Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 616
Filtrar
1.
Yonsei Med J ; 61(6): 553-555, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32469180

RESUMO

Cerebral venous thrombosis (CVT) is an uncommon cause of stroke that mainly affects young adults with known risk factors of prothrombotic conditions, pregnancy, infection, malignancy, and drugs. Dutasteride is a 5α-reductase inhibitor that is used for benign prostate hypertrophy and androgenetic alopecia. To date, CVT caused by dutasteride use has not been reported. A 25-year-old male presented with headache and diplopia. He had taken 0.5 mg of dutasteride every other day for 9 months to treat alopecia. A headache developed 7 months after he started taking medication, and horizontal diplopia occurred 1 month after the onset of headache. Fundus examination showed bilateral papilledema. Brain magnetic resonance imaging showed thrombosis in the left sigmoid and transverse sinuses. Headache and diplopia improved after discontinuing dutasteride and starting anticoagulation. The results from this case report indicated dutasteride as a potential cause of CVT. Presumably, the increased estrogen level due to dutasteride use caused the formation of a thrombus.


Assuntos
Veias Cerebrais/patologia , Dutasterida/efeitos adversos , Trombose dos Seios Intracranianos/induzido quimicamente , Inibidores de 5-alfa Redutase/efeitos adversos , Adulto , Fundo de Olho , Humanos , Imagem por Ressonância Magnética , Masculino , Fatores de Risco
2.
PLoS One ; 15(3): e0229754, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32134978

RESUMO

PURPOSE: To determine whether SRD5A2 promoter methylation is associated with cancer progression during androgen deprivation therapy (ADT) in CRPC. PATIENTS AND METHODS: In a Local CRPC cohort, 42 prostatic specimens were collected from patients who were diagnosed as CRPC and underwent transurethral resection of the prostate (TURP) at Massachusetts General Hospital (MGH). In a metastatic CRPC (Met CRPC) cohort, 12 metastatic biopsies were collected from CRPC patients who would be treated with abiraterone plus dutasteride (Clinical Trial NCT01393730). As controls, 36 benign prostatic specimens were collected from patients undergoing prostate reduction surgery for symptoms of bladder outlet obstruction secondary to benign prostatic hyperplasia (BPH). The methylation status of cytosine-phosphate-guanine (CpG) site(s) at SRD5A2 promoter regions was tested. RESULTS: Compared with benign prostatic tissue, CRPC samples demonstrated higher SRD5A2 methylation in the whole promoter region (Local CRPC cohort: P < 0.001; Met CRPC cohort: P <0.05). In Local CRPC cohort, a higher ratio of methylation was correlated with better OS (R2 = 0.33, P = 0.013). Hypermethylation of specific regions (nucleotides -434 to -4 [CpG# -39 to CpG# -2]) was associated with a better OS (11.3±5.8 vs 6.4±4.4 years, P = 0.001) and PFS (8.4±5.4 vs 4.5±3.9 years, P = 0.003) with cutoff value of 37.9%. Multivariate analysis showed that SRD5A2 methylation was associated with OS independently (whole promoter region: P = 0.035; specific region: P = 0.02). CONCLUSION: Our study demonstrate that SRD5A2 methylation in promoter regions, specifically at CpG# -39 to -2, is significantly associated with better survival for CRPC patients treated with ADT. Recognition of epigenetic modifications of SRD5A2 may affect the choices and sequence of available therapies for management of CRPC.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Inibidores de 5-alfa Redutase/uso terapêutico , Androstenos/uso terapêutico , Dutasterida/uso terapêutico , Proteínas de Membrana/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Humanos , Masculino , Prognóstico , Regiões Promotoras Genéticas/efeitos dos fármacos , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Resultado do Tratamento
4.
Int J Clin Pharmacol Ther ; 58(1): 37-49, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31670653

RESUMO

OBJECTIVE: To evaluate real-world persistence and adherence in patients with benign prostate hyperplasia (BPH) receiving a fixed-dose combination of dutasteride plus tamsulosin (DUT-TAM FDC) versus α-blocker plus 5-α reductase inhibitor (AB/5ARI) free-combination therapy. MATERIALS AND METHODS: This retrospective, observational cohort study utilized the German IMS LRx (IQVIA) database. Patients ≥ 45 years old with BPH receiving DUT-TAM FDC or AB/5ARI free-combination therapy from July 1, 2011 to November 30, 2017 were included. Data were analyzed for 48 months from index date (date of first prescription). Persistence, measured as time to discontinuation (defined as a 90-day gap in therapy), was evaluated using Kaplan-Meier curves (log-rank tests). Adherence, measured as medication possession ratio (MPR), was based on a comparison of mean prescribing duration and expected treatment duration. RESULTS: A total of 141,667 patients were included (DUT-TAM FDC, n = 86,057; free AB/5ARI: n = 55,610). Small differences in persistence were observed between treatment arms. At month 12, 41.8% of DUT-TAM FDC-treated and 41.0% of AB/5ARI free-combination therapy-treated patients were persistent; at month 24, 28.2% and 27.1% were persistent, respectively. A higher proportion of DUT-TAM FDC-treated patients had MPR ≥ 0.80, ≥ 0.75 and ≥ 0.70 compared with AB/5ARI free-combination therapy (p < 0.0001). CONCLUSION: Small differences observed in persistence between treatment arms may not translate to meaningful clinical relevance. Adherence was significantly better in the FDC arm, which may be clinically relevant as improved adherence is associated with better outcomes. Persistence and adherence to BPH therapy in Germany is low; further studies exploring the reasons behind this are required.


Assuntos
Inibidores de 5-alfa Redutase/uso terapêutico , Dutasterida/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Hiperplasia Prostática/tratamento farmacológico , Tansulosina/uso terapêutico , Quimioterapia Combinada , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
5.
Urology ; 137: 97-101, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31733275

RESUMO

OBJECTIVE: To evaluate whether total serum PSA, free-PSA ratio and PSA density have similar diagnostic properties for detecting prostate cancer (PCa) and clinically-significant (cs) PCa in men with normal testosterone compared to men with low testosterone with a prior negative biopsy. METHODS: We conducted a retrospective analysis of 3295 men undergoing a 2-year prostate biopsy following a negative prestudy biopsy in the placebo arm of the Reduction by Dutasteride of PCa Events (REDUCE) study. Men were divided in 2 groups based on testosterone level < or ≥300 ng/dL. Diagnostic properties of total serum PSA, free-PSA ratio, and PSA density to predict PCa and csPCa, defined as Gleason score ≥7, were determined for several thresholds and plotted as receiver operator characteristic curves. RESULTS: A total of 603 men (18.3%) had low testosterone. The prevalence of PCa and csPCa was 92 (15.3%) and 27 (4.5%), respectively, for low testosterone men compared to 458 (17.0%) and 138 (5.1%), correspondingly, for normal testosterone men. Total PSA, free-PSA ratio and PSA density showed similar sensitivity, specificity, and accuracy to predict PCa and csPCa among low testosterone men compared to normal testosterone men. CONCLUSION: Among subjects in a clinical trial with a prior negative biopsy, total PSA, free-PSA ratio and PSA density have comparable diagnostic characteristics for PCa screening in low and normal testosterone men.


Assuntos
Dutasterida/uso terapêutico , Antígeno Prostático Específico/sangue , Próstata/patologia , Neoplasias da Próstata , Testosterona/sangue , Inibidores de 5-alfa Redutase/uso terapêutico , Idoso , Biópsia/métodos , Método Duplo-Cego , Detecção Precoce de Câncer/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Avaliação de Resultados em Cuidados de Saúde , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Sensibilidade e Especificidade
6.
Colloids Surf B Biointerfaces ; 185: 110573, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31675643

RESUMO

Benign prostatic hyperplasia (BPH) is a condition characterized by a benign enlargement of the prostate that interferes with the normal flow of urine. This disease is treated with the oral administration of combination therapy comprising α-blockers (tamsulosin) and 5α-reductase inhibitors (dutasteride). However, these compounds have low bioavailability. Thus, transdermal microemulsions aimed at promoting permeation and efficient targeted drug delivery through the skin are used. The objectives of this study were to obtain microemulsions of the combined doses of dutasteride and tamsulosin and evaluate their anti-hyperplastic activity in vivo. A phase diagram (4:1) was obtained for the choice of microemulsions. The microemulsions were characterized in terms of the droplet size, rheology, pH, conductivity, refractive index, in vitro release profile, and antihyperplastic effect in vivo. A method for the simultaneous quantification of drugs was developed using UV-vis spectroscopy. The microemulsions had an average size less than 116 nm, an acidic pH and low viscosity. The conductivity ranged from 6.18 to 185.2 µS/cm. The in vitro release profile was sustained for 6 h. Microemulsions promoted the reduction in the size of testosterone-dependent organs (prostate and seminal vesicles). Transdermal formulations for the treatment of BPH were obtained as a therapeutic alternative to conventional treatments.


Assuntos
Dutasterida/uso terapêutico , Emulsões/química , Hiperplasia Prostática/tratamento farmacológico , Tansulosina/uso terapêutico , Animais , Liberação Controlada de Fármacos , Masculino , Transição de Fase , Próstata/efeitos dos fármacos , Próstata/patologia , Ratos Wistar , Reprodutibilidade dos Testes
7.
Prostate ; 80(1): 83-87, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31634418

RESUMO

BACKGROUND: Several polygenic risk score (PRS) methods are available for measuring the cumulative effect of multiple risk-associated single nucleotide polymorphisms (SNPs). Their performance in predicting risk at the individual level has not been well studied. METHODS: We compared the performance of three PRS methods for prostate cancer risk assessment in a clinical trial cohort, including genetic risk score (GRS), pruning and thresholding (P + T), and linkage disequilibrium prediction (LDpred). Performance was evaluated for score deciles (broad-sense validity) and score values (narrow-sense validity). RESULTS: A training process was required to identify the best P + T model (397 SNPs) and LDpred model (3 011 362 SNPs). In contrast, GRS was directly calculated based on 110 established risk-associated SNPs. For broad-sense validity in the testing population, higher deciles were significantly associated with higher observed risk; Ptrend was 7.40 × 10-11 , 7.64 × 10-13 , and 7.51 × 10-10 for GRS, P + T, and LDpred, respectively. For narrow-sense validity, the calibration slope (1 is best) was 1.03, 0.77, and 0.87, and mean bias score (0 is best) was 0.09, 0.21, and 0.10 for GRS, P + T, and LDpred, respectively. CONCLUSIONS: The performance of GRS was better than P + T and LDpred. Fewer and well-established SNPs of GRS also make it more feasible and interpretable for genetic testing at the individual level.


Assuntos
Modelos Genéticos , Neoplasias da Próstata/genética , Dutasterida/administração & dosagem , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Reprodutibilidade dos Testes , Medição de Risco/métodos
8.
Urologiia ; (5): 156-160, 2019 Dec.
Artigo em Russo | MEDLINE | ID: mdl-31808653

RESUMO

In the treatment of lower urinary tract in combination with benign prostatic hyperplasia, alpha-blockers are most often prescribed, but in certain cases, the appointment of 5-reductase inhibitors is justified. This article analyzes relevant studies of recent years regarding the validity of the use of dutasteride (Gardium) 0.5 mg per day. Dutasteride can effectively reduce the total score of IPSS to 30%. It increases a volumetric urine flow rate 2-3 ml/sec, significantly reduces the chance of acute urinary retention in 70-88% in various studies, and reduces the frequency of hospitalization by 66%. Dutasteride also increases the likelihood of timely diagnosis of prostate cancer by 23%. Erectile dysfunction is a common side effect, serving as a reason for refusal of therapy is erectile dysfunction, which occurs in 16% of cases, and the probability of which is the highest in the first months during conservative therapy.


Assuntos
Inibidores de 5-alfa Redutase/administração & dosagem , Dutasterida/administração & dosagem , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Hiperplasia Prostática/complicações , Inibidores de 5-alfa Redutase/uso terapêutico , Dutasterida/uso terapêutico , Humanos , Sintomas do Trato Urinário Inferior/diagnóstico , Sintomas do Trato Urinário Inferior/microbiologia , Masculino , Resultado do Tratamento , Retenção Urinária/prevenção & controle
9.
JAMA Netw Open ; 2(12): e1918145, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31880795

RESUMO

Importance: Few studies have evaluated the association between a single-nucleotide polymorphism-based genetic risk score (GRS) and patient age at prostate cancer (PCa) diagnosis. Objectives: To test the association between a GRS and patient age at PCa diagnosis and to compare the performance of a GRS with that of family history (FH) in PCa risk stratification. Design, Setting, and Participants: A cohort study of 3225 white men was conducted as a secondary analysis of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) chemoprevention trial, a 4-year, randomized, double-blind, placebo-controlled multicenter study conducted from March 2003 to April 2009 to evaluate the safety and efficacy of dutasteride in reducing PCa events. Participants were confirmed to be cancer free by prostate biopsy (6-12 cores) within 6 months prior to the study and underwent 10 core biopsies every 2 years per protocol. The dates for performing data analysis were from July 2016 to October 2019. Interventions: A well-established, population-standardized GRS was calculated for each participant based on 110 known PCa risk-associated single-nucleotide polymorphisms, which is a relative risk compared with the general population. Men were classified into 3 GRS risk groups based on predetermined cutoff values: low (<0.50), average (0.50-1.49), and high (≥1.50). Main Outcomes and Measures: Prostate cancer diagnosis-free survival among men of different risk groups. Results: Among 3225 men (median age, 63 years [interquartile range, 58-67 years]) in the study, 683 (21%) were classified as low risk, 1937 (60%) as average risk, and 605 (19%) as high risk based on GRS alone. In comparison, 2789 (86%) were classified as low or average risk and 436 (14%) as high risk based on FH alone. Men in higher GRS risk groups had a PCa diagnosis-free survival rate that was worse than that of those in the lower GRS risk group (χ2 = 53.3; P < .001 for trend) and in participants with a negative FH of PCa (χ2 = 45.5; P < .001 for trend). Combining GRS and FH further stratified overall genetic risk, indicating that 957 men (30%) were at high genetic risk (either high GRS or positive FH), 1667 men (52%) were at average genetic risk (average GRS and negative FH), and 601 men (19%) were at low genetic risk (low GRS and negative FH). The median PCa diagnosis-free survival was 74 years (95% CI, 73-75 years) for men at high genetic risk, 77 years (95% CI, 75 to >80 years) for men at average genetic risk, and more than 80 years (95% CI, >80 to >80 years) for men at low genetic risk. In contrast, the median PCa diagnosis-free survival was 73 years (95% CI, 71-76 years) for men with a positive FH and 77 years (95% CI, 76-79 years) for men with a negative FH. Conclusions and Relevance: This study suggests that a GRS is significantly associated with patient age at PCa diagnosis. Combining FH and GRS may better stratify inherited risk than FH alone for developing personalized PCa screening strategies.


Assuntos
Inibidores de 5-alfa Redutase/uso terapêutico , Dutasterida/uso terapêutico , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Predisposição Genética para Doença , Humanos , Masculino , Anamnese , Pessoa de Meia-Idade , Neoplasias da Próstata/tratamento farmacológico , Medição de Risco/métodos
10.
Drug Test Anal ; 11(11-12): 1737-1746, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31747487

RESUMO

An analytical procedure based on ultra-performance liquid chromatography-mass spectrometry was developed to screen and to confirm dutasteride and its metabolites in human urine. Sample preparation included an enzymatic hydrolysis followed by solid-phase extraction using the strong cation exchange cartridges OASIS® MCX. The chromatographic separation was carried out on C18 column, employing as mobile phases ultra purified water and acetonitrile, both containing 0.1% formic acid. Detection was achieved using a triple quadrupole as a mass spectrometric analyzer, with positive ion electrospray ionization and multiple reaction monitoring as acquisition mode. The analytical procedure developed was validated according to ISO 17025 and World Anti-Doping Agency guidelines. The extraction efficiency was estimated to be greater than 75% for both dutasteride and its hydroxylated metabolites. Detection capability was determined in the range of 0.1-0.4 ng/mL. Specificity and repeatability of the relative retention times (CV% < 0.5) and of the relative abundances of the characteristic ion transitions selected (CV% < 10) were confirmed to be fit for purpose to ensure the unambiguous identification of dutasteride and its metabolites in human urine. The developed method was used to characterize the urinary excretion profile of dutasteride after both chronic and acute administration of therapeutic doses. After chronic administration, dutasteride and its hydroxylated metabolites were easily detected and confirmed. After acute administration, instead, only the two hydroxylated metabolites were detected for 3-4 days.


Assuntos
Inibidores de 5-alfa Redutase/urina , Dutasterida/urina , Espectrometria de Massas em Tandem/métodos , Inibidores de 5-alfa Redutase/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Dutasterida/metabolismo , Feminino , Humanos , Limite de Detecção , Masculino , Espectrometria de Massas por Ionização por Electrospray/métodos , Detecção do Abuso de Substâncias/métodos
12.
PLoS One ; 14(9): e0222533, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31525235

RESUMO

Dutasteride, a dual inhibitor of both type I and II 5α-reductases, is used to treat male pattern hair loss (MPHL). However, patient response to dutasteride varies in each individual, the cause of which is yet to be identified. To identify genetic variants associated with response to dutasteride treatment for MPHL, a total of 42 men with moderate MPHL who had been treated with dutasteride for 6 months were genotyped and analysed by quantitative linear regression, case-control association tests, and Fisher's exact test. The synonymous single nucleotide polymorphism (SNP) rs72623193 in DHRS9 was most significantly associated with response to dutasteride, followed by the non-synonymous SNP rs2241057 in CYP26B1. Additionally, variants in ESR1, SRD5A1, CYP19A1, and RXRG are suggested to be associated with response to dutasteride. Cumulative effect and interaction among these SNPs were presented in both additive and non-additive models.


Assuntos
Inibidores de 5-alfa Redutase/uso terapêutico , Alopecia/tratamento farmacológico , Alopecia/genética , Dutasterida/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Adulto , Estudos de Casos e Controles , Cabelo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
Urologiia ; (4): 175-179, 2019 Sep.
Artigo em Russo | MEDLINE | ID: mdl-31535827

RESUMO

The results of studies comparing the therapy of benign prostatic hyperplasia with 5-reductase inhibitors and 1-blockers are presented in the article. Benign prostatic hyperplasia is a common disease in older men. Pathogenetic treatment allows to block a progression of prostatic hyperplasia and is of greatest interest in the treatment of this disease. The obtained data reliably demonstrate the advantage and safety of long-term pathogenetic therapy with dutasteride compared with symptomatic tamsulosin monotherapy with regard to quality of life and subjective symptoms. In addition, pathogenetic therapy provides better results in preventing the progression of benign prostatic hyperplasia.


Assuntos
Inibidores de 5-alfa Redutase/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Idoso , Azasteroides , Quimioterapia Combinada , Dutasterida , Humanos , Masculino , Oxirredutases , Qualidade de Vida , Sulfonamidas , Resultado do Tratamento
14.
Endocrinology ; 160(9): 2061-2073, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31199473

RESUMO

Inhibition of 5α-reductases impairs androgen and glucocorticoid metabolism and induces insulin resistance in humans and rodents. The contribution of hepatic glucocorticoids to these adverse metabolic changes was assessed using a liver-selective glucocorticoid receptor (GR) antagonist, A-348441. Mice lacking 5α-reductase 1 (5αR1-KO) and their littermate controls were studied during consumption of a high-fat diet, with or without A-348441(120 mg/kg/d). Male C57BL/6 mice (age, 12 weeks) receiving dutasteride (1.8 mg/kg/d)) or vehicle with consumption of a high-fat diet, with or without A-348441, were also studied. In the 5αR1-KO mice, hepatic GR antagonism improved diet-induced insulin resistance but not more than that of the controls. Liver steatosis was not affected by hepatic GR antagonism in either 5αR1KO mice or littermate controls. In a second model of 5α-reductase inhibition using dutasteride and hepatic GR antagonism with A-348441 attenuated the excess weight gain resulting from dutasteride (mean ± SEM, 7.03 ± 0.5 vs 2.13 ± 0.4 g; dutasteride vs dutasteride plus A-348441; P < 0.05) and normalized the associated hyperinsulinemia after glucose challenge (area under the curve, 235.9 ± 17 vs 329.3 ± 16 vs 198.4 ± 25 ng/mL/min; high fat vs high fat plus dutasteride vs high fat plus dutasteride plus A-348441, respectively; P < 0.05). However, A-348441 again did not reverse dutasteride-induced liver steatosis. Thus, overall hepatic GR antagonism improved the insulin resistance but not the steatosis induced by a high-fat diet. Moreover, it attenuated the excessive insulin resistance caused by pharmacological inhibition of 5α-reductases but not genetic disruption of 5αR1. The use of dutasteride might increase the risk of type 2 diabetes mellitus and reduced exposure to glucocorticoids might be beneficial.


Assuntos
Colestenona 5 alfa-Redutase/deficiência , Fígado/fisiologia , Receptores de Glucocorticoides/fisiologia , Animais , Colestenona 5 alfa-Redutase/fisiologia , Ácidos Cólicos/farmacologia , Dieta Hiperlipídica , Dutasterida/farmacologia , Estrona/análogos & derivados , Estrona/farmacologia , Gluconeogênese , Resistência à Insulina , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
Prostate ; 79(12): 1450-1456, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31233227

RESUMO

BACKGROUND: Prostate-specific membrane antigen (PSMA)-based imaging and therapy are increasingly used in the management of prostate cancer. However, low PSMA surface expression in certain patients is a limitation for PSMA-based technologies. We have previously shown that high doses of dutasteride, a 5α-reductase inhibitor generally used for the treatment of benign prostatic enlargement, increase the PSMA expression in vitro. We now further analyzed the concentration- and time-dependent effects of dutasteride in LNCaP cells. METHODS: Androgen receptor (AR) expressing prostate cancer cells (LNCaP) were treated for 7 to 14 days with vehicle control (0.1% dimethyl sulfoxide) or different concentrations of dutasteride (0.25 , 0.5 , 1 , and 5 µM). In addition to cell proliferation, PSMA surface expression was assessed using flow cytometry (FACS) and immunocytochemistry. Total PSMA and AR expression was analyzed by capillary western immunoassay (WES). In addition, tumor cell uptake and internalization assays of 177 Lu-PSMA-617 were performed. RESULTS: Dutasteride treatment resulted in a significant upregulation of PSMA surface expression compared to vehicle control after 7 days in all tested concentrations. After 14 days a further, concentration-dependent increase of PSMA surface expression was detectable. Total PSMA protein expression significantly increased after treatment of cells with high concentrations of dutasteride using 5 µM for 7 or 14 days. However, when lower concentrations were used total PSMA expression was not significantly altered compared to vehicle control. Further testing revealed a dose-dependent increase in uptake and internalization of 177Lu -PSMA-617 after 7 and 14 days. Though, a significantly increased uptake was only observed using a 5 µM dutasteride concentration for 7 days as well as 1 and 5 µM for 14 days. CONCLUSION: Our investigations revealed a concentration- and time-dependent effect of dutasteride on PSMA expression and uptake of 177Lu -PSMA-617 in LNCaP cells. A short-term treatment of patients with high doses of dutasteride might increase the detection rate of PSMA-based imaging and increase the effect of 177Lu -PSMA-617 therapy via upregulation of PSMA expression.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Antígenos de Superfície/biossíntese , Dutasterida/farmacologia , Glutamato Carboxipeptidase II/biossíntese , Próstata/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Linhagem Celular Tumoral , Dipeptídeos/metabolismo , Relação Dose-Resposta a Droga , Compostos Heterocíclicos com 1 Anel/metabolismo , Humanos , Lutécio/metabolismo , Masculino , Próstata/metabolismo , Radioisótopos/metabolismo , Receptores Androgênicos/biossíntese , Regulação para Cima
16.
Int J Biol Macromol ; 133: 1081-1089, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047928

RESUMO

Dutasteride is a pharmacologically important drug employed to treat prostate cancer. Alpha-2-macroglobulin (α2M) is the primary proteinase inhibitor and is abundant in vertebrate plasma. Previous studies have shown that α2M levels were down regulated in prostate cancer. Our results of functional assay shows 50% decrease in the antiproteolytic potential ofα2Mupon its interaction with dutasteride. Fluorescence quenching revealed that dutasteride binds with α2M via static mechanism, resulting in the formation of dutasteride-α2M complex. Synchronous fluorescence studies suggest alteration in the microenvironment around tryptophan residues. Changes in the UV-visible spectra hints at formation of complex between the drug and protein. Secondary structural perturbations in α2M are confirmed by circular dichroism studies. Molecular docking discloses the involvement of hydrogen bonding during the interaction process and suggests the site of interaction of dutasteride on α2M monomer as Asn173, Lys171, Asp1178, Lys1236, His1182, Lys1177, Ser1180 and Lys1240.Isothermal titration calorimetry affirms the binding process to be spontaneous and exothermic. The results of this study may potentially be important should it be shown that dutasteride interacts with α2M under physiological conditions.


Assuntos
Calorimetria , Dutasterida/metabolismo , Simulação de Acoplamento Molecular , alfa 2-Macroglobulinas Associadas à Gravidez/metabolismo , Humanos , alfa 2-Macroglobulinas Associadas à Gravidez/química , Ligação Proteica , Conformação Proteica , Proteólise/efeitos dos fármacos
18.
Gerontology ; 65(5): 458-464, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30943489

RESUMO

Benign prostatic hyperplasia (BPH), benign prostatic enlargement (BPE) and lower urinary tract symptoms (LUTS) belong to the most frequent diseases in ageing men. Beyond the 6th decade of life, more than 30% of men suffer from moderate to severe LUTS requiring intervention. The pathophysiology of BPH/BPE is still incompletely understood. The dominant role of the androgen system and the androgen receptor is well defined. Androgen receptors are expressed in BPH tissue in which they are activated by the potent androgen dihydrotestosterone. Synthesis of dihydrotestosterone is under control of the 5α-reductase enzyme, activity of which is antagonized by finasteride and dutasteride. More recently, the impact of prostatic inflammation and metabolic parameters particularly for the development of BPE and LUTS has increasingly been recognized. A better understanding of the pathophysiology is a prerequisite for the development of novel, more effective medical treatment options.


Assuntos
Envelhecimento/metabolismo , Sintomas do Trato Urinário Inferior/metabolismo , Hiperplasia Prostática/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Inibidores de 5-alfa Redutase/uso terapêutico , Envelhecimento/imunologia , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/metabolismo , Di-Hidrotestosterona/metabolismo , Dutasterida/uso terapêutico , Dislipidemias/epidemiologia , Dislipidemias/metabolismo , Finasterida/uso terapêutico , Humanos , Inflamação/imunologia , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Sintomas do Trato Urinário Inferior/epidemiologia , Sintomas do Trato Urinário Inferior/imunologia , Masculino , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/metabolismo , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/epidemiologia , Hiperplasia Prostática/imunologia , Receptores Androgênicos/metabolismo
19.
BMJ ; 365: l1204, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30971393

RESUMO

OBJECTIVE: To investigate the incidence of new onset type 2 diabetes mellitus in men receiving steroid 5α-reductase inhibitors (dutasteride or finasteride) for long term treatment of benign prostatic hyperplasia. DESIGN: Population based cohort study. SETTING: UK Clinical Practice Research Datalink (CPRD; 2003-14) and Taiwanese National Health Insurance Research Database (NHIRD; 2002-12). PARTICIPANTS: Men in the CPRD who received dutasteride (n=8231), finasteride (n=30 774), or tamsulosin (n=16 270) were evaluated. Propensity score matching (2:1; dutasteride to finasteride or tamsulosin) produced cohorts of 2090, 3445, and 4018, respectively. In the NHIRD, initial numbers were 1251 (dutasteride), 4194 (finasteride), and 86 263 (tamsulosin), reducing to 1251, 2445, and 2502, respectively, after propensity score matching. MAIN OUTCOMES MEASURE: Incident type 2 diabetes using a Cox proportional hazard model. RESULTS: In the CPRD, 2081 new onset type 2 diabetes events (368 dutasteride, 1207 finasteride, and 506 tamsulosin) were recorded during a mean follow-up time of 5.2 years (SD 3.1 years). The event rate per 10 000 person years was 76.2 (95% confidence interval 68.4 to 84.0) for dutasteride, 76.6 (72.3 to 80.9) for finasteride, and 60.3 (55.1 to 65.5) for tamsulosin. There was a modest increased risk of type 2 diabetes for dutasteride (adjusted hazard ratio 1.32, 95% confidence interval 1.08 to 1.61) and finasteride (1.26, 1.10 to 1.45) compared with tamsulosin. Results for the NHIRD were consistent with the findings for the CPRD (adjusted hazard ratio 1.34, 95% confidence interval 1.17 to 1.54 for dutasteride, and 1.49, 1.38 to 1.61 for finasteride compared with tamsulosin). Propensity score matched analyses showed similar results. CONCLUSIONS: The risk of developing new onset type 2 diabetes appears to be higher in men with benign prostatic hyperplasia exposed to 5α-reductase inhibitors than in men receiving tamsulosin, but did not differ between men receiving dutasteride and those receiving finasteride. Additional monitoring might be required for men starting these drugs, particularly in those with other risk factors for type 2 diabetes.


Assuntos
Inibidores de 5-alfa Redutase/efeitos adversos , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/epidemiologia , Hiperplasia Prostática/tratamento farmacológico , Inibidores de 5-alfa Redutase/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Dutasterida/efeitos adversos , Dutasterida/uso terapêutico , Finasterida/efeitos adversos , Finasterida/uso terapêutico , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Hiperplasia Prostática/complicações , Tansulosina/efeitos adversos , Tansulosina/uso terapêutico
20.
Urology ; 129: 160-164, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30914334

RESUMO

OBJECTIVES: To evaluate whether the presence of basal cell hyperplasia (BCH) in negative biopsies is associated with concurrent lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH), clinical prostatitis, and future prostate cancer (PCa) in repeat prostate biopsy. METHODS: We performed a retrospective analysis of 6471 men, 50-75 years old with prostate-specific antigen between 2.5 and 10 ng/ml and prior negative biopsy who were enrolled in the Reduction by Dutasteride of PCa Events trial and underwent a 2-year repeat biopsy. The association between baseline BCH and risk of PCa, BPH/LUTS and clinical prostatitis measured at baseline were evaluated with logistic regression in uni/multivariable analysis, controlling for baseline patient characteristics. RESULTS: Among 6471 men enrolled, 84 (1.3%) had BCH in the baseline prostate biopsy. BCH was associated less chronic inflammation and more prostate atrophy (P < 0.05) and was unrelated to baseline patient characteristics. In both uni/multivariable analyses, BCH was not associated with PCa in repeat biopsy (univariable odds ratio [OR] = 0.98, 95% confidence interval [CI] = 0.53-1.82, P > 0.05; multivariable OR=1.15, 95% CI = 0.61-2.16, P > 0.05), BPH/LUTS (univariable OR = 1.13, 95% CI = 0.71-1.81, P > 0.05; multivariable OR = 1.20, 95% CI = 0.74-1.94, P > 0.05), or clinical prostatitis (univariable OR = 0.56, 95% CI = 0.18-1.81, P > 0.05; multivariable OR = 0.57, 95% CI = 0.18-1.83, P > 0.05). CONCLUSION: Among men undergoing repeat prostate biopsy with a baseline negative biopsy, BCH was associated with more histological atrophy and less chronic prostatitis, but was unrelated to LUTS/BPH, clinical prostatitis or future PCa risk.


Assuntos
Biópsia/métodos , Dutasterida/administração & dosagem , Sintomas do Trato Urinário Inferior/diagnóstico , Próstata/patologia , Hiperplasia Prostática/diagnóstico , Prostatite/diagnóstico , Inibidores de 5-alfa Redutase/administração & dosagem , Administração Oral , Idoso , Doença Crônica , Diagnóstico Diferencial , Relação Dose-Resposta a Droga , Humanos , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Sintomas do Trato Urinário Inferior/etiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Hiperplasia Prostática/complicações , Hiperplasia Prostática/tratamento farmacológico , Neoplasias da Próstata , Prostatite/complicações , Estudos Retrospectivos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA