipigs. Periosteal cells were isolated from four minipigs, expanded in vitro and seeded with fibrin glue into Ethisorb 510 fleeces. Tissue constructs were used to repair critical size mandibular defects and compared with two minipigs with untreated bone defects. Bone healing was evaluated after 90 and 180 days by radiographs and a histological scoring system. The radiographs showed increased radiodensity of defects filled with the cell-fibrin-fleece-constructs compared with the untreated control group after 90 and 180 days in vivo. The defects repaired by the cell-fibrin-scaffolds (180 days in vivo) obtained the highest histological mean score 2.9 (range 2-3), while defects filled by cell-fibrin-scaffolds (90 days in vivo) achieved a mean score of 2.1 (range 2-3). In contrast, the control group (n = 2) scored 1 and 2. The results show that a combination of periosteal cells and polymer fleeces may be a promising approach for clinical mandibular augmentation.     

Psychiatrische Notfälle

Pre-clinical psychiatric emergency situations (PES) have been identified to be the third major reason for emergency physician (EP) calls with a frequency of approximately 10%. Until now, there are no investigations about regional differences between urban and rural regions in frequencies, diagnoses, or treatment necessities of PES. A retrospective analysis of all anonymised EP protocols of one year in a metropolitan (Hamburg) and a rural region (Schaumburg County) was performed with the same methodological approach. In both regions, the frequency of PES was revealed to be near 10%. Gender and age of psychiatric patients as well as reasons for calls were comparable. In Schaumburg County, much less disturbances due to illegal drugs were observed. However, more patients had to be treated because of suicide attempts and alcoholism. All in all, disturbances seemed less life-threatening than in the metropolitan region. In conclusion, frequency and kind of PES do not differ substantially between rural and urban regions. Considering the prevalence of PES, the particularities in diagnosis and treatment and the dissipation of institutionalised psychiatric care mainly in rural regions, more training in psychiatric subjects is needed.     

Biotransformation of the trapidil (rocornal) derivative AR 12463 in the rat

After p.o. administration of 5-piperidino-7-[N-pentyl-N-(beta- hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine (1; AR 12463) more than 15 metabolites were isolated from urine and feces of male Wistar rats. Only small amounts of unchanged 1 were observed. The structure of 12 metabolites was elucidated or proposed on the basis of UV-, 13C NMR- and mass spectra. Main metabolites are 5-piperidin-4'-olyl-7-[N-pentyl-N-(beta- hydroxyethyl)]amino-s-triazolo[1,5-a]pyrimidine and 5-piperidin-4'-olyl-7-[N-pent-4-olyl-N-(beta-hydroxyet hyl)]amino-s- triazolo[1,5-a]pyrimidine. The other metabolites are mainly hydroxy- or ketopentyl derivatives and piperidinoles or piperidinones, respectively. Conjugates of most of the metabolites were identified, but the ratio phase-I/II metabolites was about 3:1. In contrast to trapidil, 5-methyl-7-diethylamino-s- triazolo[1,5-a]pyrimidine, no hydroxy derivatives of the bicyclic system were observed. The major part of unchanged 1 and metabolites is excreted via kidneys.     

Attempt of preventive treatment of striae gravidarum using preventive massage ointment administration]

Striae distensae are an appreciable cosmetic problem for many pregnant women. Preventive application of a water/oil massage cream was tested in a group of 24 gravidae (control group: 26 patients). In the untreated control group striae distensae were observed in two-thirds of the patients, whereas the prophylactically-treated gravidae showed development of striae in only one third of the group given the test preparation. Better results were obtained in women with a favourable constitutional predisposition than in patients with a tendency to overweight. The massage cream was well tolerated by all gravidae.