Microwave-assisted one-pot synthesis of new ionic iridium complexes of [Ir(bzq)2(N

Iridium C,N-cyclometalated complexes with an ionic structure are considered to be promising candidates for application in host/guest solid-state phosphorescent single-layer devices because the employment of such dopants offers the possibility of reducing their concentration in organic matrices as well as allows obtaining organic light emitting devices (OLEDs) with interesting emission parameters. We report herein a methodology enabling the synthesis of cyclometalated ionic iridium(iii) complexes of the type [Ir(C^N)2(N^N)]+A- according to a three-component one-pot strategy involving the acceleration of the reaction via microwave irradiation. The developed protocol allowed efficient synthesis of a series of new cationic iridium(iii) coordination derivatives, which were isolated and spectroscopically characterized, while the structures of two of them were determined by the X-ray method. Moreover, the iridium(iii) derivatives were subjected to the cyclic voltammetry studies in order to determine the energies of the HOMO and LUMO levels as well as to estimate their electrochemical properties and to predict some electronic properties. Additionally, the ONIOM calculation scheme that was used to predict HOMO-LUMO gaps for the studied Ir(iii) complexes showed a good correlation between the experimental and calculated values. In order to determine the influence of the structure and nature of the ancillary ligand on the location of the maximum emission band, the photophysical properties of the synthesized iridium complexes were characterized. Finally, the selected compounds were used as emitters for the construction of polymer light emitting diodes (PLEDs) based on a poly(N-vinylcarbazole)/2-(4-tert-butylphenyl)-5-(4-biphenyl)-1,3,4-oxadiazole (PVK/PBD) matrix. The highest luminance, above 10 000 cd m-2, was recorded for the device containing only 1.0 wt% of [Ir(bzq)2(1,10-phenanthroline)]+PF6- in the PVK/PBD. The fabricated PLEDs exhibit current efficiency in the range of 1.0 to 2.2 cd A-1.

Adjuvant sequential chemoradiation therapy in high-risk endometrial cancer: results of a prospective, multicenter phase-II study of the NOGGO (North-Eastern German Society of Gynaecological Oncology).

PURPOSE: The management of high-risk endometrial cancer (HREC) remains controversial. We conducted a prospective multicenter phase-II clinical trial to evaluate an adjuvant chemotherapy (CT) with sequential radiotherapy (RT) in patients with HREC. METHODS: Patients with HREC from 8 institutions in Germany were enrolled. After surgery, patients received four cycles of paclitaxel 175 mg/m² (P) and carboplatin AUC5 (C) (d1, q21d) and subsequent external pelvic radiation therapy (1.8 Gy/d, d1-5) at a total dose of 45 Gy with vaginal brachytherapy (3 × 5 Gy). Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire. Primary endpoints were tolerability, toxicity and QoL. Progression-free survival (PFS) was defined as secondary endpoint. RESULTS: Thirty-five patients were enrolled from 2004 through 2008. Median follow-up was 24 months (range 3-24 months). All patients received 4 cycles of P and C and completed RT. Overall, grade 3/4 haematological toxicity was 25.6 %. Three cycles were delayed because of leukopenia. Grade 3/4 non-haematologic toxicities were rare (≤3 %). No overall change in QoL occurred during treatment. Two-year median PFS and OS rates were both 75.8 %. CONCLUSIONS: Adjuvant combination CT with P + C and sequential RT is well tolerated and a feasible regimen in patients with HREC. Subsequent phase-III trials are warranted.

A phase II study of topotecan plus gemcitabine in the treatment of patients with relapsed ovarian cancer after failure of first-line chemotherapy.

BACKGROUND: Second-line chemotherapy for patients with ovarian cancer who failed platinum and paclitaxel treatment remains a therapeutic challenge. We investigated the toxicity profile and therapeutic efficacy of a novel combination regimen, topotecan plus gemcitabine, in a clinical phase II study. PATIENTS AND METHODS: Women with relapsed epithelial ovarian cancer after platinum and paclitaxel treatment were eligible to participate in this trial. Topotecan was given at an initial dose of 0.5 mg/m(2) daily (days 1-5), combined with gemcitabine 800 mg/m(2) and 600 mg/m(2) on days 1 and 8, respectively. Precluding good tolerability, this protocol facilitated subsequent dose increases of topotecan up to 1.0 mg/m(2). The primary objective was to determine the dose-limiting toxicity, whereas secondary objectives comprised measurable and CA-125 response rates, disease-free and overall survival. RESULTS: The twenty-one patients (median age 57 years, range 37-70 years) who were allocated to this trial received a total of 94 courses of chemotherapy. Median follow-up was 20.5 months. Topotecan dosage could be escalated to 0.75 mg/m(2) in nine patients and 1 mg/m(2) in another two patients. Dose reduction was not necessary in any case. There were no episodes of neutropenic fever, sepsis or chemotherapy-related fatalities. Only one patient developed CTC grade 4 leukopenia after the first treatment cycle, whereas three patients showed grade 3/4 anaemia. Five patients experienced thrombocytopenia grade 4 without clinical sequelae. Non-hematological toxicities were mild and rare. Eleven patients could be evaluated for clinical tumour response, with three complete, and four partial remissions. Two patients each had stable and progressive diseases. The median progression-free survival rate was 8.8 months [95% confidence interval (CI) 6.3-13.4 months]. The median overall survival rate was 21.1 months (95% CI 14.8-22.1 months). CONCLUSIONS: Topotecan combined with gemcitabine has a favourable toxicity profile and encouraging efficacy in patients with recurrent ovarian cancer.

Evidence that desensitization of the negative feedback of oestrogen and priming for the positive feedback of oestrogen depend upon a common mechanism of oestrogen action in rats.

Oestrogen priming of the central nervous system is required for the positive feedback of oestrogen, and the sensitivity of the negative feedback of oestrogen can be reduced by oestrogen itself. Using adult female and male rats we examined the possibility that these effects depend upon a common mechanism of oestrogen action that is mediated by the medial preoptic area (MPOA). Guide cannulae were implanted in the MPOA of 4-day cyclic rats which were ovariectomized during the evening of day 1 of dioestrus. Glass capillary tubes containing different substances were placed in the cannulae between 09.00 and 12.00 h on the presumptive day 2 of dioestrus. The effectiveness of oestrogen priming was evaluated by examining whether an s.c. implant of oestradiol-17 beta (OE2) induced an LH surge, and the inhibitory effect of oestrogen on tonic LH secretion was investigated by injecting the rats with 3 micrograms oestradiol benzoate (OB)/100 g body weight. The priming effect of an s.c. implant of OE2 could be imitated by the bilateral implantation in the MPOA of a mixture of OB and cholesterol at a ratio of 1:360 for 3 h only. Similar medial preoptic oestrogen implantation also significantly reduced the LH-inhibiting effect of OB. In accord with findings obtained in former studies on desensitization of the negative oestrogen feedback, oestrogen priming resulting from the s.c. administration of OE2 could be suppressed by short-term medial preoptic implantation of clomiphene citrate or apomorphine; bilateral electrical stimulation of the medial amygdaloid nucleus induced an increase in the serum concentration of LH in ovariectomized females implanted with OB in the MPOA, but not in castrated males pretreated and implanted with OB.(ABSTRACT TRUNCATED AT 250 WORDS)

Oestrogen priming for the positive oestrogen feedback: site of action.

The significance of oestrogen priming for efficacy of the positive, ovulation-inducing oestrogen feedback has been known for more than 15 years, but the site and mechanism of oestrogen action in the priming effect have not yet been elucidated. Long-term ovariectomized adult female rats were injected once or twice with 20 micrograms oestradiol benzoate (OB), and the serum LH concentration was estimated. Whereas a single injection of OB induced significant inhibition of LH secretion, high circulating LH levels were recorded in rats injected twice with the hormone at an interval of 48 h. This increase was prevented in ovariectomized females fitted with guide cannulae, if the antioestrogen clomiphene citrate was implanted into the medial preoptic area (MPOA) before the first injection of oestrogen and removed prior to the second. On the other hand, replacement of the first oestrogen administration by the implantation of a very low dose of OB into the MPOA resulted in stimulation of LH secretion. OB implants placed into the hypothalamic ventromedial-arcuate region were ineffective in this regard. Taken together, the findings suggest that the priming effect of oestrogen is mediated in rats, at least in part, by the MPOA.