Assuntos
Alopecia , Dutasterida , Humanos , Alopecia/tratamento farmacológico , Dutasterida/administração & dosagem , Dutasterida/uso terapêutico , Masculino , Feminino , Administração Oral , Pessoa de Meia-Idade , Inibidores de 5-alfa Redutase/administração & dosagem , Inibidores de 5-alfa Redutase/uso terapêutico , Fibrose/tratamento farmacológico , Adulto , IdosoRESUMO
BACKGROUND: Prior studies indicate that neuroactive steroids mediate some of alcohol's effects. Dutasteride, widely used to treat benign prostatic hypertrophy, is an inhibitor of 5-alpha reductase enzymes, which play a central role in the production of 5α-reduced neuroactive steroids. The purpose of this study was to test dutasteride's tolerability and efficacy for reducing drinking. METHODS: Men (n = 142) with heavy drinking (>24 drinks per week) and a goal to either stop or reduce drinking to nonhazardous levels were randomized to placebo or 1 mg dutasteride daily for 12 weeks. We hypothesized that dutasteride-treated patients would be more successful in reducing drinking. RESULTS: Generalized linear mixed models that included baseline drinking, treatment, time and their 2-way interaction identified significant interactions of treatment-time, such that dutasteride treatment reduced drinking more than placebo. During the last month of treatment, 25% of dutasteride-treated participants had no hazardous drinking (no heavy drinking days and not more than 14 drinks per week) compared with 6% of placebo-treated participants (P = 0.006; NNT = 6). Sensitivity analysis identified baseline drinking to cope as a factor associated with larger reductions in drinking for dutasteride compared with placebo-treated participants. Dutasteride was well tolerated. Adverse events more common in the dutasteride group were stomach discomfort and reduced libido. CONCLUSION: Dutasteride 1 mg daily was efficacious in reducing the number of heavy drinking days and drinks per week in treatment-seeking men. The benefit of dutasteride compared with placebo was greatest for participants with elevated baseline drinking to cope motives.
Assuntos
Inibidores de 5-alfa Redutase , Consumo de Bebidas Alcoólicas , Dutasterida , Humanos , Dutasterida/farmacologia , Dutasterida/administração & dosagem , Dutasterida/efeitos adversos , Masculino , Inibidores de 5-alfa Redutase/farmacologia , Inibidores de 5-alfa Redutase/administração & dosagem , Inibidores de 5-alfa Redutase/efeitos adversos , Pessoa de Meia-Idade , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Adulto , Método Duplo-Cego , Resultado do Tratamento , Idoso , Azasteroides/farmacologia , Azasteroides/administração & dosagem , Azasteroides/uso terapêutico , Azasteroides/efeitos adversosRESUMO
Dutasteride 0.5 mg is a dual inhibitor of 5α-reductase type I and II and was approved in Korea in 2009 for treating androgenetic alopecia (AGA) in men. We investigated the 5-year efficacy and safety of dutasteride 0.5 mg in Korean men with AGA using the basic and specific (BASP) classification. This retrospective analysis included 99 male AGA patients aged ≥18 years who were treated with dutasteride 0.5 mg for at least 5 years from October 2009 to December 2016 at Kyung Hee University Hospital in Gangdong. Patient photographs were scored using the BASP classification, and the Investigator Global Assessment (IGA) was performed using a seven-point scale. Patient improvement (IGA score ≥1) and prevention of disease progression (IGA score ≥0) were 89.9% (89/99) and 93.9% (93/99), respectively. According to the BASP classification, 52.5% (52/99) of the basic type, 75% (15/20) of the specific F type, and 82.2% (60/73) of the specific V type showed clinical improvement after 5 years of treatment. Dutasteride demonstrated long-term safety and efficacy in Korean male patients with AGA over a period of at least 5 years, with results comparable to those of other long-term efficacy studies of finasteride 1 mg in male patients with AGA.
Assuntos
Inibidores de 5-alfa Redutase , Alopecia , Dutasterida , Humanos , Masculino , Alopecia/tratamento farmacológico , Dutasterida/efeitos adversos , Dutasterida/administração & dosagem , Dutasterida/uso terapêutico , Estudos Retrospectivos , Adulto , Inibidores de 5-alfa Redutase/efeitos adversos , Inibidores de 5-alfa Redutase/administração & dosagem , Inibidores de 5-alfa Redutase/uso terapêutico , República da Coreia , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem , Progressão da Doença , Fatores de Tempo , IdosoRESUMO
Frontal fibrosing alopecia (FFA) is a scarring alopecia with fronto-temporo-parietal hairline recession. Although no proven treatment for FFA exists, dutasteride has been suggested as a potential treatment option. We aimed to evaluate the therapeutic response of oral dutasteride in FFA patients. The identification and selection of studies were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis 2020 criteria. To assess the risk of bias for each study, we used the Cochrane's risk of bias in non-randomized studies of interventions (ROBINS-I) assessment tool. A random effects model meta-analysis was performed. Estimated proportion of stabilization for eligible studies was calculated to evaluate the effectiveness of dutasteride for treating FFA. Among patients who achieved stabilization, subgroup analysis was conducted on those showing improvement. Seven studies including 366 patients who received oral dutasteride were identified. The estimated proportion of patients who experienced stabilization of FFA with oral dutasteride was 0.628 (95% CI: 0.398-0.859). In subgroup analyses of patients who experienced improvement, the estimated proportion of improvement was 0.356 (95% CI: 0.163-0.549). In this systematic review and meta-analysis, oral dutasteride revealed to be a good treatment option for disease stabilization or improvement in patients with FFA.
Assuntos
Alopecia , Dutasterida , Dutasterida/uso terapêutico , Dutasterida/administração & dosagem , Alopecia/tratamento farmacológico , Humanos , Fibrose/tratamento farmacológico , Administração Oral , Inibidores de 5-alfa Redutase/uso terapêuticoRESUMO
La alopecia frontal fibrosante es una alopecia cicatricial que se caracteriza por la recesión de la línea de implantación frontotemporal que afecta principalmente a mujeres caucásicas en edad posmenopáusica y rara vez a hombres. Actualmente los mecanismos específicos de desarrollo continúan en estudio; sin embargo hay varias hipótesis sobre la asociación de la alopecia frontal fibrosante con otros trastornos autoinmunitarios. Se comunica el caso de un paciente masculino de 58 años con alopecia frontal fibrosante en áreas comprometidas por vitiligo. (AU)
Frontal fibrosing alopecia is a cicatricial alopecic characterized by progressive regression of the frontotemporal hairline. It usually affects postmenopausal caucasian women, and rarely men. Currently the specific mechanisms of development remain unknown, however there are several hypotheses about the association of frontal fibrosing alopecia with other autoimmune disorders. The case of a 58-year-old male patient with frontal fibrosing alopecia in areas affected by vitiligo. (AU)
Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Vitiligo/complicações , Alopecia/complicações , Alopecia/diagnóstico , Alopecia/tratamento farmacológico , Vitiligo/patologia , Clobetasol/administração & dosagem , Tacrolimo/administração & dosagem , Alopecia/patologia , Dutasterida/administração & dosagemRESUMO
PURPOSE: To identify the clinical factors resulting in the failure of dutasteride add-on treatment to alpha-adrenergic antagonist for patients with lower urinary tract symptoms and benign prostatic enlargement (BPE). METHODS: We retrospectively surveyed the patient cohort who had been enrolled in the study of dutasteride add-on treatment to alpha-adrenergic antagonist from December 2009 to November 2011. Treatment failure was defined as receiving surgery for BPE or requiring intermittent catheterization or permanent bladder catheter for urinary retention or huge postvoid residual urine. Clinical parameters before dutasteride treatment were compared between the successful and failed group. RESULTS: Of 92 patients, 23 (25%) were defined as treatment failure at 7-109 months (mean: 38 months) after dutasteride add-on treatment. In the failed group, the patient' age was younger (71.6 ± 6.8 vs 75.4 ± 8.4, p = 0.033), prostatic volume (PV) was larger (76 ± 41 vs 49 ± 26 ml, p = 0.005), voiding efficiency was lower (54 ± 27 vs 68 ± 24%, p = 0.045) and bladder outlet obstruction index was higher (73 ± 30 vs 48 ± 30, p = 0.015). The cox proportional-hazards model indicated that only intravesical prostatic protrusion (IPP) was associated with treatment failure. Non-failure rate at 3 years after dutasteride add-on treatment was 89% with patients of IPP < 13 mm versus 51% with those of IPP ≥ 13 mm (p < 0.001). CONCLUSION: IPP ≥ 13 mm is the risk factor resulting in the failure of dutasteride add-on treatment to alpha-adrenergic antagonist. This kind of information should be provided to the patients early in the clinical practice so that they could consider the necessity of BPE surgery in the long run.
Assuntos
Inibidores de 5-alfa Redutase/administração & dosagem , Antagonistas Adrenérgicos alfa/administração & dosagem , Dutasterida/administração & dosagem , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Hiperplasia Prostática/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Combinada , Humanos , Sintomas do Trato Urinário Inferior/etiologia , Masculino , Hiperplasia Prostática/complicações , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Falha de TratamentoRESUMO
PURPOSE: Benign prostatic hyperplasia (BPH) is a common disease often manifested by lower urinary tract symptoms (LUTS). We previously found statins were associated with modest attenuations in prostate growth over time in REDUCE. We tested whether statins were associated with LUTS incidence in asymptomatic men and LUTS progression in symptomatic men. MATERIALS AND METHODS: We performed a post-hoc analysis of REDUCE in 3,060 "asymptomatic" men with baseline International Prostate Symptom Score (IPSS) <8 and in 2,198 symptomatic men with baseline IPSS ≥8 not taking α-blockers or 5α-reductase inhibitors. We used multivariable Cox regression models to assess associations between statin use at baseline and LUTS incidence and progression. Among asymptomatic men, incident LUTS was defined as the first reported medical or surgical treatment for BPH or sustained clinically significant LUTS (2 reports of IPSS >14). Among symptomatic men, LUTS progression was defined as IPSS increase ≥4 points from baseline, any surgical procedure for BPH, or initiation of a BPH drug. RESULTS: Among asymptomatic and symptomatic men, 550 (18%) and 392 (18%) used statins at baseline, respectively. On multivariable analysis, statin use was not associated with LUTS incidence (HR 1.05; 95% CI 0.78-1.41, p=0.74) in asymptomatic men, or with LUTS progression (HR 1.13; 95% CI 0.96-1.33, p=0.15) in symptomatic men. Similar results were seen in the dutasteride and placebo arms when stratified by treatment assignment. CONCLUSIONS: In REDUCE, statin use was not associated with either incident LUTS in asymptomatic men or LUTS progression in symptomatic men. These data do not support a role for statins in LUTS prevention or management.
Assuntos
Dutasterida/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Sintomas do Trato Urinário Inferior/epidemiologia , Hiperplasia Prostática/tratamento farmacológico , Neoplasias da Próstata/epidemiologia , Idoso , Doenças Assintomáticas/terapia , Progressão da Doença , Método Duplo-Cego , Humanos , Incidência , Sintomas do Trato Urinário Inferior/etiologia , Sintomas do Trato Urinário Inferior/prevenção & controle , Masculino , Pessoa de Meia-Idade , Próstata/efeitos dos fármacos , Próstata/patologia , Hiperplasia Prostática/patologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/prevenção & controle , Resultado do TratamentoRESUMO
OBJECTIVE: To assess the use and safety of free combination therapy (dutasteride and tamsulosin), dutasteride monotherapy, or tamsulosin monotherapy in patients with benign prostatic hyperplasia (BPH). METHODS: This non-interventional retrospective cohort study used claims data from the Korea Health Insurance Review and Assessment-National Patient Sample database. Patients with BPH ≥ 40 years of age receiving combination therapy (dutasteride 0.5 mg and tamsulosin 0.4 mg daily) or dutasteride 0.5 mg, or tamsulosin 0.4 mg daily dose between 2012 and 2017 were included. The frequency, duration of treatment and risk of any adverse event (AE) or serious AE (SAE) was compared for combination therapy versus each monotherapy using non-inferiority testing. RESULTS: Of 14,755 eligible patients, 1529 (10.4%) received combination therapy, 6660 (45.1%) dutasteride monotherapy, and 6566 (44.5%) tamsulosin monotherapy. The proportion of patients treated with combination therapy exceeded the pre-specified 3% threshold for 'frequent' use. Safety results indicated a similar risk of any AE and SAE irrespective of treatment group. The adjusted relative risk for any AE over the treatment observation period comparing combination therapy with dutasteride monotherapy was 1.07 (95% confidence interval [CI] 1.03, 1.12), and with tamsulosin monotherapy was 0.98 (95% CI 0.95, 1.02) demonstrating non-inferiority. The adjusted relative risk for any SAE was 1.07 (95% CI 0.66, 1.74) and 0.90 (95% CI 0.56, 1.45), compared with dutasteride and tamsulosin monotherapy, respectively. Although the SAE results did not statistically demonstrate non-inferiority of combination therapy based on pre-specified margins, the 95% CI for the risk ratio estimates included the null with a lower limit below the non-inferiority margins, indicating no meaningful differences in SAE risk between groups. Absolute SAE risks were low. CONCLUSION: Combination therapy with dutasteride and tamsulosin is frequently used in real-world practice in South Korea for treatment of BPH and demonstrates a safety profile similar to either monotherapy.
Assuntos
Inibidores de 5-alfa Redutase/administração & dosagem , Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Dutasterida/administração & dosagem , Hiperplasia Prostática/tratamento farmacológico , Tansulosina/administração & dosagem , Inibidores de 5-alfa Redutase/efeitos adversos , Antagonistas de Receptores Adrenérgicos alfa 1/efeitos adversos , Adulto , Idoso , Bases de Dados Factuais , Quimioterapia Combinada , Dutasterida/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia , Estudos Retrospectivos , Tansulosina/efeitos adversosRESUMO
The main neuropathological feature of Parkinson's disease (PD) is degeneration of dopamine (DA) neurons in the substantia nigra (SN); PD prevalence is higher in men, suggesting a role of sex hormones in neuroprotection. This study sought the effects of sex hormones in the brain in a mouse model of PD and modulation of steroid metabolism/synthesis with the 5α-reductase inhibitor dutasteride shown to protect 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) male mice. Male and female mice were gonadectomized (GDX) or SHAM operated. They were treated with vehicle or dutasteride (5 mg/kg) for 10 days and administered a low dose of MPTP (5.5 mg/kg) or saline on the 5th day to model early PD; brains were collected thereafter. Striatal measures of the active metabolite 1-methyl-4-phenylpyridinium (MPP+) contents showed no difference supporting an effect of the experimental conditions investigated. In SHAM MPTP male mice loss of striatal DA and metabolites, DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) specific binding in the striatum and SN was prevented by dutasteride treatment; these changes were inversely correlated with glial fibrillary acidic protein (GFAP, an astrogliosis marker) levels. In SHAM female mice MPTP treatment had little or no effect on striatal and SN DA markers and GFAP levels whereas GDX male and female mice showed a similar loss of striatal DA markers and increase of GFAP. No effect of dutasteride treatment was observed in GDX male and female mice. In conclusion, sex differences in mice MPTP toxicity and response to dutasteride were observed that were lost upon gonadectomy implicating neuroinflammation.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/metabolismo , Castração , Corpo Estriado/metabolismo , Dutasterida/administração & dosagem , Dutasterida/farmacologia , Doença de Parkinson/metabolismo , Caracteres Sexuais , Substância Negra/metabolismo , Animais , Modelos Animais de Doenças , Dopamina/metabolismo , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BLAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Androstenos/administração & dosagem , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Dutasterida/administração & dosagem , Humanos , Masculino , Prednisona/administração & dosagem , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/patologiaRESUMO
PURPOSE: To evaluate the effect of delayed start of combination therapy (CT) with dutasteride 0.5 mg and tamsulosin 0.4 mg on the risk of acute urinary retention or benign prostatic hyperplasia (BPH)-related surgery (AUR/S) in patients with moderate-to-severe lower urinary tract symptoms (LUTS) at risk of disease progression. METHODS: Using a time-to-event model based on pooled data from 10,238 patients from Phase III/IV dutasteride trials, clinical trial simulations (CTS) were performed to assess the risk of AUR/S up to 48 months in moderate-to-severe LUTS/BPH patients following immediate and delayed start of CT for those not responding to tamsulosin monotherapy. Simulation scenarios (1300 subjects/arm) were investigated, including immediate start (reference) and alternative delayed start (six scenarios 1-24 months). AUR/S incidence was described by Kaplan-Meier survival curves and analysed using log-rank test. The cumulative incidence of events as well as the relative and attributable risks were summarised stratified by treatment. RESULTS: Survival curves for patients starting CT at month 1 and 3 did not differ from those who initiated CT immediately. By contrast, significant differences (p < 0.001) were observed when switch to CT occurs ≥ 6 months from the initial treatment. At month 48, AUR/S incidence was 4.6% vs 9.5%, 11.0% and 11.3% in patients receiving immediate CT vs. switchers after 6, 12 and 24 months, respectively. CONCLUSIONS: Start of CT before month 6 appears to significantly reduce the risk of AUR/S compared with delayed start by ≥ 6 months. This has implications for the treatment algorithm for men with LUTS/BPH at risk of disease progression.
Assuntos
Inibidores de 5-alfa Redutase/administração & dosagem , Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Dutasterida/administração & dosagem , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/cirurgia , Tansulosina/administração & dosagem , Retenção Urinária/cirurgia , Doença Aguda , Progressão da Doença , Combinação de Medicamentos , Humanos , Masculino , Medição de Risco , Índice de Gravidade de Doença , Avaliação de Sintomas , Fatores de TempoRESUMO
BACKGROUND: Dutasteride has been proposed as an effective therapy for frontal fibrosing alopecia (FFA). OBJECTIVES: We sought to describe the therapeutic response to dutasteride and the most effective dosage in FFA compared with other therapeutic options or no treatment. METHODS: This was a retrospective observational study including patients with FFA with a minimum follow-up of 12 months. Therapeutic response was evaluated according to the stabilization of the hairline recession. RESULTS: A total of 224 patients (222 females) with a median follow-up of 24 months (range 12-108 months) were included. The stabilization rate for the frontal, right, and left temporal regions after 12 months was 62%, 64%, and 62% in the dutasteride group (n = 148), 60%, 35%, and 35% with other systemic therapies (n = 20), and 30%, 41%, and 38% without systemic treatment (n = 56; P = .000, .006, and .006, respectively). Stabilization showed a statistically significant association with an increasing dose of dutasteride (88%, 91%, and 84% with a weekly treatment of 5 or 7 doses of 0.5 mg [n = 32], P < .005). Dutasteride was well tolerated in all patients. LIMITATIONS: Limitations included the observational and retrospective design. CONCLUSIONS: Oral dutasteride was the most effective therapy with a dose-dependent response for FFA in real clinical practice compared with other systemic therapies or no systemic treatment.
Assuntos
Alopecia/tratamento farmacológico , Dutasterida/administração & dosagem , Testa/patologia , Couro Cabeludo/patologia , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Alopecia/patologia , Relação Dose-Resposta a Droga , Feminino , Fibrose , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Couro Cabeludo/efeitos dos fármacos , Resultado do TratamentoRESUMO
BACKGROUND: 5α-reductase inhibitors (5-ARIs) inhibit the pathway of converting the testosterone to dihydrotestosterone and are widely used in benign prostatic hyperplasia patients. Since androgen receptor activation may play a role in urothelial tumorigenesis, we conducted this retrospective cohort study to determine whether 5α-reductase inhibitors (5-ARIs) administration is associated with bladder cancer mortality, bladder cancer recurrence and upper tract urothelial carcinoma mortality, using the Taiwan National Health Insurance database. METHODS: The data of this retrospective cohort study were sourced from the Longitudinal Health Insurance Database of Taiwan, compiled by the Taiwan National Health Insurance database from 1996 to 2010. It consists of 18,530 men with bladder cancer, of whom 474 were 5-ARIs recipients and 4384 men with upper tract urothelial carcinoma, of whom 109 were 5-ARIs recipients. Propensity Score Matching on the age and geographic data was done at the ratio of 1:10. We analyzed the odds ratios (OR) and 95% confidence interval (CI) of the risk of bladder cancer death, bladder cancer recurrence rate and upper tract urothelial carcinoma related death by the 5-ARIs administration. RESULTS: Those who received 5-ARIs showed a lower risk of bladder cancer related death compared to nonusers in multivariable adjusted analysis (OR 0.835, 95% CI 0.71-0.98). However, there was no significant difference in the bladder cancer recurrence rate (OR 0.956, 95% CI 0.82-1.11) and upper tract urothelial carcinoma related mortality in multivariable adjusted analysis (OR 0.814, 95% CI 0.6-1.1). CONCLUSIONS: Patients who receive 5-ARIs have lower bladder cancer related mortality compared to those who don't. 5-ARIs may prove to be a viable strategy to improve bladder cancer outcomes.
Assuntos
Inibidores de 5-alfa Redutase/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma/tratamento farmacológico , Colestenona 5 alfa-Redutase/genética , Inibidores de 5-alfa Redutase/efeitos adversos , Idoso , Carcinoma/genética , Carcinoma/mortalidade , Carcinoma/patologia , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Dutasterida/administração & dosagem , Finasterida/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Prognóstico , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/genética , Hiperplasia Prostática/mortalidade , Hiperplasia Prostática/patologia , Receptores Androgênicos/genética , Taiwan/epidemiologia , Urotélio/efeitos dos fármacos , Urotélio/patologiaRESUMO
Glioblastoma (GB) is the most common and aggressive primary brain tumor in adult humans. Therapeutic resistance and tumor recurrence after surgical resection contributes to a poor prognosis for glioblastoma patients. Men are known to be more likely than women to develop an aggressive form of GB. Although the reasons for this disparity remain poorly understood, differences in sex steroids have emerged as a leading explanation. Studies indicate that GB-derived cells express androgen receptors (ARs) and synthesize androgens, suggesting that androgens may have a role in the tumor pathogenesis. Thus, our objective was to investigate the effects of the 5α-reductase enzyme inhibitor dutasteride, the AR antagonists cyproterone and flutamide, and combinations of these drugs on the metabolism, proliferation, and invasion capacity of GB-derived U87 cells. We also examined the effects of three natural androgens testosterone, androstenedione and dihydrotestosterone (T, A4, and DHT) on these cells. Cell metabolism was investigated by MTT assay, proliferation was assessed by the bromodeoxyuridine (BrdU) incorporation assay, and invasion was assessed by Boyden chamber assay. The results revealed that T and especially DHT, but not A4, increased U87 cell metabolism and proliferation. Following these findings, we examined the effect of adding dutasteride, cyproterone, or flutamide to the culture media and found that they all significantly decreased cell metabolism and proliferation. Dutasteride also significantly reduced cell invasion. Moreover, any combination of these drugs enhanced their inhibitory effects; the combination of dutasteride to flutamide was most effective at decreasing GB cell proliferation. Our results suggest that administering a combination of AR antagonists and enzyme blockers may be a more effective alternative treatment for GB.
Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Antagonistas de Androgênios/farmacologia , Androgênios/fisiologia , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Dutasterida/farmacologia , Glioblastoma/patologia , Invasividade Neoplásica/prevenção & controle , Inibidores de 5-alfa Redutase/administração & dosagem , Antagonistas de Androgênios/administração & dosagem , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Dutasterida/administração & dosagem , Glioblastoma/metabolismo , HumanosRESUMO
CONTEXT: Glucocorticoids (GCs) are commonly prescribed, but their use is associated with adverse metabolic effects. 5α-reductase inhibitors (5α-RI) are also frequently prescribed, mainly to inhibit testosterone conversion to dihydrotestosterone. However, they also prevent the inactivation of GCs. OBJECTIVE: We hypothesized that 5α-RI may worsen the adverse effects of GCs. DESIGN: Prospective, randomized study. PATIENTS: A total of 19 healthy male volunteers (age 45â ±â 2 years; body mass index 27.1â ±â 0.7kg/m2). INTERVENTIONS: Participants underwent metabolic assessments; 2-step hyperinsulinemic, euglycemic clamp incorporating stable isotopes, adipose tissue microdialysis, and biopsy. Participants were then randomized to either prednisolone (10 mg daily) or prednisolone (10 mg daily) plus a 5α-RI (finasteride 5 mg daily or dutasteride 0.5 mg daily) for 7 days; metabolic assessments were then repeated. MAIN OUTCOME MEASURES: Ra glucose, glucose utilization (M-value), glucose oxidation, and nonesterified fatty acids (NEFA) levels. RESULTS: Co-administration of prednisolone with a 5α-RI increased circulating prednisolone levels (482â ±â 96 vs 761â ±â 57 nmol/L, Pâ =â 0.029). Prednisolone alone did not alter Ra glucose (2.55â ±â 0.34 vs 2.62â ±â 0.19 mg/kg/minute, Pâ =â 0.86), M-value (3.2â ±â 0.5 vs 2.7â ±â 0.7 mg/kg/minute, Pâ =â 0.37), or glucose oxidation (0.042â ±â 0.007 vs 0.040â ±â 0.004 mmol/hr/kg/minute, Pâ =â 0.79). However, co-administration with a 5α-RI increased Ra glucose (2.67â ±â 0.16 vs 3.05â ±â 0.18 mg/kg/minute, Pâ <â 0.05) and decreased M-value (4.0â ±â 0.5 vs 2.6â ±â 0.4 mg/kg/minute, Pâ <â 0.05), and oxidation (0.043â ±â 0.003 vs 0.036â ±â 0.002 mmol/hr/kg, Pâ <â 0.01). Similarly, prednisolone did not impair insulin-mediated suppression of circulating NEFA (43.1â ±â 28.9 vs 36.8â ±â 14.3 µmol/L, Pâ =â 0.81), unless co-administered with a 5α-RI (49.8â ±â 8.6 vs 88.5â ±â 13.5 µmol/L, Pâ <â 0.01). CONCLUSIONS: We have demonstrated that 5α-RIs exacerbate the adverse effects of prednisolone. This study has significant translational implications, including the need to consider GC dose adjustments, but also the necessity for increased vigilance for the development of adverse effects.
Assuntos
Inibidores de 5-alfa Redutase/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Metabolismo Energético/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Inibidores de 5-alfa Redutase/efeitos adversos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Adolescente , Adulto , Idoso , Progressão da Doença , Interações Medicamentosas , Quimioterapia Combinada/efeitos adversos , Dutasterida/administração & dosagem , Dutasterida/efeitos adversos , Finasterida/administração & dosagem , Finasterida/efeitos adversos , Técnica Clamp de Glucose , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Medicamentos sob Prescrição/efeitos adversos , Estudo de Prova de Conceito , Adulto JovemAssuntos
Alopecia/imunologia , Inflamação/diagnóstico , Pele/patologia , Adulto , Idoso , Alopecia/diagnóstico , Alopecia/tratamento farmacológico , Alopecia/patologia , Clobetasol/administração & dosagem , Dermoscopia , Progressão da Doença , Quimioterapia Combinada/métodos , Dutasterida/administração & dosagem , Feminino , Fibrose , Seguimentos , Folículo Piloso/diagnóstico por imagem , Folículo Piloso/imunologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Pele/diagnóstico por imagem , Pele/imunologia , Resultado do Tratamento , Triancinolona/administração & dosagemRESUMO
Androgenetic alopecia (AGA) is the most common hair loss disorder in men and women. The characteristic and reproducible balding pattern in AGA negatively affects self-image and the external perceptions of the balding patient. The phenotypical changes are driven by dihydrotestosterone (DHT) and its precursor testosterone. DHT induces follicle miniaturization and hair cycle changes until resulting hairs no longer extrude through the skin surface. AGA is inherited in a polygenetic pattern and is susceptible to epigenetic and environmental factors. Currently, minoxidil, finasteride, and photolaser therapy are the only Food and Drug Administration-approved medical treatments for AGA.
Assuntos
Alopecia/fisiopatologia , Alopecia/terapia , Preparações para Cabelo/administração & dosagem , Alopecia/etiologia , Alopecia/metabolismo , Di-Hidrotestosterona/metabolismo , Dutasterida/administração & dosagem , Finasterida/administração & dosagem , Humanos , Terapia com Luz de Baixa Intensidade , Minoxidil/administração & dosagemRESUMO
Androgen deprivation therapy (ADT) is the mainstay for the treatment of advanced prostate cancer. Since the clinical evolution from surgical orchiectomy, we have typically used ADT and orchiectomy to be synonymous terms for castration. The goal of this study is to determine if, in contemporary medical practice, surgical and chemical castration provide for similar levels of diminishment of total and free testosterone. Further, what approaches should be used to most accurately measure testosterone levels in men with advanced prostate cancer and what cutoff values, for example for total testosterone 50 ng dl-1 or 20 ng dl-1, should be utilized. Studies available in the literature have been analyzed and compiled to address these questions. Finally, evidence is provided that free testosterone, the biologically active component, should be utilized to provide clinically relevant state of castration.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/cirurgia , Testosterona/sangue , Antagonistas de Androgênios/administração & dosagem , Cromatografia Líquida , Terapia Combinada , Dutasterida/administração & dosagem , Finasterida/administração & dosagem , Hormônio Liberador de Gonadotropina/agonistas , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Humanos , Luminescência , Masculino , Espectrometria de Massas , Orquiectomia , Guias de Prática Clínica como Assunto , Radioimunoensaio , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidoresRESUMO
BACKGROUND AND OBJECTIVE: Dutasteride, an analog of testosterone, a 5α-reductase inhibitor is widely used in the treatment of moderate to severe symptomatic benign prostatic hyperplasia. The aim of this study was to compare the pharmacokinetic characteristics of dutasteride in beagle dogs after oral administration of a conventional soft gelatin capsule (Avodart®) and a novel solid-supersaturatable soft-microemulsifying drug delivery system (SMEDDS) tablet. METHODS: In this comparative dissolution study, the dissolution of dutasteride was pH-independent for both formulations. Noncompartmental analysis and modeling approaches were carried out to determine the pharmacokinetic parameters of dutasteride. RESULTS: Approximately 90% of the drug dissolved in all media within 15 min, indicating that there was little difference in the dissolution rate of the solid-supersaturatable SMEDDS tablets and that of the commercial soft gelatin capsules. Using t test analysis, no statistically significant difference was detected in the pharmacokinetic parameters of the two formulations. The test/reference geometric mean ratios were 1.087 (90% confidence intervals 0.8529-1.3854) for the area under the plasma concentration versus time curve from 0 to the last time point (48 h) with a measurable concentration and 1.094 (90% confidence intervals 0.8909-1.3454) for maximum plasma concentration. Unfortunately, the bioequivalent criterium (0.8-1.25) was not met due to the small sample size, but the results of this study suggest a possible bioequivalence of dutasteride in the two formulations. CONCLUSION: Based on the results of this study, the development of a tablet dosage form of dutasteride using a solid-supersaturatable SMEDDS should be considered for humans.
Assuntos
Inibidores de 5-alfa Redutase/farmacocinética , Sistemas de Liberação de Medicamentos , Dutasterida/farmacocinética , Inibidores de 5-alfa Redutase/administração & dosagem , Administração Oral , Animais , Cápsulas , Cães , Liberação Controlada de Fármacos , Dutasterida/administração & dosagem , Emulsões , Gelatina , Masculino , Comprimidos , Equivalência TerapêuticaRESUMO
The objective of our study was to describe the effectiveness and safety of oral dutasteride (OD) for male androgenetic alopecia in real clinical practice. A retrospective, monocentric, and descriptive study was designed. Male patients with androgenetic alopecia that had received OD for at least 12 months were included. Three or less capsules of 0.5 mg per week were considered low doses. Therapeutic response was assessed by comparison of pre- and post-treatment (at month 12) clinical images by three independent dermatologists with expertise in hair disorders, using a four-point scale (worsening, stabilization, mild improvement or marked improvement). In all, 307 patients with a mean age of 35.3 years (range 18-79) were included. Eight patients (2.6%) required the discontinuation of the drug due to decreased libido (n = 4), gynecomastia (n = 2), mood disorder (n = 1) and erectile dysfunction (n = 1). All these AE resolved after stopping the medication. No AE were detected in patients receiving low doses of OD. The effectiveness was evaluated in the subgroup of 42 patients (13.7%) who received OD in monotherapy: 38 patients improved (90%), 10 of them (23.8%) presenting a marked improvement, 4 patients (9.5%) were stable and none patient worsened. In conclusion, OD is an effective treatment for male androgenetic alopecia in real clinical practice, presenting a good safety profile, especially at lower doses.