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51.
Rolf W. Hartmann Martin Frotscher Dorothea Ledergerber Gerald A. Wchter Gertrud L. Grün Tom F. Sergejew 《Archiv der Pharmazie》1996,329(5):251-261
In search of potential drugs for the treatment of estrogen- and androgen-dependent cancer as well as the prophylaxis of metastases, tetralones, tetralins, and dihydronaphthalenes bearing a OCH3 substituent at the benzene nucleus and an imidazol-4-yl, imidazol-1-yl, or 1,2,4-triazol-1-yl substituent in 2-position were synthesized with and without C1-spacer between the rings (compounds 2 – 26 ). The compounds were tested in vitro for inhibition of the three target enzymes P450 arom (human placental microsomes), P450 17 (rat testicular microsomes), and P450 TxA2 (citrated human whole blood). To examine selectivity, some compounds were further tested in vitro for inhibition of P450 18 (bovine adrenal mitochondria), P450 see (bovine adrenal mitochondria) and corticoid formation (aldosterone, corticosterone; ACTH stimulated rat adrenal tissue). In vivo, selected compounds were examined in Sprague Dawley rats regarding P450 TxA2 inhibition, reduction of plasma testosterone concentration, antiuterotrophic activity (inhibition of the uterotrophic activity of androstenedione), reduction of plasma estradiol concentration (pregnant mares' serum gonadotropin-primed rats), and mammary tumor inhibiting activity (dimethylbenzanthracene-induced tumor; pre- and postmenopausal model). In the series of imidazol-4-yl compounds, which represent a novelty in the field of azole inhibitors of steroidogenic P450 enzymes, strong inhibitors of P450 arom and/or P450 17 were found: 7-OCH3-2-(imidazol-4-ylmethylene)-1-tetralone ( 4 ) and 7-OCH3-2-(imidazol-4-ylmethyl)-tetralin ( 12 ) are among the most potent inhibitors of P450 arom in vitro known so far. Compound 4 is a selective inhibitor, whereas 12 shows in addition strong inhibition of P450 17. In contrast to 12 , the 6-OCH3 derivative (compound 11 ) is a selective inhibitor of P450 17, being 50 times more potent than ketoconazole. Some imidazol-1-yl compounds show a marked inhibition of P450 TxA2: 2-(imidazol-1-ylmethyl)-1-tetralone ( 13 ) is a selective inhibitor of P450 TxA2, whereas 7-OCH3-2-(imidazol-1-ylmethyl)-tetralin ( 17 ) as well as 2-(imidazol-1-ylmethyl)-tetralin ( 16 ) and 7-OCH3-2-imidazol-1-yl-3,4-dihydronaphthalene ( 25 ) additionally show strong inhibition of P450 arom and P450 17. Regarding the other steroidogenic P450 enzymes as well as corticosterone formation, the compounds show only little inhibitory activity. Aldosterone formation, however, is inhibited at low concentrations. Nevertheless, 4 and 12 are more selective, i.e. inhibit aldosterone synthesis less than the well known inhibitor of P450 arom fadrozole. The compounds show activity in the aforementioned in vivo tests. 相似文献
52.
Andrea von Berg Renate Engelstätter Predrag Minic Miodrag Sréckovic Maria Luz Garcia Garcia Tadeusz Lato Jan H. Vermeulen Stefan Leichtl Stefan Hellbardt Thomas D. Bethke 《Pediatric allergy and immunology》2007,18(5):391-400
Ciclesonide is an onsite-activated inhaled corticosteroid (ICS) for the treatment of asthma. This study compared the efficacy, safety and effect on quality of life (QOL) of ciclesonide 160 microg (ex-actuator; nominal dose 200 microg) vs. budesonide 400 microg (nominal dose) in children with asthma. Six hundred and twenty-one children (aged 6-11 yr) with asthma were randomized to receive ciclesonide 160 microg (ex-actuator) once daily (via hydrofluoroalkane metered-dose inhaler and AeroChamber Plus spacer) or budesonide 400 microg once daily (via Turbohaler) both given in the evening for 12 wk. The primary efficacy end-point was change in forced expiratory volume in 1 s (FEV1). Additional measurements included change in daily peak expiratory flow (PEF), change in asthma symptom score sum, change in use of rescue medication, paediatric and caregiver asthma QOL questionnaire [PAQLQ(S) and PACQLQ, respectively] scores, change in body height assessed by stadiometry, change in 24-h urinary cortisol adjusted for creatinine and adverse events. Both ciclesonide and budesonide increased FEV1, morning PEF and PAQLQ(S) and PACQLQ scores, and improved asthma symptom score sums and the need for rescue medication after 12 wk vs. baseline. The non-inferiority of ciclesonide vs. budesonide was demonstrated for the change in FEV1 (95% confidence interval: -75, 10 ml, p = 0.0009, one-sided non-inferiority, per-protocol). In addition, ciclesonide and budesonide showed similar efficacy in improving asthma symptoms, morning PEF, use of rescue medication and QOL. Ciclesonide was superior to budesonide with regard to increases in body height (p = 0.003, two-sided). The effect on the hypothalamic-pituitary-adrenal axis was significantly different in favor of ciclesonide treatment (p < 0.001, one-sided). Both ciclesonide and budesonide were well tolerated. Ciclesonide 160 microg once daily and budesonide 400 microg once daily were effective in children with asthma. In addition, in children treated with ciclesonide there was significantly less reduction in body height and suppression of 24-h urinary cortisol excretion compared with children treated with budesonide after 12 wk. 相似文献
53.
Abstract Kyphoplasty and vertebroplasty have become recognized procedures for the treatment of vertebral fractures, especially in patients
with osteoporosis. In most cases of osteoporotic spinal vertebral fracture in elderly patients, polymethylmethacrylate (PMMA)
cement is used to fill the defect and stabilize the vertebral body. The techniques of vertebroplasty and kyphoplasty differ
in the possibility of realignment and reconstruction of the vertebral body and spinal column. Long-term results in terms of
integration of the cement and bioreactivity of the vertebral body are still lacking; so, these procedures are still no options
in the treatment of younger patients. Vertebroplasty and kyphoplasty show different success in the management of fresh traumatic
spine fractures. The acute traumatic vertebral fracture has to be classified sensitively, to find the right indication for
cement augmentation. Mild acute compression fractures can be treated by vertebroplasty or kyphoplasty, severe compression
and burst fractures by combination of internal fixation and kyphoplasty. The indications for use of biological or osteoinductive
cement in spinal fracture management must still be regarded as restricted owing to the lack of basic biomechanical research
data. Such cement should not be used except in clinical studies. 相似文献
54.
55.
Stefan Whrl Robert Loewe Winfried F. Pickl Georg Stingl Stephan N. Wagner 《Journal der Deutschen Dermatologischen Gesellschaft》2005,3(1):39-43
Background: Seizure prophylaxis with phenytoin is a common measure in oncologic patients with brain metastases. In these patients, generalized severe adverse drug reactions such as erythema multiforme (EEM) may occur. However, in a subgroup of patients with brain radiation therapy, EEM‐like lesions develop particularly in the radiation field. Most recently, the acronym EMPACT ( E rythema M ultiforme associated with P henytoin A nd C ranial radiation T herapy) was proposed to specifically describe this syndrome. Patient/Method: Here, we report on EMPACT syndrome in a 46‐year‐old woman. Therapeutic measures included seizure prophylaxis with phenytoin and total brain radiation therapy of brain metastases from bronchial carcinoma. Three weeks after introduction of phenytoin, the patient presented with EEM‐like skin lesions restricted to the original radiation field and facial mucocutaneous involvement. After a few days, the rash spread to the upper part of the body. She was also in poor general condition. Results: The immediate cessation of phenytoin therapy, combined with administration of systemic corticosteroids and high dose immunoglobulins along with intensive local treatment and pain medications, resulted in complete resolution of the skin eruption. Patch testing to phenytoin was positive after 72 hours. Conclusion: EMPACT should be classified as an specific entity among the EEM‐like drug reactions as it only appears after radiotherapy and seizure prophylaxis with the anticonvulsant phenytoin. We propose including specific type IV‐sensitization to phenytoin into the definition of EMPACT. 相似文献
56.
Falk Wehrhan Gerhard G. Grabenbauer Franz Rödel Kerstin Amann PD Stefan Schultze-Mosgau MD DMD PhD 《Strahlentherapie und Onkologie》2004,180(8):526-533
BACKGROUND AND PURPOSE: Following preoperative radiotherapy prior to ablative surgery of squamous epithelial cell carcinomas of the head and neck region, wound-healing disorders occur. Previous experimental studies showed altered expression of transforming growth factor-(TGF-)beta isoforms following surgery in irradiated graft beds. Altered levels of TGF-beta(1) are reported to promote fibrosis and to suppress vascularization during wound healing, whereas expression of TGF-beta receptor-III (TGF-betaR-III) is associated with vascularization. The aim of the study was to analyze the influence of anti-TGF-beta(1) treatment on TGF-betaR-III-associated vascularization in the transition area between irradiated graft bed and graft. MATERIAL AND METHODS: Wistar rats (male, weight 300-500 g) underwent preoperative irradiation of the head and neck region with 40 Gy (four fractions of 10 Gy each; n = 16 animals). A free myocutaneous gracilis flap taken from the groin was then transplanted to the neck in all rats. The time interval between operation and transplantation was 4 weeks. Eight animals received 1 micro g anti-TGF-beta(1) into the graft bed by intradermal injection on days 1-7 after surgery. On days 3, 7, 14, 28, 56, and 120, skin samples were taken from the transition area between transplant and graft bed and from the graft bed itself. Immunohistochemistry was performed using the ABC-POX method to analyze the TGF-betaR-III and E-selectin expression. Histomorphometry was performed to analyze the percentage and the area of positively stained vessels. RESULTS: A significantly higher expression of TGF-betaR-III was seen in the irradiated and anti-TGF-beta(1)-treated graft bed in comparison to the group receiving preoperative irradiation followed by transplantation alone. The percentage of TGF-betaR-III positively staining capillaries from the total amount of capillaries in the anti-TGF-beta(1)-treated graft bed was higher than in the group irradiated only. The total area of capillaries was also higher in the TGF-beta(1)-treated group. CONCLUSION: Neutralizing of TGF-beta(1) activity in irradiated tissue undergoing surgery leads to a higher expression of TGF-betaR-III and increased vascularization. TGF-betaR-III seems to be associated with newly formed blood vessels during neovascularization in wound healing. 相似文献
57.
Differential Stripping: Determination of the Amount of Topically Applied Substances Penetrated into the Hair Follicles
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Alexa Teichmann Ute Jacobi Michael Ossadnik† Heike Richter Stefan Koch† Wolfram Sterry Jürgen Lademann 《Journal of general internal medicine》2005,20(5):264-269
The determination of penetration pathways of topically applied substances into the skin is the subject of several investigations. Recently, follicular penetration has become a major focus of interest. To date, a direct, non-invasive quantification of the amount of topically applied substance penetrated into the follicles had not been possible. The development of such a method was the aim of this study. Therefore, the advantages of both stripping techniques, tape stripping and cyanoacrylate skin surface biopsy, were combined and evaluated. Tape stripping was used to remove the part of the stratum corneum that contained the topically applied dye. Subsequently, the follicular contents were ripped off by cyanoacrylate skin surface biopsy. The combined method termed "differential stripping" was evaluated in vitro and in vivo , and the amount of topically applied fluorescent dye penetrated into the hair follicles was quantified after different penetration times. After 30 min, 5% of the recovered concentration of sodium fluorescein was found in the follicular infundibula, where it was still detectable after 48 h. Altogether, the results of this investigation revealed that differential stripping is a new method that can be used to study the penetration of topically applied substances into the follicular infundibula non-invasively and selectively. 相似文献
58.
Stefan Biedert Ralph Winter Heribert Betz Roland Reuther 《European archives of psychiatry and clinical neuroscience》1986,235(5):315-322
Zusammenfassung Wir berichten fiber die Doppler-sonographischen Ergebnisse bei 33 Patienten mit einer Anastomose zwischen der A. temporalis superficialis and der A. cerebri media. Die Indikation zur Bypass-Operation beinhaltete rezidivierende TIA oder ein kurz zuvor erworbenes leichtes neurologisches Defizit bei angiographischem Nachweis einseitiger oder beidseitiger tiefer Obliterationen der A. carotis interna und hochgradiger Stenosen oder Verschlüsse im distalen Abschnitt der A. carotis interna bzw. im proximalen Abschnitt der A. cerebri media. Die Funktionsfahigkeit der Anastomose wurde überpriift durch die Berechnung der modifizier ten Pourcelot-Indices (relative enddiastolische Strömungsgeschwindigkeit) der A. temporalis superficialis praeauriculär und am Bohrlochrand Bowie durch den EinfluB der intermittierenden Kompression des den Bypass-versorgenden Gefäßes auf den modifizierten Pourcelot-Index der ipsilateralen A. carotis communis. Bei allen Patienten mit funktionsfahigen Anastomosen, definiert durch einen modifizierten Pourcelot-Index von zumindest 0,20 am Bohrlochrand, kam es zu einer Reduktion dieses Parameters um durchschnittlich 0,08 an der A. carotis communis bei kurzfristiger Kompression des den Bypass-versorgenden Astes. Bei den 18 Patienten mit unilateraler Obliteration der A. carotis interna war der Bypass über-wiegend dann funktionsfähig, wenn die summierten modifizierten Pourcelot-Indices der verbliebenen hirnversorgenden Gefäße um zumindest 10% gegenüber einem vergleichbaren Normalkollektiv reduziert waren. Das Vorhandensein bzw. das Fehlen von Ophthalmica-Kollateralen hatte dabei keinen Einfluß auf den Prozentsatz der funktionsfahigen Anastomosen in diesen Untergruppen. Bei den vier Patienten mit bilateraler Obliteration der A. carotis interna war die angelegte Anastomose in jedem Fall funktionsfähig, während die Hälfte der Patienten mit Stenosen and Verschlüssen im distalen Abschnitt der Carotisstrombahn nur eine ungeniigende Bypass-Funktion zeigten. Die zwei Patienten mit einer Mediahauptstammstenose bzw. -obliteration hatten Indices von 0,45 bzw. 0,46 am Bohrlochrand als Hinweis auf die Funktionstüchtigkeit. Wir Bind der Auffassung, daß man mittels Doppler-sonographischer Kriterien die Funktionsfahigkeit einer Temporalis superficialis-Cerebri media-Anastomose überprüfen kann. Der praeoperativ berechnete summierte modifizierte Pourcelot-Index der verbliebenen hirnversorgenden Arterien kann zumindest bei uni- and bilateraler Internaobliteration als zusatzlicher Parameter herangezogen werden, um die Indikation zur Bypass-Operation zu klären. 相似文献
59.
60.
Stefan Beckers Michael Fries Johannes Bickenbach Matthias Derwall Ralf Kuhlen Rolf Rossaint 《Critical care (London, England)》2004,9(2):R110