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1.
Brain Res Bull ; 178: 29-36, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34798218

RESUMO

The benign prostatic hyperplasia (BPH) is the main source of lower urinary tract symptoms. The BPH is a common age-dependent disease and tamsulosin is an α1-adrenoceptor blocker widely prescribed for BPH. Beyond the common adverse effects of tamsulosin, increased diagnosis of dementia after prescription was observed. Importantly, a clinical study suggested that tamsulosin may exert antidepressant effects in BPH patients. Considering the expression of α1-adrenoceptors in the brain, this study aimed to investigate the effects of tamsulosin in the forced swimming and open field tests in mice. For this, tamsulosin (0.001-1 mg/kg) was orally administered subacutely (1, 5 and 23 hr) and acutely (60 min) before tests. Mifepristone (10 mg/kg), a glucocorticoid receptor antagonist, and aminoglutethimide (10 mg/kg), a streoidogenesis inhibitor, were intraperitoneally injected before tamsulosin to investigate the role of the hypothalamic-pituitary-adrenal axis in the mediation of tamsulosin-induced effects. Subacute and acute administrations of tamsulosin increased the immobility time in the first exposition to an inescapable stressful situation. In the re-exposition to the swim task, controls displayed a natural increase in the immobility time, and the treatment with tamsulosin further increased this behavioral parameter. Tamsuslosin did not affect spontaneous locomotion neither in naïve nor in stressed mice. Our findings also showed that mifepristone and aminoglutethimide prevented the tamsulosin-induced increase in the immobility time in the first and second swimming sessions, respectively. In conclusion, tamsulosin may contribute to increased susceptibility to depressive-like behaviors, by facilitating the acquisition of a passive stress-copying strategy. These effects seem to be dependent on endogenous glucocorticoids.


Assuntos
Adaptação Psicológica/efeitos dos fármacos , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Inibidores da Aromatase/farmacologia , Depressão/induzido quimicamente , Antagonistas de Hormônios/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Receptores de Glucocorticoides/antagonistas & inibidores , Tansulosina/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Aminoglutetimida/farmacologia , Animais , Inibidores da Aromatase/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Antagonistas de Hormônios/administração & dosagem , Camundongos , Mifepristona/farmacologia , Tansulosina/administração & dosagem
2.
J Chromatogr A ; 1634: 461672, 2020 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-33220588

RESUMO

The VariCol process is a variant of the conventional simulated moving bed (SMB) process, distinguished by the asynchronous shifting of the inlet and outlet ports of the chromatographic column train. This feature allows for a more flexible operation in column utilization and can also achieve higher separation performances. However, to take full benefit out of it, the operating parameters, such as the strategy for port switching, must be optimal. in this paper, a novel methodology for optimizing those parameters, based on a single NLP (non-linear programming), is proposed. The main advantage of this approach is that it significantly reduces the complexity of the original MINLP (mixed-integer non-linear programming) formulation currently discussed in the literature. The proposed optimization problem is built, considering that the average column configuration of three zones provides the necessary and sufficient information to describe the VariCol process. Several optimization scenarios for the enantioseparation of 1,1´-bi-2-naphthol and aminoglutethimide were considered to evaluate the proposed methodology and to compare the performance of VariCol and SMB processes. The results have shown that with the single NLP approach, it is possible to explore the optimal solution in all the VariCol process domains with less computational effort than other optimization strategies reported in the literature. That is a great advantage, especially in the context of real-time applications.


Assuntos
Cromatografia/instrumentação , Cromatografia/normas , Adsorção , Aminoglutetimida/isolamento & purificação , Naftóis/isolamento & purificação
3.
Pharm Res ; 37(10): 193, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32914377

RESUMO

PURPOSE: The incidence of breast cancer worldwide has been on the rise since the late 1970s, and it has become a common tumor that threatens women's health. Aminoglutethimide (AG) is a common treatment of breast cancer. However, current treatments require frequent dosing that results in unstable plasma concentration and low bioavailability, risking serious adverse reactions. Our goal was to develop a molecularly imprinted polymer (MIP) based delivery system to control the release of AG and demonstrate the availability of this drug delivery system (DDS), which was doped with carbon nanotube with aid of metal-organic gel. METHODS: Preparation of MIP was optimized by key factors including composition of formula, ratio of monomers and drug loading concentration. RESULTS: By using multi-walled carbon nanotubes (MWCNT) and metal-organic gels (MOGs), MIP doubled the specific surface area, pore volume tripled and the IF was 1.6 times than the reference. Compared with commercial tablets, the relative bioavailability was 143.3% and a more stable release appeared. CONCLUSIONS: The results highlight the influence of MWCNT and MOGs on MIP, which has great potential as a DDS.


Assuntos
Aminoglutetimida/química , Antineoplásicos Hormonais/química , Complexos de Coordenação/química , Sistemas de Liberação de Medicamentos/métodos , Nanotubos de Carbono/química , Aminoglutetimida/administração & dosagem , Aminoglutetimida/farmacocinética , Animais , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/farmacocinética , Complexos de Coordenação/administração & dosagem , Compostos Férricos/química , Géis/administração & dosagem , Géis/química , Humanos , Células MCF-7 , Masculino , Impressão Molecular/métodos , Ratos , Ácidos Tricarboxílicos/química
4.
PLoS One ; 15(6): e0233563, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497050

RESUMO

Activation of the steroidogenic enzyme CYP11A1 was shown to be necessary for the development of peanut-induced intestinal anaphylaxis and IL-13 production in allergic mice. We determined if levels of CYP11A1 in peripheral blood T cells from peanut-allergic (PA) children compared to non-allergic controls were increased and if levels correlated to IL-13 production and oral challenge outcomes to peanut. CYP11A1 mRNA and protein levels were significantly increased in activated CD4+ T cells from PA patients. In parallel, IL-13 production was significantly increased; IFNγ levels were not different between groups. There were significant correlations between expression levels of CYP11A1 mRNA and levels of IL13 mRNA and protein, levels of serum IgE anti-Ara h 2 and to outcomes of peanut challenge. The importance of CYP11A1 on cytokine production was tested using a CYP11A1 CRISPR/Cas9 KO plasmid or an inhibitor of enzymatic CYP11A1 activity. Inhibition of CYP11A1 activation in patient cells treated with the inhibitor, aminoglutethimide, or CD4+ T cell line transfected with the CYP11A1 KO plasmid resulted in reduced IL-13 production. These data suggest that the CYP11A1-CD4+Tcell-IL-13 axis in activated CD4+ T cells from PA children is associated with development of PA reactions. CYP11A1 may represent a novel target for therapeutic intervention in PA children.


Assuntos
Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Interleucina-13/biossíntese , Hipersensibilidade a Amendoim/imunologia , Células Th2/imunologia , Adolescente , Aminoglutetimida/farmacologia , Linhagem Celular , Criança , Pré-Escolar , Enzima de Clivagem da Cadeia Lateral do Colesterol/antagonistas & inibidores , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Feminino , Técnicas de Inativação de Genes , Humanos , Ativação Linfocitária , Masculino , Hipersensibilidade a Amendoim/sangue , RNA Mensageiro/genética , Transfecção , Adulto Jovem
5.
Physiol Res ; 69(3): 415-426, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32469228

RESUMO

Glucocorticoids (GCS) are known to modulate cardiovascular response during stress conditions. The present study was aimed to test the hypothesis that permissive and/or stimulating effect of GCs is essential for the maintenance of peripheral vascular resistance and for the adequate response of cardiovascular system to stressor exposure. The effects of acute pharmacological adrenalectomy (PhADX) on humoral and cardiovascular parameters were studied in adult Wistar rats under the basal conditions and during the acute restraint stress. Acute PhADX was performed by the administration of metyrapone and aminoglutethimide (100 mg/kg s.c. of each drug) resulting in a suppression of endogenous glucocorticoid synthesis. Blood pressure (BP), heart rate (HR) and core body temperature were measured using radiotelemetry. BP responses to administration of vasoactive agents were determined in pentobarbital-anesthetized animals. PhADX considerably attenuated stress-induced increase of BP, HR and core body temperature. PhADX did not abolish BP and HR lowering effects of ganglionic blocker pentolinium indicating preserved sympathetic function in PhADX rats. BP response to exogenous norepinephrine administration was attenuated in PhADX rats, suggesting reduced sensitivity of cardiovascular system. Suppression of corticosterone synthesis by PhADX increased basal plasma levels of ACTH, aldosterone and plasma renin activity in unstressed animals but there was no further increase of these hormones following stressor exposure. In conclusion, PhADX attenuated stress-induced rise of blood pressure, heart rate and core body temperature indicating an important permissive and/or stimulating role of glucocorticoids in the maintenance of the adequate response of cardiovascular system and thermoregulation to several stimuli including acute exposure to stressor.


Assuntos
Aminoglutetimida/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Glucocorticoides/antagonistas & inibidores , Frequência Cardíaca/efeitos dos fármacos , Metirapona/farmacologia , Restrição Física/fisiologia , Adrenalectomia , Animais , Antimetabólitos/farmacologia , Inibidores da Aromatase/farmacologia , Modelos Animais de Doenças , Glucocorticoides/biossíntese , Masculino , Ratos , Ratos Wistar , Resistência Vascular/efeitos dos fármacos
6.
Int J Mol Sci ; 20(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31510070

RESUMO

A key role of the mitochondrial Translocator Protein 18 KDa (TSPO) in neuroinflammation has been recently proposed. However, little is known about TSPO-activated pathways underlying the modulation of reactive microglia. In the present work, the TSPO activation was explored in an in vitro human primary microglia model (immortalized C20 cells) under inflammatory stimulus. Two different approaches were used with the aim to (i) pharmacologically amplify or (ii) silence, by the lentiviral short hairpin RNA, the TSPO physiological function. In the TSPO pharmacological stimulation model, the synthetic steroidogenic selective ligand XBD-173 attenuated the activation of microglia. Indeed, it reduces and increases the release of pro-inflammatory and anti-inflammatory cytokines, respectively. Such ligand-induced effects were abolished when C20 cells were treated with the steroidogenesis inhibitor aminoglutethimide. This suggests a role for neurosteroids in modulating the interleukin production. The highly steroidogenic ligand XBD-173 attenuated the neuroinflammatory response more effectively than the poorly steroidogenic ones, which suggests that the observed modulation on the cytokine release may be influenced by the levels of produced neurosteroids. In the TSPO silencing model, the reduction of TSPO caused a more inflamed phenotype with respect to scrambled cells. Similarly, during the inflammatory response, the TSPO silencing increased and reduced the release of pro-inflammatory and anti-inflammatory cytokines, respectively. In conclusion, the obtained results are in favor of a homeostatic role for TSPO in the context of dynamic balance between anti-inflammatory and pro-inflammatory mediators in the human microglia-mediated inflammatory response. Interestingly, our preliminary results propose that the TSPO expression could be stimulated by NF-κB during activation of the inflammatory response.


Assuntos
Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Microglia/efeitos dos fármacos , Purinas/farmacologia , Interferência de RNA , Receptores de GABA/metabolismo , Aminoglutetimida/farmacologia , Anti-Inflamatórios/farmacologia , Inibidores da Aromatase/farmacologia , Sequência de Bases , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Citocinas/farmacologia , Expressão Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/farmacologia , Microglia/metabolismo , NF-kappa B/metabolismo , Fenótipo , Receptores de GABA/genética
7.
Biomaterials ; 186: 8-21, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30278346

RESUMO

The intrinsic characteristics of the tumor microenvironment (TME), including acidic pH and overexpression of hydrolytic enzymes, offer an exciting opportunity for the rational design of TME-drug delivery systems (DDS). We developed and characterized a pH-responsive biodegradable poly-L-glutamic acid (PGA)-based combination conjugate family with the aim of optimizing anticancer effects. We obtained combination conjugates bearing Doxorubicin (Dox) and aminoglutethimide (AGM) with two Dox loadings and two different hydrazone pH-sensitive linkers that promote the specific release of Dox from the polymeric backbone within the TME. Low Dox loading coupled with a short hydrazone linker yielded optimal effects on primary tumor growth, lung metastasis (∼90% reduction), and toxicological profile in a preclinical metastatic triple-negative breast cancer (TNBC) murine model. The use of transcriptomic analysis helped us to identify the molecular mechanisms responsible for such results including a differential immunomodulation and cell death pathways among the conjugates. This data highlights the advantages of targeting the TME, the therapeutic value of polymer-based combination approaches, and the utility of -omics-based analysis to accelerate anticancer DDS.


Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/química , Ácido Poliglutâmico/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Microambiente Tumoral , Aminoglutetimida/administração & dosagem , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Liberação Controlada de Fármacos , Feminino , Xenoenxertos , Humanos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos BALB C , Neoplasias de Mama Triplo Negativas/patologia
8.
Mol Hum Reprod ; 24(1): 2-13, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29177442

RESUMO

STUDY QUESTION: Does 27-hydroxycholesterol (27OH) actively facilitate the progression of luteolysis? SUMMARY ANSWER: There is increased mRNA expression of the enzyme that produces 27OH during luteolysis in vivo in rhesus macaques and sheep, and 27OH reduces progesterone secretion from human luteinized granulosa cells. WHAT IS KNOWN ALREADY: There is an increase in mRNA expression of liver x receptor (LXR) and a decrease in sterol regulatory element binding protein 2 (SREBP2) target genes during spontaneous luteolysis in primates, which could result in reduced cholesterol availability for steroidogenesis. Concentrations of 27OH are also increased in primate corpora lutea (CL) during luteolysis, and 27OH is a dual LXR agonist and SREBP2 inhibitor. STUDY DESIGN SIZE, DURATION: This was an in vitro study using primary human luteinized granulosa cells in a control versus treatment(s) design. Analyses of CL from sheep undergoing induced or spontaneous luteolysis were also performed, along with database mining of microarray data from rhesus macaque CL. PARTICIPANTS/MATERIALS, SETTING, METHODS: Primary luteinizing granulosa cells were obtained from 37 women aged 24-44 who were undergoing oocyte donation or IVF for male factor or idiopathic infertility, and cells were further luteinized in vitro using human chorionic gonadotropin. Three approaches to test the effect of 27OH produced via CYP27A1 (cytochrome p450, family 27, subfamily A, polypeptide 1) on luteinized granulosa cells were used: (i) direct 27OH supplementation, (ii) induction of endogenous CYP27A1 activity via pharmacologic inhibition of steroidogenesis, and (iii) siRNA-mediated knockdown to directly inhibit CYP27A1 as well as cholesterol transport into the mitochondria via the steroidogenic acute regulatory protein (STAR). Endpoints included: progesterone (P4) secretion into culture media determined by enzyme immunoassay, cholesterol efflux and uptake assays using fluorescent lipid analogs, and mRNA expression determined via semi-quantitative real-time PCR (QPCR). An additional experiment involved QPCR analysis of 40 CL collected from ewes undergoing induced or spontaneous luteolysis, as well as database mining of microarray data generated from 16 rhesus macaque CL collected during spontaneous luteolysis and 13 macaque CL collected during a luteinizing hormone ablation and replacement protocol. MAIN RESULTS AND THE ROLE OF CHANCE: The mRNA expression of CYP27A1 was significantly increased during luteolysis in rhesus macaques and sheep in vivo, and CYP27A1 transcription was suppressed by luteinizing hormone and hCG. There was a significant decrease in hCG-stimulated P4 secretion from human luteinized granulosa cells caused by 27OH treatment, and a significant increase in basal and hCG-stimulated P4 synthesis when endogenous 27OH production was inhibited via CYP27A1 knockdown, indicating that 27OH inhibits steroidogenesis. Pharmacologic inhibition of steroidogenesis by aminoglutethimide significantly induced LXR and inhibited SREBP2 target gene mRNA expression, indicating that increased oxysterol production occurs when steroidogenesis is suppressed. Inhibiting cholesterol delivery into the mitochondria via knockdown of STAR resulted in reduced SREBP2 target gene mRNA expression, indicating that STAR function is necessary to maintain SREBP2-mediated transcription. The effects of 27OH treatment on markers of LXR and SREBP2 activity were moderate, and knockdown of CYP27A1 did not prevent aminoglutethimide-induced changes in LXR and SREBP2 target gene mRNA expression. These observations indicate that 27OH inhibits P4 secretion partially via mechanisms separate from its role as an LXR agonist and SREBP2 inhibitor, and also demonstrate that other oxysterols are involved in modulating LXR and SREBP2-mediated transcription when steroidogenesis is suppressed. LARGE SCALE DATA: None. LIMITATIONS REASONS FOR CAUTION: Luteinized granulosa cells may differ from luteal cells, and the effect on luteal function in vivo was not directly tested. The mechanisms that cause the initial rise in CYP27A1 mRNA expression during luteolysis are also not clear. WIDER IMPLICATIONS OF THE FINDINGS: The factors causing luteolysis in primates have not yet been determined. This study provides functional evidence of a novel mechanism via increased 27OH synthesis during luteolysis, which subsequently represses progesterone secretion. Increased 27OH may also facilitate the progression of luteolysis in domestic animal species. STUDY FUNDING AND COMPETING INTEREST(S): The authors have nothing to disclose. Support was provided by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) of the National Institutes of Health (NIH), award number R00HD067678 to R.L.B.


Assuntos
Colestanotriol 26-Mono-Oxigenase/metabolismo , Hidroxicolesteróis/metabolismo , Luteólise/metabolismo , Progesterona/metabolismo , Adulto , Aminoglutetimida/farmacologia , Células Cultivadas , Colestanotriol 26-Mono-Oxigenase/genética , Colesterol/metabolismo , Gonadotropina Coriônica/farmacologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Hormônio Luteinizante/farmacologia , Luteólise/efeitos dos fármacos , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Proteína de Ligação a Elemento Regulador de Esterol 2/genética
9.
Medicine (Baltimore) ; 96(28): e7411, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28700478

RESUMO

Steroid profiling was introduced to determine the endogenous steroid misuse in sports. Thus, screening for the exogenous use of these prohibited substances can be established by monitoring a range of endogenous steroids, which constitute the steroid profile and evaluate their concentrations and ratios against reference values. The steroid profiling is currently based on population statistics. As large interindividual variations exist, athlete biological passport (ABP) analysis is ongoing. This study aimed to identify new biomarker(s) for aromatase inhibitor detection in sports using statistical analysis and adapt the model into ABP analysis.Forty-one Chinese nonathlete volunteers (21 males and 20 females) were administered 3 nonsteroidal aromatase inhibitors (aminoglutethimide, letrozole, and anastrozole) independently. Statistical analysis was performed on 16 steroid profile parameters.After administration, the concentrations of endogenous androgen biomarkers including testosterone (T), epitestosterone, androsterone (AN), etiocholanolone (ETIO), 5α-diol, 5ß-diol, and dehydroepiandrosterone were increased, while the level of estrogen was decreased. These biomarkers returned to the baselines levels within 1 month. In females, the concentrations of endogenous biomarkers were affected by nonsteroidal aromatase inhibitors, without a common trend. Three new endogenous biomarkers (AN/estrone, ETIO/estrone, and T/estrone) elevated significantly after treatment. The 3 new models were more sensitive than the World Anti-Doping Agency ratio biomarkers. They were also effective in exponentially weighted moving average chart analysis.Verification experiment demonstrated that the biomarker T/estrone was valid in judging the steroidal aromatase inhibitor abuse. The screening of these new endogenous biomarkers can provide additional parameters to support ABP monitoring and specific information regarding the administered steroids.


Assuntos
Aminoglutetimida/farmacologia , Inibidores da Aromatase/farmacologia , Hormônios/sangue , Nitrilas/farmacologia , Esteroides/sangue , Triazóis/farmacologia , Anastrozol , Biomarcadores Farmacológicos/sangue , Doping nos Esportes , Feminino , Humanos , Letrozol , Masculino , Modelos Biológicos , Método Simples-Cego , Transtornos Relacionados ao Uso de Substâncias/sangue , Adulto Jovem
10.
Exp Toxicol Pathol ; 69(7): 424-429, 2017 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-28410883

RESUMO

Aminoglutethimide is a steroidogenesis inhibitor and inhibits a cholesterol side-chain cleavage enzyme (CYP11A1) that converts cholesterol to pregnenolone in mitochondria. We investigated histopathological changes induced by 5-day administration of AG in mice. Cytoplasmic vacuoles of various sizes and single cell necrosis were found in zona fasciculata cells in AG-treated mice. Some vacuoles were positive for adipophilin, whereas others were positive for lysosome-associated membrane protein-2 on immunohistochemical staining, indicating they were enlarged lipid droplets and lysosomes, respectively. Electron microscopy revealed enlarged lysosomes containing damaged mitochondria and lamellar bodies in zona fasciculata cells, and they were considered to reflect the intracellular protein degradation processes, mitophagy and lipophagy. From these results, we showed that AG induces excessive lipid accumulation and mitochondrial damage in zona fasciculata cells, which leads to an accelerated lysosomal degradation in mice.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/patologia , Aminoglutetimida/toxicidade , Inibidores da Aromatase/toxicidade , Lisossomos/efeitos dos fármacos , Animais , Lisossomos/patologia , Masculino , Camundongos
11.
J Chromatogr A ; 1467: 347-355, 2016 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-27544751

RESUMO

The separation of aminoglutethimide enantiomers by the continuous multicolumn chromatographic processes were investigated experimentally and theoretically, where the columns were packed with cellulose tris 3,5-dimethylphenyl-carbamate stationary phase (brand name Chiralcel OD) and mobile phase was a mixture of n-hexane and ethanol with monoethanolamine additive. The continuous enantioseparation processes included a synchronous shifting process (SMB) and an asynchronous shifting process (VARICOL), which allowed reducing the column number (here from six-column SMB to five-column VARICOL process). Transport-dispersive model with the consideration of both intraparticle mass transfer resistance and axial dispersion was adopted to design and optimize the operation conditions for the separation of aminoglutethimide enantiomers by SMB process and VARICOL process. According to the optimized operation conditions, experiments were carried out on VARICOL-Micro unit using five-column VARICOL process with 1/1.5/1.5/1 configuration and six-column SMB process with 1/2/2/1 configuration. Products of R-aminoglutethimide (R-AG) enantiomer and S-aminoglutethimide (S-AG) enantiomer with more than 99.0% purity were obtained continuously from extract stream and raffinate stream, respectively. Furthermore, the experiemntal data obtained from five-column VARICOL process were compared with that from six-column SMB process, the feasibility and efficiency for the separation of guaifenesin enantiomers by VARICOL processes were evaluated.


Assuntos
Aminoglutetimida/química , Cromatografia/instrumentação , Aminoglutetimida/isolamento & purificação , Celulose/análogos & derivados , Etanol , Guaifenesina/química , Guaifenesina/isolamento & purificação , Hexanos , Indicadores e Reagentes , Organofosfatos , Fenilcarbamatos , Estereoisomerismo
12.
Leukemia ; 30(6): 1230-6, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26859081

RESUMO

We randomized 3375 adults with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome to test whether increasingly intensive chemotherapies assigned at study-entry and analyzed on an intent-to-treat basis improved outcomes. In total, 1529 subjects <60 years were randomized to receive: (1) a first course of induction therapy with high-dose cytarabine and mitoxantrone (HAM) or with standard-dose cytarabine, daunorubicin and 6-thioguanine (TAD) followed by a second course of HAM; (2) granulocyte-colony stimulating factor (G-CSF) or no G-CSF before induction and consolidation courses; and (3) high-dose therapy and an autotransplant or maintenance chemotherapy. In total, 1846 subjects ⩾60 years were randomized to receive: (1) a first induction course of HAM or TAD and second induction course of HAM (if they had bone marrow blasts ⩾5% after the first course); and (2) G-CSF or no G-CSF as above. Median follow-up was 7.4 years (range, 1 day to 14.7 years). Five-year event-free survivals (EFSs) for subjects receiving a first induction course of HAM vs TAD were 17% (95% confidence interval, 15, 18%) vs 16% (95% confidence interval 14, 18%; P=0.719). Five-year EFSs for subjects randomized to receive or not receive G-CSF were 19% (95% confidence interval 16, 21%) vs 16% (95% confidence interval 14, 19%; P=0.266). Five-year relapse-free survivals (RFSs) for subjects <60 years receiving an autotransplant vs maintenance therapy were 43% (95% confidence interval 40, 47%) vs 40 (95% confidence interval 35, 44%; P=0.535). Many subjects never achieved pre-specified landmarks and consequently did not receive their assigned therapies. These data indicate the limited impact of more intensive therapies on outcomes of adults with AML. Moreover, none of the more intensive therapies we tested improved 5-year EFS, RFS or any other outcomes.


Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Adulto , Aminoglutetimida/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/uso terapêutico , Danazol/uso terapêutico , Intervalo Livre de Doença , Fator Estimulador de Colônias de Granulócitos , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Pessoa de Meia-Idade , Mitoxantrona/uso terapêutico , Transplante de Células-Tronco , Taxa de Sobrevida , Tamoxifeno/uso terapêutico , Transplante Autólogo , Resultado do Tratamento , Adulto Jovem
13.
J Steroid Biochem Mol Biol ; 155(Pt B): 199-206, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25460300

RESUMO

The adrenal has been neglected in endocrine disruption regulatory testing strategy. The adrenal is a vital organ, adrenocortical insufficiency is recognised in life threatening "adrenal crises" and Addison's disease, and the consequences of off-target toxicological inhibition of adrenocortical steroidogenesis is well recognised in clinical medicine, where drugs such as aminoglutethimide and etomidate killed patients via unrecognised inhibition of adrenocortical steroidogenic enzymes (e.g. CYP11B1) along the cortisol and aldosterone pathways. The consequences of adrenocortical dysfunction during early development are also recognised in the congenital salt wasting and adrenogenital syndromes presenting neonatally, yet despite a remit to focus on developmental and reproductive toxicity mechanisms of endocrine disruption by many regulatory agencies (USEPA EDSTAC; REACH) the assessment of adrenocortical function has largely been ignored. Further, every step in the adrenocortical steroidogenic pathway (ACTH receptor, StAR, CYP's 11A1, 17, 21, 11B1, 11B2, and 3-hydroxysteroid dehydrogenase Δ4,5 isomerase) is known to be a potential target with multiple examples of chemicals inhibiting these targets. Many of these chemicals have been detected in human and wildlife tissues. This raises the question of whether exposure to low level environmental chemicals may be affecting adrenocortical function. This review examines the omission of adrenocortical testing in the current regulatory frameworks; the characteristics that make the adrenal cortex particularly vulnerable to toxic insult; chemicals and their toxicological targets within the adrenocortical steroidogenic pathways; the typical manifestations of adrenocortical toxicity (e.g. human iatrogenically induced pharmacotoxicological adrenal insufficiency, manifestations in typical mammalian regulatory general toxicology studies, manifestations in wildlife) and models of adrenocortical functional assessment. The utility of the in vivo ACTH challenge test to prove adrenocortical competency, and the H295R cell line to examine molecular mechanisms of steroidogenic pathway toxicity, are discussed. Finally, because of the central role of the adrenal in the physiologically adaptive stress response, the distinguishing features of stress, compared with adrenocortical toxicity, are discussed with reference to the evidence required to claim that adrenal hypertrophy results from stress rather than adrenocortical enzyme inhibition which is a serious adverse toxicological finding. This article is part of a special issue entitled 'Endocrine disruptors and steroids'.


Assuntos
Córtex Suprarrenal/efeitos dos fármacos , Insuficiência Adrenal/induzido quimicamente , Aminoglutetimida/toxicidade , Disruptores Endócrinos/toxicidade , Etomidato/toxicidade , Córtex Suprarrenal/fisiopatologia , Insuficiência Adrenal/genética , Insuficiência Adrenal/metabolismo , Insuficiência Adrenal/fisiopatologia , Animais , Linhagem Celular Tumoral , Corticosterona/agonistas , Corticosterona/biossíntese , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/fisiopatologia , Receptores da Corticotropina/genética , Receptores da Corticotropina/metabolismo , Transdução de Sinais , Estresse Fisiológico
14.
J Chromatogr A ; 1424: 59-68, 2015 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-26589944

RESUMO

The multifunctional alkoxysilane precursor, 2,6-bis(propyl-trimethoxysilylurelene)pyridine (DPS) was designed and synthesized, envisaging a multiple hydrogen-bond interaction in the molecular imprinting of the drug aminoglutethimide (AGT). Imprinted xerogels were obtained in bulk and spherical formats. The spherical format was achieved by pore-filling onto spherical mesoporous silica, as a straightforward technique to generate the spherical format. The bulk gels presented better selectivity for the template against its glutarimide (GLU) analogue (selectivity factor: bulk 13.4; spherical 4.6), and good capacity (bulk 5521µmol/L; spherical 2679µmol/L) and imprinting factor parameters (bulk 11.3; spherical 1.4). On the other hand, the microspherical format exhibited better dynamic properties associated to chromatographic efficiency (theoretical plates: bulk 6.8; spherical 75) and mass transfer, due mainly to the existence of a mesoporous network, lacking in the bulk material. The performance of the imprinted xerogels was not as remarkable as that of their acrylic counterparts, previously described. Overall it was demonstrated that the use of designed new "breeds" of organo-alkoxysilanes may be a strategy to achieve satisfactory imprints by the sol-gel processes. DPS may in principle be applied even more effectively to other templates bearing better-matching spatially compatible acceptor-donor-acceptor arrays.


Assuntos
Aminoglutetimida/química , Antineoplásicos/química , Piridinas/química , Géis , Ligação de Hidrogênio , Impressão Molecular , Transição de Fase , Dióxido de Silício/química
15.
Int J Pharm ; 496(2): 822-33, 2015 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-26474963

RESUMO

This paper reported the facile fabrication of drug delivery devices for zero-order sustained release by molecular crowding strategy of molecularly imprinting technology. Crowding-assisted molecularly imprinting polymers (MIPs) matrices were prepared by free-radical precipitation polymerization using aminoglutethimide (AG) as a model drug. The crowding effect was achieved by adding polystyrene as a macromolecular co-solute in pre-polymerization mixture. The MIP prepared under the non-MMC condition and the two corresponding non-imprinted particles were tested as controlled vehicles. The release profiles presented zero-order behaviors from two crowding-assisted polymers, the duration of approximately 18h for the crowding-assisted MIP and 10h for the crowding-assisted NIP, respectively while AG were all very rapid released from the other two controlled particles (85% occurring in the first hour). The BET surface area and pore volume of the crowding-assisted MIP were about ten times than those of the controlled MIP. The value of imprinting factor is 6.02 for the crowding-assisted MIP and 1.19 for the controlled MIP evaluated by the equilibrium adsorption experiment. Furthermore, the values of effective diffusivity (Deff) obtained from crowding-assisted MIP (10(-17)cm(2)/s) was about two orders of magnitude smaller than those from the controlled MIP, although the values of free drug diffusivity (D) were all found in the order of 10(-13)cm(2)/s. Compared with the commercial AG tablet, the MMC-assisted MIP gave a markedly high relative bioavailability of 266.3%, whereas the MMC-assisted NIP gave only 57.7%. The results indicated that the MMC condition can modulate the polymer networks approaciate to zero-order release of the drug and maintain the molecular memory pockets, even if under the poor polymerization conditions of MIPs preparation.


Assuntos
Sistemas de Liberação de Medicamentos/instrumentação , Impressão Molecular/métodos , Aminoglutetimida/química , Animais , Preparações de Ação Retardada , Matemática , Polimerização , Poliestirenos/química , Ratos , Ratos Wistar , Solubilidade
16.
Chem Biol Interact ; 239: 129-38, 2015 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-26102013

RESUMO

In this study, the cellular effects resulting from the metabolism of aminoglutethimide by myeloperoxidase were investigated. Human promyelocytic leukemia (HL-60) cells were treated with aminoglutethimide (AG), an arylamine drug that has a risk of adverse drug reactions, including drug-induced agranulocytosis. HL-60 cells contain abundant amounts of myeloperoxidase (MPO), a hemoprotein, which catalyzes one-electron oxidation of arylamines using H2O2 as a cofactor. Previous studies have shown that arylamine metabolism by MPO results in protein radical formation. The purpose of this study was to determine if pathways associated with a toxic response could be determined from conditions that produced protein radicals. Conditions for AG-induced protein radical formation (with minimal cytotoxicity) were optimized, and these conditions were used to carry out proteomic studies. We identified 43 proteins that were changed significantly upon AG treatment among which 18 were up-regulated and 25 were down-regulated. The quantitative proteomic data showed that AG peroxidative metabolism led to the down-regulation of critical anti-apoptotic proteins responsible for inhibiting the release of pro-apoptotic factors from the mitochondria as well as cytoskeletal proteins such as nuclear lamina. This overall pro-apoptotic response was confirmed with flow cytometry which demonstrated apoptosis to be the main mode of cell death, and this was attenuated by MPO inhibition. This response correlated with the intensity of AG-induced protein radical formation in HL-60 cells, which may play a role in cell death signaling mechanisms.


Assuntos
Aminoglutetimida/farmacologia , Apoptose/efeitos dos fármacos , Radicais Livres/metabolismo , Peroxidase/metabolismo , Proteínas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Glucose/farmacologia , Glucose Oxidase/farmacologia , Células HL-60/efeitos dos fármacos , Células HL-60/metabolismo , Humanos , Proteômica/métodos
17.
Neurosci Res ; 95: 38-50, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25598212

RESUMO

Anteroventral third ventricular region (AV3V) that regulates autonomic functions through a GABAergic mechanism possesses neuroactive steroid (NS)-synthesizing ability. Although NS can exert effects by acting on a certain type of GABAA-receptor (R), it is not clear whether NS may operate to modulate AV3V GABAergic activity for controlling autonomic functions. This study aimed to investigate the issue. AV3V infusion with a GABAA antagonist bicuculline increased plasma vasopressin (AVP), glucose, blood pressure (BP), and heart rate in rats. These events were abolished by preinjecting its agonist muscimol, whereas the infusion with allopregnanolone, a NS capable of potentiating GABAA-R function, affected none of the variables in the absence or presence of such bicuculline actions. Similarly, AV3V infusion with pregnanolone sulfate, a NS capable of antagonizing GABAA-R, produced no effect on those variables. AV3V infusion with muscimol was effective in inhibiting the responses of plasma AVP or glucose, or BP to an osmotic loading or bleeding. However, AV3V infusion with aminoglutethimide, a NS synthesis inhibitor, did not affect any of the variables in the absence or presence of those stimuli. These results suggest that NS may not cause acute effects on the AV3V GABAergic mechanism involved in regulating AVP release and other autonomic function.


Assuntos
Sistema Nervoso Autônomo/fisiologia , Pregnanolona/fisiologia , Prosencéfalo/fisiologia , Receptores de GABA/fisiologia , Vasopressinas/metabolismo , Aminoglutetimida/farmacologia , Animais , Inibidores da Aromatase/farmacologia , Sistema Nervoso Autônomo/efeitos dos fármacos , Bicuculina/farmacologia , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Agonistas de Receptores de GABA-A/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Muscimol/farmacologia , Pregnanolona/farmacologia , Prosencéfalo/efeitos dos fármacos , Ratos , Ratos Wistar , Vasopressinas/sangue
18.
J Immunotoxicol ; 12(1): 24-32, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-24350727

RESUMO

Primary aromatic amine drugs are structural alerts in drug development because of their association with a high incidence of idiosyncratic drug reactions (IDRs). If biomarkers could be found that predict IDR risk, it would have a major impact on drug development. Previous attempts to do this through screening of hepatic gene expression profiles in rodents treated with aromatic amine drugs found limited changes. Of the drugs studied, aminoglutethimide (AMG) induced the most changes, and this led to a more comprehensive study of its effects on the liver. Brown Norway rats treated with AMG for up to 14 days showed only a transient elevation of glutamate dehydrogenase. Pathway-specific PCR arrays found few AMG-induced gene changes associated with an immune response and, of these changes, the majority were involved with innate immunity such as Tlr2, Ticam2, CD14, and C3. AMG treatment also led to significant changes in the apoptosis and mitochondrial panel of genes. It was recently found that AMG does induce significant changes in the bone marrow of rats, and agranulocytosis is a common IDR caused by AMG. In contrast, liver injury is not a common IDR associated with AMG. Therefore, the liver may be able to effectively deal with AMG reactive metabolites, and changes observed in this study may be involved in adaptation. Myeloperoxidase is also known to be able to oxidize aromatic amines to reactive metabolites, and these observations suggest that metabolism outside of the liver may be important for the mechanism of aromatic amine-induced IDRs.


Assuntos
Agranulocitose/imunologia , Aminoglutetimida/efeitos adversos , Glutamato Desidrogenase/metabolismo , Fígado/efeitos dos fármacos , Mitocôndrias/metabolismo , 3,3'-Diaminobenzidina/química , Agranulocitose/induzido quimicamente , Aminoglutetimida/administração & dosagem , Aminoglutetimida/química , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Complemento C3/genética , Complemento C3/metabolismo , Humanos , Imunidade Inata/efeitos dos fármacos , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/metabolismo , Fígado/imunologia , Masculino , Mitocôndrias/genética , Peroxidase/metabolismo , Ratos Endogâmicos , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo
19.
Se Pu ; 32(8): 880-5, 2014 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-25434126

RESUMO

Aminoglutethimide (AG) has been used clinically as a drug in the treatment of hormone-dependent metastatic breast cancer. It was reported that S-(-)-AG enantiomer had small activity and sometimes might cause side effects. Therefore, it was of great significance to obtain the high-purity R-(+)-AG by enantioseparation. In this work, aminoglutethimide enantiomers were separated by high performance liquid chromatography (HPLC) using an analytical column which was packed with cellulose tris(3,5-dimethylphenylcarbamate) stationary phase (Chiralcel OD-H). The solubilities of racemic AG in two different solvent compositions, n-hexane/ethanol and n-hexane/isopropanol, were measured, separately. The effects of alcohol content and monoethanolamine additive on the separation performance of racemic AG by HPLC were investigated. According to the experiments, n-hexane-ethanol (30:70, v/v) with 0.1% monoethanolamine additive was selected as the mobile phase. The separation factor, resolution, asymmetry factor, number of theoretical plates and maximum column capacity were measured and analyzed for the chromatographic separation of racemic AG at a flow-rate of 0. 6 mL/min and column temperature of 25-40 °C, with Chiralcel OD-H as stationary phase and n-hexane-ethanol (30:70, v/v) with 0. 1% monoethanolamine as mobile phase. This work provides the basic information of chromatographic separation for the batch and continuous production of aminoglutethimide enantiomers.


Assuntos
Aminoglutetimida/química , Aminoglutetimida/normas , Celulose/análogos & derivados , Cromatografia Líquida de Alta Pressão , Hexanos , Organofosfatos , Fenilcarbamatos , Controle de Qualidade , Solventes , Estereoisomerismo , Temperatura
20.
J Chromatogr A ; 1358: 93-101, 2014 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-25042439

RESUMO

Straightforward crushing and sieving bulk polymeric R-aminoglutethimide-imprinted materials were prepared by classical free radical polymerization, whereas nano thin walled grafted imprinted materials were prepared using RAFT mediated control polymerization technique. A stoichiometric non-covalent approach based on a triply hydrogen bonding functional monomer-template 1:1 complex (K=599mol(-1)L(-1)) led to chiral selectors far outperforming previously used selectors for resolving this racemate. The recognitive materials produced here (enantioselectivity factors, α∼10) also have no match within the previously reported enantioselective imprinted polymers (α 1.2-4.5). We here demonstrate a potentially generic solution to produce good quality grafted MIPs for templates interacting by hydrogen bonding alone, relying on solvent polarity tuning, significantly extending the range of templates compatible with this format.


Assuntos
Aminoglutetimida/isolamento & purificação , Antineoplásicos Hormonais/isolamento & purificação , Nanocompostos/química , Aminoglutetimida/química , Antineoplásicos Hormonais/química , Neoplasias da Mama , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Ligação de Hidrogênio , Metástase Neoplásica , Estereoisomerismo , Propriedades de Superfície
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