RESUMO
BACKGROUND: Different nutritional screening instruments can be used to identify the risk of malnutrition in advanced chronic liver disease patients. The present study aimed to evaluate and compare two nutrition screening tools with the Global Leadership Initiative on Malnutrition (GLIM) diagnostic criteria for malnutrition in patients with advanced chronic liver disease. METHODS: Two nutritional screening tools, Nutritional Risk Screening 2002 (NRS-2002) and Royal Free Hospital Nutritional Prioritizing Tool (RFH-NPT), were assessed for 166 patients with liver cirrhosis. We compared medium/high nutritional risk screening with the diagnosis of malnutrition, using the GLIM criteria as the reference standard. RESULTS: According to the GLIM criteria, 57.3% of the patients were malnourished. NRS and RFH-NPT identified, respectively, 36.1% and 52.4% of patients with nutritional risk. RFH-NPT presented better agreement with the diagnosis according to GLIM criteria (k = 0.64; 95% confidence interval = 0.52-0.75), higher sensitivity (80%), higher negative predictive value (79%) and larger area under the curve (82.3%) compared to the NRS. CONCLUSIONS: RFH-NPT, when compared with the GLIM method, has substantial agreement in identifying nutritional risk, good sensitivity and good value for diagnosing malnutrition in patients with advanced chronic liver disease.
Assuntos
Doença Hepática Terminal/classificação , Desnutrição/diagnóstico , Programas de Rastreamento/métodos , Avaliação Nutricional , Medição de Risco/métodos , Idoso , Estudos Transversais , Doença Hepática Terminal/complicações , Doença Hepática Terminal/fisiopatologia , Feminino , Humanos , Masculino , Desnutrição/etiologia , Pessoa de Meia-Idade , Estado Nutricional , Índice de Gravidade de DoençaRESUMO
Anthropogenic activities such as agriculture, industry, and mining have contributed significantly to the accumulation of heavy metals in the soil, which in turn cause problems to human health and to the environment. The present work aims to study the effects of nickel (Ni) on the development of tomato plants, the risks to human health associated to the consumption of contaminated tomatoes, and the consequences to the environment. The experiment was carried out in greenhouse environment for a period of 120 days, and the plants were cultivated in soils with four different concentrations of Ni: 0, 35, 70, and 105 mg kg-1. The concentration of nickel in each part (root, stem, leaf, and fruit) of the tomato plant was measured at four different stages of the cycle: 30, 60, 90, and 120 days, by inductively coupled plasma optical emission spectrometer (ICP-OES). At the end of the cycle, the concentration of certain macro- and micronutrients was also determined and related to the corresponding Ni concentration in the soil. The distribution of Ni in the parts of the plant was analyzed from the bioaccumulation factor temporal behavior. Nickel concentrations found in the fruit were too low to pose a risk to human health. As a result of this research, it was verified that soils with nickel concentrations close to 70 mg kg-1, which is the limit established by the CONAMA resolution (420/2009), may actually represent an optimum concentration value for the development of tomato plants. It also increases productivity per plant and reduces the use of resources such as water and agricultural inputs.
Assuntos
Níquel/metabolismo , Poluentes do Solo/metabolismo , Solanum lycopersicum/metabolismo , Agricultura , Exposição Dietética/estatística & dados numéricos , Monitoramento Ambiental , Frutas/química , Humanos , Solanum lycopersicum/crescimento & desenvolvimento , Metais Pesados/análise , Mineração , Níquel/análise , Raízes de Plantas/química , Solo/química , Poluentes do Solo/análiseRESUMO
BACKGROUND: Insulin resistance promotes liver disease progression and may be associated with a lower response rate in treated hepatitis C virus (HCV) infected patients. n-3 polyunsaturated fatty acid (PUFA) supplementation may reduce insulin resistance. The present study aimed to evaluate the effect of n-3 PUFA supplementation on insulin resistance in these patients. METHODS: In a randomised, double-blind clinical trial, 154 patients were screened. After applying inclusion criteria, 52 patients [homeostasis model assessment index of insulin resistance (HOMA-IR ≥2.5)] were randomly divided into two groups: n-3 PUFA (n = 25/6000 mg day(-1) of fish oil) or control (n = 27/6000 mg day(-1) of soybean oil). Both groups were supplemented for 12 weeks and underwent monthly nutritional consultation. Biochemical tests were performed at baseline and after intervention. Statistical analysis was performed using the Wilcoxon Mann-Whitney test for comparisons and the Wilcoxon test for paired data. Statistical package r, version 3.02 (The R Project for Statistical Computing) was used and P < 0.05 (two-tailed) was considered statistically significant. RESULTS: Comparisons between groups showed that n-3 PUFA supplementation was more effective than the control for reducing HOMA-IR (P = 0.015) and serum insulin (P = 0.016). The n-3 PUFA group not only showed a significant reduction in HOMA-IR 3.8 (3.2-5.0) versus 2.4 (1.8-3.3) (P = 0.002); serum insulin 17.1 (13.8-20.6) µIU mL(-1) versus 10.9 (8.6-14.6) µIU mL(-1) (P = 0.001); and glycated haemoglobin 5.4% (5.0-5.7%) versus 5.1% (4.8-5.6%) (P = 0.011), but also presented an increase in interleukin-1 97.5 (0.0-199.8) pg mL(-1) versus 192.4 (102.2-266.8) pg mL(-1) (P = 0.003) and tumour necrosis factor 121.2 (0.0-171.3) pg mL(-1) versus 185.7 (98.0-246.9) pg mL(-1) (P = 0.003). CONCLUSIONS: n-3 PUFA supplementation reduces insulin resistance in genotype 1 HCV infected patients.
Assuntos
Ácidos Graxos Ômega-3/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Resistência à Insulina , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Suplementos Nutricionais , Fígado Gorduroso/complicações , Feminino , Óleos de Peixe/administração & dosagem , Genótipo , Hepatite C Crônica/sangue , Hepatite C Crônica/complicações , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Human homeobox genes encode nuclear proteins that act as transcription factors involved in the control of differentiation and proliferation. Currently, the role of these genes in development and tumor progression has been extensively studied. Recently, increased expression of HOXB7 homeobox gene (HOXB7) in pancreatic ductal adenocarcinomas (PDAC) was shown to correlate with an invasive phenotype, lymph node metastasis and worse survival outcomes, but no influence on cell proliferation or viability was detected. In the present study, the effects arising from the knockdown of HOXB7 in PDAC cell lines was investigated. METHODS: Real time quantitative PCR (qRT-PCR) (Taqman) was employed to assess HOXB7 mRNA expression in 29 PDAC, 6 metastatic tissues, 24 peritumoral tissues and two PDAC cell lines. siRNA was used to knockdown HOXB7 mRNA in the cell lines and its consequences on apoptosis rate and cell proliferation were measured by flow cytometry and MTT assay respectively. RESULTS: Overexpression of HOXB7 mRNA was observed in the tumoral tissues and in the cell lines MIA PaCa-2 and Capan-1. HOXB7 knockdown elicited (1) an increase in the expression of the pro-apoptotic proteins BAX and BAD in both cell lines; (2) a decrease in the expression of the anti-apoptotic protein BCL-2 and in cyclin D1 and an increase in the number of apoptotic cells in the MIA PaCa-2 cell line; (3) accumulation of cell in sub-G1 phase in both cell lines; (4) the modulation of several biological processes, especially in MIA PaCa-2, such as proteasomal ubiquitin-dependent catabolic process and cell cycle. CONCLUSION: The present study confirms the overexpression of HOXB7 mRNA expression in PDAC and demonstrates that decreasing its protein level by siRNA could significantly increase apoptosis and modulate several biological processes. HOXB7 might be a promising target for future therapies.
Assuntos
Apoptose/genética , Carcinoma Ductal Pancreático/genética , Pontos de Checagem do Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Neoplasias Pancreáticas/genética , RNA Mensageiro , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Fatores de Transcrição E2F/genética , Dosagem de Genes , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Inativação Gênica , Humanos , Neoplasias Pancreáticas/metabolismo , RNA Interferente Pequeno/genética , Reprodutibilidade dos Testes , Proteína do Retinoblastoma/genéticaRESUMO
Bipolar Disorder (BD) has recently been related to a process of accelerated aging, with shortened leukocyte telomere length (LTL) in this population. It has also been observed that the suicide rate in BD patients is higher than in the general population, and more recently the telomere length variation has been described as shorter in suicide completers compared with control subjects. Objectives The aim of the present study was to investigate if there is an association between LTL and BD in families where two or more members have BD including clinical symptomatology variables, along with suicide behavior. Methods Telomere length and single copy gene ratio (T/S ratio) was measured using quantitative polymerase chain reaction in a sample of 143 relatives from 22 families, of which 60 had BD. The statistical analysis was performed with a polygenic mixed model. Results LTL was associated with suicidal ideation (p = 0.02) as that there is an interaction between suicidal ideation and course of the disorder (p = 0.02). The estimated heritability for LTL in these families was 0.68. In addition, covariates that relate to severity of disease, i.e. suicidal ideation and course of the disorder, showed an association with shorter LTL in BD patients. No difference in LTL between BD patients and healthy relatives was observed. Conclusion LTL are shorter in subjects with familial BD suggesting that stress related sub-phenotypes possibly accelerate the process of cellular aging and correlate with disease severity and suicidal ideation.
Assuntos
Transtorno Bipolar , Suicídio , Humanos , Transtorno Bipolar/genética , Ideação Suicida , Telômero/genética , Leucócitos , Encurtamento do Telômero/genéticaRESUMO
The present study was aimed at evaluating the antinociceptive and anti-inflammatory effects of the ethanol extract from Vernonia condensata leaves in animal models, in order to afford a better understanding of these properties. The extract reduced the number of abdominal contortions at doses of 100 (51.00 ± 3.00), 200 (42.00 ± 2.98) and 400 mg/kg (39.00 ± 4.00). In formalin tests, a significant reduction in the licking time (p < 0.01) was observed in the first phase by 25.14 (200 mg/kg = 51.50 ± 4.44) and 31.15% (400 mg/kg = 48.00 ± 4.37). The doses of 100 (43.37 ± 5.15), 200 (34.62 ± 4.16) and 400 mg/kg (28.37 ± 3.98) inhibited (p < 0.001) the second phase. After 60 and 90 min of treatment, a dose of 400 mg/kg (10.13 ± 0.39 and 11.14 ± 1.33, respectively) increased the latency time. Doses of 200 and 400 mg/kg potentiated the sleeping time induced by diazepam, pentobarbital and meprobamate. The extracts (100, 200 and 400 mg/kg) showed anti-inflammatory effects by a decrease in paw edema. The extracts also reduced the exudate volume at the doses of 200 and 400 mg/kg. The leukocyte migration had significant effect (p < 0.001) at doses of 100, 200 and 400 mg/kg. The completion of additional experiments in the investigation of the antinociceptive and anti-inflammatory activities of V. condensata allowed a better understanding of the central and peripheral mechanisms involved.
Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Extratos Vegetais/farmacologia , Veronica/química , Analgésicos/efeitos adversos , Animais , Etanol/química , Masculino , Camundongos , Nociceptividade/efeitos dos fármacos , Extratos Vegetais/efeitos adversos , Folhas de Planta/química , Ratos , Ratos Wistar , Sono/efeitos dos fármacosRESUMO
Antinociceptive and anti-inflammatory activities of the ethanol extract from Annona muricata L. leaves were investigated in animal models. The extract delivered per oral route (p.o.) reduced the number of abdominal contortions by 14.42% (at a dose of 200 mg/kg) and 41.41% (400 mg/kg). Doses of 200 and 400 mg/kg (p.o) inhibited both phases of the time paw licking: first phase (23.67% and 45.02%) and the second phase (30.09% and 50.02%), respectively. The extract (p.o.) increased the reaction time on a hot plate at doses of 200 (30.77% and 37.04%) and 400 mg/kg (82.61% and 96.30%) after 60 and 90 minutes of treatment, respectively. The paw edema was reduced by the ethanol extract (p.o.) at doses of 200 (23.16% and 29.33%) and 400 mg/kg (29.50% and 37.33%) after 3 to 4 h of application of carrageenan, respectively. Doses of 200 and 400 mg/kg (p.o.), administered 4 h before the carrageenan injection, reduced the exudate volume (29.25 and 45.74%) and leukocyte migration (18.19 and 27.95%) significantly. These results suggest that A. muricata can be an active source of substances with antinociceptive and anti-inflammatory activities.
Assuntos
Analgésicos/farmacologia , Annona/química , Anti-Inflamatórios/farmacologia , Etanol/química , Extratos Vegetais/farmacologia , Analgésicos/química , Animais , Anti-Inflamatórios/química , Modelos Animais de Doenças , Masculino , Camundongos , Extratos Vegetais/química , Ratos , Ratos WistarRESUMO
Antinociceptive and anti-inflammatory activities of the Muehlenbeckia platyclada leaves' ethanol extract were investigated in animal models. The extract (p.o.) reduced the number of abdominal contortions induced by acetic acid by 21.57% (400 mg/kg). After intraplantar injection of formalin, a dose of 400 mg/kg (p.o.) inhibited the time spent paw licking in the first phase (26.43%), while the second phase was inhibited by 10.90 and 36.65% at the doses of 200 and 400 mg/kg, respectively. The extract (p.o.) increased the reaction time on a hot plate at a dose of 400 mg/kg (32.68 and 40.30%) after 60 and 90 minutes of treatment, respectively. The paw edema was reduced by extract (p.o.) at doses of 100 (15.46 and 16.67%), 200 (22.68 and 25.64%) and 400 mg/kg (29.50 and 37.33%) after 3 to 4 h of carrageenan application, respectively. Doses of 100, 200 and 400 mg/kg (p.o.), administered 4 h after the carrageenan injection, reduced the exudate volume (11.28, 21.54 and 45.13%), while leukocyte migration was reduced by 21.21 and 29.70% at the doses of 200 and 400 mg/kg, respectively. These results indicate that the ethanol extract from M. platyclada may constitute a potential target for the discovery of new molecules with antinociceptive and anti-inflammatory activities that can be explored for their therapeutic use.
Assuntos
Analgésicos/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta/química , Polygonaceae/química , Analgésicos/química , Animais , Etanol/química , Camundongos , Nociceptividade/efeitos dos fármacos , Extratos Vegetais/química , Ratos , Ratos WistarRESUMO
OBJECTIVES: The aim of the present study was to evaluate the anti-Streptococcus mutans activity of Hyptis pectinata essential oil, and present its promising potential against oral diseases. MATERIALS AND METHODS: The essential oil of H. pectinata was obtained by hydrodistillation from dried leaves and analyzed by GC / MS. The effectiveness of this essential oil regarding the antimicrobial activity against several S. mutans strains was investigated by the agar diffusion and microdilution methods, and chlorohexidine was used as a standard control. RESULTS: The H. pectinata essential oil exhibited considerable inhibitory effect against either all the clinical isolates obtained from patients' saliva or the ATCC strains tested, with minimum inhibitory and bactericidal concentrations of 200 microg ml(-1). The study also compared the efficiency of the emulsifying agents Tween 20, Tween 80, dimethyl sulfoxide and propylene glycol in H. pectinata essential oil when tested against S. mutans. The data obtained confirmed the better inhibitory effect of the oil when using all tested diluents, although Tween 80 seemed to be more suitable for emulsification. CONCLUSION: According to our results, H. pectinata essential oil can be considered a promising alternative to chlorhexidine for the control of oral bacteria-related diseases and hygiene.
Assuntos
Antibacterianos/farmacologia , Hyptis/química , Óleos Voláteis/farmacologia , Streptococcus mutans/efeitos dos fármacos , Adulto , Anti-Infecciosos Locais/farmacologia , Clorexidina/farmacologia , Contagem de Colônia Microbiana , Dimetil Sulfóxido/farmacologia , Emulsificantes/farmacologia , Excipientes/farmacologia , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Testes de Sensibilidade Microbiana , Extratos Vegetais/farmacologia , Folhas de Planta/química , Polissorbatos/farmacologia , Propilenoglicol/farmacologia , Saliva/microbiologia , Solventes/farmacologia , Adulto JovemRESUMO
SETTING: Tuberculosis (TB) remains a challenge in Brazil, particularly among prison inmates. OBJECTIVE: To assess TB prevalence by active case finding in a public prison in southern Brazil. DESIGN: Prison inmates were screened for TB using the presence of cough and chest X-ray (CXR) from October 2014 to August 2016. Presence of cough, irrespective of duration, and abnormal CXRs were further investigated using laboratory tests. RESULTS: Of 10 326 inmates screened, 196 had confirmed TB (1898/100 000 inmates screened). At the first screening, 1759 inmates presented with cough only, 16 of whom had TB; among those with only abnormal CXR (n = 1273), 92 had TB. Xpert was positive in 155 patients, and negative in 15; these results were confirmed using culture. The remaining 26 patients did not undergo Xpert testing and were confirmed using microscopy (27%), culture (42%) or both (31%). CONCLUSION: The combined use of symptom screening (cough) and CXR was much more effective in maximising TB yield than using either method alone. If patients presenting with cough alone had not been investigated, 10% of TB patients would have been missed; if those with abnormal CXR but no cough had not been investigated, 51% of TB patients would have been missed. We detected high TB prevalence in this prison by using active case finding.
Assuntos
Programas de Rastreamento/métodos , Prisioneiros/estatística & dados numéricos , Tuberculose/epidemiologia , Adolescente , Adulto , Brasil/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Tuberculose/diagnóstico , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: Acute invasive fungal rhinosinusitis carries a high mortality rate. An easy-to-use and accurate predictive imaging model is currently lacking. We assessed the performance of various CT findings for the identification of acute invasive fungal rhinosinusitis and synthesized a simple and robust diagnostic model to serve as an easily applicable screening tool for at-risk patients. MATERIALS AND METHODS: Two blinded neuroradiologists retrospectively graded 23 prespecified imaging abnormalities in the craniofacial region on craniofacial CT examinations from 42 patients with pathology-proven acute invasive fungal rhinosinusitis and 42 control patients proved negative for acute invasive fungal rhinosinusitis from the same high-risk population. A third blinded neuroradiologist decided discrepancies. Specificity, sensitivity, positive predictive value, and negative predictive value were determined for all individual variables. The 23 variables were evaluated for intercorrelations and univariate correlations and were interrogated by using stepwise linear regression. RESULTS: Given the low predictive value of any individual variable, a 7-variable model (periantral fat, bone dehiscence, orbital invasion, septal ulceration, pterygopalatine fossa, nasolacrimal duct, and lacrimal sac) was synthesized on the basis of multivariate analysis. The presence of abnormality involving a single variable in the model has an 87% positive predictive value, 95% negative predictive value, 95% sensitivity, and 86% specificity (R(2) = 0.661). A positive outcome in any 2 of the model variables predicted acute invasive fungal rhinosinusitis with 100% specificity and 100% positive predictive value. CONCLUSIONS: Our 7-variable CT-based model provides an easily applicable and robust screening tool to triage patients at risk for acute invasive fungal rhinosinusitis into a disease-positive or -negative category with a high degree of confidence.
Assuntos
Micoses/diagnóstico por imagem , Rinite/diagnóstico por imagem , Sinusite/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Doença Aguda , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Rinite/microbiologia , Sensibilidade e Especificidade , Sinusite/microbiologiaRESUMO
The design, synthesis, and biochemical profile of meta-substituted benzofused macrocyclic lactams are described. The meta-substituted benzofused macrocyclic lactams were designed to have a degree of flexibility allowing the amide bond to occupy two completely different conformations while maintaining sufficient rigidity to allow for strong interaction between enzyme and inhibitor. Using TFIT, a novel molecular superimposition program, it was shown that the meta analogs could be readily superimposed onto our ACE inhibitor template whereas no low-energy superimpositions of the ortho-substituted macrocycles could be found. The macrocycles were prepared by tethering aldehyde 1 derived from S-glutamic acid or S-aspartic acid to a meta-substituted phosphonium bromide 2. Homologation to a monocarboxylic acid methyl ester malonate followed by deprotection and cyclization gave the macrocyclic frame. Further manipulation gave the desired compounds. Unlike the ortho-substituted benzofused macrocyclic lactams described in the previous paper which are selective NEP inhibitors, the meta-substituted compounds are dual inhibitors of both NEP and ACE. The most potent member of this new series, compound 16a, inhibited both enzymes with an IC50 = 8 nM in NEP and 4 nM in ACE.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/síntese química , Lactamas/síntese química , Neprilisina/antagonistas & inibidores , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Lactamas/química , Lactamas/farmacologia , Modelos Moleculares , Conformação Proteica , Software , Moldes GenéticosRESUMO
The design and preparation of ortho-substituted benzofused macrocyclic lactams are described. The benzofused macrocyclic lactams were designed as neutral endopeptidase 24.11 (NEP) inhibitors. Docking studies were carried out in a model of thermolysin (TLN) using the MACROMODEL and QXP modeling programs to select suitable ring sizes. These studies predicted that the 11-, 12-, and 13-membered ring macrocyclic lactams would be active in both enzymes TLN and NEP. Good predictability of experimental results, within this series, of binding to thermolysin and to a lesser extent to NEP was observed. A visual comparison, docked at the active site of TLN, is presented for thiorphan, a 10-membered ring macrocycle and an 11-membered ring benzofused macrocyclic lactam. Potent inhibition of both NEP and thermolysin was obtained. The 11-membered ring macrocycle 25a is the most potent inhibitor from this series of compounds (TLN IC50 = 68 nM; NEP IC50 = 0.9 nM). The effects of prodrug 44b administered at 10 mg/kg po on plasma atrial natriuretic peptide (ANP) levels in conscious rats was greater than 200% over a 4 h period.
Assuntos
Lactamas/química , Neprilisina/antagonistas & inibidores , Animais , Fator Natriurético Atrial/metabolismo , Sítios de Ligação , Sinergismo Farmacológico , Lactamas/síntese química , Lactamas/farmacologia , Modelos Químicos , Modelos Moleculares , Ratos , Software , Tiorfano/químicaRESUMO
Two general synthetic approaches to a novel series of 2H-[1]benzopyrano[3,4-b]pyridines are described together with their receptor binding profile at a variety of monoamine receptors in mammalian brain tissue. The biologically active members of this series fall into into one of two broad classes: 3,4,4a,5-tetrahydro-2H-[1]benzopyrano[3,4-b]pyridines or trans-1,3,4,4a,5,10b-hexahydro-2H-[1]benzopyrano[3,4-b]pyridines. By appropriate pharmacophoric modification potent selective ligands for D2, alpha-2, 5HT1A, and 5HT2 receptors may be obtained. The previously published in vivo data on certain key representatives of these series are also summarized.
Assuntos
Piridinas/síntese química , Receptores de Neurotransmissores/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fenômenos Químicos , Química , Modelos Moleculares , Piridinas/metabolismo , Piridinas/farmacologia , Ratos , Receptores Adrenérgicos alfa/efeitos dos fármacos , Receptores Adrenérgicos alfa/metabolismo , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Relação Estrutura-AtividadeRESUMO
A general synthetic approach to a novel series of cis-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols is described together with their receptor-binding profile on opioid-receptor subtypes (mu, kappa, delta). In addition, their in vivo antinociceptive activity was assessed. A number of the analogues synthesized showed potent affinity for opioid receptors and have potent antinociceptive activity in a mouse phenylquinone abdominal stretching model. In addition, the SAR for nitrogen substitution in the above series is explored with respect to the overall opioid receptor subtype binding profile. In general it was found that substituents which enhanced mu and kappa binding affinity in the benzomorphan series had a similar effect in the benzofuropyridine series described in this manuscript. An overlap hypothesis topologically connecting the benzomorphan nucleus to the cis-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridine nucleus is also presented.
Assuntos
Analgésicos/síntese química , Piridinas/síntese química , Receptores Opioides/metabolismo , Analgésicos/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Fenômenos Químicos , Química , Cobaias , Masculino , Camundongos , Piridinas/metabolismo , Reflexo de Estiramento/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthesis and receptor-binding profiles at adenosine receptor subtypes for a series of 2-(arylalkylamino)-adenosin-5'-uronamides is described. Halogenated 2-phenethylamino analogues such as 3e show greater than 200-fold selectivity for the A2 receptor subtype on the basis of rat brain receptor binding. The general structure-activity relationship of this series of compounds is discussed both in terms of potency at A2 receptors as well as receptor subtype selectivity. It is possible to introduce a hydrophilic carboxyalkyl substituent to this series such as in CGS 21680A (3h) and still retain good potency and selectivity for A2 receptors. In addition, functional data in a perfused working rat heart model shows that these compounds possess full agonist properties at A2 receptors with 3h having a greater than 1500-fold separation between A2 (coronary vasodilatory) and A1 (negative chronotropic) receptor mediated events.
Assuntos
Adenosina/análogos & derivados , Adenosina/síntese química , Receptores Purinérgicos/metabolismo , Adenosina/farmacologia , Animais , Encéfalo/metabolismo , Circulação Coronária/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Indicadores e Reagentes , Ligantes , Espectroscopia de Ressonância Magnética , Masculino , Estrutura Molecular , Ratos , Ratos Endogâmicos , Relação Estrutura-Atividade , Vasodilatação/efeitos dos fármacosRESUMO
A series of 4-(phosphonoalkyl)- and 4-(phosphonoalkenyl)-2-piperidinecarboxylic acids were synthesized, and their biological activity was assessed as competitive ligands for the NMDA receptor, both in vitro by using a receptor binding assay ([3H]CGS 19755 binding) and in vivo by using an NMDA seizure model in mice. The analogues were also evaluated in [3H]AMPA and [3H]kainate binding to assess their affinity for non-NMDA excitatory amino acid receptor subtypes. A number of these analogues show potent and selective NMDA antagonistic activity both in vitro and in vivo. Most notable are 4-(phosphonomethyl)-2-piperidinecarboxylic acid (1a) (CGS 19755) and the phosphonopropenyl analogue 1i, both of which show anticonvulsant activity in the 1-2 mg/kg ip range. With the aid of computer-assisted modeling, a putative bioactive conformation for AP-5 is hypothesized from the SAR data presented and a preliminary model for the antagonist-preferring state of the NMDA receptor is presented.
Assuntos
Anticonvulsivantes/síntese química , Ácido Aspártico/análogos & derivados , Ácidos Pipecólicos , Piperidinas/síntese química , Receptores de Neurotransmissores/metabolismo , Animais , Anticonvulsivantes/metabolismo , Anticonvulsivantes/farmacologia , Ácido Aspártico/metabolismo , Fenômenos Químicos , Química , Masculino , Camundongos , N-Metilaspartato , Piperidinas/metabolismo , Piperidinas/farmacologia , Receptores de N-Metil-D-Aspartato , Receptores de Neurotransmissores/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The Philippines is an archipelago of about 7000 islands, with an area about the size of England, situated just above the equator in Southeast Asia. It has a population of 70 million. The Philippines has had extensive commercial and social contact with Asian neighbors, specifically the Chinese, even before the 377 years of Spanish colonization from 1521 to 1898 and the 48 years of American rule from 1898 to 1946. More than 80% of Filipinos are Catholics; the rest are Muslims and Protestants of various denominations, including those who belong to Filipino church groups. Infectious diseases such as tuberculosis, amoebiasis, typhoid fever, and malaria are still prevalent, and arteriosclerosis, cancer, and stroke are common and on the rise.
Assuntos
Cirurgia Geral/educação , Currículo , Educação de Graduação em Medicina , Cirurgia Geral/história , Sistemas Pré-Pagos de Saúde , História do Século XVI , História do Século XVII , História do Século XVIII , História do Século XIX , História do Século XX , Internato e Residência , Filipinas , Pesquisa , Faculdades de Medicina , Recursos HumanosRESUMO
A microdissection study was carried out on ten injected, cleared human sternal specimens. Three types of vessel were identified that have the potential to carry blood to the sternum after mobilization of the internal thoracic artery (ITA): (1) branches of the ITA that supply both the sternum and the pectoralis major ("sternal/perforating branches"), (2) branches of the ITA that supply both the sternum and an adjoining intercostal space ("sternal/intercostal branches"), and (3) posterior intercostal arteries that do not anastomose with an ITA branch but continue past the ITA to reach the sternum. All three types of vessel were found more frequently in the proximal than in the distal half of the sternum. For sternal/perforating and sternal/intercostal vessels to function as collaterals after ITA bypass grafting, their short common trunks of origin must remain intact. The data support the recommendation that the branches of the ITA be ligated as close as possible to the ITA itself to preserve collateral blood flow to the sternum.
Assuntos
Circulação Colateral , Esterno/irrigação sanguínea , Idoso , Idoso de 80 Anos ou mais , Humanos , Artérias Torácicas/anatomia & histologia , Artérias Torácicas/transplanteRESUMO
The aim is to describe the technique of preoperative CT-guided hookwire localization of small, but suspicious, cervical lymph nodes. We present 3 patients who underwent the procedure for nonpalpable cervical nodes detected on PET/CT prior to complete surgical resection of the nodes. The details of the radiological procedure, surgical outcomes, and pathologic results are described. The mean intervention time for preoperative hookwire localization was 9 minutes (range 7-14 minutes). There were no complications. All surgeons felt that the lengths of the surgical skin incision and operative times were reduced because of localization. The pathologic diagnoses were 2 benign nodes and 1 case of metastatic ovarian carcinoma. In conclusion, preoperative CT-guided hookwire localization is a useful technique for guiding surgical excision, especially when cervical nodes are small and deep in location.