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991.
G R Cohen W F O'Brien L Lewis R A Knuppel 《American journal of obstetrics and gynecology》1987,157(5):1174-1177
The aggressive management of early labor has been suggested as a means to lower the cesarean section rate for dystocia. The aim of our study was to prospectively evaluate a protocol of early intervention in primigravid women with infrequent uterine contractions during early labor in relation to the course of labor, the cesarean section rate, and the perinatal morbidity. In our population the active management of labor did not alter the mode of delivery or the perinatal outcome. Furthermore, the course and duration of labor were not significantly different between the management and control groups. 相似文献
992.
M. Yudelev A. Kuten M. Tatcher R. Rubinov R. Karmeli Y. Cohen E. Robinson 《Gynecologic oncology》1986,23(3):310-315
Treatment results and side effects were analyzed for 57 patients with stage IB-IIIA cancer of the uterine cervix who received external beam radiotherapy combined with intracavitary insertion of cesium-137 sources. The total dosage and time-dose-fractionation (TDF) factors were calculated at point A and at points of maximum exposure in the rectum and bladder. The overall 5-year survival was 62%, and 78% of the complete responders were free of disease at 5 years. A total of 12 patients (21%) developed rectal complications. Two patients (4%) had rectal fibrosis and proctitis; seven cases of rectal bleeding occurred (12%), and 3 patients (5%) developed rectovaginal fistulas. There was no correlation between dose and TDF at point A and treatment failure or appearance of rectal complications. However, the occurrence of radiation damage in the rectum was consistently associated with high values of TDF when they were calculated in the region of maximal exposure in the rectum. The results suggest that TDF may be a useful parameter for predicting radiation damage in combined external beam and intracavitary treatment of cervical cancer. 相似文献
993.
994.
Holladay JT Piers PA Koranyi G van der Mooren M Norrby NE 《Journal of refractive surgery (Thorofare, N.J. : 1995)》2002,18(6):683-691
PURPOSE: The aim of this study was to design and evaluate in the laboratory a new intraocular lens (IOL) intended to provide superior ocular optical quality by reducing spherical aberration. METHODS: Corneal topography measurements were performed on 71 cataract patients using an Orbscan I. The measured corneal surface shapes were used to determine the wavefront aberration of each cornea. A model cornea was then designed to reproduce the measured average spherical aberration. This model cornea was used to design IOLs having a fixed amount of negative spherical aberration that partially compensates for the average positive spherical aberration of the cornea. Theoretical and physical eye models were used to assess the expected improvement in optical quality of an eye implanted with this lens. RESULTS: Measurements of optical quality provided evidence that if this modified prolate IOL was centered within 0.4 mm and tilted less than 7 degrees, it would exceed the optical performance of a conventional spherical IOL. This improvement occurred without an apparent loss in depth of focus. CONCLUSION: A new IOL with a prolate anterior surface, designed to partially compensate for the average spherical aberration of the cornea, is intended to improve the ocular optical quality of pseudophakic patients. 相似文献
995.
Preclinical and first‐in‐human phase I studies of KW‐2450, an oral tyrosine kinase inhibitor with insulin‐like growth factor receptor‐1/insulin receptor selectivity 下载免费PDF全文
Gary K. Schwartz Mark A. Dickson Patricia M. LoRusso Edward A. Sausville Yoshimi Maekawa Yasuo Watanabe Naomi Kashima Daisuke Nakashima Shiro Akinaga 《Cancer science》2016,107(4):499-506
Numerous solid tumors overexpress or have excessively activated insulin‐like growth factor receptor‐1 (IGF‐1R). We summarize preclinical studies and the first‐in‐human study of KW‐2450, an oral tyrosine kinase inhibitor with IGF‐1R and insulin receptor (IR) inhibitory activity. Preclinical activity of KW‐2450 was evaluated in various in vitro and in vivo models. It was then evaluated in a phase I clinical trial in 13 patients with advanced solid tumors (NCT00921336). In vitro, KW‐2450 inhibited human IGF‐1R and IR kinases (IC50 7.39 and 5.64 nmol/L, respectively) and the growth of various human malignant cell lines. KW‐2450 40 mg/kg showed modest growth inhibitory activity and inhibited IGF‐1‐induced signal transduction in the murine HT‐29/GFP colon carcinoma xenograft model. The maximum tolerated dose of KW‐2450 was 37.5 mg once daily continuously; dose‐limiting toxicity occurred in two of six patients at 50 mg/day (both grade 3 hyperglycemia) and in one of seven patients at 37.5 mg/day (grade 3 rash). Four of 10 evaluable patients showed stable disease. Single‐agent KW‐2450 was associated with modest antitumor activity in heavily pretreated patients with solid tumors and is being further investigated in combination therapy with lapatinib/letrozole in patients with human epidermal growth factor receptor 2‐postive metastatic breast cancer. 相似文献
996.
997.
998.
McCauley TG Kurz JC Merlino PG Lewis SD Gilbert M Epstein DM Marsh HN 《Pharmaceutical research》2006,23(2):303-311
Purpose The aim of the study is to determine the bioactivity and effects of PEGylation on the pharmacokinetics in rabbit aqueous humor
and plasma of an aptamer directed against TGFβ2.
Methods Pharmacological activity of anti-TGFβ2 aptamer in rabbit ocular fluid was demonstrated using a mink lung epithelial cell proliferation
assay. For pharmacokinetic analyses, concentrations of aptamers in plasma and aqueous humor were determined over time following
bilateral subconjunctival administration to Dutch-belted rabbits using a hybridization-based pseudo-enzyme-linked immunosorbent
assay (ELISA) assay.
Results Anti-TGFβ2 aptamer (ARC81) binds to human TGFβ2 with a KD of approximately 5 nM and inhibits the activity of human TGFβ2 in vitro in a cell-based assay with an IC50 of approximately 100 nM. ARC81 blocks endogenously derived TGFβ2 in rabbit aqueous humor in vitro with an IC50 of approximately 200 nM and an IC90 of approximately 1 μM. In vivo in rabbit, ARC81 [no polyethylene glycol (PEG)] entered systemic circulation rapidly (tmax = 1 h in plasma) relative to aptamer conjugates ARC117 (20 kDa PEG) and ARC119 (40 kDa PEG), which showed prolonged residence
in the subconjunctival space and aqueous compartment (tmax = 6 and 12 h, respectively, in plasma). Both 20- and 40-kDa aptamer conjugates reached maximal concentrations (Cmax) in aqueous humor of 23–30 nM and remained at or above 1 nM for as long as 12 h.
Conclusions Pharmacologically active levels of anti-TGFβ2 aptamers can be sustained in the ocular fluid and local tissue environment over
a 12-h period after single administration. Daily subconjunctival administration of PEGylated anti-TGFβ2 aptamers should allow
further pharmacological evaluation of these agents in a rabbit conjunctival scarring model. Perioperative administration,
via subconjunctival injection, may prove to be an effective means to deliver therapeutic quantities of TGFβ2 aptamer conjugates
in trabeculectomy procedures. 相似文献
999.
Shafaee N Houng M Truong A Viseshakul N Figl A Sandhu S Forsayeth JR Dwoskin LP Crooks PA Cohen BN 《British journal of pharmacology》1999,128(6):1291-1299
1 We studied the pharmacological properties of native rat brain and heterologously expressed rat alpha4beta2 nicotinic receptors immunoprecipitated onto a fixed substrate with the anti-alpha4 antibody mAb 299. 2 Immunodepletion with the anti-beta2 antibody mAb 270 showed that 89% of the mAb-299-precipitated rat brain receptors contained beta2. 3 The association and dissociation rate constants for 30 pM +/-[3H]-epibatidine binding to alpha4beta2 receptors expressed in oocytes were 0.02+/-0.01 and 0.03+/-0.01 min-1 (+/-standard error, degrees of freedom=7 - 8) at 20 - 23 degrees C. 4 The Hill coefficients for +/-[3H]epibatidine binding to the native brain, alpha4beta2 receptors expressed in oocytes, and alpha4beta2 receptors expressed in CV-1 cells (using recombinant adenovirus) were 0.69 - 0.70 suggesting a heterogeneous receptor population. Fits of the +/-[3H]-epibatidine concentration-binding data to a two-site model gave KD s of 8 - 30 and 560 - 1,200 pM. The high-affinity sites comprised 73 - 74% of the native brain and oocyte alpha4beta2 receptor population, 85% of the CV-1 alpha4beta2 receptor population. 5 The expression of rat alpha4beta2 receptors in CV-1 cells using vaccinia viral infection-transfection resulted in a more homogeneous receptor population (Hill coefficient of 1. 0+/-0.2). Fits of the +/-[3H]-epibatidine binding data to a single-site model gave a KD of 40+/-3 pM. 6 DHbetaE (IC50=260-470 nM) and the novel nicotine analogue NDNI (IC50=7-10 microM) inhibited 30 pM+/-[3H]-epibatidine binding to the native brain and heterologously expressed alpha4beta2 receptors equally well. 7 The results show that alpha4beta2-containing nicotinic receptors in the rat brain and heterologously expressed rat alpha4beta2 receptors have similar affinities for +/-[3H]-epibatidine, DHbetaE, and NDNI. 相似文献
1000.
Davis AJ Gelmon KA Siu LL Moore MJ Britten CD Mistry N Klamut H D'Aloisio S MacLean M Wainman N Ayers D Firby P Besterman JM Reid GK Eisenhauer EA 《Investigational new drugs》2003,21(1):85-97
Purpose: MG98 is a second generation phosphorothioate antisense oligodeoxynucleotide which is a highly specific inhibitor of translation of the mRNA for human DNA MeTase I (DNMT 1). This phase I study examined the toxicity and pharmacologic profile of MG98 administered as a continuous 21-day intravenous infusion every 4 weeks. Patients and methods: Fourteen patients with solid cancers received a total of 25 cycles of MG98 at doses ranging from 40 to 240 mg/m2/day. Steady-state concentrations of MG98 were measured as were several pharmacodynamic assessments including mRNA of the target gene, DNMT1, in PBMC. In addition, other potential surrogate markers of drug effects were explored, including hemoglobin F, Vimentin and GADD45. Results: Dose limiting effects were drug-related reversible transaminase elevation and fatigue seen at doses of 240, 200 and 160 mg/m2/day. The dose level of 80 mg/m2/day was felt to be safe and tolerable when delivered on this schedule. No evidence of antitumor activity was observed. Although pharmacokinetic analysis revealed that at the higher dose levels, mean Css values of MG98 were approximately 10-fold times the IC50 values associated with target inhibition in vitro, the extent of MG98 penetration into target tumors in this trial was not determined. No consistent, dose-related changes in correlative markers including DNMT1 mRNA, hemoglobin F, Vimentin and GADD45, were observed. Conclusions: This schedule of MG98 given as a 21-day continuous intravenous infusion every 4 weeks was poorly tolerated in the highest doses; therefore, further disease-site specific evaluation of the efficacy of this agent will utilize a more favorable, intermittent dosing schedule. Pharmacodynamic evaluations undertaken in an attempt to explore and validate the biological mechanisms of MG98 did not show dose-related effects. 相似文献