RESUMO
BACKGROUND: Recent studies suggest that 5α-reductase inhibitors (5ARIs) for benign prostate hyperplasia (BPH) result in abnormal retinal anatomical alteration. OBJECTIVE: To compare age-related macular degeneration (AMD) incidence in BPH patients receiving 5ARIs or tamsulosin. DESIGN: Retrospective, population-based cohort study using new-user and active-comparator design. SETTING: General population. SUBJECTS: Males with BPH, newly receiving 5ARIs or tamsulosin from 2010 to 2018. METHODS: Data were extracted from Taiwan's National Health Insurance Research Database. We used Cox proportional hazards model with 1:4 propensity score (PS) matching, based on intention-to-treat analysis to determine the risk of incident AMD. Sensitivity analyses included an as-treated approach and weighting-based PS methods. We also separately reported the risks of incident AMD in patients receiving finasteride and dutasteride to determine risk differences among different 5ARIs. RESULTS: We included 13 586 5ARIs users (mean age: 69 years) and 54 344 tamsulosin users (mean age: 68.37 years). After a mean follow-up of 3.7 years, no differences were observed in the risk of incident AMD between 5ARIs and tamsulosin users [hazard ratio (HR): 1.06; 95% confidence intervals (95% CI): 0.98-1.15], with similar results from sensitivity analyses. However, increased risk of incident age-related macular degeneration was observed in patients receiving dutasteride [HR: 1.13; 95% CI: 1.02-1.25], but not in those receiving finasteride [HR: 0.99; 95% CI: 0.87-1.12], in the subgroup analyses. CONCLUSIONS: We found no difference between 5ARIs and tamsulosin regarding the incidence of AMD in BPH patients. However, the risk profiles for AMD differed slightly between dutasteride and finasteride, suggesting that the potency of androgen inhibition is a factor related to AMD incidence.
Assuntos
Inibidores de 5-alfa Redutase , Dutasterida , Finasterida , Degeneração Macular , Hiperplasia Prostática , Tansulosina , Humanos , Inibidores de 5-alfa Redutase/efeitos adversos , Inibidores de 5-alfa Redutase/uso terapêutico , Masculino , Idoso , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/epidemiologia , Estudos Retrospectivos , Taiwan/epidemiologia , Incidência , Degeneração Macular/epidemiologia , Degeneração Macular/diagnóstico , Degeneração Macular/induzido quimicamente , Dutasterida/uso terapêutico , Dutasterida/efeitos adversos , Tansulosina/uso terapêutico , Tansulosina/efeitos adversos , Finasterida/efeitos adversos , Finasterida/uso terapêutico , Fatores de Risco , Pessoa de Meia-Idade , Medição de Risco , Bases de Dados FactuaisAssuntos
Inibidores de 5-alfa Redutase , Finasterida , Humanos , Finasterida/efeitos adversos , Finasterida/uso terapêutico , Inibidores de 5-alfa Redutase/efeitos adversos , Masculino , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/induzido quimicamente , Hiperplasia Prostática/tratamento farmacológicoRESUMO
INTRODUCTION: Hair loss is driven by multiple factors, including genetics. Androgenetic alopecia (AGA) is a condition in which treatments necessitate prolonged compliance with prescribed medications. We have developed IVL3001, a long-acting injectable (LAI) formulation of finasteride encapsulated within poly lactic-co-glycolic acid microspheres, to enhance the efficacy of the finasteride and to achieve consistent positive outcomes in adults. An open-label, sequential, single-dose phase I clinical trial was designed to evaluate the safety, pharmacokinetic (PK), and pharmacodynamic (PD) of IVL3001. METHODS: A total of 40 non-smoking, healthy adult males were divided into three cohorts where the IVL3001 group received a single subcutaneous injection of 12-36 mg IVL3001 and 1 mg finasteride (Propecia®) once daily for 28 days. The plasma concentrations of finasteride, dihydrotestosterone (DHT), and testosterone were measured using liquid chromatography-tandem mass spectrometry. The tolerability of the injections was assessed, and compartment models were developed to predict the effective dose and assess PK/PD profiles. RESULTS: IVL3001 and finasteride 1 mg tablets were well tolerated. IVL3001 showed consistent plasma concentrations without bursts or fluctuations. Consistent with its mechanism of action, IVL3001 reduced DHT levels. Simulation data showed that the administration of 12-36 mg of IVL3001 every 4 weeks achieved plasma concentrations similar to finasteride, with comparable DHT reduction. CONCLUSION: The present study represents the first clinical trial to evaluate the safety, pharmacokinetic (PK), pharmacodynamic (PD), and tolerability of finasteride long-acting injectables (LAI) in adults. The rapid onset of action sustained effective drug concentration and the prolonged half-life of IVL3001 suggest that it offers multiple benefits over conventional oral formulations in terms of therapeutic response and compliance. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04945226.
Assuntos
Inibidores de 5-alfa Redutase , Alopecia , Finasterida , Humanos , Finasterida/farmacocinética , Finasterida/administração & dosagem , Finasterida/efeitos adversos , Alopecia/tratamento farmacológico , Masculino , Adulto , Inibidores de 5-alfa Redutase/farmacocinética , Inibidores de 5-alfa Redutase/administração & dosagem , Inibidores de 5-alfa Redutase/efeitos adversos , Inibidores de 5-alfa Redutase/farmacologia , Di-Hidrotestosterona/farmacocinética , Di-Hidrotestosterona/administração & dosagem , Di-Hidrotestosterona/sangue , Pessoa de Meia-Idade , Preparações de Ação Retardada , Testosterona/farmacocinética , Testosterona/sangue , Injeções Subcutâneas , Adulto Jovem , MicroesferasRESUMO
Finasteride is used in female-pattern hair loss, hirsutism, and polycystic ovarian syndrome. It inhibits 5α-reductase, which is an important enzyme in the biosynthesis of neurosteroids. The effects of finasteride treatment on mental health in female patients as well as the effects of repeated/chronic finasteride administration in female rodents are still unknown. Accordingly, in our study, we administered finasteride (10, 30, or 100 mg/Kg, s.c.) for 6 days in female rats and evaluated behavior, plasma steroid levels, and synaptic plasticity. Depression-like behavior was evaluated using forced swim test (FST) and splash test. Anxiety-like behavior was evaluated using novelty-suppressed feeding task (NSFT), elevated plus maze (EPM), open field test (OFT), and light-dark test (LDT). Plasma steroid levels were assessed using ELISA and synaptic plasticity by field potential recordings. We observed that finasteride decreased total immobility duration in FST, indicating antidepressant-like effect and decreased the latency to first bite in NSFT, showing anxiolytic-like effect. We also found a significant increase in plasma estradiol and a significant decrease in plasma corticosterone level. Furthermore, field potential recordings showed that finasteride increased hippocampal long-term potentiation. These results indicate that repeated finasteride administration in female rats may have antidepressant- and anxiolytic-like effect, which might be mediated by enhanced estradiol levels or decreased corticosterone levels. Further studies are required to validate the molecular mechanisms underlying the effects of finasteride in female rats. Understanding the mechanisms will help us in developing novel neurosteroid-based therapeutics in the treatment of neuropsychiatric disorders in women.
Assuntos
Ansiolíticos , Finasterida , Humanos , Ratos , Feminino , Animais , Finasterida/efeitos adversos , Ansiolíticos/farmacologia , Corticosterona , Depressão/tratamento farmacológico , Esteroides , Estradiol , Antidepressivos/farmacologia , Plasticidade NeuronalRESUMO
Androgenetic alopecia is a common type of hair loss, which is generally influenced by genetic factors and systemic androgens resulting in follicular miniaturization.1 It can cause cosmetic problems leading to psychological distress among affected men and women. Effective standard medical treatments available are topical minoxidil 2 to 5%, oral finasteride, oral dutasteride, and hair transplantation.1 However, some patients do not achieve favorable results with standard treatments. For these reasons, other novel treatments have been developed, including new medications, regenerative medicines (autologous platelet-rich plasma, adipose-derived stem cells, micrograft generation, and exosome), and low-level laser therapy.
Assuntos
Terapia com Luz de Baixa Intensidade , Plasma Rico em Plaquetas , Masculino , Humanos , Feminino , Alopecia/tratamento farmacológico , Finasterida/uso terapêutico , Finasterida/efeitos adversos , Minoxidil/uso terapêutico , Minoxidil/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Finasteride is commonly prescribed for androgenic alopecia and benign prostatic hyperplasia. However, concerns regarding its safety have been growing as cases of cognitive dysfunction have been reported. METHODS: A disproportionality analysis was conducted on data collected between 1967 and 2022 to explore the potential association. Cases of cognitive dysfunction associated with finasteride use were identified, and the reporting odds ratio (rOR) was calculated with 95% confidence intervals to determine the strength of the association between the two variables. Sensitivity analyses were conducted to account for confounding by indication. RESULTS: Among the 54,766 cases of adverse events reported for finasteride use, 1,624 (2.97%) were associated with cognitive dysfunction. The study found a significant disproportionality for cognitive dysfunction related to finasteride use (rOR 5.43, 95% CI 5.17-5.71). Most cases were considered serious (65.83%), with no signs of recovery (58.37%). Sensitivity analyses showed that patients younger than 45 years (rOR 7.30, 95% CI 6.39-8.35) and those with alopecia (rOR 5.52, 95% CI 5.15-5.91) reported more cognitive dysfunctions than their counterparts. CONCLUSION: This study showed an increased reporting of cognitive dysfunction associated with finasteride use, especially among younger alopecia patients. Finasteride should be prescribed with caution, especially to younger alopecia patients.
Assuntos
Inibidores de 5-alfa Redutase , Sistemas de Notificação de Reações Adversas a Medicamentos , Alopecia , Disfunção Cognitiva , Bases de Dados Factuais , Finasterida , Farmacovigilância , Hiperplasia Prostática , Finasterida/efeitos adversos , Finasterida/administração & dosagem , Humanos , Masculino , Alopecia/induzido quimicamente , Alopecia/epidemiologia , Inibidores de 5-alfa Redutase/efeitos adversos , Inibidores de 5-alfa Redutase/administração & dosagem , Pessoa de Meia-Idade , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/epidemiologia , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Hiperplasia Prostática/tratamento farmacológico , Adulto , Idoso , Fatores Etários , Adulto Jovem , Feminino , Adolescente , Idoso de 80 Anos ou maisRESUMO
Finasteride, a 5α-reductase inhibitor used in benign prostatic hyperplasia and androgenetic alopecia, has been associated with an increased suicidal risk, whereas it is unclear whether such risk is similar to that for another 5α-reductase inhibitor, dutasteride. We aimed to assess the risk of suicidal behaviours with finasteride relative to dutasteride. A nationwide cohort study was conducted using the French National Health Data System (SNDS). Men aged 50 years or older initiating finasteride 5 mg or dutasteride 0.5 mg in France between 01-01-2012 and 30-06-2016 were included and followed until outcome (suicide death identified from death certificate or self-harm hospitalisation), treatment discontinuation or switch, death, or 31-12-2016. Self-harm by violent means or resulting in admission to an intensive care unit were also examined. Cox proportional hazards models controlled for age and psychiatric and non-psychiatric conditions by inverse probability of treatment weighting (IPTW). Analyses were stratified according to psychiatric history. The study compared 69,786 finasteride new users to 217,577 dutasteride new users (median age: 72.0 years [Q1-Q3 = 64.5-80.2] vs. 71.1 [Q1-Q3 = 65.0-79.2]). During follow-up, 18 suicide deaths (0.57/1000 person-years) and 34 self-harm hospitalisations (1.08/1000) occurred among finasteride users versus 47 deaths (0.43/1000) and 87 hospitalisations (0.79/1000) among dutasteride users. Overall, finasteride was not associated with an increased risk of any suicidal outcome (IPTW-adjusted Hazard Ratio = 1.21 [95% Confidence Interval .87-1.67]), suicide death or self-harm hospitalisation. However, among individuals with a history of mood disorders, finasteride was associated with an increased risk of any suicidal outcome (25 versus 46 events; HR = 1.64 [95% CI 1.00-2.68]), suicide death (8 versus 10 events; HR = 2.71 [95% CI 1.07-6.91]), self-harm by violent means (6 versus 6 events; HR = 3.11 [95% CI 1.01-9.61]), and self-harm with admission to an intensive care unit (7 versus 5 events; HR = 3.97 [95% CI 1.26-12.5]). None of these risks was significantly increased among individuals without a psychiatric history. These findings do not support an increased risk of suicide with finasteride used in the treatment of benign prostatic hyperplasia. However, an increased risk cannot be excluded among men with a history of mood disorder, but this result based on a limited number of events should be interpreted with caution.
Assuntos
Finasterida , Hiperplasia Prostática , Masculino , Humanos , Idoso , Dutasterida/efeitos adversos , Finasterida/efeitos adversos , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/induzido quimicamente , Estudos de Coortes , Ideação Suicida , OxirredutasesRESUMO
A limited number of studies have described patients on finasteride showing findings which were consistent with Peyronie's disease (PD). We aimed to detect a pharmacovigilance signal of possible association between finasteride and PD-related clinical features. The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database was queried to identify the ten drugs which were associated the most with the adverse drug reactions (ADRs) recorded as "penile curvature" and/or "Peyronie's disease". A similar analysis, including the same drugs, was carried out for the EMA (European Medicines Agency) EudraVigilance (EV) database. Descriptive data have been analyzed, and Proportional Reporting Ratios (PRRs) have been computed against the other nine drugs of the database. Overall, 860 reports of "penile curvature" and/or "Peyronie's disease", were identified in the FAERS database, 214 of which (24.9%) were associated with finasteride. Most reports (56.9%) were submitted by healthcare professionals. Where a treatment-indication was stated, the vast majority of reports (176/210; 83.8%) were associated with androgenetic alopecia. The outcome of most ADRs was "serious" (82.2%), with 96 ADRs resulting in levels of permanent disability. For 97/214 individual cases, penile curvature/PD reports were not part of a syndromic cluster suggestive of post-finasteride syndrome (PFS). The PRR resulted 6.6 (95% CI: 5.6-7.8) and 11.8 (95% CI: 9.08-15.33), respectively, in the FAERS and in the EV databases. Notwithstanding the related limitations and biasing factors of pharmacovigilance studies based on spontaneous reporting, the PRR values here identified should be interpreted as strong signals of disproportionality. These findings, per se, are however not useful to confirm any causal association. Clinical studies are needed to investigate on the possible role for finasteride in causing PD-related clinical features, an hypothesis which remains highly speculative due to the very questionable quality of present data.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Doenças do Pênis , Induração Peniana , Masculino , Estados Unidos , Humanos , Finasterida/efeitos adversos , Farmacovigilância , United States Food and Drug Administration , Sistemas de Notificação de Reações Adversas a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Bases de Dados FactuaisRESUMO
Importance: In recent decades, there has been increased interest in the possible adverse neurological effects of 5α-reductase inhibitors (5-ARIs), which have been used mainly for benign prostatic hyperplasia and androgenic alopecia. Numerous studies and reports have indicated associations of 5-ARIs with depression and suicide. However, most of these studies had methodological shortcomings, and very little is known about the potential association of 5-ARIs with dementia. Objective: To investigate the association of 5-ARI use with all-cause dementia, Alzheimer disease, vascular dementia, depression, and suicide. Design, Setting, and Participants: This Swedish register-based cohort study included 2â¯236â¯876 men aged 50 to 90 years between July 1, 2005, and December 31, 2018. Statistical analyses were performed from September 15, 2021, to May 25, 2022. Main Outcomes and Measures: A diagnosis of all-cause dementia, Alzheimer disease, vascular dementia, depression, or completed suicide. Exposures: A recorded prescription in the Swedish national prescription register of finasteride or dutasteride and duration of use. Results: Of 2â¯236â¯876 men (median age at the start of follow-up, 55 years [IQR, 50-65 years] and at treatment initiation, 73 years [IQR, 66-80 years]), 70â¯645 (3.2%) started finasteride treatment, and 8774 (0.4%) started dutasteride treatment. Men taking finasteride or dutasteride were at increased risk of all-cause dementia (finasteride: hazard ratio [HR], 1.22 [95% CI, 1.17-1.28]; dutasteride: HR, 1.10 [95% CI, 1.01-1.20]), Alzheimer disease (finasteride: HR, 1.20 [95% CI, 1.10-1.31]; dutasteride: HR, 1.28 [95% CI, 1.09-1.50]), vascular dementia (finasteride: HR, 1.44 [95% CI, 1.30-1.58]; dutasteride: HR, 1.31 [95% CI, 1.08-1.59]), and depression (finasteride: HR, 1.61 [95% CI, 1.48-1.75]; dutasteride: HR, 1.68 [95% CI, 1.43-1.96]). However, the magnitude of the association decreased over time, and the findings became statistically nonsignificant with continuous exposures over 4 years, except for depression, which showed a constant risk over time, with no differences between finasteride and dutasteride. In contrast, 5-ARIs were not associated with suicide (finasteride: HR, 1.22 [95% CI, 0.99-1.49]; dutasteride: HR, 0.98 [95% CI, 0.62-1.54]). Conclusions and Relevance: This cohort study found that, while men receiving 5-ARI treatment showed a higher risk for dementia in the initial periods after starting treatment, the decreasing magnitude of the association over time suggested that the risk may be, entirely or in part, due to increased dementia detection among patients with benign prostate enlargement. Both finasteride and dutasteride were similarly associated with depression with a constant risk over time, while neither drug was associated with suicide. Prescribing clinicians and potential users should be aware of the possible risks for depression associated with 5-ARI use.
Assuntos
Inibidores de 5-alfa Redutase , Doença de Alzheimer , Antineoplásicos , Depressão , Suicídio , Humanos , Masculino , Inibidores de 5-alfa Redutase/efeitos adversos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/epidemiologia , Estudos de Coortes , Demência Vascular/induzido quimicamente , Demência Vascular/epidemiologia , Depressão/induzido quimicamente , Depressão/epidemiologia , Dutasterida/efeitos adversos , Finasterida/efeitos adversos , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/epidemiologia , Estudos Retrospectivos , Antineoplásicos/efeitos adversosRESUMO
Centella asiatica (L.) Urban (C. asiatica) is a traditional herbal medicine that has been used for wound healing and anti-inflammation since ancient times. Various biological effects of C. asiatica ethanolic extract (CAE) were previously reported. However, in our previous study, C. asiatica aqueous extract (CAA) exhibited higher inhibitory activity on benign prostatic hyperplasia (BPH) than CAE. Therefore, the aim of this study was to investigate the effect of CAA on BPH, and elucidate the inhibitory mechanism through in vitro and in vivo experiments as well as metabolite analysis of CAA. A BPH rat model was induced by daily subcutaneous injection of testosterone propionate (TP, 3 mg kg-1) dissolved in corn oil for 4 weeks after castration. The experimental group, the CAA treatment group, was orally administered CAA (100 mg kg-1) for 4 weeks while inducing prostatic hyperplasia. Saw palmetto extract (Saw, 100 mg kg-1) and Finasteride (Fi, 1 mg kg-1) were used as positive controls and were administered orally for 4 weeks. CAA significantly inhibited androgen receptor signaling related factors overexpressed by dihydrotestosterone (DHT) treatment in prostate cell lines. Afterwards, the testosterone-induced BPH model was used to verify the alleviation efficacy of CAA in prostatic hyperplasia. Prostate size and the thickness of the prostate tissue epithelium were significantly decreased in the group treated with CAA compared to those in the BPH group. The results of protein expression in the prostate tissue confirmed that CAA inhibited androgen receptor signaling in BPH and decreased the expression of growth factors. Moreover, CAA suppressed the expression of the PI3K/Akt pathway and cell proliferation-related factors compared to the BPH group. Taken together, these results indicate that CAA improves the inhibitory efficacy of BPH by inhibiting the androgen receptor and PI3K/Akt pathways, suggesting that CAA may be a promising candidate for biopharmaceutical formulations of BPH.
Assuntos
Centella , Hiperplasia Prostática , Propionato de Testosterona , Animais , Centella/metabolismo , Óleo de Milho , Di-Hidrotestosterona/efeitos adversos , Finasterida/efeitos adversos , Humanos , Masculino , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais , Próstata , Hiperplasia Prostática/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Transdução de Sinais , Testosterona/metabolismo , Propionato de Testosterona/efeitos adversos , TriterpenosRESUMO
INTRODUCTION AND OBJECTIVES: Post-finasteride syndrome (PFS) is a little known adverse effect of 5α-reductase inhibitor (5-ARI) drugs used in benign prostatic hyperplasia (BPH) and androgenetic alopecia. Five articles on the syndrome have been published in Spain, although no review has been published.The objectives of this article are to review the world literature, including the Spanish literature. MATERIAL AND METHODS: A retrospective review on post-finasteride syndrome was performed between 2011 and 2020. The search for information in PubMed/Medline was performed using the English terms "post-finasteride, post-finasteride syndrome" and in Google with the Spanish "post-finasteride, síndrome post-finasteride". The results of the variables studied were analyzed using descriptive statistics. RESULTS: A total of 64 worldwide articles on post-finasteride syndrome were found, discarding 24 (37.5%) that did not deal with the symptoms of the syndrome, and 40 articles (62.5%) by 37 authors were included for study, corresponding to 29 publications on case series (72.5%) and 11 reviews (27.5%). Of the 40 articles, 37 referred to male post-finasteride syndrome (92.5%) and 3 to female (7.5%), the number of patients studied in the review was 87,887 corresponding to 87,224 men (99.2%) and 663 women (0.7%), with the number of articles on general symptoms being 23 (57.5%), male sexual symptoms 20 (50%) and female sexual symptoms 1 (2.5%). The articles came from 14 specialties, with Dermatology 14 publications (35%), Urology-Andrology 7 (17.5%) and Pharmacology 6 (15%). The countries with the highest number of publications were the USA 15 (37.5%), Italy 7 (17.5%) and Spain 5 (12.5%). CONCLUSIONS: Finasteride is rarely associated with sexual and systemic adverse effects that constitute the so-called post-finasteride syndrome. There are still few studies on this syndrome in the world. This is the first review of this syndrome in Spain.
Assuntos
Finasterida , Hiperplasia Prostática , Inibidores de 5-alfa Redutase/efeitos adversos , Alopecia/induzido quimicamente , Alopecia/tratamento farmacológico , Feminino , Finasterida/efeitos adversos , Humanos , Doença Iatrogênica , Masculino , Hiperplasia Prostática/tratamento farmacológico , Estudos Retrospectivos , SíndromeRESUMO
Approximately 40% of women with epilepsy experience perimenstrual seizure exacerbation, referred to as catamenial epilepsy. These seizures result from cyclic changes in circulating progesterone and estradiol levels and there is no effective treatment for this form of intractable epilepsy. We artificially increased progesterone levels and neurosteroid levels (pseudo-pregnancy) in adult Swiss albino female mice (19-23 g) by injecting them with pregnant mares' serum gonadotropin (5 IU s.c.), followed by human chorionic gonadotropin (5 IU s.c.) after 46 h. After this, ferulic acid (25, 50, 100 mg/kg i.p.) treatment was given for 10 days. During treatment, progesterone, estradiol, and corticosterone levels were estimated in blood on days 1, 5, and 10. Neurosteroid withdrawal was induced by finasteride (50 mg/kg, i.p.) on treatment day 9. Twenty-four hours after finasteride administration (day 10 of treatment), seizure susceptibility was evaluated with the sub-convulsant pentylenetetrazol (PTZ) dose (40 mg/kg i.p.). Four to six hours after PTZ, animals were assessed for depression like phenotypes using tail-suspension test (TST). Four to six hours following TST, animals were euthanized, and discrete brain parts (cortex and hippocampus) were separated for estimation of norepinephrine, serotonin, and dopamine as well as glutamic acid decarboxylase (GAD) enzyme activity. PMSG and HCG treatment elevated progesterone and estradiol levels, assessed on days 1, 5, and 10 causing a state of pseudo-pregnancy. Treatment with finasteride increased seizure susceptibility and depression-like characteristics possibly due to decreased progesterone and elevated estrogen levels coupled with decreased monoamine and elevated corticosterone levels. Ferulic acid treatment, on the other hand, significantly decreased seizure susceptibility and depression like behavior, possibly because of increased progesterone, restored estradiol, corticosterone, monoamines, and GAD enzyme activity. We concluded anticonvulsant effect of ferulic acid in a mouse model of catamenial epilepsy, evidenced by favourable seizure attenuation and curative effect on the circulating progesterone, estradiol, and corticosterone levels along with restorative effect on GAD enzyme activity and monoamine levels.
Assuntos
Epilepsia , Neuroesteroides , Adulto , Feminino , Animais , Cavalos , Camundongos , Humanos , Progesterona/farmacologia , Progesterona/uso terapêutico , Finasterida/efeitos adversos , Corticosterona , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Pentilenotetrazol/toxicidade , Convulsões/tratamento farmacológico , Estradiol/uso terapêuticoRESUMO
Benign prostatic hyperplasia (BPH) is a chronic male disease characterized by the enlarged prostate. Celtis chosenianaNakai (C. choseniana) is medicinally used to alleviate pain, gastric disease, and lung abscess. In this study, the effect of C. choseniana extract on BPH was investigated using testosterone-induced rats. Sprague Dawley rats were divided into five groups: control, BPH (testosterone 5 mg·kg-1), Fina (finasteride 2 mg·kg-1), and C. choseniana (50 and 100 mg·kg-1). After four weeks of TP treatment with finasteride or C. choseniana, prostate weights and DHT levels were measured. In addition, the prostates were histopathologically examined and measured for protein kinase B (Akt)/nuclear factor-κB (NF-κB)/AR signaling, proliferation, apoptosis, and autophagy. Prostate weight and epithelial thickness were reduced in the C. choseniana groups compared with that in the BPH group. The extract of C. choseniana acted as a 5α reductase inhibitor, reducing DHT levels in the prostate. Furthermore, the extract of C. choseniana blocked the activation of p-Akt, nuclear NF-κB activation and reduced the expression of AR and PSA compared with BPH. Moreover, the expression of Bax, PARP-1, and p53 increased, while the expression of bcl-2 decreased. The present study demonstrated that C. choseniana extract alleviated testosterone-induced BPH by suppressing 5α reductase and Akt/NF-κB activation, reducing AR signaling and inducing apoptosis and autophagy in the prostate. These results suggested that C. choseniana probably contain potential herbal agents to alleviate BPH.
Assuntos
Hiperplasia Prostática , Animais , Colestenona 5 alfa-Redutase/metabolismo , Finasterida/efeitos adversos , Masculino , NF-kappa B/genética , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/metabolismo , Testosterona , Ulmaceae/metabolismoRESUMO
BACKGROUND: Autism is a clinically defined neurodevelopmental disorder with unknown origin characterized by significant social, communication and behavioral challenges. Although it can be a lifelong condition, treatments can help alleviate symptoms and enhance a patient's quality of life. PURPOSE: We aimed to assess the therapeutic potential of finasteride in autism with biochemical markers, histopathological evaluation, behavioral tests and radiological imaging. MATERIALS AND METHODS: Propionic acid (PPA) was injected intraperitoneally into 20 out of 30 rats for 5 days to establish an autism model. Rats were randomly assigned into four groups: control group (no procedure was applied, n = 10), placebo group (intraperitoneal PPA + 1 ml/kg/day % 0.9 NaCl saline was given via oral gavage for 15 days, n = 10) and treated group (intraperitoneal PPA + 5 mg/kg/day of finasteride was given via oral gavage for 15 days, n = 10). After 4 days of behavioral tests, magnetic resonance spectroscopy (MRS) was performed for measuring creatine and lactate levels. All animals were sacrificed for histopathological examination and biochemical analysis of brain tissue. RESULTS: MDA, NFκB, TNF-α, IL-2, IL-17A and lactate levels in brain homogenates were significantly increased in the placebo group compared to the control group, while Nfr2 levels were decreased; and the levels of all biochemical markers were reversed by finasteride treatment. A significant improvement was observed in autism-like behaviors in rats treated with finasteride compared to the placebo group. Further, the creatine and lactate levels in corpus striatum in MRS, the neuronal counts and glial activity of the hippocampus and cerebellum were closer to the control group in the finasteride-treated group compared to the placebo group. CONCLUSION: Finasteride led significant improvement in autism-like symptoms with its antioxidant effect through Nrf2 modulation in addition to its anti androgen effect.
Assuntos
Transtorno Autístico , Animais , Antioxidantes/uso terapêutico , Transtorno Autístico/induzido quimicamente , Transtorno Autístico/tratamento farmacológico , Escala de Avaliação Comportamental , Creatina , Finasterida/efeitos adversos , Ácido Láctico , Espectroscopia de Ressonância Magnética , Propionatos , Qualidade de Vida , RatosRESUMO
BACKGROUND: 5α-reductase inhibitors are commonly prescribed medications with multiple side effects used in the treatment of male pattern hair loss and benign prostatic hyperplasia. These side effects including "post-finasteride syndrome" may result in lawsuits. OBJECTIVES: To characterize lawsuits involving the adverse side effects of 5α-reductase inhibitor to better understand drivers of litigation and outcomes. METHODS: Legal cases were queried from Nexis Uni using the search terms "5-alpha reductase inhibitor" as well as specific agents "finasteride," "dutasteride" in combination with "malpractice," "negligence," "damage," "loss," "side effect," and "complication." Secondary review was performed with publicly available data on "In Re: Propecia." Relevant cases were reviewed and pertinent characteristics were extracted and summarized using descriptive statistics. RESULTS: Our search yielded 156 unique legal cases in the Nexis Uni database from April 2003 to May 2021. Only 18 of these cases met the inclusion criteria. Adverse events experienced by patients included medication side effects (n = 12, 66.7%), delayed cancer diagnosis (n = 3, 16.7%), and lack of symptom improvement (n = 3, 16.7%). The identity of the plaintiffs were most commonly patients themselves (n = 15, 83.3%). Defendants include pharmaceutical companies (n = 6, 33.3%), a combination of parties (n = 5, 27.8%), and physicians (n = 5, 27.8%) alone. The allegations included sexual side effects such as erectile dysfunction (n = 6, 33.3%) and decreased libido (n = 4, 22.2%). These prescriptions were made for benign prostatic hyperplasia (n = 9, 50%), male pattern hair loss (n = 7, 38.9%), and feminizing hormone therapy (n = 2, 11.1%). Several of these cases involved the same plaintiffs in related cases. No verdicts were against physicians. We noted a largely settled lawsuit involving more than 1000 plaintiffs with limited data on harms alleged and a $4.3 million settled amount. Of the total cases that resulted in a verdict, 9/18 were within the last 3 years. DISCUSSION: The most common complications experienced by patients in our legal review were those involving sexual dysfunction with erectile dysfunction and decreased libido. The growing number of cases in the later years of our review suggests litigation may continue to increase in the coming future. Our review did not identify any individual cases that resulted in a monetary payout beyond a $4.3 million settlement outside of court. CONCLUSION: 5α-reductase inhibitor was alleged to have sexual, mental, and physical side effects, resulting in legal litigation. Despite this, no judgment against a physician or pharmaceutical company was identified. We do note and discuss a large number of lawsuits settled out of court. Given the increase in the number of lawsuits resulting in verdicts over the last 3 years, we suspect that the frequency of litigation around 5α-reductase inhibitors will continue for the foreseeable future.
Assuntos
Disfunção Erétil , Imperícia , Inibidores de 5-alfa Redutase/efeitos adversos , Dutasterida , Disfunção Erétil/induzido quimicamente , Disfunção Erétil/tratamento farmacológico , Finasterida/efeitos adversos , Humanos , MasculinoRESUMO
Importance: Benign prostatic hyperplasia (BPH) in older men can cause lower urinary tract symptoms (LUTS), which are increasingly managed with medications. Frailty may contribute to both symptom progression and serious adverse events (SAEs), shifting the balance of benefits and harms of drug therapy. Objective: To assess the association between a deficit accumulation frailty index and clinical BPH progression or SAE. Design, Setting, and Participants: This cohort study used data from the Medical Therapy of Prostatic Symptoms trial, which compared placebo, doxazosin, finasteride, and combination therapy in men with moderate-to-severe LUTS, reduced urinary flow rate, and no prior BPH interventions, hypotension, or elevated prostate-specific antigen. Enrollment was from 1995 to 1998, and follow-up was through 2001. Data were assessed in February 2021. Exposures: A frailty index (score range, 0-1) using 68 potential deficits collected at baseline was used to categorized men as robust (score ≤0.1), prefrail (score 0.1 to <0.25), or frail (score ≥0.25). Main Outcomes and Measures: Primary outcomes were time to clinical BPH progression and time to SAE, as defined in the parent trial. Adjusted hazard ratios (AHRs) were estimated using Cox proportional hazards regressions adjusted for demographic variables, treatment group, measures of obstruction, and comorbidities. Results: Among 3047 men (mean [SD] age, 62.6 [7.3] years; range, 50-89 years) in this analysis, 745 (24%) were robust, 1824 (60%) were prefrail, and 478 (16%) were frail at baseline. Compared with robust men, frail men were older (age ≥75 years, 12 men [2%] vs 62 men [13%]), less likely to be White (646 men [87%] vs 344 men [72%]), less likely to be married (599 men [80%] vs 342 men [72%]), and less likely to have 16 years or more of education (471 men [63%] vs 150 men [31%]). During mean (SD) follow-up of 4.0 (1.5) years, the incidence rate of clinical BPH progression was 2.2 events per 100 person-years among robust men, 2.9 events per 100 person-years among prefrail men (AHR, 1.36; 95% CI, 1.02-1.83), and 4.0 events per 100 person-years among frail men (AHR, 1.82; 95% CI, 1.24-2.67; linear P = .005). Larger point estimates were seen among men who received doxazosin or combination therapy, although the test for interaction between frailty index and treatment group did not reach statistical significance (P for interaction = .06). Risk of SAE was higher among prefrail and frail men (prefrail vs robust AHR, 1.81; 95% CI, 1.48-2.23; frail vs robust AHR, 2.86; 95% CI, 2.21-3.69; linear P < .001); this association was similar across treatment groups (P for interaction = .76). Conclusions and Relevance: These findings suggest that frailty is independently associated with greater risk of both clinical BPH progression and SAEs. Older frail men with BPH considering initiation of drug therapy should be counseled regarding their higher risk of progression despite combination therapy and their likelihood of experiencing SAEs regardless of treatment choice.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Fragilidade/diagnóstico , Hiperplasia Prostática/tratamento farmacológico , Índice de Gravidade de Doença , Agentes Urológicos/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Doxazossina/administração & dosagem , Doxazossina/efeitos adversos , Quimioterapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Finasterida/administração & dosagem , Finasterida/efeitos adversos , Seguimentos , Idoso Fragilizado , Fragilidade/complicações , Avaliação Geriátrica , Humanos , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Sintomas do Trato Urinário Inferior/etiologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Hiperplasia Prostática/complicações , Hiperplasia Prostática/patologia , Agentes Urológicos/administração & dosagemRESUMO
BACKGROUND: Finasteride is one of several inhibitors of the 5α-reductase that converts testosterone to dihydrotestosterone used to treat hair loss and benign prostatic enlargement. Emerging clinical observations indicate that such treatment may be associated with depression, anxiety, and possibly increased suicidal risks, in addition to sexual dysfunction, even after its discontinuation. METHODS: We carried out a systematic review of reports pertaining to association of finasteride treatment with clinical depression or other adverse psychiatric effects. We analyzed reported risks of depression by pooling of rates and by meta-analysis of comparisons of subjects treated with finasteride or not. FINDINGS: Crude pooled rates of depressive symptoms with versus without finasteride were 3.33% (confidence interval, 3.22%-3.44%) versus 2.54% (2.44%-2.64%); random-effects meta-analysis yielded an odds ratio of 2.14 (1.40-3.27) (both P < 0.0001). In addition, risk of suicidal ideation or behavior was greater with versus without finasteride (21.2% [21.0%-21.5%] vs 14.0% [13.8%-14.2%], P < 0.0001), and risk of sustained sexual dysfunction was high (60.1% [37.3%-82.9%]). CONCLUSIONS: The findings support a growing impression that finasteride is associated with adverse psychiatric effects that can persist in association with sexual dysfunction after discontinuing finasteride treatment.
Assuntos
Inibidores de 5-alfa Redutase/efeitos adversos , Depressão/induzido quimicamente , Finasterida/efeitos adversos , Inibidores de 5-alfa Redutase/administração & dosagem , Alopecia/tratamento farmacológico , Depressão/epidemiologia , Finasterida/administração & dosagem , Humanos , Masculino , Hiperplasia Prostática/tratamento farmacológico , Disfunções Sexuais Fisiológicas/induzido quimicamente , Disfunções Sexuais Fisiológicas/epidemiologia , Ideação SuicidaRESUMO
OBJECTIVE: To investigate the sexual, physical, and mental adverse effects associated with exposure to 5-alpha reductase inhibitors (5ARIs). METHODS: FAERS data containing finasteride and dutasteride reports were analyzed from January 2000 to April 2019. Reports identified one or more adverse effects, along with all concurrent medications. Cases of monotherapy of finasteride or dutasteride were identified. We conducted a chi-square test of independence to assess the relationship between the three drug groups and adverse event (AE) occurrence across 19 sexual, physical, and mental AE categories. The frequency procedure in SAS was utilized to summarize rates of AEs between various dosages of each drug. RESULTS: A total of 16,014 case reports were obtained. After excluding females, 7436 case reports of 5ARI monotherapy were identified: 2628 of dutasteride 0.5 mg, 3266 of finasteride 1 mg, and 744 of finasteride 5 mg. Differences in rates of AEs occurrence were statistically significant across all 19 variables (p < 0.001) with a significantly higher proportion of AEs attributed to finasteride 1 mg, with gynecomastia being the only exception. Case report submissions rose dramatically following FDA-mandated finasteride label change. CONCLUSIONS: Analysis of FAERS data suggests AEs of 5ARIs are dose-independent with greater likelihood of occurrence in younger patients, particularly in sexual and mental domains. The causality and the rate of AEs are not certain based on the FAERS data and future prospective studies are necessary to determine the true rates.
Assuntos
Inibidores de 5-alfa Redutase/efeitos adversos , Sistemas de Notificação de Reações Adversas a Medicamentos , Dutasterida/efeitos adversos , Finasterida/efeitos adversos , Hiperplasia Prostática/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Estados UnidosRESUMO
Importance: There is ongoing controversy about the adverse events of finasteride, a drug used in the management of alopecia and benign prostatic hyperplasia (BPH). In 2012, reports started emerging on men who had used finasteride and either attempted or completed suicide. Objective: To investigate the association of suicidality (ideation, attempt, and completed suicide) and psychological adverse events (depression and anxiety) with finasteride use. Design, Setting, and Participants: This pharmacovigilance case-noncase study used disproportionality analysis (case-noncase design) to detect signals of adverse reaction of interest reported with finasteride in VigiBase, the World Health Organization's global database of individual case safety reports. To explore the strength of association, the reporting odds ratio (ROR), a surrogate measure of association used in disproportionality analysis, was used. Extensive sensitivity analyses included stratifying by indication (BPH and alopecia) and age (≤45 and >45 years); comparing finasteride signals with those of drugs with different mechanisms but used for similar indications (minoxidil for alopecia and tamsulosin hydrochloride for BPH); comparing finasteride with a drug with a similar mechanism of action and adverse event profile (dutasteride); and comparing reports of suicidality before and after 2012. Data were obtained in June 2019 and analyzed from January 25 to February 28, 2020. Exposures: Reported finasteride use. Main Outcomes and Measures: Suicidality and psychological adverse events. Results: VigiBase contained 356 reports of suicidality and 2926 reports of psychological adverse events (total of 3282 adverse events of interest) in finasteride users (3206 male [98.9%]; 615 of 868 [70.9%] with data available aged 18-44 years). A significant disproportionality signal for suicidality (ROR, 1.63; 95% CI, 1.47-1.81) and psychological adverse events (ROR, 4.33; 95% CI, 4.17-4.49) in finasteride was identified. In sensitivity analyses, younger patients (ROR, 3.47; 95% CI, 2.90-4.15) and those with alopecia (ROR, 2.06; 95% CI, 1.81-2.34) had significant disproportionality signals for increased suicidality; such signals were not detected in older patients with BPH. Sensitivity analyses also showed that the reports of these adverse events significantly increased after 2012 (ROR, 2.13; 95% CI, 1.91-2.39). Conclusions and Relevance: In this pharmacovigilance case-noncase study, significant RORs of suicidality and psychological adverse events were associated with finasteride use in patients younger than 45 years who used finasteride for alopecia. The sensitivity analyses suggest that these disproportional signals of adverse events may be due to stimulated reporting and/or younger patients being more vulnerable to finasteride's adverse effects.