Spectroscopic and Theoretical Studies of Some 3-(4 '-Substituted phenylsulfanyl)-1-methyl-2-piperidones

The analysis of the IR carbonyl bands of some 3-(4 '-substituted phenylsulfanyl)1- methyl-2-piperidones 1-6 bearing substituents: NO2 (compound 1), Br (compound 2), Cl (compound 3), H (compound 4) Me (compound 5) and OMe (compound 6) supported by B3LYP/ 6-31+ G(d, p) and PCM calculations along with NBO analysis (for compound 4) and X-ray diffraction (for 2) indicated the existence of two stable conformations, i.e., axial (ax) and equatorial (eq), the former corresponding to the most stable and the least polar one in the gas phase calculations. the sum of the energy contributions of the orbital interactions (NBO analysis) and the electrostatic interactions correlate well with the populations and the vCO frequencies of the ax and eq conformers found in the gas phase. Unusually, in solution of the non-polar solvents n-C6H14 and CCl4, the more intense higher IR carbonyl frequency can be ascribed to the ax conformer, while the less intense lower IR doublet component to the eq one. the same.CO frequency trend also holds in polar solvents, that is nu(CO(eq)) < nu(CO(ax)). However, a reversal of the ax/eq intensity ratio occurs going from non-polar to polar solvents, with the ax conformer component that progressively decreases with respect to the eq one in CHCl3 and CH2Cl2, and is no longer detectable in the most polar solvent CH3CN. the PCM method applied to compound 4 supports these findings. in fact, it predicts the progressive increase of the eq/ax population ratio as the relative permittivity of the solvent increases. Moreover, it indicates that the computed.CO frequencies of the ax and eq conformers do not change in the non-polar solvents n-C6H14 and CCl4, while the.CO frequencies of the eq conformer become progressively lower than that of the ax one going from CHCl3 to CH2Cl2 and to CH3CN, in agreement with the experimental IR values. the analysis of the geometries of the ax and eq conformers shows that the carbonyl oxygen atom of the eq conformer is free for solvation, while the O-[CO]center dot center dot center dot H[o-Ph] hydrogen bond that takes place in the ax conformer partially hinders the approach of the solvent molecules to the carbonyl oxygen atom. Therefore, the larger solvation that occurs in the carbonyl oxygen atom of the eq conformer is responsible for the observed and calculated decrease of the corresponding frequency. the X-ray single crystal analysis of 2 indicates that this compound adopts the most polar eq geometry in the solid. in fact, in order to obtain the largest energy gain, the molecules are arranged in the crystal in a helical fashion due to dipole moment coupling along with C-H center dot center dot center dot O and C-H center dot center dot center dot pi(Ph) hydrogen bonds.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)MIUR (PRIN)Univ São Paulo, Inst Chem, Conformat Anal & Elect Interact Lab, BR-05513970 São Paulo, BrazilUniversidade Federal de São Paulo, UNIFESP, Inst Environm Chem & Pharmaceut Sci, BR-09972270 Diadema, SP, BrazilUniv Fed Sao Carlos, Dept Chem, BR-13565905 Sao Carlos, SP, BrazilUniv Ferrara, Dept Chem, I-44100 Ferrara, ItalyUniversidade Federal de São Paulo, UNIFESP, Inst Environm Chem & Pharmaceut Sci, BR-09972270 Diadema, SP, BrazilCAPES: 808/2009Web of Scienc

Atividade de Bacillus thuringiensis no desenvolvimento de fungos fitopatogênicos.

Bacillus thuringiensis e uma bactéria com atividade inseticida. Sua produção industrial baseia-se no processo fermentativo, ao final do qual apenas a fração sólida do caldo de fermentação tem interesse comercial. Esse estudo teve por objetivo detectar a possibilidade de uso da fração liquida do caldo fermentado de Bacillus thuringiensis contra alguns fitopatogênicos. As fermentações foram realizadas sob condições controladas de agitação e temperatura. Após 24 e 48 horas, uma alíquota do caldo foi armazenada e o restante foi submetido a centrifugação (3000 rpm/7 min), sendo que a fração sobrenadante foi então denominada SN e, o precipitado, PPT. As frações NC, SN e PPT foram padronizadas em termos de volume e concentração de células e, a seguir, utilizadas em testes de inibição contra Fusarium solani e Colletotrichum sp. "in vitro". Os resultados obtidos demonstram o potencial de alguns dos caldos testados no controle dos fungos fitopatogênicos. A utilizacao da fração SN, entretanto, devera ser objeto de novos estudos para ser confirmada em vasos e casa-de-vegetação

Modified Glasgow Prognostic Score as a Predictor of Recurrence in Patients with High Grade Non-Muscle Invasive Bladder Cancer Undergoing Intravesical Bacillus Calmette–Guerin Immunotherapy

Background: A systemic inflammatory marker, the modified Glasgow prognostic score (mGPS), could predict outcomes in non-muscle-invasive bladder cancer (NIMBC). We aimed to investigate the predictive power of mGPS in oncological outcomes in HG/G3 T1 NMIBC patients undergoing Bacillus Calmette–Guérin (BCG) therapy. Methods: We retrospectively reviewed patient’s medical data from multicenter institutions. A total of 1382 patients with HG/G3 T1 NMIBC have been administered adjuvant intravesical BCG therapy, every week for 3 weeks given at 3, 6, 12, 18, 24, 30 and 36 months. The analysis of mGPS for recurrence and progression was performed using multivariable and univariable Cox regression models. Results: During follow-up, 659 patients (47.68%) suffered recurrence, 441 (31.91%) suffered progression, 156 (11.28%) died of all causes, and 67 (4.84%) died of bladder cancer. At multivariable analysis, neutrophil to lymphocyte ratio [hazard ratio (HR): 7.471; p = 0.0001] and erythrocyte sedimentation rate (ESR) (HR: 0.706; p = 0.006 were significantly associated with recurrence. mGPS has no statistical significance for progression (p = 0.076). Kaplan–Meier survival analysis showed a significant difference in survival among patients from different mGPS subgroups. Five-year OS was 93% (CI 95% 92–94), in patients with mGPS 0, 82.2% (CI 95% 78.9–85.5) in patients with mGPS 1 and 78.1% (CI 95% 60.4–70) in mGPS 2 patients. Five-year CSS was 98% (CI 95% 97–99) in patients with mGPS 0, 90% (CI 95% 87–94) in patients with mGPS 1, and 100% in mGPS 2 patients. Limitations are applicable to a retrospective study. Conclusions: mGPS may have the potential to predict recurrence in HG/G3 T1 NMIBC patients, but more prospective, with large cohorts, studies are needed to study the influence of systemic inflammatory markers in prediction of outcomes in NMIBC for a definitive conclusion

Predictive clinico-pathological factors to identify BCG, unresponsive patients, after re-resection for T1 high grade non-muscle invasive bladder cancer

Introduction: Seventy-five percent of bladder cancers are non-muscle invasive. The treatment strategy includes the transurethral resection of bladder tumor (TURB) followed by intravesical immunotherapy with the bacillus of Calmette-Guerin (BCG) or chemotherapy, depending on the grade of bladder tumor. Despite a proper BCG intravesical instillations schedule, up to 40% of patients present a failure within 2 years. The aim of this retrospective study was to investigate the predictive factors in the response to BCG in patients with a high-grade non-muscle invasive bladder cancer diagnosis. Materials and methods: Patients with non-muscle invasive bladder cancer from 13 hospitals and academic institutions were identified and treated, from January 1, 2002, until December 31, 2012, with TURB and a subsequent re-TURB for restaging before receiving BCG. Follow-up was performed with urine cytology and cystoscopy every 3 months for 1 year and, successively every 6 months. Univariate and multivariate Cox regression models addressed the response to BCG therapy. Kaplan-Meier overall survival (OS) and cancer-specific survival (CSS) estimates were determined for BCG responsive vs. BCG unresponsive patients. Results: A total of 1,228 patients with non-muscle invasive bladder cancer were enrolled. Of 257 (20.9%) patients were BCG unresponsive. Independent predictive factors for response to BCG were: multifocality (HR: 1.4; 95% CI 1.05-1.86; P = 0.019), lymphovascular invasion (HR: 1.75; 95% CI 1.22-2.49; P = 0.002) and high-grade on re-TURB (HR: 1.39; 95% CI 1.02-1.91; P = 0.037). Overall survival was significantly reduced in BCG-unresponsive patients compared to BCG-responsive patients at 5 years (82.9% vs. 92.4%, P &lt; 0.0001) and at 10 years (44.2% vs. 74.4%, P &lt; 0.0001). Similarly, cancer-specific survival was reduced in BCG-unresponsive patients at 5 years (90.6% vs. 97.3%, P &lt; 0.0001) and at 10 years (72.3% vs. 87.2%, P &lt; 0.0001). Conclusion: Multifocality, lymphovascular invasion, and high-grade on re-TURB were independent predictors for response to BCG treatment. BCG-unresponsive patients reported worse oncological outcomes

Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease: Results from the CREDENCE trial and meta-analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-Analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-Analysis. RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: Total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]). CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction &gt;0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease