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1.
Molecules ; 22(1)2017 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-28075411

RESUMO

Chemical investigation of Tamarix ramosissima Ledeb, a traditional herbal medicine used for rheumatoid arthritis (RA) treatment in northwest China, led to the discovery of a new phenolic aromatic rings substituted lactam, tamaractam (1), together with the previously reported compounds cis-N-feruloyl-3-O-methyldopamine (2) and trans-N-feruloyl-3-O-methyldopamine (3). The structures of the compounds were determined by high resolution electrospray ionization mass spectroscopy (HRESIMS) and 1D and 2D-NMR experiments, as well as comparison with the literature data. The effects of the three compounds on the viability of RA fibroblast-like synoviocytes (RA-FLS) were assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Pro-apoptosis effect of compound 1 in RA-FLS was further investigated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, activated caspase-3/7 level assessment using luminescence assay, and sub-G1 fraction measurement using flow cytometry. It was found that these three compounds displayed variable proliferation inhibitory activity in RA-FLS, and compound 1 exhibited the strongest effect. Compound 1 could remarkably induce cellular apoptosis of RA-FLS, increase activated caspase-3/7 levels, and significantly increase sub-G1 fraction in the cell cycle. The results suggested that compound 1 may inhibit the proliferation of RA-FLS through apoptosis-inducing effect, and these compounds may contribute to the anti-RA effect of T. ramosissima.


Assuntos
Apoptose/efeitos dos fármacos , Artrite Reumatoide/tratamento farmacológico , Desoxiepinefrina/química , Lactamas/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Desoxiepinefrina/análogos & derivados , Desoxiepinefrina/farmacologia , Fibroblastos/efeitos dos fármacos , Humanos , Lactamas/isolamento & purificação , Lactamas/farmacologia , Medicina Tradicional Chinesa , Sinoviócitos/efeitos dos fármacos , Tamaricaceae/química
2.
Eye (Lond) ; 30(6): 784-95, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27174381

RESUMO

PurposeTo evaluate the ability of baseline clinical, morphological, and functional factors to predict the conversion to primary open-angle glaucoma (POAG) in ocular hypertensive (OHT) patients.MethodsThis single-center prospective longitudinal observational study included 116 eyes of 116 OHT patients followed for a 10-year period. All patients had intraocular pressure (IOP) ≥24 mm Hg in one eye and >21 mm Hg in the other eye, normal visual fields (VFs) and normal optic disc (OD) appearance in both eyes at baseline. All OHT patients were untreated at baseline with subsequent treatment upon need according to clinical judgement. Only one eye per subject was randomly selected. Patient age, gender, IOP, central corneal thickness (CCT), and ibopamine test results were collected at baseline. All patients underwent standard automated perimetry, short-wavelength automated perimetry (SWAP), frequency-doubling technology, confocal scanning laser ophthalmoscopy (CSLO), and scanning laser polarimetry (SLP) at baseline and every 6 months thereafter. Main outcome measure was the conversion to POAG, defined as the development of reproducible VF and/or OD abnormalities attributable to glaucoma. Cox proportional hazards models were used to identify the baseline factors predictive of POAG conversion.ResultsDuring the 10-year follow-up, 25% of eyes converted to POAG. In multivariate Cox models, baseline factors that were significant predictors of POAG development included: older age (hazard ratio (HR) 1.0, 99% confidence intervals (CIs) 1.0-1.2, per 1 year older); SWAP Glaucoma Hemifield test 'outside normal limits' (HR 4.3, 99% CIs 1.2-17.9); greater SLP 'Inter-eye Symmetry' (HR 1.1, 99% CIs 0.4-3.0, per 1 unit lower); lower CSLO Rim Volume (HR 1.1, 99% CIs 0.3-3.2, per 0.1 mm(3) lower); and greater CSLO cup-to-disc ratio (HR 6.0, 99% CIs 3.6-16.8, per 0.1 unit greater).ConclusionsThe baseline parameters that proved to be useful in assessing the likelihood of an OHT patient to develop POAG included age, functional variables provided by SWAP, and structural variables provided by SLP and CSLO. In this cohort of patients, baseline IOP, CCT, and ibopamine provocative test results were not significant predictors of POAG conversion.


Assuntos
Glaucoma de Ângulo Aberto/diagnóstico , Hipertensão Ocular/diagnóstico , Idoso , Desoxiepinefrina/administração & dosagem , Desoxiepinefrina/análogos & derivados , Progressão da Doença , Feminino , Seguimentos , Humanos , Pressão Intraocular/fisiologia , Masculino , Pessoa de Meia-Idade , Midriáticos/administração & dosagem , Oftalmoscopia , Estudos Prospectivos , Fatores de Risco , Tonometria Ocular , Testes de Campo Visual , Campos Visuais/fisiologia
3.
Clin Exp Ophthalmol ; 44(3): 166-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26575026

RESUMO

BACKGROUND: The ibopamine challenge test correlates well with a patient's peak diurnal intraocular pressure (IOP) measurement. We aimed to investigate the effect that a functioning trabeculectomy has on the ibopamine challenge test. DESIGN: Non-randomized prospective clinical trial evaluating a diagnostic test. PARTICIPANTS: Thirteen patients were recruited through glaucoma clinics at the Flinders Medical Centre. Of these, seven required surgical management with trabeculectomy surgery, whilst the remainder were managed medically. METHODS: Patients underwent IOP measurement, and then two drops of Ibopamine 2% solution were instilled into the study eye of each patient. After 45 min, IOP was reassesed. A positive challenge test was considered to be a rise in IOP of greater than 3 mmHg. Changes from baseline were determined and compared between groups. Twelve months later, this test was then repeated in all patients. MAIN OUTCOME MEASURE: Change in IOP after ibopamine challenge. RESULTS: Following the ibopamine challenge, IOP increased by 9.2 mmHg (SD 2.8) (100% positive) for medically managed patients and 7.2 mmHg (SD 2.0) (100% positive) for surgically managed patients (P = 0.18). The surgically managed group then underwent trabeculectomy surgery. Twelve months later, the ibopamine challenge was repeated. Following the repeat ibopamine challenge, IOP increased by 7.2 mmHg (SD 2.3) for medically managed patients and 0.3 mmHg (SD 1.3) for surgically managed patients (P < 0.0001). The medically managed group remained 100% positive, whilst the surgically manage group became 0% positive (Fisher Exact P = 0.044). CONCLUSIONS: A glaucoma patient with a positive ibopamine challenge will show a negative challenge result when re-tested following trabeculectomy surgery.


Assuntos
Desoxiepinefrina/análogos & derivados , Agonistas de Dopamina/administração & dosagem , Glaucoma/diagnóstico , Glaucoma/cirurgia , Pressão Intraocular/efeitos dos fármacos , Trabeculectomia , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/administração & dosagem , Desoxiepinefrina/administração & dosagem , Progressão da Doença , Feminino , Glaucoma/fisiopatologia , Humanos , Masculino , Estudos Prospectivos , Tonometria Ocular
4.
J Glaucoma ; 25(5): e441-5, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26709501

RESUMO

PURPOSE: To evaluate the diagnostic ability of the ibopamine provocative test for early glaucoma detection. METHOD: A sample of 44 patients with suspicious optic discs was recruited and compared with 37 controls with normal optic discs and no ocular pathology. The ibopamine test was performed in all patients who were then followed up with diagnostic tests for glaucoma, visual fields, and spectral-domain optical coherence tomography. RESULTS: Early glaucoma was diagnosed in 26 patients. The sensitivity of the ibopamine test to discriminate patients who had early glaucoma was 78.7%, with a specificity of 71.6%. In multivariable analyses adjusted for demographic and clinical variables, participants with a positive ibopamine test at baseline had an 8-fold higher risk of glaucoma compared with those who had a negative test; glaucoma risk was highest among ibopamine-positive subjects with initial clinical diagnostic impression of glaucoma. CONCLUSIONS: The ibopamine test showed an adequate diagnostic performance to detect individuals at increased risk of glaucoma in a very early stage of the disease. While further studies are required, the provocative ibopamine test for the diagnosis of early glaucoma is promissory.


Assuntos
Desoxiepinefrina/análogos & derivados , Técnicas de Diagnóstico Oftalmológico , Agonistas de Dopamina/administração & dosagem , Glaucoma de Ângulo Aberto/diagnóstico , Pressão Intraocular/efeitos dos fármacos , Idoso , Desoxiepinefrina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Disco Óptico/patologia , Sensibilidade e Especificidade , Tomografia de Coerência Óptica/métodos , Tonometria Ocular , Campos Visuais
5.
Dis Model Mech ; 8(10): 1213-25, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26438694

RESUMO

Fatty liver disease is one of the main hepatic complications associated with obesity. To date, there are no effective treatments for this pathology apart from the use of classical fibrates. In this study, we have characterized the in vivo effects of a novel conjugation of oleic acid with an amphetamine derivative (OLHHA) in an animal model of genetic obesity. Lean and obese Zucker rats received a daily intraperitoneal administration of OLHHA (5 mg kg(-1)) for 15 days. Plasma and liver samples were collected for the biochemical and molecular biological analyses, including both immunohistochemical and histological studies. The expression of key enzymes and proteins that are involved in lipid metabolism and energy homeostasis was evaluated in the liver samples. The potential of OLHHA to produce adverse drug reactions or toxicity was also evaluated through the monitoring of interactions with hERG channel and liver cytochrome. We found that OLHHA is a drug with a safe pharmacological profile. Treatment for 15 days with OLHHA reduced the liver fat content and plasma triglyceride levels, and this was accompanied by a general improvement in the profile of plasma parameters related to liver damage in the obese rats. A decrease in fat accumulation in the liver was confirmed using histological staining. Additionally, OLHHA was observed to exert anti-apoptotic effects. This hepatoprotective activity in obese rats was associated with an increase in the mRNA and protein expression of the cannabinoid type 1 receptor and a decrease in the expression of the lipogenic enzymes FAS and HMGCR primarily. However, changes in the mRNA expression of certain proteins were not associated with changes in the protein expression (i.e. L-FABP and INSIG2). The present results demonstrate that OLHHA is a potential anti-steatotic drug that ameliorates the obesity-associated fatty liver and suggest the potential use of this new drug for the treatment of non-alcoholic fatty liver disease.


Assuntos
Desoxiepinefrina/análogos & derivados , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/complicações , Obesidade/tratamento farmacológico , Ácido Oleico/uso terapêutico , Adiposidade/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Desoxiepinefrina/farmacologia , Desoxiepinefrina/uso terapêutico , Canais de Potássio Éter-A-Go-Go/metabolismo , Comportamento Alimentar/efeitos dos fármacos , Genótipo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/sangue , Ácido Oleico/farmacologia , PPAR alfa/genética , PPAR alfa/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Zucker , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Fatores de Transcrição/metabolismo
6.
Clin Exp Ophthalmol ; 43(9): 808-14, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26140527

RESUMO

BACKGROUND: An ibopamine challenge is a novel technique for assessing glaucoma using ibopamine, a topical drug which temporarily increases aqueous production. We aimed to determine whether change in intraocular pressure (IOP) and/or optic cup volume (OCV) during the test differentiated between glaucoma patients at different stages of disease; namely, glaucoma suspects (GS), glaucoma patients who are stable (SG) and glaucoma patients who have demonstrated rapid progression (PG). DESIGN: Non-randomized clinical trial evaluating a diagnostic test. PARTICIPANTS: Sixty-one patients were recruited through glaucoma clinics at the Flinders Medical Centre (24 GS, 24 SG and 13 PG). METHODS: Patients underwent IOP measurement and OCV assessment using optical coherence tomography. Two drops of ibopamine 2% solution were instilled into the study eye of each patient. After 45 min, IOP and OCV were reassessed. Changes from baseline were compared between groups. MAIN OUTCOME MEASURE: Change in IOP and OCV after ibopamine challenge. RESULTS: Following the ibopamine challenge, IOP increased by 1.8 mmHg for GS patients, 4.5 mmHg for SG patients (P = 0.003) and 8.1 mmHg for PG patients (P < 0.0001). OCV increased by 0.2% for GS patients, 0.6% for SG patients and 5.5% for PG patients. This was not significantly different between GS patients and SG patients; however, it was significantly different between GS patients and PG patients (P < 0.0001), and between SG and PG patients (P = 0.001). CONCLUSION: GS patients may be differentiated from those with SG or PG by their IOP response, and SG may be differentiated from PG patients by their change in OCV following an ibopamine challenge.


Assuntos
Desoxiepinefrina/análogos & derivados , Agonistas de Dopamina/administração & dosagem , Glaucoma/diagnóstico , Pressão Intraocular/efeitos dos fármacos , Hipertensão Ocular/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Desoxiepinefrina/administração & dosagem , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas , Pupila/efeitos dos fármacos , Tomografia de Coerência Óptica , Tonometria Ocular , Campos Visuais
7.
Anal Chim Acta ; 822: 37-50, 2014 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-24725746

RESUMO

Methylenedioxy designer drugs of abuse such as 3,4-methylenedioxymethamphetamine (MDMA) can be selectively toxic to serotonergic neurons and glutathione (GSH) adducts have been implicated in its neurotoxicity. The catecholic demethylenyl metabolites of MDMA, 3,4-dihydroxymethamphetamine and 3,4-dihydroxyamphetamine, are metabolically oxidized to the corresponding ortho-quinones, which are highly reactive intermediates. These intermediates can then be conjugated with GSH preventing cellular damage. Furthermore, glutathionyl transferase (GST) activity was described to be irreversibly inhibited by the catechols dopamine, α-methyldopa and their GSH conjugates. Therefore, the aims of the present work were the detection and characterization of GSH conjugates of ten methylenedioxy drugs of abuse and their phase I metabolites as well as to assess their inhibition potency on GST activity. The substrates were incubated using human placental GST with or without preincubation by cytochrome P450 enzymes preparations. GST inhibition was tested using chlorodinitrobenzene GSH conjugation as marker reaction. GSH conjugates were analyzed and characterized using LC-high-resolution-MS/MS. For confirmation of postulated fragmentation patterns, formation of GSH conjugates of selected deuterated analogs (deuterated analogue approach, DAA) of the investigated drugs was explored. For the methylenedioxy amphetamines the following steps could be identified: conjugation of the parent compounds at position 2, 5, 6, of the demethylenyl metabolites at position 2 and 5, and of the further deaminated demethylenyl metabolites at position 2. For the ß-keto-phenylalkylamine and pyrrolidinophenone, conjugation of the demethylenyl metabolites and of the deaminated demethylenyl metabolites at position 2 could be identified. The DAA allowed the differentiation of the 2 and 5/6 isomers by confirmation of the postulated mass spectral fragments. Finally, the tested drugs and phase I metabolites showed no inhibition potency on GST activity.


Assuntos
Glutationa Transferase/metabolismo , Glutationa/química , N-Metil-3,4-Metilenodioxianfetamina/metabolismo , Cromatografia Líquida de Alta Pressão , Sistema Enzimático do Citocromo P-450/metabolismo , Desoxiepinefrina/análogos & derivados , Desoxiepinefrina/análise , Desoxiepinefrina/química , Dinitroclorobenzeno/química , Ensaios Enzimáticos , Feminino , Glutationa Transferase/antagonistas & inibidores , Humanos , Isomerismo , N-Metil-3,4-Metilenodioxianfetamina/química , Placenta/enzimologia , Gravidez , Espectrofotometria Ultravioleta , Espectrometria de Massas em Tandem
8.
J Appl Toxicol ; 34(6): 618-27, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23670916

RESUMO

Hepatic injury after 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) intoxications is highly unpredictable and does not seem to correlate with either dosage or frequency of use. The mechanisms involved include the drug metabolic bioactivation and the hyperthermic state of the liver triggered by its thermogenic action and exacerbated by the environmental circumstances of abuse at hot and crowded venues. We became interested in understanding the interaction between ecstasy and its metabolites generated in vivo as users are always exposed to mixtures of parent drug and metabolites. With this purpose, Hep G2 cells were incubated with MDMA and its main human metabolites methylenedioxyamphetamine (MDA), α-methyldopamine (α-MeDA) and N-methyl-α-methyldopamine (N-Me-α-MeDA), individually and in mixture (drugs combined in proportion to their individual EC01 ), at normal (37 °C) and hyperthermic (40.5 °C) conditions. After 48 h, viability was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Extensive concentration-response analysis was performed with single drugs and the parameters of the individual non-linear logit fits were used to predict joint effects using the well-founded models of concentration addition (CA) and independent action (IA). Experimental testing revealed that mixture effects on cell viability conformed to CA, for both temperature settings. Additionally, substantial combination effects were attained even when each substance was present at concentrations that individually produced unnoticeable effects. Hyperthermic incubations dramatically increased the toxicity of the tested drug and metabolites, both individually and combined. These outcomes suggest that MDMA metabolism has hazard implications to liver cells even when metabolites are found in low concentrations, as they contribute additively to the overall toxic effect of MDMA.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Hepatócitos/efeitos dos fármacos , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , 3,4-Metilenodioxianfetamina/metabolismo , 3,4-Metilenodioxianfetamina/toxicidade , Biotransformação , Sobrevivência Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Desoxiepinefrina/análogos & derivados , Desoxiepinefrina/metabolismo , Desoxiepinefrina/toxicidade , Relação Dose-Resposta a Droga , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , N-Metil-3,4-Metilenodioxianfetamina/metabolismo , Dinâmica não Linear , Medição de Risco , Temperatura , Fatores de Tempo
9.
Clin Exp Ophthalmol ; 42(4): 342-6, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24034130

RESUMO

BACKGROUND: Many countries face the challenge of a rising number of patients with or at risk of developing glaucoma. A test to differentiate between people who are unlikely to develop glaucoma and those at risk for the disease could be clinically useful. Ibopamine, when administered topically, temporarily increases aqueous production. Normal eyes with healthy trabecular meshwork show no significant change in intraocular pressure (IOP) following an ibopamine challenge; however, those with glaucoma demonstrate elevated IOP. DESIGN: The study was designed as a prospective case-control study in a tertiary hospital. PARTICIPANTS: Patients were recruited consecutively as they presented to glaucoma clinics at Flinders Medical Centre (n = 39); the sample included 18 glaucoma suspects and 21 patients with glaucoma. All patients had open anterior chamber angles and no evidence of secondary glaucoma. METHODS: Patients underwent IOP measurements followed by instillation of ibopamine 2% solution and subsequent repeated IOP assessment. The difference between the baseline measurement and that taken at 45 min was determined and compared between groups. MAIN OUTCOME MEASURE: The outcome measure was the positivity of the ibopamine challenge test, defined by an increase in IOP > 3 mmHg. RESULTS: We observed a mean increase in IOP of 1.9 ± 1.6 mmHg or 12.5 ± 10.3%) for glaucoma suspects and 7.4 ± 4 mmHg or 52.4 ± 26.5% for glaucoma patients (P < 0.0001). Four glaucoma suspects (22%) and 19 glaucoma patients (90%) tested positive (P < 0.0001). CONCLUSION: This study demonstrates that ibopamine has potential as a test to differentiate glaucoma suspects from patients with glaucoma.


Assuntos
Desoxiepinefrina/análogos & derivados , Agonistas de Dopamina , Glaucoma de Ângulo Aberto/diagnóstico , Midriáticos , Hipertensão Ocular/diagnóstico , Administração Tópica , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Pressão Intraocular/efeitos dos fármacos , Masculino , Soluções Oftálmicas , Estudos Prospectivos
10.
Arch Toxicol ; 88(2): 455-73, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24101030

RESUMO

The neurotoxicity of "ecstasy" (3,4-methylenedioxymethamphetamine, MDMA) is thought to involve hepatic metabolism, though its real contribution is not completely understood. Most in vitro neurotoxicity studies concern isolated exposures of MDMA or its metabolites, at high concentrations, not considering their mixture, as expected in vivo. Therefore, our postulate is that combined deleterious effects of MDMA and its metabolites, at low micromolar concentrations that may be attained into the brain, may elicit neurotoxicity. Using human SH-SY5Y differentiated cells as dopaminergic neuronal model, we studied the neurotoxicity of MDMA and its MDMA metabolites α-methyldopamine and N-methyl-α-methyldopamine and their correspondent glutathione and N-acetylcysteine monoconjugates, under isolated exposure and as a mixture, at normothermic or hyperthermic conditions. The results showed that the mixture of MDMA and its metabolites was toxic to SH-SY5Y differentiated cells, an effect potentiated by hyperthermia and prevented by N-acetylcysteine. As a mixture, MDMA and its metabolites presented a different toxicity profile, compared to each compound alone, even at equimolar concentrations. Caspase 3 activation, increased reactive oxygen species production, and intracellular Ca(2+) raises were implicated in the toxic effect. The mixture increased intracellular glutathione levels by increasing its de novo synthesis. In conclusion, this study demonstrated, for the first time, that the mixture of MDMA and its metabolites, at low micromolar concentrations, which represents a more realistic approach of the in vivo scenario, elicited toxicity to human SH-SY5Y differentiated cells, thus constituting a new insight into the context of MDMA-related neurotoxicity.


Assuntos
Diferenciação Celular/efeitos dos fármacos , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Neurônios/efeitos dos fármacos , Acetilcisteína/farmacologia , Cálcio/metabolismo , Caspase 3/metabolismo , Linhagem Celular/efeitos dos fármacos , Desoxiepinefrina/análogos & derivados , Desoxiepinefrina/toxicidade , Dopamina/metabolismo , Dopamina/farmacocinética , Neurônios Dopaminérgicos/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , N-Metil-3,4-Metilenodioxianfetamina/administração & dosagem , N-Metil-3,4-Metilenodioxianfetamina/metabolismo , Neurônios/patologia , Síndromes Neurotóxicas/patologia , Espécies Reativas de Oxigênio/metabolismo
11.
Br J Pharmacol ; 171(1): 83-91, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24328722

RESUMO

BACKGROUND AND PURPOSE: The cardiovascular effects produced by 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') contribute to its acute toxicity, but the potential role of its metabolites in these cardiovascular effects is not known. Here we examined the effects of MDMA metabolites on cardiovascular function in rats. EXPERIMENTAL APPROACH: Radiotelemetry was employed to evaluate the effects of s.c. administration of racemic MDMA and its phase I metabolites on BP, heart rate (HR) and locomotor activity in conscious male rats. KEY RESULTS: MDMA (1-20 mg·kg(-1)) produced dose-related increases in BP, HR and activity. The peak effects on HR occurred at a lower dose than peak effects on BP or activity. The N-demethylated metabolite, 3,4-methylenedioxyamphetamine (MDA), produced effects that mimicked those of MDMA. The metabolite 3,4-dihydroxymethamphetamine (HHMA; 1-10 mg·kg(-1)) increased HR more potently and to a greater extent than MDMA, whereas 3,4-dihydroxyamphetamine (HHA) increased HR, but to a lesser extent than HHMA. Neither dihydroxy metabolite altered motor activity. The metabolites 4-hydroxy-3-methoxymethamphetamine (HMMA) and 4-hydroxy-3-methoxyamphetamine (HMA) did not affect any of the parameters measured. The tachycardia produced by MDMA and HHMA was blocked by the ß-adrenoceptor antagonist propranolol. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that HHMA may contribute significantly to the cardiovascular effects of MDMA in vivo. As such, determining the molecular mechanism of action of HHMA and the other hydroxyl metabolites of MDMA warrants further study.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Alucinógenos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , 3,4-Metilenodioxianfetamina/metabolismo , 3,4-Metilenodioxianfetamina/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Estado de Consciência , Desoxiepinefrina/análogos & derivados , Desoxiepinefrina/metabolismo , Desoxiepinefrina/farmacologia , Dopamina/análogos & derivados , Dopamina/farmacologia , Relação Dose-Resposta a Droga , Alucinógenos/metabolismo , Masculino , Desentoxicação Metabólica Fase I , Metanfetamina/análogos & derivados , Metanfetamina/metabolismo , Metanfetamina/farmacologia , Atividade Motora/efeitos dos fármacos , N-Metil-3,4-Metilenodioxianfetamina/metabolismo , Ratos , Ratos Sprague-Dawley , Telemetria , Fatores de Tempo
12.
Arch Toxicol ; 88(2): 515-31, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24177245

RESUMO

3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a recreational hallucinogenic drug of abuse known to elicit neurotoxic properties. Hepatic formation of neurotoxic metabolites is thought to play a major role in MDMA-related neurotoxicity, though the mechanisms involved are still unclear. Here, we studied the neurotoxicity mechanisms and stability of MDMA and 6 of its major human metabolites, namely α-methyldopamine (α-MeDA) and N-methyl-α-methyldopamine (N-Me-α-MeDA) and their correspondent glutathione (GSH) and N-acetyl-cysteine (NAC) conjugates, under normothermic (37 °C) or hyperthermic conditions (40 °C), using cultured SH-SY5Y differentiated cells. We showed that MDMA metabolites exhibited toxicity to SH-SY5Y differentiated cells, being the GSH and NAC conjugates more toxic than their catecholic precursors and MDMA. Furthermore, whereas the toxicity of the catechol metabolites was potentiated by hyperthermia, NAC-conjugated metabolites revealed higher toxicity under normothermia and GSH-conjugated metabolites-induced toxicity was temperature-independent. Moreover, a time-dependent decrease in extracellular concentration of MDMA metabolites was observed, which was potentiated by hyperthermia. The antioxidant NAC significantly protected against the neurotoxic effects of MDMA metabolites. MDMA metabolites increased intracellular glutathione levels, though depletion in thiol content was observed in MDMA-exposed cells. Finally, the neurotoxic effects induced by the MDMA metabolite N-Me-α-MeDA involved caspase 3 activation. In conclusion, this study evaluated the stability of MDMA metabolites in vitro, and demonstrated that the catechol MDMA metabolites and their GSH and NAC conjugates, rather than MDMA itself, exhibited neurotoxic actions in SH-SY5Y differentiated cells, which were differently affected by hyperthermia, thus highlighting a major role for reactive metabolites and hyperthermia in MDMA's neurotoxicity.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Febre/induzido quimicamente , N-Metil-3,4-Metilenodioxianfetamina/metabolismo , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Neurônios/efeitos dos fármacos , 3,4-Metilenodioxianfetamina/metabolismo , 3,4-Metilenodioxianfetamina/toxicidade , Acetilcisteína/metabolismo , Acetilcisteína/farmacologia , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular/efeitos dos fármacos , Desoxiepinefrina/análogos & derivados , Desoxiepinefrina/metabolismo , Desoxiepinefrina/toxicidade , Febre/metabolismo , Glutationa/metabolismo , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , N-Metil-3,4-Metilenodioxianfetamina/farmacocinética , Neurônios/metabolismo , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Temperatura
13.
Eur J Ophthalmol ; 23(6): 819-22, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23813108

RESUMO

PURPOSE: To determine the change in pattern electroretinogram (PERG) amplitude during the ibopamine test in patients with ocular hypertension (OHT). METHODS: A total of 32 eyes (16 patients) with OHT (8 male, 8 female), mean age 54.19 years (range 22-76 years), mean baseline intraocular pressure (IOP) 23 ± 2 mm Hg, received a PERG assessment in both eyes every 5 minutes from baseline to 60 minutes. All the patients were pretreated by thymoxamine eyedrops to avoid the mydriatic effect of ibopamine. All the data were evaluated by descriptive statistics and paired t test. The results were considered with a significance level of p<0.05. RESULTS: All the patients enrolled matched the inclusion criteria and they did not have any local or systemic effects with the ibopamine test. The mean PERG amplitude decreased significantly from baseline after 45 minutes during the ibopamine test (paired t test = 0.05). The results were statistically not correlated with the positivity to the ibopamine test (p = 0.5). CONCLUSIONS: These data stress that, even in presence of a moderate and transient IOP increase, inner retinal function of patients with OHT may be transiently affected.


Assuntos
Desoxiepinefrina/análogos & derivados , Eletrorretinografia , Pressão Intraocular/efeitos dos fármacos , Midriáticos/administração & dosagem , Hipertensão Ocular/fisiopatologia , Retina/fisiopatologia , Adolescente , Adulto , Idoso , Desoxiepinefrina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas , Reconhecimento Visual de Modelos/fisiologia , Tonometria Ocular , Adulto Jovem
14.
J Anal Toxicol ; 37(6): 357-61, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23729636

RESUMO

3,4-Methylenedioxymethamphetamine (MDMA) is one of the most commonly abused illicit drugs in the world. We developed a rapid and simple high-performance liquid chromatography with a fluorescence (FL) detector method to determine MDMA and its metabolites, such as 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxyamphetamine (HMA) and its main unstable metabolite 3,4-dihydroxymethamphetamine (HHMA) besides the internal standards, in a perfusion medium. The separation of analytes was performed at 25°C on a Chromolith® C18 (100 × 4.6 mm) column from Merck (Darmstadt, Germany) without any derivatization. The FL detector wavelength was fixed at 285 nm for excitation and at 320 nm for emission. Acetonitrile:phosphate buffer (0.02 M) at pH = 3 (5:95 v/v) was used as the mobile phase. The elution order was HHMA, HMA, MDA and MDMA with a retention time of 1.7, 2.6, 6.1 and 7.4 min, respectively. The method was validated according to the FDA bioanalytical method validation guideline. The limits of quantifications (LOQs) obtained for MDMA, MDA, HMA and HHMA were 1, 1, 1.5 and 5 ng/mL, respectively. The repeatability of relative standard deviation was  <11% (except for LOQs). This method was applied successfully to determine MDMA and its metabolites in rat liver perfusion samples. To our knowledge, this is the first method introduced for the determination of HHMA as a free form with an FL detector.


Assuntos
Drogas Ilícitas/análise , Fígado/efeitos dos fármacos , N-Metil-3,4-Metilenodioxianfetamina/metabolismo , 3,4-Metilenodioxianfetamina/metabolismo , Animais , Cromatografia Líquida de Alta Pressão/métodos , Desoxiepinefrina/análogos & derivados , Desoxiepinefrina/metabolismo , Dopamina/análogos & derivados , Dopamina/metabolismo , Drogas Ilícitas/efeitos adversos , Limite de Detecção , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Detecção do Abuso de Substâncias/métodos
16.
J Glaucoma ; 22(1): 5-9, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21946546

RESUMO

PURPOSE: The purpose of the study was to assess the effect of ibopamine (3,4 di-isobutyrrylester of N-methyldopamine), a D1-dopamine agonist, on intraocular pressure (IOP) in offspring of parents with primary openangle glaucoma as a consequence of outflow structures impairment. MATERIALS AND METHODS: We included participants aged between 8 and 40 years: group 1, 163 offspring of at least 1 parent with primary openangle glaucoma with normal IOP and without glaucomatous damages; group 2, 108 offspring of healthy parents (without history or existing glaucoma). Ibopamine test was performed by instilling 2 drops, 5 minutes apart, in both eyes followed by repeated IOP measurements over a 45-minute period. The test is considered positive if there is an IOP increase of ≥3 mm Hg 45 minutes after instillation. RESULTS: Baseline IOP before the test was 15.73±2.31 and 15.31±1.86 mm Hg in groups 1 and 2, respectively. Test was positive in 44.33% of cases in group 1 with a mean increase in IOP of 5.57 mm Hg (P<0.001), whereas in all participants of group 2 the test was negative with even 1 to 2 mm Hg IOP reduction. CONCLUSIONS: D1-dopaminergic stimulation due to ibopamine increases IOP as a result of increased production of the aqueous humor in participants with an impaired outflow. The study showed that offspring of at least 1 parent with primary openangle glaucoma--offspring without glaucomatous damages--show an increase of IOP after ibopamine administration, which signifies an impaired function of outflow structures and, therefore, a predisposition to intraocular hypertension and possible glaucoma.


Assuntos
Desoxiepinefrina/análogos & derivados , Agonistas de Dopamina , Glaucoma de Ângulo Aberto/diagnóstico , Pressão Intraocular/efeitos dos fármacos , Receptores de Dopamina D1/agonistas , Adolescente , Adulto , Criança , Desoxiepinefrina/efeitos adversos , Agonistas de Dopamina/efeitos adversos , Feminino , Humanos , Masculino , Soluções Oftálmicas , Tonometria Ocular , Adulto Jovem
17.
Appl Radiat Isot ; 70(8): 1475-9, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22728836

RESUMO

A rapid and efficient n.c.a. radiosynthesis of 6-[(11)C]methyldopamine ([(11)C]MeDA) using the Stille cross-coupling reaction as a key step was developed. The labeling conditions for the formation of the intermediate compound (protected [(11)C]MeDA, [(11)C]7) were determined with respect to reaction temperature and time. The radiochemical yield 89 ± 1.4% (decay-corrected) of the protected intermediate [(11)C]7 was obtained at a reaction temperature of 60°C and a reaction time of 5 min using Pd(2)(dba)(3)/P(o-tolyl)(3) and CsF/CuBr as a co-catalyst system. The overall yield after deprotection with 45% HBr at 140°C for 10 min was 64 ± 3.9% (decay-corrected) within a total preparation time of 40 min, including hydrolysis, HPLC purification and formulation.


Assuntos
Radioisótopos de Carbono/química , Desoxiepinefrina/síntese química , Temperatura Alta
18.
Reprod Toxicol ; 34(1): 57-65, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22391229

RESUMO

MDMA consumers are young people of childbearing age. Consequently, developmental exposure to this drug is a potential public health concern. Several studies have addressed MDMA neurotoxicity in adults; however, knowledge of the effects of MDMA on developing embryos is limited. After administration, MDMA is metabolized species specifically via two main pathways. One leads to the formation of MDA and the other to the formation of HHMA. Here we evaluated the embryotoxic effects of MDMA, and also those of MDA, a main metabolite of MDMA in rats, and HHMA, a main metabolite in humans. For this purpose, we used the whole embryo culture (WEC). Our results show a concentration-dependent embryotoxic effect of MDMA, MDA and HHMA at a concentration range of 25-50µg/ml. The embryotoxic potential of the parent compound and the two metabolites was comparable in vitro.


Assuntos
3,4-Metilenodioxianfetamina/toxicidade , Desoxiepinefrina/análogos & derivados , Desenvolvimento Embrionário/efeitos dos fármacos , Alucinógenos/toxicidade , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Animais , Desoxiepinefrina/toxicidade , Embrião de Mamíferos/efeitos dos fármacos , Feminino , Técnicas In Vitro , Gravidez , Ratos , Ratos Sprague-Dawley
19.
PLoS Negl Trop Dis ; 6(2): e1523, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22389736

RESUMO

Schistosomes have a well developed nervous system that coordinates virtually every activity of the parasite and therefore is considered to be a promising target for chemotherapeutic intervention. Neurotransmitter receptors, in particular those involved in neuromuscular control, are proven drug targets in other helminths but very few of these receptors have been identified in schistosomes and little is known about their roles in the biology of the worm. Here we describe a novel Schistosoma mansoni G protein-coupled receptor (named SmGPR-3) that was cloned, expressed heterologously and shown to be activated by dopamine, a well established neurotransmitter of the schistosome nervous system. SmGPR-3 belongs to a new clade of "orphan" amine-like receptors that exist in schistosomes but not the mammalian host. Further analysis of the recombinant protein showed that SmGPR-3 can also be activated by other catecholamines, including the dopamine metabolite, epinine, and it has an unusual antagonist profile when compared to mammalian receptors. Confocal immunofluorescence experiments using a specific peptide antibody showed that SmGPR-3 is abundantly expressed in the nervous system of schistosomes, particularly in the main nerve cords and the peripheral innervation of the body wall muscles. In addition, we show that dopamine, epinine and other dopaminergic agents have strong effects on the motility of larval schistosomes in culture. Together, the results suggest that SmGPR-3 is an important neuronal receptor and is probably involved in the control of motor activity in schistosomes. We have conducted a first analysis of the structure of SmGPR-3 by means of homology modeling and virtual ligand-docking simulations. This investigation has identified potentially important differences between SmGPR-3 and host dopamine receptors that could be exploited to develop new, parasite-selective anti-schistosomal drugs.


Assuntos
Dopamina/metabolismo , Expressão Gênica , Sistema Nervoso/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/genética , Schistosoma mansoni/genética , Schistosoma mansoni/metabolismo , Sequência de Aminoácidos , Animais , Clonagem Molecular , Desoxiepinefrina/metabolismo , Locomoção/efeitos dos fármacos , Dados de Sequência Molecular , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Schistosoma mansoni/fisiologia , Homologia de Sequência de Aminoácidos
20.
Org Biomol Chem ; 10(18): 3739-48, 2012 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-22456797

RESUMO

(±)-3,4-Methylenedioxymethamphetamine (MDMA, also known as "ecstasy") is a psychoactive drug with selective neurotoxic potential toward brain serotonin (5-HT) neurons. One hypothesis holds that MDMA neurotoxicity may at least partially be a consequence of its metabolism. In most species (including primates), O-demethylenated MDMA metabolites such as N-methyl-α-methyldopamine (HHMA) have been postulated to serve as precursors for toxic thioether conjugates. As yet, chirality of MDMA was not considered in previously reported in vivo studies because HHMA was used as the racemate. Since the stereochemistry of this chiral drug needs to be considered, the total synthesis of enantiomerically pure precursors, R-(-)-HHMA and S-(+)-HHMA, was envisioned with the ultimate goal to prepare substantial amounts of optically active thioether conjugates. Recently, we reported the first total synthesis of the R-enantiomer. In this paper, a novel synthesis of the S-enantiomer is described, in 45% overall yield (six steps) and 99% ee, using commercially available l-Boc-alanine (99% ee) as the chiral source. Having at our disposal suitable amounts of R-(-)-HHMA and S-(+)-HHMA precursors, a straightforward one-pot electrochemical procedure has been further developed for the synthesis of several catechol-thioether conjugates in acceptable yields (40-53%) and high degree of purity (99%), with complete diastereoselectivity. The availability of these newly synthesized optically active catechol-thioether conjugates is crucial for ongoing future in vivo studies about their role in MDMA neurotoxicity.


Assuntos
Materiais Biomiméticos/síntese química , Desoxiepinefrina/análogos & derivados , N-Metil-3,4-Metilenodioxianfetamina/síntese química , Materiais Biomiméticos/química , Materiais Biomiméticos/metabolismo , Desoxiepinefrina/química , Conformação Molecular , N-Metil-3,4-Metilenodioxianfetamina/química , N-Metil-3,4-Metilenodioxianfetamina/metabolismo , Fenômenos Ópticos , Estereoisomerismo
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