RESUMO
In general, nanometer-sized drug delivery systems have a natural tendency for accommodation in the follicular cavities, which makes them advantageous in the treatment of conditions affecting these structures. Still, follicular targeting enhancement can improve therapy outcomes. Here, we compare two strategies to further promote dutasteride follicular-targeted delivery: the chemical modulation of nanosystem surface properties by coating with the natural polymer chitosan, and the application of a massage. For this, poly-(É-caprolactone)-lipid-core nanocapsules (NC) containing dutasteride were developed and had their permeation profile compared to chitosan-coated nanocapsules (NC-CS). Nanocapsules showed high drug encapsulation efficiency (>94%), and stability for up to 90 days of storage. As expected, chitosan coating increased the size and zeta potential, from 199.0 ± 0.5 nm (PdI of 0.12) and - 13.6 ± 0.6 mV to 224.9 ± 3.4 nm (PdI 0.23) and + 40.2 ± 0.8 mV, respectively. Both coated and non-coated nanoparticles targeted the hair follicles compared to a drug solution. Enhanced hair follicles targeting was observed after the massage procedure, with 5 and 2-fold increases relative to NC and NC-CS, respectively. In conclusion, this work demonstrates dutasteride nanocapsules can target the follicular casts, and a simple physical stimulation can enhance 5-times the drug amount accumulated.
Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Dutasterida/farmacologia , Folículo Piloso/efeitos dos fármacos , Nanocápsulas/química , Inibidores de 5-alfa Redutase/química , Fenômenos Químicos , Quitosana/química , Portadores de Fármacos/química , Estabilidade de Medicamentos , Dutasterida/química , Humanos , Lipídeos/química , Nanocápsulas/ultraestrutura , Estimulação FísicaRESUMO
Benign prostatic hyperplasia (BPH) is a pathology characterised by an increase in prostate size associated with low urinary tract symptoms. Finasteride (F), a 5a-reductase inhibitor, is the standard treatment for BPH reducing prostate weight but also sexual desire. The Peruvian plant known as Red Maca (RM) (Lepidium meyenii) inhibits BPH in rats and mice. The aim of the study was to assess the inflammatory effect of RM and finasteride in rats with testosterone enanthate (TE)-induced BPH. Thirty rats were divided into 5 groups: Control, TE (50 mg/rat), TE + F (0.6 mg/kg), and two groups of TE + RM 40/80 (40 or 80 mg). After treatments, tumour necrosis factor alpha (TNFa), interleukin 4 (IL4) and interferon gamma (INFg) as well as testosterone and oestradiol were evaluated and inflammatory cells (neutrophils, mast cells and lymphocytes) in prostate were quantified. Red Maca and finasteride treatments decreased inflammatory cells counts in prostate, inhibiting TNFa by different pathways. Finasteride increased IL4 whereas Red Maca increased INFg. In conclusion, data suggest that finasteride acts on Th2 response by increasing IL4 in prostate, while Red Maca acts on Th1 response mediated by INFg.
Assuntos
Lepidium/química , Extratos Vegetais/farmacologia , Próstata/efeitos dos fármacos , Hiperplasia Prostática/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Inibidores de 5-alfa Redutase/farmacologia , Inibidores de 5-alfa Redutase/uso terapêutico , Animais , Modelos Animais de Doenças , Finasterida/farmacologia , Finasterida/uso terapêutico , Humanos , Interferon gama/metabolismo , Interleucina-4/metabolismo , Masculino , Extratos Vegetais/uso terapêutico , Próstata/citologia , Próstata/imunologia , Próstata/patologia , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/imunologia , Hiperplasia Prostática/patologia , Ratos , Transdução de Sinais/imunologia , Testosterona/análogos & derivados , Testosterona/toxicidade , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
It is known that the growth of prostate metastatic bone tumor depends on androgens, and tumor formation can start from migratory malignant cells produced in that organ. These cells exhibit grater type 1 5α-reductase (5α-R1) activity than type 2 5α-reductase. Noteworthy, both isozymes convert testosterone (T) to the more active androgen dihydrotestosterone (DHT) in the target tissues. Thus, in order to potentially improve the prognosis of this disease, in this work, seven derivatives of 17-(1H-benzimidazol-1-yl)-16-formillandrosta-5,16-dien-3ß-yl benzoate (4a-f) and 17-(1H-benzimidazol-1-yl)-3-hydroxy-16-formylandrost-5,16-diene (4) were synthesized, characterized and identified as inhibitors of type 1 5α-reductase (5αR1). These derivatives having the advantage of improved plasma half-life. The inhibitory activity of the compounds towards 5α-R1 isoenzyme was determined by conversion of T into DHT in the presence or absence of compounds 4, 4a-f. Further, in vivo experiments were also carried out, treating gonadectomized hamsters with T and/or 4, 4a-f and evaluating their effect on the diameter of hamster flank organs and on the weight of the prostatic and seminal vesicles. Results indicated that compounds 4, 4b, 4c, served as in vitro inhibitors of the enzyme 5α-R1 and pharmacological experiments showed that 4 and derivatives 4a-f decreased the diameter of the flank glands, the weight of the prostate and seminal vesicles of treated hamsters without any appreciable toxicity during observation. Noteworthy the fact that compound 4 is the product, in all cases, of the hydrolysis of the series of esters 4a-f, thus they can serve as precursors (prodrugs) of the active form 4.
Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Benzoatos/farmacologia , Colestenona 5 alfa-Redutase/metabolismo , Inibidores de 5-alfa Redutase/administração & dosagem , Inibidores de 5-alfa Redutase/química , Animais , Benzoatos/administração & dosagem , Benzoatos/química , Cricetinae , Relação Dose-Resposta a Droga , Injeções Subcutâneas , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Conformação Molecular , Ratos , Solubilidade , Relação Estrutura-AtividadeRESUMO
Erectile dysfunction is a common side effect of finasteride and dutasteride treatments. The objective of this study was to investigate the structural changes in the penis using a benign prostatic hyperplasia (BPH) rodent model treated with dutasteride or finasteride. Sixty male rats were divided into the following groups: C, untreated control rats; C + D, control rats receiving dutasteride; C + F, control rats receiving finasteride; H, untreated spontaneously hypertensive rats (SHRs); H + D, SHRs treated with dutasteride; and H + F, SHRs treated with finasteride. Treatments were performed for 40 days, and penises were collected immediately thereafter. The organs were analyzed using histomorphometric methods to determine the cross-sectional penile area, as well as the surface density (Sv) of smooth muscle fibers, connective tissue, elastic system fibers, and sinusoidal spaces of the corpus cavernosum. The results were compared using a one-way ANOVA with Bonferroni's posttest. Groups C + D and C + F had a significantly smaller penile cross-sectional area, but more elastic system fiber Sv compared to Group C. Group C + D showed less smooth muscle Sv, and Group H showed more connective tissue but a smaller sinusoidal space Sv in the corpus cavernosum compared to Group C. Groups H + D and H + F had less smooth muscle Sv than Group H. Group H + D also had more connective tissue and elastic system fiber Sv than Group H. Both dutasteride and finasteride promoted penile modifications in the control rat penis, although this affect was greater in Group H animals. In this rodent model, dutasteride was the drug that most affected the corpus cavernosum.
Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Dutasterida/farmacologia , Finasterida/farmacologia , Músculo Liso/efeitos dos fármacos , Pênis/efeitos dos fármacos , Hiperplasia Prostática/patologia , Inibidores de 5-alfa Redutase/uso terapêutico , Animais , Modelos Animais de Doenças , Dutasterida/uso terapêutico , Finasterida/uso terapêutico , Masculino , Músculo Liso/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Pênis/patologia , Próstata/efeitos dos fármacos , Próstata/patologia , Hiperplasia Prostática/tratamento farmacológico , RatosRESUMO
Glioblastomas (GBM) are the most frequent and aggressive brain tumors. In these malignancies, progesterone (P4) promotes proliferation, migration, and invasion. The P4 metabolite allopregnanolone (3α-THP) similarly promotes cell proliferation in the U87 human GBM cell line. Here, we evaluated global changes in gene expression of U87 cells treated with 3α-THP, P4, and the 5α-reductase inhibitor, finasteride (F). 3α-THP modified the expression of 137 genes, while F changed 90. Besides, both steroids regulated the expression of 69 genes. After performing an over-representation analysis of gene ontology terms, we selected 10 genes whose products are cytoskeleton components, transcription factors, and proteins involved in the maintenance of DNA stability and replication to validate their expression changes by RT-qPCR. 3α-THP up-regulated six genes, two of them were also up-regulated by F. Two genes were up-regulated by P4 alone, however, such an effect was blocked by F when cells were treated with both steroids. The remaining genes were regulated by the combined treatments of 3α-THP + F or P4 + F. An in-silico analysis revealed that promoters of the six up-regulated genes by 3α-THP possess cyclic adenosine monophosphate (cAMP) responsive elements along with CCAAT/Enhancer binding protein alpha (CEBPα) binding sites. These findings suggest that P4 and 3α-THP regulate different sets of genes that participate in the growth of GBMs.
Assuntos
Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Pregnanolona/farmacologia , Transcriptoma/efeitos dos fármacos , Inibidores de 5-alfa Redutase/farmacologia , Linhagem Celular Tumoral , Citoesqueleto/genética , Citoesqueleto/metabolismo , Finasterida/farmacologia , Humanos , Regiões Promotoras Genéticas , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação para CimaRESUMO
BACKGROUND: Testosterone protects male rats from Temporomandibular Joint (TMJ) pain. This study investigated whether this protective effect is mediated by an organizational action of testosterone during nervous system development, by central estrogen and androgen receptors and by the 5α-reduced metabolite of testosterone, dihydrotestosterone. METHODS: A pharmacological approach was used to assess the ability of the androgen receptor antagonist flutamide, the estrogen receptor antagonist ICI 182 780 and the 5-α reductase inhibitor dutasteride to block the protective effect of testosterone, evaluated through the behavioral response induced by a TMJ injection of 0.5% formalin. Flutamide and ICI 182 780 were injected into the medullary subarachnoid space, and dutasteride and testosterone were systemically administered. RESULTS: The TMJ injection of 0.5% formalin induced a significant nociceptive behavioral response in gonadectomized male and naïve female, but not in sham gonadectomized male rats, confirming that endogenous testosterone prevents TMJ nociception in males. Testosterone administration prevented formalin-induced TMJ nociception in males gonadectomized either in the neonatal (at the day of birth) or adult period and in naïve female rats, suggesting that the protective effect of testosterone on TMJ nociception does not depend on its organizational actions during critical periods of development. The administration of flutamide and dutasteride but not of ICI 182 780 blocked the protective effect of testosterone. CONCLUSIONS: We conclude that the protective effect of testosterone on TMJ nociception depends on activational actions of dihydrotestosterone on androgen receptors rather than on organizational androgenic actions during central nervous system development or estrogenic actions.
Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Antagonistas de Androgênios/farmacologia , Medição da Dor/efeitos dos fármacos , Dor/prevenção & controle , Receptores Androgênicos/metabolismo , Articulação Temporomandibular/efeitos dos fármacos , Testosterona/farmacologia , Animais , Dutasterida/farmacologia , Estradiol/análogos & derivados , Estradiol/farmacologia , Antagonistas do Receptor de Estrogênio/farmacologia , Feminino , Flutamida/farmacologia , Formaldeído , Fulvestranto , Masculino , Ratos , Articulação Temporomandibular/fisiopatologia , Testosterona/antagonistas & inibidoresRESUMO
Studies with rodents and humans show the relationship between female sex hormones and cognitive/emotional tasks. However, despite the greater incidence of anxiety disorders in women, the data are still inconclusive regarding the mechanisms related to this phenomenon. We evaluated the effects of a classical anxiolytic/amnestic drug (diazepam; DZP) on female (at different estrous cycle phases) and male rats tested in the plus-maze discriminative avoidance task (PMDAT), that allows the concomitant evaluation of memory and anxiety-like behavior. Further, in order to investigate the role of progesterone and its metabolites in the effects of DZP in the PMDAT, female rats were pre-treated with the progesterone receptor antagonist mifepristone or the 5-alpha-reductase inhibitor finasteride. The main findings were: (1) DZP caused memory impairment and anxiolysis in both sexes, but only the highest dose induced the anxiolytic effect in females; (2) females in proestrus did not present the amnestic and anxiolytic effects of DZP (at 2.0 and 4.0mg/kg, respectively) and (3) the co-administration of mifepristone reestablished both amnestic and anxiolytic effects of DZP, while finasteride reinstated the amnestic effect in proestrus female rats. These results suggest that changes in the endogenous levels of progesterone and its metabolites are important in the modulation of emotional/cognitive behavior in female rats. Based on the influence on different aspects of DZP action, the mechanisms related to this modulation are probably linked to GABAergic transmission, but this point remains to be investigated. Further, the variation in therapeutic and adverse effects of DZP depending on sex and hormonal state is of great relevance considering the higher prevalence of anxiety disorders in women.
Assuntos
Ansiedade/tratamento farmacológico , Diazepam/farmacologia , Ciclo Estral/efeitos dos fármacos , Memória/efeitos dos fármacos , Psicotrópicos/farmacologia , Caracteres Sexuais , Inibidores de 5-alfa Redutase/farmacologia , Animais , Ansiedade/fisiopatologia , Relação Dose-Resposta a Droga , Ciclo Estral/fisiologia , Feminino , Finasterida/farmacologia , Antagonistas de Hormônios/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Transtornos da Memória/induzido quimicamente , Mifepristona/farmacologia , Progesterona/metabolismo , Distribuição Aleatória , Ratos Wistar , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/metabolismoRESUMO
Inhibitors of the enzyme 5[Formula: see text]-reductase (5aR) are promising therapeutic agents for the treatment of benign prostatic hyperplasia (BPH) and prostate cancer. The lack of structural data of the enzyme 5aR prompts the application of ligand-based approaches to systematically explore the activity landscape of 5aR inhibitors. As part of an effort to develop inhibitors of this enzyme for the treatment of BPH, herein we discuss a chemoinformatic-based analysis of the activity landscape of a novel set of 53 novel pregnane and androstene compounds. It was found that, in general, for each pair of compounds in the set, as the structure similarity of the compounds increases the corresponding potency difference decreases. These results are in agreement with an overall smooth activity landscape. However, two potent activity cliff generators were identified pointing to specific small structural changes that have a large impact on the inhibition of 5aR.
Assuntos
Inibidores de 5-alfa Redutase/química , Androstenos/química , Pregnanos/química , Inibidores de 5-alfa Redutase/farmacologia , Androstenos/farmacologia , Bases de Dados de Compostos Químicos , Humanos , Masculino , Estrutura Molecular , Pregnanos/farmacologia , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/enzimologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/enzimologia , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Aging is considered one of the main predisposing factors for the development of prostate malignancies. Angiogenesis is fundamental for tumor growth and its inhibition represents a promising therapeutic approach in cancer treatment. Thus, we sought to determine angiogenic responses and the effects of antiangiogenic therapy in the mouse prostate during late life, comparing these findings with the prostatic microenvironment in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model. METHODS: Male mice (52 week-old FVB) were submitted to treatments with SU5416 (6 mg/kg; i.p.) and/or TNP-470 (15 mg/kg; s.c.). Finasteride was administered (20 mg/kg; s.c.), alone or in association to both inhibitors. The dorsolateral prostate was collected for VEGF, HIF-1α, FGF-2 and endostatin immunohistochemical and Western Blotting analyses and for microvessel density (MVD) count. RESULTS: Senescence led to increased MVD and VEGF, HIF-1α and FGF-2 protein levels in the prostatic microenvironment, similarly to what was observed in TRAMP mice prostate. The angiogenic process was impaired in all the treated groups, demonstrating significantly decreased MVD. Antiangiogenic and/or finasteride treatments resulted in decreased VEGF and HIF-1α levels, especially following TNP-470 administration, either alone or associated to SU5416. The combination of these agents resulted in increased endostatin levels, regardless of the presence of finasteride. CONCLUSIONS: Prostatic angiogenesis stimulation during senescence favored the development of neoplastic lesions, considering the pro-angiogenic microenvironment as a common aspect also observed during cancer progression in TRAMP mice. The combined antiangiogenic therapy was more efficient, leading to enhanced imbalance towards angiogenic inhibition in the organ. Finally, finasteride administration might secondarily upregulate the expression of pro-angiogenic factors, pointing to the harmful effects of this therapy.
Assuntos
Adenocarcinoma/irrigação sanguínea , Inibidores da Angiogênese/uso terapêutico , Modelos Animais de Doenças , Neovascularização Patológica/tratamento farmacológico , Neoplasias da Próstata/irrigação sanguínea , Microambiente Tumoral , Inibidores de 5-alfa Redutase/farmacologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Animais , Western Blotting , Cicloexanos/uso terapêutico , Endostatinas/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Finasterida/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imuno-Histoquímica , Indóis/uso terapêutico , Masculino , Camundongos , Camundongos Transgênicos , O-(Cloroacetilcarbamoil)fumagilol , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Pirróis/uso terapêutico , Sesquiterpenos/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
The role of testosterone in cardiovascular (CV) homeostasis is in controversy, and the exact effects of testosterone on the cardiovascular system remain poorly understood. Testosterone is metabolized by aromatase into 17ß-estradiol and by 5α-reductase into dihydrotestosterone (DHT). Thus, identification of these metabolites in the heart may help to explain the controversy regarding the cardiovascular effects of testosterone. We analyzed the expression patterns of these testosterone-metabolizing enzymes and assessed the effect of its enzymatic activity inhibition on ischemia (40 min)/reperfusion (4h, I/R) via the left anterior descendent coronary artery in intact and gonadectomized male rats. Myocardial damage was measured as percentage of infarcted area vs. area at risk. Aromatase and 5α-reductase protein expression was found in the left ventricle of intact and orchidectomized rats. Exogenous testosterone had no effect on I/R induced myocardial damage in intact male rats, meanwhile exogenous testosterone protects against I/R injury in orchidectomized rats. However, enzymatic inhibition of aromatase increased myocardial damage in the presence of testosterone, while enzymatic inhibition of 5α-reductase significantly decreased the level of myocardial damage. Our results also showed that sub-chronic inhibition of 5α-reductase resulted in myocardial protection in both groups. Furthermore, in orchidectomized and intact male rats IV treatment with DHT induces a significant increase in the myocardial damage induced by I/R. Thus, the effect of testosterone on cardiovascular pathophysiology could be related, at least in part to changes in the balance of testosterone 5α-reduction and aromatization.