RESUMO
Lead compounds 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-benzamide (1), tetrahydro-pyran-4-carboxylic acid [((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-amide (2), and 3,5-dimethyl-isoxazole-4-carboxylic acid [((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-amide (3) discovered in our laboratory, displayed high histamine H3 receptor (H3R) affinity, good selectivity and weak human Ether-à-go-go-Related Gene (hERG) channel affinity with desirable overall physico-chemical and pharmacokinetic (PK) profiles. Herein, we describe the design and synthesis of a novel series of H3R antagonists utilizing a scaffold hopping strategy. Further structure-activity relationship (SAR) studies of the series culminated in the identification of ((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-naphthalene-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide (4c) and -[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-N-(tetrahydro-pyran-4-yl)-acetamide (4d), which exhibited good H3R affinity in vitro, good selectivity, and desirable PK properties. Compounds 4c and 4d were also assessed in cardiac safety experiments. In particular, the effects of the compounds on action potentials recorded from ventricular myocytes isolated from guinea pigs were used to screen compounds that not only displayed a low affinity towards hERG channel, but also had lower interference with other cardiac ion channels. Compound 4c did not alter the major parameters in this model system at ⩽10 µM, and no significant induction of any major haemodynamic effect when intravenously administered at 3mg/kg dose to anaesthetized mongrel dogs. Compound 4c is a new promising lead as orally potent and selective H3R antagonist belonging to a distinct structural class.
Assuntos
Antagonistas dos Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos H3/síntese química , Animais , Células CHO , Cricetulus , Cães , Desenho de Fármacos , Feminino , Cobaias , Antagonistas dos Receptores Histamínicos H3/farmacologia , Humanos , Masculino , Técnicas de Patch-Clamp , Estereoisomerismo , Relação Estrutura-Atividade , Transativadores/metabolismo , Regulador Transcricional ERGRESUMO
PURPOSE: To investigate risk factors for urine leak in patients undergoing minimally invasive partial nephrectomy (MIPN) and to determine the role of intraoperative ureteral catheterization in preventing this postoperative complication. MATERIALS AND METHODS: MIPN procedures done from September 1999 to July 2012 at our Center were reviewed from our IRB-approved database. Patient and tumor characteristics, operative techniques and outcomes were analyzed. Patients with evidence of urine leak were identified. Outcomes were compared between patients with preoperative ureteral catheterization (C-group) and those without (NC-group). Univariable and multivariable analyses were performed to identify factors predicting postoperative urine leak. RESULTS: A total of 1,019 cases were included (452 robotic partial nephrectomy cases and 567 laparoscopic partial nephrectomy cases). Five hundred twenty eight patients (51.8%) were in the C-group, whereas 491 of them (48.2%) in the NC-group. Urine leak occurred in 31(3%) cases, 4.6% in the C-group and 1.4% in the NC-group (p<0.001). Tumors in NC-group had significantly higher RENAL score, shorter operative and warm ischemic times. On multivariable analysis, tumor proximity to collecting system (OR=9.2; p<0.01), surgeon's early operative experience (OR=7.8; p<0.01) and preoperative moderate to severe CKD (OR=3.1; p<0.01) significantly increased the odds of the occurrence of a postoperative urine leak. CONCLUSION: Clinically significant urine leak after MIPN in a high volume institution setting is uncommon. This event is more likely to occur in cases of renal masses that are close to the collecting system, in patients with preoperative CKD and when operating surgeon is still in the learning curve for the procedure. Our findings suggest that routine intraoperative ureteral catheterization during MIPN does not reduce the probability of postoperative urine leak. In addition, it adds to the overall operative time.
Assuntos
Nefrectomia/efeitos adversos , Cateterismo Urinário/métodos , Incontinência Urinária/etiologia , Incontinência Urinária/prevenção & controle , Idoso , Feminino , Taxa de Filtração Glomerular , Humanos , Cuidados Intraoperatórios , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos/efeitos adversos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Análise Multivariada , Nefrectomia/métodos , Duração da Cirurgia , Insuficiência Renal Crônica/cirurgia , Reprodutibilidade dos Testes , Fatores de Risco , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Fatores de Tempo , Resultado do TratamentoRESUMO
Lead optimization guided by histamine H3 receptor (H3R) affinity and calculated physico-chemical properties enabled simultaneous improvement in potency and PK properties leading to the identification of a potent, selective, devoid of hERG issues, orally bioavailable, and CNS penetrable H3R antagonist/inverse agonist 3h. The compound was active in forced-swimming tests suggesting its potential therapeutic utility as an anti-depressive agent. This Letter further includes its cardiovascular and neuropsychological/behavioral safety assessments.
Assuntos
Amidas/química , Antidepressivos/química , Antagonistas dos Receptores Histamínicos/química , Pirrolidinas/química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Antidepressivos/farmacocinética , Antidepressivos/farmacologia , Células CHO , Cricetulus , Antagonistas dos Receptores Histamínicos/farmacocinética , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Cinética , Masculino , Camundongos , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos H3/química , Receptores Histamínicos H3/metabolismoRESUMO
This Letter describes the asymmetric synthesis of the four stereoisomers (8a-8d) of a potent and highly selective histamine H3 receptor (H3R) antagonist, 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3']bipyrrolidinyl-1'-yl) phenyl]benzamide (1). The physico-chemical properties, in vitro H3R affinities and ADME of 8a-8d were determined. Stereoisomer 8c (2S,3'S) displayed superior in vitro H3R affinity over other three stereoisomers and was selected for further profiling in in vivo PK and drug safety. Compound 8c exhibited excellent PK properties with high exposure, desired brain to plasma ratio and reasonable brain half life. However, all stereoisomers showed similar unwanted hERG affinities.
Assuntos
Benzamidas/química , Benzamidas/síntese química , Antagonistas dos Receptores Histamínicos/síntese química , Pirrolidinas/síntese química , Receptores Histamínicos H3/química , Animais , Benzamidas/farmacocinética , Encéfalo/metabolismo , Meia-Vida , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacocinética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratos , Receptores Histamínicos H3/metabolismo , EstereoisomerismoRESUMO
Previous studies have shown that compound 1 displayed high affinity towards histamine H3 receptor (H3R), (human (h-H3R), K(i)=8.6 nM, rhesus monkey (rh-H3R), K(i)=1.2 nM, and rat (r-H3R), K(i)=16.5 nM), but exhibited high affinity for hERG channel. Herein, we report the discovery of a novel, potent, and highly selective H3R antagonist/inverse agonist 5a(SS) (SAR110068) with acceptable hERG channel selectivity and desirable pharmacological and pharmacokinetic properties through lead optimization sequence. The significant awakening effects of 5a(SS) on sleep-wake cycles studied by using EEG recording in rats during their light phase support its potential therapeutic utility in human sleep-wake disorders.
Assuntos
Antagonistas dos Receptores Histamínicos H3/farmacologia , Piranos/farmacologia , Pirrolidinas/farmacologia , Transtornos do Sono do Ritmo Circadiano/tratamento farmacológico , Administração Oral , Animais , Cães , Estabilidade de Medicamentos , Cobaias , Haplorrinos , Antagonistas dos Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Masculino , Camundongos , Piranos/química , Piranos/farmacocinética , Pirrolidinas/química , Pirrolidinas/farmacocinética , Coelhos , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos H3/química , Receptores Histamínicos H3/metabolismo , Ovinos , Transtornos do Sono do Ritmo Circadiano/metabolismo , Especificidade por SubstratoRESUMO
A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective histamine H3 receptor (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey H3R binding assays.
Assuntos
Amidas/química , Antagonistas dos Receptores Histamínicos H3/química , Receptores Histamínicos H3/química , Ureia/química , Amidas/metabolismo , Amidas/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Antagonistas dos Receptores Histamínicos H3/metabolismo , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Humanos , Macaca mulatta , Obesidade/tratamento farmacológico , Ligação Proteica , Ratos , Receptores Histamínicos H3/genética , Receptores Histamínicos H3/metabolismo , Relação Estrutura-Atividade , Ureia/metabolismo , Ureia/uso terapêuticoRESUMO
A novel series of histamine H3 receptor (H3R) antagonists was derived from an arylurea lead series (1) via bioisosteric replacement of the urea functionality by an amide linkage. The arylamide series was optimized through SAR studies by a broad variation of substituents in the left-hand side benzoyl residue (analogs 2a-2ag) or replacement of the benzoyl moiety by heteroarylcarbonyl residues (analogs 5a-5n). Compounds 2p and 2q were identified within the series as potent and selective H3R antagonists/inverse agonists with acceptable overall profile. Compound 2q was orally active in food intake inhibition in diet-induced obese (DIO) mice. Compound 2q represents a novel H3R antagonist template with improved in vitro potency and oral efficacy and has its merits as a new lead for further optimization.
Assuntos
Amidas/química , Benzamidas/química , Antagonistas dos Receptores Histamínicos H3/química , Pirrolidinas/química , Receptores Histamínicos H3/química , Ureia/química , Administração Oral , Amidas/metabolismo , Amidas/uso terapêutico , Animais , Benzamidas/metabolismo , Benzamidas/uso terapêutico , Células CACO-2 , Avaliação Pré-Clínica de Medicamentos , Agonismo Inverso de Drogas , Antagonistas dos Receptores Histamínicos H3/metabolismo , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Humanos , Camundongos , Microssomos/metabolismo , Obesidade/tratamento farmacológico , Ligação Proteica , Pirrolidinas/metabolismo , Pirrolidinas/uso terapêutico , Ratos , Receptores Histamínicos H3/genética , Receptores Histamínicos H3/metabolismo , Relação Estrutura-Atividade , Ureia/metabolismo , Ureia/uso terapêuticoRESUMO
Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) recently attracted attention due to their central involvement in various pathologies. We here describe a family of DYRK/CLK inhibitors derived from Leucettines and the marine natural product Leucettamine B. Forty-five N2-functionalized 2-aminoimidazolin-4-ones bearing a fused [6 + 5]-heteroarylmethylene were synthesized. Benzothiazol-6-ylmethylene was selected as the most potent residue among 15 different heteroarylmethylenes. 186 N2-substituted 2-aminoimidazolin-4-ones bearing a benzothiazol-6-ylmethylene, collectively named Leucettinibs, were synthesized and extensively characterized. Subnanomolar IC50 (0.5-20 nM on DYRK1A) inhibitors were identified and one Leucettinib was modeled in DYRK1A and co-crystallized with CLK1 and the weaker inhibited off-target CSNK2A1. Kinase-inactive isomers of Leucettinibs (>3-10 µM on DYRK1A), named iso-Leucettinibs, were synthesized and characterized as suitable negative control compounds for functional experiments. Leucettinibs, but not iso-Leucettinibs, inhibit the phosphorylation of DYRK1A substrates in cells. Leucettinibs provide new research tools and potential leads for further optimization toward therapeutic drug candidates.
Assuntos
Imidazóis , Poríferos , Animais , Fosforilação , Imidazóis/química , Poríferos/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/químicaRESUMO
Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) play a large variety of cellular functions and are involved in several diseases (cognitive disorders, diabetes, cancers, etc.). There is, thus, growing interest in pharmacological inhibitors as chemical probes and potential drug candidates. This study presents an unbiased evaluation of the kinase inhibitory activity of a library of 56 reported DYRK/CLK inhibitors on the basis of comparative, side-by-side, catalytic activity assays on a panel of 12 recombinant human kinases, enzyme kinetics (residence time and Kd), in-cell inhibition of Thr-212-Tau phosphorylation, and cytotoxicity. The 26 most active inhibitors were modeled in the crystal structure of DYRK1A. The results show a rather large diversity of potencies and selectivities among the reported inhibitors and emphasize the difficulties to avoid "off-targets" in this area of the kinome. The use of a panel of DYRKs/CLKs inhibitors is suggested to analyze the functions of these kinases in cellular processes.
Assuntos
Proteínas Quinases , Processamento de Proteína Pós-Traducional , Humanos , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/químicaRESUMO
Leucettinibs are substituted 2-aminoimidazolin-4-ones (inspired by the marine sponge natural product Leucettamine B) developed as pharmacological inhibitors of DYRK1A (dual-specificity, tyrosine phosphorylation-regulated kinase 1A), a therapeutic target for indications such as Down syndrome and Alzheimer's disease. Leucettinib-21 was selected as a drug candidate following extensive structure/activity studies and multiparametric evaluations. We here report its physicochemical properties (X-ray powder diffraction, differential scanning calorimetry, stability, solubility, crystal structure) and drug-like profile. Leucettinib-21's selectivity (analyzed by radiometric, fluorescence, interaction, thermal shift, residence time assays) reveals DYRK1A as the first target but also some "off-targets" which may contribute to the drug's biological effects. Leucettinib-21 was cocrystallized with CLK1 and modeled in the DYRK1A structure. Leucettinib-21 inhibits DYRK1A in cells (demonstrated by direct catalytic activity and phosphorylation levels of Thr286-cyclin D1 or Thr212-Tau). Leucettinib-21 corrects memory disorders in the Down syndrome mouse model Ts65Dn and is now entering safety/tolerance phase 1 clinical trials.
Assuntos
Doença de Alzheimer , Síndrome de Down , Animais , Camundongos , Doença de Alzheimer/tratamento farmacológico , Síndrome de Down/tratamento farmacológico , Fosforilação , Proteínas Serina-Treonina Quinases , Proteínas Tirosina Quinases , Imidazolidinas/química , Imidazolidinas/farmacologiaRESUMO
An in-depth study of the cobalt-catalyzed [2+2+2] cycloaddition between yne-ynamides and nitriles to afford aminopyridines has been carried out. About 30 nitriles exhibiting a broad range of steric demand and electronic properties have been evaluated, some of which open new perspectives in metal-catalyzed arene formation. In particular, the use of [CpCo(CO)(dmfu)] (dmfu=dimethyl fumarate) as a precatalyst made possible the incorporation of electron-deficient nitriles into the pyridine core. Modification of the substitution pattern at the yne-ynamide allows the regioselectivity to be switched toward 3- or 4-aminopyridines. Application of this synthetic methodology to the construction of the aminopyridone framework using a yne-ynamide and an isocyanate was also briefly examined. DFT computations suggest that 3-aminopyridines are formed by formal [4+2] cycloaddition between the nitrile and the intermediate cobaltacyclopentadiene, whereas 4-aminopyridines arise from an insertion pathway.
Assuntos
Alcinos/química , Amidas/química , Aminopiridinas/síntese química , Cobalto/química , Nitrilas/química , Piridonas/síntese química , Aminopiridinas/química , Catálise , Ciclização , Estrutura Molecular , Piridonas/química , EstereoisomerismoRESUMO
UNLABELLED: What's known on the subject? and What does the study add? Single port transvesical enucleation of the prostate (STEP) performed through a solitary suprapubic incision using a single access port inserted directly into the bladder has been demonstrated to be technically feasible but still challenging.3. Despite being feasible and providing adequate relief of bladder outlet obstruction, robotic STEP carries a high risk of complications. Further evolution of the technique is likely to be strictly dependent on the development of instrumentation. OBJECTIVE: To report our initial experience with a novel robot assisted single port procedure for the management of benign prostatic hyperplasia (BPH). METHODS: Between March 2009 and July 2010, nine patients with symptomatic BPH were scheduled for robotic single port suprapubic transvesical enucleation of the prostate (R-STEP). Prior to intervention, all were submitted to preoperative transrectal ultrasound of the prostate and uroflowmetry. The surgical procedure included an initial transurethral incision of the prostatic apex. With the patient in the supine position, an approximate 3 cm lower midline incision was made. A cystotomy was created and a GelPort(®) laparoscopic system positioned in the bladder. The da Vinci S™ robotic operating system was docked through the GelPort(®) platform and enucleation was performed. Perioperative outcomes and short-term postoperative functional outcomes were assessed. Intra-operative and postoperative complications, graded according to the Dindo-Clavien system, were recorded. RESULTS: One patient was excluded from the analysis as the procedure was aborted and converted to open simple prostatectomy. Median operative time was 3.9 h. Median visual analogue pain scale on discharge was 2. Estimated blood loss was 425 mL. Two patients required intra-operative blood transfusion. Postoperatively, two patients developed clot retention and required evacuation and fulguration (grade IIIb), one of them had a deep vein thrombosis (grade II) and a urinary tract infection (grade II). One patient was admitted to the intensive care unit after a myocardial infarction (grade IVa). All patients were discharged after a median of 4.5 days. There was almost three and four times postoperative improvement in both median maximum flow (Qmax) and average flow (Qave) rates, respectively. CONCLUSION: The first series of R-STEP is reported herein. Despite being feasible and providing adequate relief of bladder outlet obstruction, the procedure carries a high risk of complications. Further evolution of the technique is likely to be strictly dependent on the development of instrumentation. Thus, its role in the surgical armamentarium of BPH remains to be determined.
Assuntos
Cistoscopia/métodos , Prostatectomia/métodos , Hiperplasia Prostática/cirurgia , Robótica/métodos , Idoso , Idoso de 80 Anos ou mais , Perda Sanguínea Cirúrgica , Estudos de Viabilidade , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Hiperplasia Prostática/fisiopatologia , Resultado do Tratamento , UrodinâmicaRESUMO
As the replacement of a hydrogen atom by a fluorine atom in a compound can have an important impact on its biological properties, the development of methods allowing the introduction of a fluorine atom is of great importance. The scope and limitations of the ring expansion of cyclic 2-hydroxymethyl amines induced by diethylaminosulfur trifluoride (DAST) to produce cyclic ß-fluoro amines was studied as well as the enantioselectivity of the process.
Assuntos
Aminas/síntese química , Amino Álcoois/química , Dietilaminas/química , Flúor/química , Aminas/química , Ciclização , Estrutura Molecular , EstereoisomerismoRESUMO
Herein, we report the discovery of a first-in-class chemotype 2-(alkylsulfonamido)thiazol-4-yl)acetamides that act as pan-selective inhibitors of cytidine 5'-triphosphate synthetase (CTPS1/2), critical enzymes in the de novo pyrimidine synthesis pathway. Weak inhibitors identified from a high-throughput screening of 240K compounds have been optimized to a potent, orally active agent, compound 27, which has shown significant pharmacological responses at 10 mg/kg dose BID in a well-established animal model of inflammation.
Assuntos
Carbono-Nitrogênio Ligases , Inibidores Enzimáticos , Animais , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Carbono-Nitrogênio Ligases/metabolismo , Proliferação de Células , Ensaios de Triagem em Larga EscalaRESUMO
[(11)C]SL-25.1188 [(S)-5-methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)-benzo[d]isoxazol-3-yl]-oxazolidin-2-one], an oxazolidinone derivative, was characterized in baboons as a radioligand for the in vivo visualization of MAO-B using positron emission tomography (PET). After i.v. injection, [(11)C]SL25.1188 presented a rapid phase of distribution in blood (about 5 min), followed by a T(1/2) elimination of 85 +/- 14 min. Plasma metabolism analysis showed that [(11)C]SL25.1188 is stable in vivo at least for 30 min. Brain uptake was rapid with the highest one observed in the striatum and thalamus, and the lowest in the pons. Calculated distribution volumes (V(T)) were as follows: striatum = 10.3, thalamus = 10.9, hippocampus = 8.9, temporal cortex = 7.7, occipital cortex = 7.2, parietal cortex = 7.4, frontal cortex = 7.4, white matter = 7.4, and pons = 6.1. Pretreatment with deprenyl (2 mg/kg, i.v.) or lazabemide (0.5 mg/kg, i.v.) reduced V(T) values in all brain areas up to 50%. In displacement experiments, injection of SL25.1188 or deprenyl (1 and 2 mg/kg, i.v., respectively) strongly reduced the specific uptake of [(11)C]SL25.1188 in all brain areas (85-100%), while a lesser displacement was observed with lazabemide (0.5 mg/kg, i.v.) (55-70% of specific binding depending on the brain area). Therefore, [(11)C]SL25.1188 is characterized in vivo by reversible binding, high brain uptake and very slow plasma metabolism, strongly suggesting that this radioligand is a potent tool for the in vivo study of brain MAO-B.
Assuntos
Encéfalo/diagnóstico por imagem , Monoaminoxidase/metabolismo , Oxazolidinonas/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Animais , Encéfalo/metabolismo , Masculino , PapioRESUMO
OBJECTIVE: To report on the initial four patients who had robotic salvage retropubic prostatectomy (SRP) for biochemical recurrence after radiation therapy, and to review the surgical outcome of robotic cystoprostatectomy for bladder cancer in two patients who previously had prostate cancer. PATIENTS AND METHODS: Since February 2006, four patients had SRP for biochemical failure after radiation and/or brachytherapy. Transrectal biopsy of the prostate confirmed locally recurrent disease and a metastatic evaluation including bone scan and computed tomography of the abdomen and pelvis were negative in all cases. The SRP was done using a six-port transperitoneal approach. An additional two patients had a robotic cystoprostatectomy for bladder cancer, in whom radiation was provided previously for prostate cancer. A retrospective analysis of the immediate and short-term surgical outcome was reviewed. RESULTS: SRP was completed in all patients with no major complication or conversion to an open approach. The mean operative duration was 125 min, the mean (range) blood loss was 117 (50-250) mL and the mean hospital stay was 2.7 days. Of the four patients undergoing SRP, three had extracapsular extension and the first two had positive margins, while no patients had rectal injuries or significant blood loss. The lymph nodes were negative in all the patients. Three patients were continent within a month while one continued to use two to three pads/day at 3 weeks of follow-up. In the two patients who had cystoprostatectomy there were no major complications or increased surgical difficulty. CONCLUSIONS: SRP is technically possible and with limited perioperative morbidity. Further studies are warranted to validate the oncological and functional outcomes of SRP after radiation and/or brachytherapy. Moreover, the robotic approach for radical cystoprostatectomy in patients who have had prostate radiation is feasible, with no increase in perioperative morbidity.
Assuntos
Recidiva Local de Neoplasia/cirurgia , Prostatectomia/métodos , Neoplasias da Próstata/cirurgia , Robótica , Terapia de Salvação/métodos , Neoplasias da Bexiga Urinária/cirurgia , Braquiterapia/métodos , Cistectomia/instrumentação , Cistectomia/métodos , Estudos de Viabilidade , Humanos , Masculino , Prostatectomia/instrumentação , Neoplasias da Próstata/radioterapia , Estudos Retrospectivos , Terapia de Salvação/instrumentação , Resultado do Tratamento , Neoplasias da Bexiga Urinária/radioterapiaRESUMO
On native human, rat and mouse glycine transporter-1(GlyT1), SSR130800 behaves as a selective inhibitor with IC50 values of 1.9, 5.3 and 6.8 nM, respectively. It reversibly blocked glycine uptake in mouse brain cortical homogenates, increased extracellular levels of glycine in the rat prefrontal cortex, and potentiated NMDA-mediated excitatory postsynaptic currents in rat hippocampal slices. SSR103800 (30 mg/kg, p.o.) decreased MK-801- and PCP-induced locomotor hyperactivity in rodents. SSR103800 (1 and 10 mg/kg, p.o.) attenuated social recognition deficit in adult rats induced by neonatal injections of PCP (10 mg/kg, s.c., on post-natal day 7, 9 and 11). SSR103800 (3 mg/kg, p.o.) counteracted the deficit in short-term visual episodic-like memory induced by a low challenge dose of PCP (1 mg/kg, i.p.), in PCP-sensitized rats (10 mg/kg, i.p.). SSR103800 (30 mg/kg, i.p.) increased the prepulse inhibition of the startle reflex in DBA/1J mice. SSR103800 decreased defensive- and despair-related behaviors in the tonic immobility test in gerbils (10 and 30 mg/kg, p.o.) and in the forced-swimming procedure in rats (1 and 3 mg/kg, p.o.), respectively. These findings suggest that SSR103800 may have a therapeutic potential in the management of the core symptoms of schizophrenia and comorbid depression states.
Assuntos
Antipsicóticos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Esquizofrenia/tratamento farmacológico , Animais , Antidepressivos/farmacologia , Discriminação Psicológica/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Gerbillinae , Glicina/metabolismo , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , N-Metilaspartato/fisiologia , Fenciclidina/farmacologia , Reconhecimento Psicológico/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Estereoisomerismo , Natação/psicologiaRESUMO
In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective alpha7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human alpha7 n-AChRs (K(i) of 22+/-4 and 14+/-1 nM, respectively). Ex vivo (3)[H]alpha-bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID(50)=8 mg/kg p.o.). In functional studies performed with human alpha7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity=51 and 36%, EC(50)=4.4 and 0.9 microM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small alpha-bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic alpha7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 muM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the alpha7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3-10 mg/kg i.p.) dose-dependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse alpha7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.
Assuntos
Agonistas Nicotínicos/farmacologia , Agonistas Nicotínicos/farmacocinética , Receptores Nicotínicos/fisiologia , Animais , Animais Recém-Nascidos , Sítios de Ligação/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Interações Medicamentosas , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Hipocampo/citologia , Humanos , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Agonistas Nicotínicos/química , Antagonistas Nicotínicos/farmacologia , Oócitos/fisiologia , Técnicas de Patch-Clamp/métodos , Subunidades Proteicas/efeitos dos fármacos , Subunidades Proteicas/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/deficiência , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Receptor Nicotínico de Acetilcolina alfa7 , Ácido gama-Aminobutírico/farmacologiaRESUMO
PURPOSE: To present the experience and efficacy of Robotic Partial Nephrectomy (RPN) for the management of renal angiomyolipomas (AMLs) with regard to renal function preservation and perioperative outcomes. PATIENTS AND METHODS: We retrospectively searched our RPN database for pathologically confirmed renal AML patients between 2006 and 2014. Clinical presentation, perioperative complications, and postoperative outcomes of the patients were analyzed. Preoperative imaging findings were reviewed to examine their ability to predict pathology of AML. RESULTS: From 1005 RPN performed in our center during the study period, 53 patients met our inclusion criteria. The mean age at presentation was 54.1 (± 13) years, and 42 (79.2%) patients were female. Median tumor size was 2.8 (interquartile range [IQR], 1.8-4.6) cm. The indication for RPN was suspicious radiologic features for malignancy in 42 (79.2%) patients and acute retroperitoneal hemorrhage risk and pain in 11 (20.8%) patients who were found to have AML according to preoperative imaging. Mean estimated blood loss was 198 (± 194) mL, and 5 (9.4%) patients required blood transfusion. Postoperative complications occurred in 8 (15%) patients. Median estimated glomerular filtration rate within the latest follow-up was 86.9 (IQR, 69.7-100.1) mL/minute/1.73 m(2) with a median of 91% (IQR, 80.4-103) preservation. None of patients developed urinary fistula or pseudoaneurysm requiring second intervention. No local recurrences occurred with a median follow-up of 7 (IQR, 1-17) months. CONCLUSION: Given the low complication rate and preservation of renal function after RPN for AML, it can be considered a reliable method for AML treatment. The majority of AMLs were not suspected based on preoperative imaging. Further diagnostic methods are needed to differentiate benign from malignant lesions.
Assuntos
Angiomiolipoma/cirurgia , Neoplasias Renais/cirurgia , Recidiva Local de Neoplasia , Nefrectomia/métodos , Procedimentos Cirúrgicos Robóticos/métodos , Adulto , Idoso , Angiomiolipoma/complicações , Angiomiolipoma/diagnóstico , Feminino , Hemorragia/etiologia , Humanos , Neoplasias Renais/complicações , Neoplasias Renais/diagnóstico , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Espaço Retroperitoneal , Estudos Retrospectivos , Carga TumoralRESUMO
Noncompetitive N-methyl-D-aspartate (NMDA) blockers induce schizophrenic-like symptoms in humans, presumably by impairing glutamatergic transmission. Therefore, a compound potentiating this neurotransmission, by increasing extracellular levels of glycine (a requisite co-agonist of glutamate), could possess antipsychotic activity. Blocking the glycine transporter-1 (GlyT1) should, by increasing extracellular glycine levels, potentiate glutamatergic neurotransmission. SSR504734, a selective and reversible inhibitor of human, rat, and mouse GlyT1 (IC50=18, 15, and 38 nM, respectively), blocked reversibly the ex vivo uptake of glycine (mouse cortical homogenates: ID50: 5 mg/kg i.p.), rapidly and for a long duration. In vivo, it increased (minimal efficacious dose (MED): 3 mg/kg i.p.) extracellular levels of glycine in the rat prefrontal cortex (PFC). This resulted in an enhanced glutamatergic neurotransmission, as SSR504734 potentiated NMDA-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices (minimal efficacious concentration (MEC): 0.5 microM) and intrastriatal glycine-induced rotations in mice (MED: 1 mg/kg i.p.). It normalized activity in rat models of hippocampal and PFC hypofunctioning (through activation of presynaptic CB1 receptors): it reversed the decrease in electrically evoked [3H]acetylcholine release in hippocampal slices (MEC: 10 nM) and the reduction of PFC neurons firing (MED: 0.3 mg/kg i.v.). SSR504734 prevented ketamine-induced metabolic activation in mice limbic areas and reversed MK-801-induced hyperactivity and increase in EEG spectral energy in mice and rats, respectively (MED: 10-30 mg/kg i.p.). In schizophrenia models, it normalized a spontaneous prepulse inhibition deficit in DBA/2 mice (MED: 15 mg/kg i.p.), and reversed hypersensitivity to locomotor effects of d-amphetamine and selective attention deficits (MED: 1-3 mg/kg i.p.) in adult rats treated neonatally with phencyclidine. Finally, it increased extracellular dopamine in rat PFC (MED: 10 mg/kg i.p.). The compound showed additional activity in depression/anxiety models, such as the chronic mild stress in mice (10 mg/kg i.p.), ultrasonic distress calls in rat pups separated from their mother (MED: 1 mg/kg s.c.), and the increased latency of paradoxical sleep in rats (MED: 30 mg/kg i.p.). In conclusion, SSR504734 is a potent and selective GlyT1 inhibitor, exhibiting activity in schizophrenia, anxiety and depression models. By targeting one of the primary causes of schizophrenia (hypoglutamatergy), it is expected to be efficacious not only against positive but also negative symptoms, cognitive deficits, and comorbid depression/anxiety states.