RESUMO
OBJECTIVE: We tested the hypothesis in sense of a proof of principle that white matter (WM) degeneration after cardiopulmonary arrest (CPA) can be assessed much earlier by diffusion tensor imaging (DTI) than by conventional MRI. METHODS: We performed DTI and T2-weighted FLAIR imaging over four serial acquisitions of a 76-year-old man with unresponsive wakefulness syndrome at day 41, 75, 173 and 284 after CPA. DTI was also performed in ten healthy control subjects. Fractional anisotropy (FA) derived from DTI was assessed in eleven regions of interest within the cerebral white matter (WM) and compared with post-mortem neuropathological findings. RESULTS: In contrast to conventional FLAIR images that revealed only circumscribed WM damage, the first DTI demonstrated significant reduction of FA across the whole WM. The following FLAIR images (MRI 2-4) revealed increasing atrophy and leukoaraiosis paralleled by clinical deterioration with reduction of wakefulness and intractable seizures. Neuropathological findings confirmed the widespread and marked brain injury following CPA. CONCLUSION: DTI may help to evaluate microstructural brain damage following CPA and may have predictive value for further evolution of cerebral degeneration in the chronic phase after CPA.
Assuntos
Lesões Encefálicas/diagnóstico , Lesões Encefálicas/patologia , Imagem de Tensor de Difusão , Progressão da Doença , Parada Cardíaca/complicações , Adulto , Idoso , Autopsia , Lesões Encefálicas/complicações , Diagnóstico Precoce , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: As compared with individual tablets, saxagliptin/metformin immediate release (IR) fixed-dose combination (FDC) tablets offer the potential for increased convenience, compliance, and adherence for patients requiring combination therapy. OBJECTIVES: Two bioequivalence studies assessed the fed-state and the fasted-state bioequivalence of saxagliptin/metformin IR 2.5 mg/500 mg FDC (study 1) and saxagliptin/metformin IR 2.5 mg/1,000 mg FDC (study 2) relative to the same dosage strengths of the individual component tablets [saxagliptin (Onglyza™) and metformin IR (Glucophage(®))] administered concurrently. STUDY DESIGNS: These were randomized, open-label, single-dose, four-period, four-treatment, crossover studies in healthy subjects (n = 24 in each study). The treatments in study 1 were a saxagliptin/metformin IR 2.5 mg/500 mg FDC tablet in the fed and fasted states on separate occasions, and saxagliptin 2.5 mg and metformin IR 500 mg tablets co-administered in the fed state and fasted states on separate occasions. The treatments in study 2 were a saxagliptin/metformin IR 2.5 mg/1,000 mg FDC tablet in the fed and fasted states on separate occasions, and saxagliptin 2.5 mg and metformin IR 1,000 mg co-administered in the fed state and fasted states on separate occasions. The pharmacokinetics, safety, and tolerability of each treatment were evaluated. RESULTS: For both studies, saxagliptin and metformin in the FDCs were bioequivalent to the individual components in both the fed and the fasted states as the limits of the 90 % confidence interval of the ratio of adjusted geometric means for all key pharmacokinetic parameters were contained within the predefined 0.800 to 1.250 bioequivalence criteria. Co-administration of saxagliptin and metformin IR was generally safe and well tolerated as the FDCs or as individual tablets. CONCLUSIONS: Saxagliptin/metformin IR 2.5 mg/500 mg and saxagliptin/metformin IR 2.5 mg/1,000 mg FDCs were bioequivalent to individual tablets of saxagliptin and metformin of the same strengths in both the fed and the fasted states. No unexpected safety findings were observed with saxagliptin/metformin IR administration. The tolerability of the FDC of saxagliptin/metformin IR was comparable to that of the co-administered individual components. These results indicate that the safety and efficacy profile of co-administration of saxagliptin and metformin can be extended to the saxagliptin/metformin IR FDC tablets.
Assuntos
Adamantano/análogos & derivados , Dipeptídeos/farmacocinética , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Adamantano/administração & dosagem , Adamantano/sangue , Adamantano/farmacocinética , Administração Oral , Adulto , Química Farmacêutica , Estudos Cross-Over , Preparações de Ação Retardada , Dipeptídeos/administração & dosagem , Dipeptídeos/sangue , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/sangue , Combinação de Medicamentos , Quimioterapia Combinada , Jejum/sangue , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Masculino , Metformina/administração & dosagem , Metformina/sangue , New Jersey , Período Pós-Prandial , Comprimidos , Equivalência Terapêutica , Adulto JovemRESUMO
INTRODUCTION: This phase III study compared efficacy and safety of topotecan-cisplatin (TP) versus topotecan-etoposide (TE) versus cisplatin-etoposide (PE) in chemo-naïve extensive disease small-cell lung cancer patients. METHODS: Seven hundred and ninety-five previously untreated patients were randomly assigned to TP (topotecan 1mg/m IV, d1-5; cisplatin 75 mg/m IV, d5; n = 358), PE (cisplatin 75 mg/m IV, d1; etoposide 100 mg/m IV, d1-3; n = 345) or TE (topotecan 1mg/m IV, d1-5; etoposide 80 mg/m IV, d3-5; n = 92). Primary endpoint was superiority of TP compared with PE, with the possibility to switch to a noninferiority test. RESULTS: The TE arm was closed after recommendations by the Independent Data Safety Monitoring Board. Median survival was similar and met the predefined endpoint of noninferiority of TP to PE (44.9 versus 40.9 weeks; p = 0.40). One-year survival rate showed 39.7% for TP versus 36.1% for PE (p = 0.29). Median time to progression was significantly longer with TP (27.4 versus 24.3 weeks, p = 0.01). Overall response rates were significantly higher for TP (55.5% versus 45.5%, p = 0.01).Hematologic toxicity was slightly higher for TP regarding G 3/4 neutropenia (35.7/35.8%), G 3/4 thrombocytopenia (18.7/4.8%), G 3/4 anemia (11.6/6.7%), febrile neutropenia (2.0/2.7%), sepsis (1.7/1.2%), and toxicity-related deaths (5.2/2.7%). CONCLUSION: TP is noninferior to PE in overall survival and superior in time to progression and overall response rates. Because of slightly worse toxicity profile TP is not a first-line standard treatment for patients with extensive disease small-cell lung cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Grandes/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Adulto , Idoso , Carcinoma de Células Grandes/patologia , Cisplatino/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Carcinoma de Pequenas Células do Pulmão/patologia , Topotecan/administração & dosagemRESUMO
BACKGROUND AND OBJECTIVE: Patients with type 2 diabetes mellitus often have impaired renal function or may have impaired hepatic function, which can pose significant safety and tolerability issues for antihyperglycaemic pharmacotherapies. Therefore, the pharmacokinetics and tolerability of saxagliptin and its pharmacologically active metabolite, 5-hydroxy saxagliptin, in nondiabetic subjects with mild, moderate or severe renal or hepatic impairment, or end-stage renal disease (ESRD) were compared with saxagliptin and metabolite pharmacokinetics and tolerability in healthy adult subjects. METHODS: Two open-label, parallel-group, single-dose studies were conducted. Subjects received a single oral dose of saxagliptin 10 mg (Onglyza™). RESULTS: Compared with healthy subjects, the geometric mean area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC∞) for saxagliptin was 16%, 41% and 108% (2.1-fold) higher in subjects with mild, moderate or severe renal impairment, respectively. AUC∞ values for 5-hydroxy saxagliptin were 67%, 192% (2.9-fold) and 347% (4.5-fold) higher in subjects with mild, moderate or severe renal impairment, respectively. As creatinine clearance (CLCR) values decreased, saxagliptin and 5-hydroxy saxagliptin AUC∞ generally increased or became more variable. Twenty-three percent of the saxagliptin dose (measured as the sum of saxagliptin and 5-hydroxy saxagliptin) was cleared by haemodialysis in a 4-hour dialysis session. In the hepatic impairment study, the differences in exposure to saxagliptin and 5-hydroxy saxagliptin were less than 2-fold across all groups. As compared with healthy subjects matched for age, bodyweight, sex and smoking status, the AUC∞ values for saxagliptin were 10%, 38% and 77% higher in subjects with mild, moderate or severe hepatic impairment, respectively. These values were 22%, 7% and 33% lower, respectively, for 5-hydroxy saxagliptin compared with matched healthy subjects. CONCLUSIONS: One-half the usual dose of saxagliptin 5 mg (i.e. 2.5 mg orally once daily) is recommended for patients with moderate (CLCR 30-50 mL/min) or severe (CLCR<30 mL/min not on dialysis) renal impairment or ESRD, but no dose adjustment is recommended for those with mild renal impairment or any degree of hepatic impairment.
Assuntos
Adamantano/análogos & derivados , Dipeptídeos/farmacocinética , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Insuficiência Hepática/metabolismo , Hipoglicemiantes/farmacocinética , Insuficiência Renal/metabolismo , Adamantano/efeitos adversos , Adamantano/análise , Adamantano/sangue , Adamantano/farmacocinética , Adamantano/urina , Adulto , Idoso , Diabetes Mellitus Tipo 2/tratamento farmacológico , Soluções para Diálise/química , Dipeptídeos/efeitos adversos , Dipeptídeos/análise , Dipeptídeos/sangue , Dipeptídeos/urina , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/análise , Feminino , Meia-Vida , Insuficiência Hepática/sangue , Insuficiência Hepática/urina , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/análise , Falência Renal Crônica/sangue , Falência Renal Crônica/metabolismo , Falência Renal Crônica/terapia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Diálise Renal , Insuficiência Renal/sangue , Insuficiência Renal/urina , Índice de Gravidade de DoençaRESUMO
PURPOSE: To determine whether adding cetuximab to irinotecan prolongs survival in patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine and oxaliplatin. PATIENTS AND METHODS: This multicenter, open-label, phase III study randomly assigned 1,298 patients with epidermal growth factor receptor-expressing mCRC who had experienced first-line fluoropyrimidine and oxaliplatin treatment failure to cetuximab (400 mg/m(2) day 1 followed by 250 mg/m(2) weekly) plus irinotecan (350 mg/m(2) every 3 weeks) or irinotecan alone. Primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate (RR), and quality of life (QOL). RESULTS: Median OS was comparable between treatments: 10.7 months (95% CI, 9.6 to 11.3) with cetuximab/irinotecan and 10.0 months (95% CI, 9.1 to 11.3) with irinotecan alone (hazard ratio [HR], 0.975; 95% CI, 0.854 to 1.114; P = .71). This lack of difference may have been due to post-trial therapy: 46.9% of patients assigned to irinotecan eventually received cetuximab (87.2% of those who did, received it with irinotecan). Cetuximab added to irinotecan significantly improved PFS (median, 4.0 v 2.6 months; HR, 0.692; 95% CI, 0.617 to 0.776; P Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
, Camptotecina/análogos & derivados
, Neoplasias Colorretais/tratamento farmacológico
, Adulto
, Idoso
, Idoso de 80 Anos ou mais
, Anticorpos Monoclonais/administração & dosagem
, Anticorpos Monoclonais/efeitos adversos
, Anticorpos Monoclonais Humanizados
, Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
, Camptotecina/administração & dosagem
, Camptotecina/efeitos adversos
, Camptotecina/uso terapêutico
, Cetuximab
, Neoplasias Colorretais/patologia
, Intervalo Livre de Doença
, Receptores ErbB/biossíntese
, Feminino
, Humanos
, Irinotecano
, Masculino
, Pessoa de Meia-Idade
, Metástase Neoplásica
, Compostos Organoplatínicos/administração & dosagem
, Compostos Organoplatínicos/efeitos adversos
, Oxaliplatina
, Pirimidinas/administração & dosagem
, Pirimidinas/efeitos adversos
, Qualidade de Vida
RESUMO
The structure-activity relationship study focused on the polar region of the HTS hit A-80040 (1) producing several series of potent and selective ACC2 inhibitors. The SAR suggests a compact lipophilic pocket that does not tolerate polar and ionic groups. Replacement of the hydroxyurea group with isoxazoles improves ACC2 selectivity while maintaining potency. Variations at the propargylic site of 11a reduce ACC2 potency.
Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Alcinos/síntese química , Alcinos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Acetil-CoA Carboxilase/genética , Fenômenos Químicos , Físico-Química , Humanos , Hidroxiureia/química , Isoxazóis/síntese química , Isoxazóis/farmacologia , Conformação Molecular , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
Potent and selective adamantane sulfone and sulfonamide inhibitors of 11-beta-HSD-1 have been discovered. Selected compounds from these series have robust pharmacokinetic profiles and strongly inhibit liver, fat, and brain HSD1 for extended periods after oral dosing.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Adamantano/síntese química , Adamantano/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , Tecido Adiposo/enzimologia , Animais , Encéfalo/enzimologia , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/farmacocinética , Humanos , Indicadores e Reagentes , Fígado/enzimologia , Camundongos , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
A series of potent and selective adamantane aminoamide 11-beta-HSD-1 inhibitors has been optimized. Chemically these studies were expedited by utilizing readily obtained amino acids as starting materials or an isocyanide multicomponent reaction. Structure-activity relationship studies resulted in the discovery of dual human and mouse 11-beta-HSD-1 potent and selective inhibitors like adamantane 11 and related compounds with high metabolic stability and robust pharmacokinetic profiles.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/síntese química , Adamantano/farmacologia , Cianetos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Adamantano/química , Adamantano/farmacocinética , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
High throughput screening efforts have identified a novel class of dichloroaniline amide 11beta-HSD1 inhibitors. SAR studies initiated from dichloroaniline 4 focused on retaining the potency and selectivity profile of the lead.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Síndrome Metabólica/tratamento farmacológico , Carbenoxolona/química , Carbenoxolona/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Conformação Molecular , Piperazinas/química , Piperazinas/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Tiazóis/química , Tiazóis/farmacologiaRESUMO
Structure-activity relationships for a recently discovered thiazolyl phenyl ether series of acetyl-CoA carboxylase (ACC) inhibitors were investigated. Preliminary efforts to optimize the series through modification of the distal aryl ether moiety of the lead scaffold resulted in the identification of compounds exhibiting low-nanomolar potency and isozyme-selective ACC2 activity.
Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Éteres Fenílicos/química , Éteres Fenílicos/farmacologia , Acetil-CoA Carboxilase/metabolismo , Inibidores Enzimáticos/química , Estrutura Molecular , Éteres Fenílicos/síntese química , Relação Estrutura-AtividadeRESUMO
A structurally novel acetyl-CoA carboxylase (ACC) inhibitor is identified from high-throughput screening. A preliminary structure-activity relationship study led to the discovery of potent dual ACC1/ACC2 and ACC2 selective inhibitors against human recombinant ACC1 and ACC2. Selective ACC2 inhibitors exhibited IC50<20 nM and >1000-fold selectivity against ACC1. (S)-Enantiomer 9p exhibited high ACC2 activity and lowered muscle malonyl-CoA dose-dependently in acute rodent studies, whereas (R)-enantiomer 9o was weak and had no effect on the malonyl-CoA level.
Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Alcinos/síntese química , Hipoglicemiantes/síntese química , Tiazóis/síntese química , Acetil-CoA Carboxilase/genética , Alcinos/farmacocinética , Alcinos/farmacologia , Animais , Linhagem Celular , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Técnicas In Vitro , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Malonil Coenzima A/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologiaRESUMO
We have sought to understand the regulation of the expression pattern of aldolase C (Zebrin II) in cerebellar Purkinje cells. Normally, aldolase C is expressed in a series of sagittal stripes of Purkinje cells interrupted by stripes of little or no expression. Genomic aldolase C:LacZ fusion genes with 1.8 kb of sequence 5' to the transcription start site drive CNS expression of LacZ only in astrocytes and cells of the pia mater. If the 5' portion of the transgene is extended to a full 5.0 kb, expression is reliably observed in Purkinje cells, yet none of the astrocyte expression is lost. We broke the additional 3.0 kb into 1.0 kb fragments and tested each for Purkinje cell enhancer activity when appended to the original 1.8 kb construct. We show that the 886 bp region from nucleotide -2796 to -3682 (relative to the start of transcription) contains virtually all of the Purkinje cell enhancer activity. However, neither the full 5.0 kb nor the 886 bp region directed a striped expression pattern, as is seen for the endogenous gene. Taken together, our study localizes a Purkinje cell enhancer to a small 5' region of the aldolase C gene and illustrates that the element(s) responsible for the normal anatomically complex pattern of aldolase C expression are separate from those conferring cell-type specificity. The relationship of these findings to previous work in other laboratories is discussed.
Assuntos
Cerebelo/citologia , Frutose-Bifosfato Aldolase/metabolismo , Regulação da Expressão Gênica , Genes Reguladores/fisiologia , Células de Purkinje/metabolismo , Animais , Western Blotting/métodos , Elementos Facilitadores Genéticos/fisiologia , Frutose-Bifosfato Aldolase/genética , Biblioteca Genômica , Imuno-Histoquímica/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Dados de Sequência MolecularRESUMO
The modulation of fatty acid metabolism and especially the stimulation of fatty acid oxidation in liver or skeletal muscle are attractive therapeutic approaches for the treatment of obesity and the associated insulin resistance. However, current beta-oxidation assays are run in very low throughput, which represents an obstacle for drug discovery in this area. Here we describe results for a 48-well beta-oxidation assay using a new instrument design. A connecting chamber links two adjacent wells to form an experimental unit, in which one well contains the beta-oxidation reaction and the other captures CO(2). The experimental units are sealed from each other and from the outside to prevent release of radioactivity from the labeled substrate. CO(2) capture in this instrument is linear with time and over the relevant experimental range of substrate concentration. Cellular viability is maintained in the sealed environment, and cells show the expected responses to modulators of beta-oxidation, such as the AMP kinase activator 5-aminoimidazole carboxamide riboside. Data are presented for different lipid substrates and cell lines. The increased throughput of this procedure compared with previously described methods should facilitate the evaluation of compounds that modulate fatty acid metabolism.
Assuntos
Bioensaio/instrumentação , Ácidos Graxos/metabolismo , Animais , Caprilatos/metabolismo , Dióxido de Carbono/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Separação Celular , Sobrevivência Celular/efeitos dos fármacos , Glucose/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Técnicas In Vitro , Neoplasias Hepáticas/metabolismo , Oxirredução , Palmitatos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
A novel and innovative high-throughput screening assay was developed to identify both activators and inhibitors of AMP-activated protein kinase (AMPK) using microarrayed compound screening (microARCS) technology. Test compounds were arrayed at a density of 8640 on a polystyrene sheet, and the enzyme and peptide substrate were introduced into the assay by incorporating them into an agarose gel followed by placement of the gels onto the compound sheet. Adenosine triphosphate (ATP) was delivered via a membrane, and the phosphorylated biotinylated substrate was captured onto a streptavidin affinity membrane (SAM trade mark ). For detection, the SAM trade mark was removed, washed, and imaged on a phosphor screen overnight. A library of more than 700,000 compounds was screened using this format to identify novel activators and inhibitors of AMPK.
Assuntos
Complexos Multienzimáticos/antagonistas & inibidores , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP , Trifosfato de Adenosina/análise , Animais , Miniaturização , Complexos Multienzimáticos/análise , Proteínas Serina-Treonina Quinases/análise , Ratos , Sensibilidade e Especificidade , Fatores de TempoAssuntos
Neoplasias do Sistema Nervoso Central/diagnóstico , Neuroborreliose de Lyme/diagnóstico , Linfoma de Células T/diagnóstico , Adulto , Neoplasias do Sistema Nervoso Central/patologia , Diagnóstico Diferencial , Feminino , Humanos , Neuroborreliose de Lyme/fisiopatologia , Linfoma de Células T/patologia , Imageamento por Ressonância MagnéticaRESUMO
PURPOSE: This trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group compares the use of high-dose therapy (HDT) as part of primary treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus etoposide followed by involved-field (IF) radiotherapy in a randomized, multicenter, phase III study. PATIENTS AND METHODS: Three hundred twelve patients with "aggressive" non-Hodgkin's lymphoma aged Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
, L-Lactato Desidrogenase/sangue
, Linfoma não Hodgkin/enzimologia
, Linfoma não Hodgkin/terapia
, Transplante de Células-Tronco
, Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
, Carmustina/administração & dosagem
, Quimioterapia Adjuvante
, Ciclofosfamida/administração & dosagem
, Citarabina/administração & dosagem
, Doxorrubicina/administração & dosagem
, Esquema de Medicação
, Etoposídeo/administração & dosagem
, Feminino
, Alemanha
, Humanos
, Linfoma não Hodgkin/tratamento farmacológico
, Linfoma não Hodgkin/radioterapia
, Masculino
, Melfalan/administração & dosagem
, Pessoa de Meia-Idade
, Prednisolona/administração & dosagem
, Prognóstico
, Estudos Prospectivos
, Radioterapia Adjuvante
, Risco
, Análise de Sobrevida
, Transplante Autólogo
, Resultado do Tratamento
, Vincristina/administração & dosagem
RESUMO
Six NAT2 single-nucleotide polymorphisms (SNPs) were analysed in 105 unrelated Ngawbe and 136 unrelated Embera Amerindians (482 chromosomes) by SNP-specific polymerase chain reaction analysis. 282C>T was the most common synonymous mutation, while 857G>A was the most frequent nonsynonymous inactivating exchange. The allelic frequency of the NAT2*5 series (containing the 341T>C exchange) was 2.4% and 9.9% for Ngawbe and Embera, respectively, five- to 20-times lower than that in Caucasians. The NAT2*6 series (590G>A) showed allelic frequencies of 0% and 3.7%, eight- to 30-times lower than in Caucasians. On the other hand, the NAT2*7 series, characterized by mutation 857G>A, had allelic frequencies (23.3% and 22.8%) that were 10-20-times higher in Amerindians than in Caucasians. Amerindians are characterized by decreased genetic diversity because they display a low number of mutated alleles (four and five for Ngawbe and Embera, respectively) that are present at low proportions (27.6% and 39%), reduced genotypic variability (seven out of 15 and 12 out of 21 possible genotypes) and low heterozygosity (40% and 55.1%) at the NAT2 locus. The NAT2 phenotype was evaluated with caffeine in a subset of 72 Embera. There were no disagreements between genotype and phenotype among rapid and slow acetylators (13/72, 18%). We conclude that, in the Embera, the analysis of three inactivating mutations was sufficient in predicting the phenotype in more than 99.5% of these subjects. NAT2 would appear to be of a selectively neutral character given that there is no evidence of adaptation to the prevailing ecology in Amerindians.
Assuntos
Arilamina N-Acetiltransferase/genética , Cafeína , Indígenas Centro-Americanos/genética , Indígenas Sul-Americanos/genética , Polimorfismo de Nucleotídeo Único/genética , Acetilação , Evolução Molecular , Frequência do Gene , Variação Genética , Genótipo , Humanos , Modelos Genéticos , Panamá , Fenótipo , Seleção GenéticaRESUMO
OBJECTIVE: To assess the influence of an oral contraceptive (OC) containing 20 microg ethinylestradiol and 150 microg desogestrel on quality of life and subjective symptoms. METHODS: In this multicenter observational evaluation performed in Germany, 3679 first-time OC users were included. They were treated by 623 physicians. The women completed quality of life questionnaires (Q-LES-Q) at baseline and after three treatment cycles. RESULTS: The mean age of users (+/- SD) was 22.5 +/- 7.1 years, with 47% of the women aged between 15 and 20 years. Half of the women reported skin problems at inclusion and, of these, 36% reported disappearance of the problems after three treatment cycles. Most women suffering from subjective symptoms (headache, nausea, nervousness, breast tenderness and depressive moods) at baseline reported improvements (57-71%) in their symptoms after using the OC for three cycles. Adverse events were reported by 4% of users; the most frequently reported were bleeding irregularities (1.7%). The total quality-of-life score and all its 13 individual items improved significantly (p < 0.0001), with the largest improvements in sex life and mood. Almost all (94%) women were either very satisfied or satisfied with the medication. CONCLUSION: The OC containing ethinylestradiol and desogestrel significantly improved the quality of life and subjective symptoms. The OC was well tolerated by first-time users.
Assuntos
Anticoncepcionais Orais Combinados/administração & dosagem , Desogestrel/administração & dosagem , Qualidade de Vida , Adolescente , Adulto , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Alemanha , Humanos , Satisfação do Paciente , Estatísticas não Paramétricas , Inquéritos e QuestionáriosRESUMO
Previous experiments indicate that the shape of maps of preferred orientation in the primary visual cortex does not depend on visual experience. We propose a network model that demonstrates that the orientation and direction selectivity of individual units and the structure of the corresponding angle maps could emerge from local recurrent connections. Our model reproduces the structure of preferred orientation and direction maps, and explains the origin of their interrelationship. The model also provides an explanation for the correlation between position shifts of receptive fields and changes of preferred orientations of single neurons across the surface of the cortex.