RESUMO
WHAT IS KNOWN AND OBJECTIVE: The anti-tacrolimus antibodies used in commercial immunoassay methods have cross-reactivity with tacrolimus metabolites. The aim of this study was to investigate differences in the effects of CYP3A5 polymorphism on tacrolimus concentrations obtained by four immunoassay methods in renal transplant patients. METHODS: Samples (n = 508) were evaluated using four immunoassays (chemiluminescence enzyme immunoassay [CLIA], affinity column-mediated immunoassay [ACMIA], electrochemiluminescence immunoassay [ECLIA] and latex agglutination turbidimetric immunoassay [LTIA]). RESULTS: Bland-Altman plots showed average biases of -0.12 (±1.96 SD: -1.30-1.05) ng/mL for CLIA, -0.30 (-1.59-1.00) ng/mL for ECLIA, 0.42 (-1.21-2.05) ng/mL for ACMIA and 1.88 (-0.51-4.28) ng/mL for LTIA, when considering the mean of the three immunoassays (CLIA, ECLIA and ACMIA). In multiple regression analysis, the difference (CLIA-mean) was affected by haematocrit levels. Differences in ECLIA were correlated with red blood cell counts. For LTIA, CYP3A5 genotype and haematocrit levels were identified as independent predictors for this bias. WHAT IS NEW AND CONCLUSION: The results obtained by CLIA, ECLIA and ACMIA were not affected by CYP3A5 polymorphism. However, in LTIA, CYP3A5*1/*3-derived data exhibited an inverse relationship in Bland-Altman analysis (slope: -0.0824). Higher cross-reactivity with 12-hydroxy tacrolimus at lower concentrations may occur in patients with the CYP3A5*1/*3 genotype. Because patients with the CYP3A5*1 allele identified using LTIA may show higher blood concentrations of tacrolimus at lower target concentrations, for example 3.0 ng/mL, compared with other immunoassay methods, there is a need for sufficient consideration of the interpretation of values measured by LTIA.
Assuntos
Citocromo P-450 CYP3A/genética , Imunoensaio/métodos , Polimorfismo Genético/genética , Tacrolimo/sangue , Alelos , Feminino , Genótipo , Humanos , Transplante de Rim/métodos , Masculino , Pessoa de Meia-IdadeRESUMO
Here, we developed a novel high-performance liquid chromatography (HPLC) method for quantification of perampanel in clinical practice and investigated the relationships between the plasma concentrations of perampanel obtained by this HPLC method and the CYP3A4*1G polymorphism. The developed HPLC method was validated based on US Food and Drug Administration. The developed HPLC method could be performed with a plasma volume of only 200 µL and had a limit of quantification (LOQ) of 2.5 ng/mL. The coefficients of variation (CVs) for intra- and inter-day assays were less than 10.4 and 7.2%, respectively, and the accuracy was <2.4% for both assays. A total of 12 patients who received 2 mg perampanel had C0 values ranging from 70.5 to 451 ng/mL, and the CV showed a large variation of 51.4%. No correlations were observed between the dose-adjusted C0 and the CYP3A4*1G polymorphism. This method was superior to previously reported methods in terms of plasma volume and LOQ and was clinically applicable. Perampanel showed high variations in individual plasma concentrations; however, individual differences could not be predicted from analysis of the CYP3A4*1G polymorphism before perampanel administration. Therefore, after beginning perampanel treatment, the dose should be determined based on the observed plasma concentration.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Citocromo P-450 CYP3A/genética , Piridonas/sangue , Piridonas/farmacocinética , Adulto , Estabilidade de Medicamentos , Feminino , Humanos , Japão , Limite de Detecção , Modelos Lineares , Masculino , Nitrilas , Piridonas/química , Reprodutibilidade dos TestesRESUMO
The aim of this study was to assess knowledge, attitude, behavior, and compliance concerning infection control among dental practitioners in a dental university hospital in Japan. A 12-item questionnaire about infection control during radiographic procedures was distributed to 686 dental personnel working at Osaka Dental University. The questionnaire collected information on occupation and the use of gloves, holders, door handles, control panels, dental chairs, protectors, tube head, tube arms, tube cones, and keyboards for personal computers. To identify misunderstandings about, and thus noncompliance with, current infection control practices, the percentage of correct answers (PCA) was calculated. Understanding and compliance with the current practices was considered low when <75% and high when ≥75%. In addition, contaminated objects in the clinical setting were examined using black light. PCA was low for one question on using gloves in film positioning and high for three questions on using protective film barriers, regardless of the respondents' occupation. PCA was generally high for three questions on practicing hand hygiene before putting on gloves, methods to protect film holders, and methods to protect radiographic equipment, but was low among some subjects. PCA was generally low for four questions on using film protective barriers, developing images from unprotected films, practicing hand hygiene after removing gloves, and awareness of a procedures manual for taking intraoral x-rays, but was high among some subjects. Saliva contamination of radiographic equipment was confirmed by direct visualization using black light. Awareness was low of infection control measures to be used during intraoral projection. This study indicates the need for additional education and training to improve infection control practices, through, for example, using a standard procedures manual for all dental practitioners and visual evidence (visualization) of contamination.
RESUMO
L cell transfectants stably expressing E-cadherin demonstrate a remarkable increase in adherence to extracellular matrix proteins, such as type IV collagen and fibronectin. This enhanced adhesion is mediated by integrin-type cell surface receptors, as assessed by inhibition with anti-receptor antibodies. Both the rate and efficiency of adhesion were enhanced 4- to 5-fold. In contrast, non-specific adhesion processes, such as cell attachment to polylysine-coated substrata, are unaffected by E-cadherin expression. Thus, integrin-mediated but not non-specific adhesion is modulated by E-cadherin expression. L cells expressing mutant E-cadherin molecules either lacking the cytoplasmic domain or bearing an amino acid substitution in the Ca2+-binding motif did not exhibit enhanced adhesion. The amount of collagen receptor, the alpha1 and beta1 integrin, did not change following expression of E-cadherin. Pull-down assays with the Cdc42/Rac interactive binding (CRIB) domain of the Rac effector, p21-activated kinase, revealed increased Rac-GTP levels in cells expressing wild-type E-cadherin. These results suggest that the activation of Rac is involved in the enhancement of integrin-mediated adhesion induced by E-cadherin expression.
Assuntos
Caderinas/fisiologia , Proteínas rac1 de Ligação ao GTP/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Sítios de Ligação/genética , Caderinas/genética , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Adesão Celular/fisiologia , Colágeno Tipo IV/metabolismo , Colágeno Tipo IV/farmacologia , Relação Dose-Resposta a Droga , Ativação Enzimática , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Expressão Gênica , Immunoblotting , Integrina beta1/imunologia , Integrina beta1/metabolismo , Cinética , Células L , Camundongos , Mutação , Polilisina/metabolismo , Polilisina/farmacologia , TransfecçãoRESUMO
BACKGROUND: A practical, simple, high-performance liquid chromatographic (HPLC) method is needed for the determination of itraconazole in clinical plasma samples. METHODS: Itraconazole and bifonazole (internal standard) were extracted from plasma using a C8-bonded solid-phase cartridge, separated by C8 reversed-phase HPLC, and quantified by ultraviolet absorption at 263 nm. RESULTS: This new method enabled the determination of itraconazole in the concentration range of 10.0-500.0 microg/L. The detection limit of itraconazole was 5.0 microg/L. The mean recovery of itraconazole added to plasma was more than 89.1%, with a coefficient of variation of less than 6.9%. We applied this method for the determination of plasma itraconazole in volunteers treated daily with a 200 mg oral capsule of itraconazole for four days. We monitored the plasma level of itraconazole for the following 24 h and obtained the mean area under the plasma concentration-time curve from 0 to 24 h (AUC(0-24) ) value of 4358.9 +/- 1933.4 microg h/L. CONCLUSION: Our new method will be clinically useful for accurately monitoring the plasma concentration of itraconazole in patients under treatment.
Assuntos
Itraconazol/sangue , Adulto , Cromatografia Líquida de Alta Pressão , Monitoramento de Medicamentos , Humanos , Itraconazol/isolamento & purificação , Itraconazol/farmacocinética , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos TestesRESUMO
In spite of the accumulation of knowledge regarding the neuropharmacological action of benzodiazepines (Bz), the physiological process by which their sedative/hypnotic effects are induced remains poorly understood. We conducted a single-blind, crossover trial to evaluate the role of the thermoregulatory process in sleepiness and impaired psychomotor performance induced by a standard Bz, diazepam (DZP). Each of the eight healthy young male volunteers (mean age, 19.75 years; range, 18-23 years) was given a single oral dose of either 5 or 10 mg of DZP or placebo 12 h after his average sleep onset time. Changes in plasma DZP concentration, proximal body temperature (p-BT), distal body temperature (d-BT), subjective sleepiness measured by the Visual Analog Scale and Stanford Sleepiness Scale, and psychomotor performance measured by Choice Reaction Time were monitored under a modified constant routine condition in which various factors affecting thermoregulation, alertness, and psychomotor performances were strictly controlled. Orally administered DZP induced a significant transient decrease in p-BT and psychomotor performance as well as an increase in d-BT and subjective sleepiness. Distal-p-BT gradient (DPG; difference between d-BT and p-BT), which is an indicator of blood flow in distal skin regions, showed a strong positive correlation with the plasma DZP concentration, indicating that DZP in clinical doses promotes heat loss in a dose-dependent manner. The DPG also correlated positively with the magnitude of subjective sleepiness and impaired psychomotor performance. These findings indicate that the sedative/hypnotic effects of Bz could be due, at least in part, to changes in thermoregulation, especially in the process of heat loss, in humans.
Assuntos
Regulação da Temperatura Corporal/efeitos dos fármacos , Diazepam/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Sono/efeitos dos fármacos , Administração Oral , Adolescente , Adulto , Análise de Variância , Regulação da Temperatura Corporal/fisiologia , Diazepam/sangue , Humanos , Masculino , Desempenho Psicomotor/fisiologia , Sono/fisiologiaRESUMO
OBJECTIVES: The relationship between clinical effects of fluvoxamine (FLV) and the steady-state plasma concentrations (Css) of FLV and its major metabolite fluvoxamino acid (FLA) was studied. METHODS: The subjects were 49 Japanese patients with major depressive disorder receiving FLV 200 mg/day for 6 weeks. Depressive symptoms and side effects were evaluated by the Montgomery Asberg Depression Rating Scale (MADRS), and the UKU Side Effect Rating Scale, respectively. The Css of FLV and FLA were measured by HPLC, and the CYP2D6 genotyping was performed by PCR methods. RESULTS: The Css of FLV and FLV+FLA showed significant negative correlations with the final MADRS score. The Css of FLV, FLA and FLV+FLA were significantly higher in the responders (final MADRS score < or =10) than in non-responders. The proportion of responders was significantly higher in the patients with the Css of FLV, FLA and FLV+FLA above 150, 55 and 180 ng/ml, respectively. In the multiple regression, the Css of FLV+FLA showed a significant negative correlation with the final MADRS score. In the logistic regression, the Css of FLA had a significant effect on the differentiation of responders from non-responders. The incidence of side effects was low, and the development of nausea, the most frequent one, was not dependent on any Css. The number of mutated CYP2D6 alleles causing absent or decreased enzyme activity was not related to the therapeutic response or development of nausea. CONCLUSIONS: The present study suggests that there is a therapeutic threshold for the Css of FLV and probably also for the Css of FLA, and the Css of FLV+FLA above 180 ng/ml best predicts a good therapeutic response.
Assuntos
Aminoácidos/sangue , Antidepressivos de Segunda Geração/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Fluvoxamina/sangue , Fluvoxamina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Adulto , Idoso , Antidepressivos de Segunda Geração/sangue , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Transtorno Depressivo Maior/sangue , Relação Dose-Resposta a Droga , Feminino , Fluvoxamina/análogos & derivados , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Inibidores Seletivos de Recaptação de Serotonina/sangue , Fumar , Resultado do TratamentoRESUMO
The effects of the cytochrome P450 (CYP)2C19 genotype and cigarette smoking on the single oral dose pharmacokinetics and pharmacodynamics of estazolam were studied in 16 healthy male volunteers. The two mutated alleles (CYP2C19*2 and CYP2C19*3) causing absent CYP2C19 activity were identified by PCR-based restriction enzyme analysis. Five subjects had no mutated allele, five had one mutated allele, and six had two mutated alleles. Seven subjects were smokers, and nine were nonsmokers. The subjects received a single oral 4-mg dose of estazolam, and blood samplings and evaluation of psychomotor function were conducted up to 72 h after dosing. There was no significant difference among the groups with no, one, and two mutated alleles for the peak plasma concentration (145.2+/-36.5 vs. 142.1+/-33.6 vs. 113.2+/-29.7 ng/ml), area under the plasma concentration-time curve (0- infinity ) (4916.0+/-1276.4 vs. 4389.6+/-736.1 vs. 4047.3+/-613.8 ng x h/ml), apparent oral clearance (0.22+/-0.05 vs. 0.25+/-0.03 vs. 0.25+/-0.03 ml/min/kg), and elimination half-life (24.4+/-4.6 vs. 29.6+/-8.5 vs. 30.7+/-3.9 h). Similarly, none of the pharmacokinetic parameters was significantly different between the nonsmoker and smoker groups. Neither the number of mutated allele nor cigarette smoking affected the psychomotor function parameters significantly. The present study suggests that neither the CYP2C19 genotype nor cigarette smoking affects the single oral dose pharmacokinetics and pharmacodynamics of estazolam.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Estazolam/administração & dosagem , Estazolam/farmacocinética , Oxigenases de Função Mista/genética , Fumar/genética , Fumar/metabolismo , Administração Oral , Adulto , Análise de Variância , Área Sob a Curva , Distribuição de Qui-Quadrado , Citocromo P-450 CYP2C19 , Estazolam/sangue , Genótipo , Humanos , MasculinoRESUMO
Monoamine oxidase A (MAOA) and tryptophan hydroxylase (TPH) are the staple enzymes in the metabolism of serotonin (5-HT). The genetic polymorphisms of these two enzymes might individually alter the production, release, reuptake or degradation of 5-HT during the treatment of selective serotonin reuptake inhibitors (SSRIs), leading to the individual differences in the antidepressant effects of SSRIs. The authors investigated whether a functional polymorphism in the MAOA gene promoter (MAOA-VNTR) and a TPH gene polymorphism in intron 7 (TPH-A218C) were associated with the antidepressant response to fluvoxamine in 66 Japanese patients with major depressive disorder during a 6-week study with a specific dosage plan. Fifty-four patients completed the study. The present study fails to demonstrate that the genetic polymorphisms of MAOA-VNTR and TPH-A218C affect the antidepressant effect of fluvoxamine in Japanese patients with major depressive disorder.
Assuntos
Antidepressivos de Segunda Geração/farmacologia , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/genética , Fluvoxamina/farmacologia , Monoaminoxidase/genética , Monoaminoxidase/farmacologia , Polimorfismo Genético , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/farmacologia , Adulto , Idoso , Transtorno Depressivo/psicologia , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Resultado do TratamentoRESUMO
The presence of the long (l) variant of the serotonin (5-hydroxytryptamine: 5-HT) transporter gene-linked polymorphic region (5-HTTLPR) is reported to be associated with a more favorable and faster antidepressant effect of selective serotonin reuptake inhibitors in Caucasians. The frequency of the l allele is lower in Japanese than in Caucasians; therefore, the antidepressant effect of fluvoxamine can be not as good in Japanese as in Caucasians. The authors investigated whether 5-HTTLPR was associated with the antidepressant response to fluvoxamine in 66 Japanese patients with major depressive disorder in a protocolized-dosing 6-week study. The short (s) allele frequency was significantly higher in the responsive individuals than in the nonresponsive ones (P = .010). The present study suggests that fluvoxamine is not less effective in depressive patients carrying the s allele than in the ones carrying the l allele and it is not less effective in Japanese than in Caucasians.
Assuntos
Antidepressivos/uso terapêutico , Proteínas de Transporte/genética , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Fluvoxamina/uso terapêutico , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Polimorfismo Genético/genética , Adulto , Idoso , Alelos , Análise de Variância , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene/genética , Ligação Genética/efeitos dos fármacos , Genótipo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
We investigated the association between serotonergic polymorphisms and incidence of nausea, which is the most frequent side-effect of selective serotonin reuptake inhibiters (SSRIs), in 66 patients treated with fluvoxamine in a protocolized-dosing method. We focused on three polymorphisms of serotonin (5-HT) neuronal systems such as 5-HT transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR), a variable number of tandem repeat (VNTR) polymorphism in the second intron of the 5-HTT gene (STin2) and tryptophan hydroxylase (TPH) gene polymorphism in intron 7 (TPH-A218C), which have been reported to possess positive association with treatment response to SSRIs. In addition to this, the relationship between development of nausea and treatment response was also analyzed. Results suggested that these three polymorphisms did not affect the development of fluvoxamine-induced nausea, and that incidence of nausea was not a phenomenon that predicts the treatment response to fluvoxamine.
Assuntos
Antidepressivos de Segunda Geração/efeitos adversos , Proteínas de Transporte/genética , Fluvoxamina/efeitos adversos , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras , Náusea/induzido quimicamente , Proteínas do Tecido Nervoso , Adulto , Idoso , Antidepressivos de Segunda Geração/sangue , Antidepressivos de Segunda Geração/uso terapêutico , Distribuição de Qui-Quadrado , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Feminino , Fluvoxamina/sangue , Fluvoxamina/uso terapêutico , Frequência do Gene , Genótipo , Humanos , Íntrons/genética , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites/genética , Polimorfismo Genético , Proteínas da Membrana Plasmática de Transporte de Serotonina , Triptofano Hidroxilase/genéticaRESUMO
A high-performance liquid chromatography (HPLC) assay was developed for the determination of estazolam in human plasma. Estazolam and alprazolam as an internal standard were detected by ultraviolet absorbance at 240 nm. Estazolam in plasma was extracted by a rapid and simple procedure based on cyanopropyl bonded-phase extraction. Chromatographic separation was achieved with a reversed-phase C8-5 column using a mobile phase of 0.5% potassium dihydrogenphosphate(pH 4.5)-acetonitrile (70:30, v/v). The determination of estazolam was possible in the concentration range of 1.0 - 200.0 ng/mL. The mean recovery of estazolam added to plasma was 96.1 +/- 1.5% with coefficients of variation of less than 5.5%. This method is applicable for accurately monitoring the plasma level of estazolam in healthy subjects participating in scientific research.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Estazolam/sangue , Hipnóticos e Sedativos/sangue , Calibragem , Estazolam/farmacocinética , Humanos , Hipnóticos e Sedativos/farmacocinética , Masculino , Padrões de Referência , Valores de Referência , Espectrofotometria UltravioletaRESUMO
A high-performance liquid chromatographic (HPLC) method has been developed for the simultaneous determination of fluvoxamine and its major metabolite fluvoxamino acid in plasma. Fluvoxamine and fluvoxamino acid in plasma were extracted using a C18 bonded-solid phase cartridge, followed by C4 reversed-phase HPLC separation.Fluvoxamine, fluvoxamino acid and moperone as an internal standard were detected by ultraviolet absorbance at 254 nm. It was possible to determine both fluvoxamine and fluvoxamino acid in the concentration range of 25.0-200.0 ng/mL, respectively. The detection limits of both fluvoxamine and fluvoxamino acid were 10.0 ng/mL, respectively. The mean recoveries of fluvoxamine and fluvoxamino acid added to plasma were more than 94.0% and 96.5%, with a coefficient of variation of less than 7.6% and 8.2%, respectively. This method has been used for the simultaneous determination of steady-state plasma concentration (Css) of fluvoxamine and fluvoxamino acid in depressive patients treated with 200 mg of oral fluvoxamine dosed as 100 mg twice-daily. The Css values of fluvoxamine and fluvoxamino acid in twelve Japanese patients were showed individual variations, which were in the range of 48.3-532.9 ng/ml and 35.6-307.1 ng/ml, respectively.
Assuntos
Aminoácidos/sangue , Antidepressivos de Segunda Geração/sangue , Fluvoxamina/sangue , Antidepressivos de Segunda Geração/uso terapêutico , Calibragem , Cromatografia Líquida de Alta Pressão , Depressão/sangue , Depressão/tratamento farmacológico , Fluvoxamina/análogos & derivados , Fluvoxamina/uso terapêutico , Humanos , Concentração de Íons de Hidrogênio , Padrões de Referência , Reprodutibilidade dos Testes , Espectrofotometria UltravioletaRESUMO
We describe a patient with dysphagia and trismus associated with lower jaw inflammation due to phlegmon who developed severe hyponatremia from water intoxication due to excessive water intake after diaphoresis caused by abnormally hot weather. A 63-year-old woman presented with severe swelling of the floor of the mouth and trismus. As she had spasms and numbness of the extremities and restlessness and water intoxication caused by excessive water intake was suspected, she was hospitalized for the treatment of inflammation and electrolyte disorder. Although swelling of the floor of the mouth subsided over time after antimicrobial therapy, vomiting, diarrhea, and numbness of the extremities continued. On day 5 of hospitalization, severe vomiting and diarrhea recurred, and serum sodium levels decreased to 108 mEq/L. Decrease in water intake is essential in the treatment of hyponatremia. However, in patients with severe vomiting and diarrhea who can swallow only liquids because of hot weather and eating disorder, the risk of sodium depletion is high. It is important to restore electrolyte balance and fluid volume through supplementation with sodium, chlorine, potassium, and glucose among others, the reduction of intravenous fluid volume, and diuresis in order to correct the sodium level slowly.
RESUMO
The aim of the present study was to clarify whether subjective sleepiness accurately reflects benzodiazepine-related decline in psychomotor function after taking benzodiazepines (BZPs) in aged people. Subjects were eight healthy, young (mean age, 19.8 years) and seven healthy, older (mean age, 60.9 years) men. Placebo and diazepam (DZP) were administered orally in a single-blind crossover manner to the young subjects (placebo, 5 mg DZP and 10 mg DZP) and to the older subjects (placebo and 5 mg DZP). Plasma drug concentration, choice reaction time (CRT) as an objective measure of psychomotor function, and the Stanford Sleepiness Scale (SSS) as a measure of subjective sleepiness were monitored every 20 min from 1000 until 1600 h, being the drug administered at 1200 h. Pharmacokinetic variables did not differ significantly between the two age groups. DZP at 10 mg in young subjects induced significant increases in both the CRT and SSS score. DZP at 5 mg induced no significant increase in SSS score in either age group but did induce a significant increase in CRT only in the older subjects that matched that in young subjects given 10 mg DZP. The older subjects suffered from dissociation between subjective sleepiness and objective psychomotor impairment under DZP treatment. Such individuals may underestimate the detrimental effects on brain function.
Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Diazepam/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Sono/efeitos dos fármacos , Adolescente , Adulto , Idoso , Envelhecimento , Análise de Variância , Atenção/efeitos dos fármacos , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/sangue , Estudos Cross-Over , Diazepam/administração & dosagem , Diazepam/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Desempenho Psicomotor/fisiologia , Método Simples-Cego , Sono/fisiologiaRESUMO
Gender differences in the treatment response to fluvoxamine (selective serotonin re-uptake inhibitor) and milnacipran (serotonin/norepinephrine re-uptake inhibitor) were investigated in Japanese major depressive patients. A total of 125 Japanese patients was included in the present study. Sixty-six patients received fluvoxamine treatment. The daily dose was 50 mg/day for the first week and increased to 100 mg after 1 week, up to 200 mg after another week. Fifty-nine patients were given milnacipran. The daily dose was 50 mg/day for the first week, and up to 100 mg/day thereafter. Patients were divided into three groups: younger women (<44 years of age), older women (> or =44 years of age) and men. Depressive symptoms were evaluated using the Montgomery and Asberg Depression Rating Scale (MADRS) before treatment and at 1, 2, 4 and 6 weeks after the beginning of the study. In comparison with other groups, younger women treated with fluvoxamine demonstrated a significant difference in the time course of MADRS score change. However, these gender/age-related differences of antidepressant response were not observed in the patients treated with milnacipran. The results suggest that fluvoxamine is more effective in younger female patients than older female patients and male patients, while milnacipran is generally effective irrespective of gender or age.
Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Ciclopropanos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Fluvoxamina/uso terapêutico , Envelhecimento , Coleta de Dados , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Japão , Masculino , Menopausa/psicologia , Pessoa de Meia-Idade , Milnaciprano , Escalas de Graduação Psiquiátrica , Caracteres SexuaisRESUMO
AIM: To examine the effect of grapefruit juice, an inhibitor of CYP3A4 in the small intestine, on the disposition of manidipine enantiomers in healthy subjects. METHODS: A randomized cross-over study with at least a 2-week wash-out period was performed. Seven healthy male volunteers received an oral 40-mg dose of racemic manidipine after an overnight fast with either grapefruit juice (GFJ) or water, as a control study. Plasma concentrations of (S)- and (R)-manidipine were monitored up to 10 h after the dosing. RESULTS: The plasma concentrations of (S)-manidipine were significantly higher (P<0.001) than those of (R)-manidipine in the control phase with an S/R ratio for the AUC0-infinity of 1.62 (95% confidence interval 1.52, 1.73). GFJ significantly increased Cmax and AUC0-infinity of (S)-manidipine by 2.4-fold (P<0.01) and 2.3-fold (P<0.01), respectively, and Cmax and AUC0-infinity of (R)-manidipine were increased by 3.4-fold (P<0.01) and 3.0-fold (P<0.01), respectively. There were significant differences (P<0.01) in GFJ-mediated percentage increases in Cmax and AUC0-infinity of (S)-manidipine compared with those of (R)-manidipine. The S/R ratio for AUC0-infinity was significantly decreased from 1.6 to 1.2 during the GFJ phase (P<0.01). CONCLUSION: These results indicate that the stereoselective disposition of manidipine was altered by GFJ, as an inhibitor of CYP3A4. GFJ appears to affect this metabolic disposal of (R)-manidipine to a greater extent than that of (S)-manidipine.
Assuntos
Bebidas , Bloqueadores dos Canais de Cálcio/farmacocinética , Citrus paradisi , Di-Hidropiridinas/farmacocinética , Interações Alimento-Droga , Administração Oral , Adulto , Área Sob a Curva , Estudos Cross-Over , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Di-Hidropiridinas/sangue , Humanos , Masculino , Nitrobenzenos , Piperazinas , Estereoisomerismo , Fatores de TempoRESUMO
A major functional component of the blood-brain barrier is P-glycoprotein. In principle, inhibition of this efflux transporter would permit greater distribution of its substrates into the brain and increased central effects. Tariquidar and elacridar, potent and selective P-glycoprotein inhibitors, were investigated in this regard using the opioid loperamide as an in vivo probe in mice. Pretreatment with both inhibitors converted intravenous loperamide from a drug without central effects to one producing antinociception. Radiolabeled loperamide tissue distribution studies indicated that inhibition was associated with increased uptake into brain and testes in the absence of changes in plasma levels, along with enhanced efflux of rhodamine 123 from CD3e+ T-lymphocytes. However, with tariquidar, the loperamide dose-response curves for testes/plasma and brain/plasma concentration ratios were shifted 6- (p = 0.07) and 25-fold (p < 0.01) to the right, respectively (ED50 = 1.48 and 5.65 mg/kg), compared with the rhodamine 123 efflux curve (ED50 0.25 mg/kg). Less pronounced shifts were noted with elacridar where the brain/plasma ratio was shifted only 2-fold relative to the rhodamine 123 efflux data (ED50 = 2.36 versus 1.34 mg/kg, respectively; p 0.01). These results indicate that the P-glycoprotein localized in the blood-brain barrier and, to a lesser extent, the testes-blood barrier is more resistant to inhibition than at other tissue sites such as the lymphocyte; moreover, the extent of this effect depends on the inhibitor. Such resistance can be overcome by a sufficiently high dose of an inhibitor; however, whether this is safely attainable in the clinical situation remains to be determined.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Analgésicos/farmacologia , Barreira Hematoencefálica/metabolismo , Loperamida/farmacologia , Quinolinas/farmacologia , Linfócitos T/metabolismo , Testículo/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Acridinas/farmacocinética , Acridinas/farmacologia , Analgésicos/farmacocinética , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Loperamida/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Dor/tratamento farmacológico , Quinolinas/farmacocinética , Linfócitos T/efeitos dos fármacos , Testículo/efeitos dos fármacos , Tetra-Hidroisoquinolinas/farmacocinética , Tetra-Hidroisoquinolinas/farmacologia , Distribuição TecidualRESUMO
Snail, a DNA-binding zinc finger protein, functions as a transcriptional repressor for genes including E-cadherin during development and the acquisition of tumor cell invasiveness. Human Snail is a 264-amino acid nuclear protein with an amino-terminal basic amino acid-rich domain (SNAG domain) and a carboxyl-terminal DNA-binding domain (zinc finger domain). A series of fusion proteins composed of green fluorescent protein (GFP) and portions of the Snail protein were generated, and their subcellular localization was examined. Fusion of the four zinc fingers to GFP led to the targeting of GFP to the nucleus, demonstrating that the zinc finger domain is sufficient for nuclear localization. Using an in vitro transport system, the nuclear import of Snail was reconstituted by importin (karyopherin) beta in the presence of Ran and NTF2. We further demonstrated that Snail binds directly to importin beta in a zinc finger domain-dependent manner. These results indicate that zinc finger domain of Snail functions as a nuclear localization signal and Snail can be transported into the nucleus in an importin beta-mediated manner.
Assuntos
Núcleo Celular/metabolismo , Sinais Direcionadores de Proteínas/fisiologia , Fatores de Transcrição/metabolismo , beta Carioferinas/metabolismo , Animais , Diferenciação Celular/fisiologia , Cães , Genes Reporter , Humanos , Estrutura Terciária de Proteína , Transporte Proteico/fisiologia , Fatores de Transcrição da Família SnailRESUMO
Snail, a transcriptional repressor of E-cadherin expression, is involved in epithelial-mesenchymal transitions during development. We demonstrate that Snail activity is not restricted to E-cadherin downregulation. Expression of tight junction proteins, including claudin-1, occludin and ZO-1, was downregulated in MDCK cells exogenously expressing Snail protein. Although occludin mRNA levels were downregulated by Snail expression, the transcription of claudin-1 and ZO-1 were unaffected. Reporter assays using the claudin-1 promoter region revealed that promoter activity was not affected by Snail overexpression. Decreased synthesis of claudin-1 protein was observed, however, suggesting that Snail may act in translation initiation. Snail expression also altered the splicing pattern of p120. The levels of mRNA encoding the epithelial variant decreased, while the fibroblastic mRNA form increased. Although ectopic E-cadherin expression resulted in a downregulation of Snail-induced fibronectin expression, fibroblastic morphology was affected only minimally; the expression of tight junctional proteins remained at low levels. These results indicate that Snail is involved in both the direct transcriptional repression of genes, such as E-cadherin and occludin, and post-transcriptional events, including downregulation of claudin-1. These data support the idea that Snail is a transcription factor possessing pleiotropic activities.