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41.
42.
Wells-Knecht KJ Ott GR Cheng M Wells GJ Breslin HJ Gingrich DE Weinberg L Mesaros EF Huang Z Yazdanian M Ator MA Aimone LD Zeigler K Dorsey BD 《Chemical research in toxicology》2011,24(11):1994-2003
There are numerous published studies establishing a link between reactive metabolite formation and toxicity of various drugs. Although the correlation between idiosyncratic reactions and reactive metabolite formation is not 1:1, the association between the two is such that many pharmaceutical companies now monitor for reactive metabolites as a standard part of drug candidate testing and selection. The most common method involves in vitro human microsomal incubations in the presence of a thiol trapping agent, such as glutathione (GSH), followed by LC/MS analysis. In this study, we describe several 2,7-disubstituted-pyrrolotriazine analogues that are extremely potent reactive metabolite precursors. Utilizing a UPLC/UV/MS method, unprecedented levels of GSH adducts were measured that are 5-10 times higher than previously reported for high reactive metabolite-forming compounds such as clozapine and troglitazone. 相似文献
43.
Giorgio Bolis Giovanna Scarfone Francesco Raspagliesi Giorgia Mangili Saverio Danese Paolo Scollo Domenica Lo Russo Antonella Villa Paola Daniela Aimone Giovanni Scambia 《European journal of cancer (Oxford, England : 1990)》2010,46(16):2905-2912
ObjectiveThe objective of this prospective randomized phase III trial was to compare paclitaxel plus carboplatin (PC) versus topotecan plus carboplatin and paclitaxel (TPC) in women with suboptimal stage III (residual tumour >1 cm) or stage IV ovarian cancer to evaluate the survival rate and toxicities.MethodsEligible for the study were patients aged at least 18 years old with histological/cytological diagnosis of FIGO stages III (residual tumour ?1 cm after primary surgery) – IV epithelial ovarian cancer. Patients were randomized to iv PC on day 1, every 21 days or iv topotecan daily for three days and PC on day 3, every 21 days.ResultsThe intention to treat population was made of 326 patients in total, 170 in the PC group and 156 in the TPC group. The life table estimates of survival probabilities at one, three and five years were, respectively, 0.94 (95% CI: 0.88–0.97), 0.53 (95% CI: 0.44–0.62) and 0.32 (95%CI: 0.23–0.42) in the PC group, and 0.92 (95% CI: 0.86–0.95), 0.52 (95% CI: 0.42–0.61), and 0.32(95%CI: 0.22–0.43) in the TPC group (log-rank test at 5 years: ns). The results of the survival analysis based on Cox regression model showed no statistically significant differences between groups (p-value: ns). The number of subjects with at least one event with possible relationship to study medication was 151 (88.8%) in the PC group and 139 (89.1%) in the TPC group (p = ns).In the PC group, 79 patients (23.6%) experienced at least one Adverse Event (AE) graded as severe and 16 patients (4.8%) at least one life-threatening AE, whilst in the TPC group, the number of patients who presented at least one severe or life-threatening AE was 86 (24%) and 37 (10.3%), respectively.ConclusionThe results of the present study show that the addition of topotecan to a standard paclitaxel/carboplatin regimen in the treatment of advanced epithelial ovarian cancer did not result in significant advantages in terms of survival rate. A slightly worse toxicity profile for TPC was observed. 相似文献
44.
Olmi S Erba L Magnone S Bertolini A Mastropasqua E Perego P Massimini D Zanandrea G Russo R Croce E 《Chirurgia italiana》2005,57(6):709-716
The aim of this study was to establish the indications, safety, efficacy, feasibility and reproducibility of laparoscopic techniques in the treatment of abdominal wall defects, even of the larger kind, in order to standardise procedures and confirm the performance of the composite mesh used (Parietex, Sofradim, Trevoux, France). From January 2001 to December 2004, 185 non-selected patients (109 females, 76 males), with a mean age of 56 years (range: 26-77) and a mean BMI of 30 (range: 26-40) were included in the study; 162 patients (87.5%) had incisional hernias and 23 patients (12.5%) primary wall defects. The size of the defects treated ranged from 4 cm to 26 cm (mean: 12.1 cm). All patients underwent laparoscopic repair and all meshes were placed intraperitoneally. Over a mean follow-up period of 29 months (range: 1-48), we observed 11 postoperative complications (6.7%): 7 seromas (4.3%) which were still present after 4 weeks, one of which turned septic after several attempts at percutaneous evacuation and in which the prosthesis had to be removed laparoscopically; 3 (1.8%) experienced persistent neuralgia which disappeared after 2 months' treatment with NSAIDs, and also one case of trocar-induced haematoma. We had 4 recurrences (2.4%), all within 1 to 3 months of surgery; 1 in the size group measuring less than 9 cm and 3 in the larger defect group. Adhesiolysis was performed in 98% of all incisional hernia cases and in 7 cases (4.3%) we had to repair iatrogenic lesions of the small bowel. In 4 patients (2.5%), because of thick adhesions (1 patient) or bowel loop fixation to the previous surgical scar (3 patients), we caused complete bowel perforation repaired by laparoscopic suture. Mean operative time was 65.6 minutes (range: 28-130) and the mean hospital stay was 2.1 days (range: 1-5). We had no conversions and no mortality. We also reviewed the main methods of mesh fixation and believe that the best system at the moment is the EndoAnchor (Ethicon Endo-Surgery, Cincinnati, Ohio) device, although in future the best option is likely to be fixation with non-traumatic biological glue (Tissucol, Baxter, Maurepas), which we have already used in a series of 16 patients with optimal results and no recurrences. The results emerging from this clinical trial confirm the safety and efficacy of laparoscopic repair techniques, of this kind of mesh and of the anchoring devices used as well as the reproducibility of this technique for the intraperitoneal repair of primary and incisional abdominal wall defects, including even those of large size. 相似文献
45.
The use of laparoscopy in pancreatic cancer offers a significant contribution to the diagnosis and treatment of this disease. Both laparoscopic staging and treatment of pancreatic cancer have proved feasible and effective. This paper reviews the literature on this topic, by a Medline search using the words laparoscopy and pancreas. Various aspects are considered: staging, treatment and palliation. Cross-references from the articles retrieved were reviewed. The efficacy and safety of diagnostic laparoscopy and ultrasonography, lowering the rate of useless laparotomies, is evident in most studies. Moreover laparoscopic resection of the body and tail of the pancreas, as well as palliation of digestive obstruction has been demonstrated as feasible. Controversy exists on feasibility of pancreatoduodenectomy. Laparoscopic gastric outlet obstruction bypass and laparoscopic biliary decompression have been reported with good results compared to open surgical procedures. Randomized controlled trials are required to validate promising results coming from the reported series, mainly retrospective. 相似文献
46.
Fosong Wang Alberto Bolognesi Attilio Immirzi Lido Porri 《Macromolecular chemistry and physics.》1981,182(12):3617-3623
The polymerization of (E,E)-2,4-hexadiene with the Al(C2H5)2Cl/Nd(OCOR)3/Al(iBu)3 system was examined. High molecular weight crystalline polymers were obtained in polymerizations carried out at room temperature or below. IR and NMR examination showed the polymers to consist predominantly of trans-1,4 units. Degradative oxidation gave the racemic form of 2,3-dimethylsuccinic acid, thus indicating a threo structure for the polymers. X-ray analysis indicated that the polymers contain stereoregular sequences with a trans-1,4-threo-diisotactic structure. 相似文献
47.
Hellas Cena Debora Porri Rachele De Giuseppe Aliki Kalmpourtzidou Fiorella Pia Salvatore Marwan El Ghoch Leila Itani Dima Kreidieh Anna Brytek-Matera Cristina Bianca Pocol Donaldo Segundo Arteta Arteta Gzde Utan Ivana Kol
i 《Nutrients》2021,13(2)
The aim of this cross-sectional study was to assess the health-related behaviors among university students, with emphasis on health sciences students from Croatia, Italy, Lebanon, Poland, Romania, Spain and Turkey. We included 6222 students in Medicine, Dentistry, Nursing, Pharmacy, Nutrition and Dietetics, Sports Sciences, Veterinary, and Economics enrolled between April 2018 and March 2020. We assessed dietary patterns, sleeping habits, physical activity and perceived stress among students by means of validated questionnaires. The median age ranged between 19 and 24 years, smoking prevalence between 12.0% and 35.4%, and body mass index (BMI) ranged between 21.1 and 23.2 kg/m2. Breakfast was less often and more often consumed daily in Turkey (36.7%), and Italy (75.7%), respectively. The highest Mediterranean diet score was recorded in Spain and Italy, and the lowest in Turkey, followed by students from Croatia, Lebanon, Poland and Romania. Sleep duration, physical activity and stress perception also differed between countries. Multivariable regression analysis revealed a small, but positive association between BMI and several characteristics, including age, female gender, smoking, physical activity, mobile phone use, and perceived stress. A negative association was found between BMI and sleep duration on non-working days. Self-rated health perception was positively associated with female gender, breakfast, physical activity, and time spent studying, and negatively with BMI, smoking and stress. Our results demonstrated diverse habits in students from different countries, some of which were less healthy than anticipated, given their educational background. Greater emphasis needs to be placed on improving the lifestyle of these adolescents and young adults, who will be tomorrow’s healthcare workers. 相似文献
48.
Dugan BJ Gingrich DE Mesaros EF Milkiewicz KL Curry MA Zulli AL Dobrzanski P Serdikoff C Jan M Angeles TS Albom MS Mason JL Aimone LD Meyer SL Huang Z Wells-Knecht KJ Ator MA Ruggeri BA Dorsey BD 《Journal of medicinal chemistry》2012,55(11):5243-5254
Members of the JAK family of nonreceptor tyrosine kinases play a critical role in the growth and progression of many cancers and in inflammatory diseases. JAK2 has emerged as a leading therapeutic target for oncology, providing a rationale for the development of a selective JAK2 inhibitor. A program to optimize selective JAK2 inhibitors to combat cancer while reducing the risk of immune suppression associated with JAK3 inhibition was undertaken. The structure-activity relationships and biological evaluation of a novel series of compounds based on a 1,2,4-triazolo[1,5-a]pyridine scaffold are reported. Para substitution on the aryl at the C8 position of the core was optimum for JAK2 potency (17). Substitution at the C2 nitrogen position was required for cell potency (21). Interestingly, meta substitution of C2-NH-aryl moiety provided exceptional selectivity for JAK2 over JAK3 (23). These efforts led to the discovery of CEP-33779 (29), a novel, selective, and orally bioavailable inhibitor of JAK2. 相似文献
49.
Brivio F Fumagalli L Chiarelli M Denova M Bertolini A Cetta M Nespoli A 《Chirurgia italiana》2007,59(5):635-640
Cancer-associated immunodeficiency is seriously worsened by surgical trauma. Short-term preoperative interleukin-2 (IL-2) immunotherapy abolishes postoperative immunodeficiency and can induce immunological control of the growth of minimal residual disease. Growth factors play an important role in oncological practice in treating neutropenia (G-CSF) or associated anaemia during chemotherapy (erythropoietin). Unfortunately, lymphocytopenia is not considered a biological marker with regard to survival. On the other hand, the role of the immune response to surgical trauma has been emphasised by many surgeons, and to counteract it immune nutrition (omega 3 fatty acid, mRNA, arginine) or thymic hormone have been tried. We believe that the obvious method of counteracting postoperative lymphocytopenia is the administration of the specific growth factor for T lymphocytes, i.e. IL-2. The aim of this study was to report on our experience with IL-2 preoperative immunoactivation in colorectal cancer and the long-term outcome of patients treated in comparison with a control group operated on without immunotherapy. In order to obtain activated lymphocytosis at the time of operation administration of IL-2 (6 million I.U. twice daily subcutaneously) for 3 preoperative days is sufficient, starting 4 days before surgery. The inclusion/exclusion criteria were histologically documented colorectal cancer, elective surgery, laparotomic surgery, no second tumour, age 20-80 years, no cardiovascular, hepatic or renal failure. From June 1992 to December 2005, 67 patients were treated (Dukes B/C: 46/21) with IL-2 immunotherapy. The clinical and biological results were compared with those of a control group of 173 patients (Dukes B/C 114/59) operated on in the same period and recruited with the same criteria. Dukes stage-C patients in both groups underwent adjuvant chemotherapy plus radiotherapy for rectal cancer. Data were statistically analysed using Fisher's exact test, Student's T-test and analysis of variance, as appropriate. The overall survival curves were plotted with the Kaplan-Mayer method. After a median follow-up of 69 months (range: 12-169) the progression rate was 15/67 (22%) vs 68/173 (39%) in controls (p = 0.02). Important results were obtained in Dukes-B patients: progression rate 7/46 (15%) vs 37/114 (32,4%) in controls (p = 0.03). We can conclude that immunotherapy is well tolerated. IL-2 is capable of counteracting surgery-induced immunodeficiency. The amplification of the immune response in the post-operative period is capable of controlling minimal residual disease after radical surgery, of reducing the progression rate, and of improving the prognosis and overall survival. 相似文献
50.
Raddatz R Hudkins RL Mathiasen JR Gruner JA Flood DG Aimone LD Le S Schaffhauser H Duzic E Gasior M Bozyczko-Coyne D Marino MJ Ator MA Bacon ER Mallamo JP Williams M 《The Journal of pharmacology and experimental therapeutics》2012,340(1):124-133
CEP-26401 [irdabisant; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one HCl] is a novel, potent histamine H? receptor (H?R) antagonist/inverse agonist with drug-like properties. High affinity of CEP-26401 for H?R was demonstrated in radioligand binding displacement assays in rat brain membranes (K(i) = 2.7 ± 0.3 nM) and recombinant rat and human H?R-expressing systems (K(i) = 7.2 ± 0.4 and 2.0 ± 1.0 nM, respectively). CEP-26401 displayed potent antagonist and inverse agonist activities in [3?S]guanosine 5'-O-(γ-thio)triphosphate binding assays. After oral dosing of CEP-26401, occupancy of H?R was estimated by the inhibition of ex vivo binding in rat cortical slices (OCC?? = 0.1 ± 0.003 mg/kg), and antagonism of the H?R agonist R-α-methylhistamine- induced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED?? = 0.06 mg/kg). CEP-26401 improved performance in the rat social recognition model of short-term memory at doses of 0.01 to 0.1 mg/kg p.o. and was wake-promoting at 3 to 30 mg/kg p.o. In DBA/2NCrl mice, CEP-26401 at 10 and 30 mg/kg i.p. increased prepulse inhibition (PPI), whereas the antipsychotic risperidone was effective at 0.3 and 1 mg/kg i.p. Coadministration of CEP-26401 and risperidone at subefficacious doses (3 and 0.1 mg/kg i.p., respectively) increased PPI. These results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H?R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders. CEP-26401 may also have therapeutic utility in treating schizophrenia or as adjunctive therapy to approved antipsychotics. 相似文献