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Pharmaceutics Jan 2022Androgenetic alopecia is a multifactorial condition characterized by noticeable hair loss, affecting both men and women and representing a debilitating and chronic... (Review)
Review
Androgenetic alopecia is a multifactorial condition characterized by noticeable hair loss, affecting both men and women and representing a debilitating and chronic disorder that considerably affects the quality of life. Available topical treatments based on minoxidil or finasteride require repeated applications and are associated with a certain number of adverse effects. The challenges associated with current treatments pave the way for the research of new therapeutic strategies, more precise and selective, and capable of providing long-term results. In this context, the present review examines the new proposed formulation strategies to deliver 5-α-reductase inhibitors in order to obtain a targeted drug delivery, for improving drug retention at the site of action in the hair follicle, contemporaneously reducing drug systemic absorption, which is the cause of important adverse effects. In particular, the research will be focused on the several aspects that influence the performance of nanostructured drug delivery systems in creating a depot in the hair follicles, such as particle size, surface charge, excipients, and combined application with external stimuli (infrared radiation, mechanical massage, ultrasounds application).
PubMed: 35214018
DOI: 10.3390/pharmaceutics14020286 -
Archivio Italiano Di Urologia,... Dec 2013To investigate differences in the risk of benign prostatic hyperplasia (BPH)- related hospitalization, for surgical and non-surgical reasons, and of new prostate cancer... (Comparative Study)
Comparative Study
OBJECTIVES
To investigate differences in the risk of benign prostatic hyperplasia (BPH)- related hospitalization, for surgical and non-surgical reasons, and of new prostate cancer (PCa) diagnosis between patients under dutasteride or finasteride treatment.
MATERIAL AND METHODS
A retrospective cohort study was conducted using data from record-linkage of administrative databases. Men aged ≥ 40 years old who had received a prescription for at least 10 boxes/year (index years: 2004-06) were included. The association of the outcomes was assessed using a multiple Cox proportional hazard model. Propensity score matched analysis and a 5-to-1, greedy 1:1 matching algorithm were performed. The budget impact analysis of dutasteride vs finasteride in BPH-treated patient was performed.
RESULTS
From an initial cohort of about 1.5 million of Italian men, 19620 were selected. The overall hospitalization for BPH-non surgical reasons, for BPH-related surgery and for new detection of PCa incidence rates (IRs) were 8.20 (95% CI, 7.62-8.23), 18.0 (95% CI, 17.12-18.93) and 8.62 (95% CI, 8.03-9.26) per 1000 person-years, respectively. The multivariate analysis after the propensity score-matching showed that dutasteride was associated with an independent reduced likelihood of hospitalization for BPH-related surgery (HR 0.82; 95% CI 0.73-0.93; p = 0.0025) and of newly detected PCa (HR: 0.76,95% CI, 0.65-0.85; p = 0.0116). The IR for BPH-non surgical reasons was 8.07 (95% CI, 7.10-9.17) and 9.25 (95% CI, 8.19-10.44) per 1000 person-years, respectively. The IR for BPH-related surgery was 18.28 (95% CI, 17.17-20.32) and 21.28 (95% CI, 19.24-23.06) per 1000 person-years among patients under dutasteride compared with those under finasteride, respectively. For new-onset PCa, the IR was 8.01 (95% CI, 7.07-9.08) and 9.38 (95% CI, 8.32-10.58) per 1000 person-years The pharmacoeconomical evaluation showed that the net budget impact of the use of dutasteride vs. finasteride in 1000 BPH-treated patient for 1 year induces a saving of 3933 €.
CONCLUSIONS
The clinical effects of dutasteride and finasteride are slightly different. The likelihood of hospitalization for BPH-related surgery and of newly detected PCa seems to be in favor of dutasteride. The budget impact analyses showed a slightly benefit for dutasteride. Comparative prospective studies are necessary to confirm these results.
Topics: 5-alpha Reductase Inhibitors; Adult; Aged; Aged, 80 and over; Azasteroids; Cohort Studies; Dutasteride; Finasteride; Humans; Italy; Lower Urinary Tract Symptoms; Male; Middle Aged; Retrospective Studies
PubMed: 24399122
DOI: 10.4081/aiua.2013.4.200 -
PloS One 2013The prostate cancer prevention trial (PCPT) and Reduction by dutasteride of Prostate Cancer Events (REDUCE) trial found that 5α-reductase (5αR) inhibitors finasteride...
BACKGROUND
The prostate cancer prevention trial (PCPT) and Reduction by dutasteride of Prostate Cancer Events (REDUCE) trial found that 5α-reductase (5αR) inhibitors finasteride and dutasteride respectively, decreased prostate cancer prevalence but also increased the incidence of high-grade tumors. 5αR2 is the main isoenzyme in normal prostate tissue; however, most prostate tumors have high 5αR1 and low 5αR2 expression. Because finasteride inhibits only 5αR2, we hypothesized that it would not be as efficacious in preventing prostate cancer development and/or progression in C57BL/6 TRAMP x FVB mice as dutasteride, which inhibits both 5αR1 and 5αR2.
METHOD/PRINCIPAL FINDINGS
Six-week-old C57BL/6 TRAMP x FVB male mice were randomized to AIN93G control or pre- and post- finasteride and dutasteride diet (83.3 mg drug/kg diet) groups (n =30-33) that began at 6 and 12 weeks of age, respectively, and were terminated at 20 weeks of age. The pre- and post- finasteride and dutasteride groups were designed to test the preventive and therapeutic efficacy of the drugs, respectively. Final body weights, genitourinary tract weights, and genitourinary tract weights as percentage of body weights were significantly decreased in the Pre- and Post-dutasteride groups compared with the control. The Post-dutasteride group showed the greatest inhibition of prostatic intraepithelial neoplasia progression and prostate cancer development. Surprisingly, the Post-dutasteride group showed improved outcomes compared with the Pre-dutasteride group, which had increased incidence of high-grade carcinoma as the most common and most severe lesions in a majority of prostate lobes. Consistent with our hypothesis, we found little benefit from the finasteride diets, and they increased the incidence of high-grade carcinoma.
CONCLUSION
Our findings have commonalities with previously reported PCPT, REDUCE, and the Reduction by dutasteride of Clinical Progression Events in Expectant Management (REDEEM) trial results. Our results may support the therapeutic use of dutasteride, but not finasteride, for therapeutic or preventive use.
Topics: 5-alpha Reductase Inhibitors; Animals; Azasteroids; Body Weight; Cholestenone 5 alpha-Reductase; Disease Progression; Dutasteride; Finasteride; Lymph Nodes; Lymphatic Metastasis; Male; Mice; Mice, Inbred C57BL; Prostatic Neoplasms; Receptors, Tumor Necrosis Factor, Member 25
PubMed: 24204943
DOI: 10.1371/journal.pone.0077738 -
Clinical Cancer Research : An Official... May 2017Prostate cancer is dependent on androgen receptor (AR) activation. Optimal AR antagonism may effectively cytoreduce local disease and suppress or eliminate... (Randomized Controlled Trial)
Randomized Controlled Trial
Prostate cancer is dependent on androgen receptor (AR) activation. Optimal AR antagonism may effectively cytoreduce local disease and suppress or eliminate micrometastases. We evaluated neoadjuvant therapy prior to prostatectomy with the potent AR antagonist enzalutamide (enza) either alone or in combination with dutasteride (dut) and leuprolide (enza/dut/luteinizing hormone-releasing hormone analogues [LHRHa]). Forty-eight of 52 men with intermediate or high-risk localized prostate cancer proceeded to prostatectomy after neoadjuvant enzalutamide or enza/dut/LHRHa for 6 months. We assessed pathologic complete response (pCR), minimal residual disease (MRD; ≤3 mm maximum diameter of residual disease), residual cancer burden (RCB), and expression of PSA and serum and tissue androgen concentrations. We compared the proportion of patients with pCR in each treatment arm with a historical control rate of 5%, based on previous reports of flutamide with LHRHa. In the enzalutamide arm, none of the 25 patients achieved pCR or MRD. In the enza/dut/LHRHa arm, one of 23 patients (4.3%) achieved pCR and 3 of 23 (13.0%) achieved MRD. Median RCB was higher in the enzalutamide arm than in the enza/dut/LHRHa arm (0.41 cm vs. 0.06 cm, respectively). Tissue testosterone and dihydrotestosterone levels correlated with RCB. No adverse events leading to study drug discontinuation were reported. Combination therapy with enza/dut/LHRHa resulted in pCR and MRD rates comparable with historical controls. Evidence of continued AR activity in residual tumor suggests that AR signaling may contribute to survival. Strategies to more effectively ablate AR activity are warranted to determine whether more substantial antitumor effects are observed. .
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Combined Modality Therapy; Dutasteride; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm, Residual; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Receptors, Androgen
PubMed: 28151719
DOI: 10.1158/1078-0432.CCR-16-1357 -
The American Journal of Managed Care Apr 2006Recently published data suggest that clinical benign prostatic hyperplasia (BPH), which is hallmarked by the occurrence of moderate-to-severe lower urinary tract... (Review)
Review
Recently published data suggest that clinical benign prostatic hyperplasia (BPH), which is hallmarked by the occurrence of moderate-to-severe lower urinary tract symptoms (LUTS), occurs in about one quarter of men in their 50s, one third of men in their 60s, and about half of all men 80 years or older. Although effective treatments for LUTS/BPH are available, this condition often occurs in the context of common, age-related comorbidities such as cardiovascular disease, hypertension, and erectile dysfunction. Alpha1-selective adrenergic receptor (a1-AR) antagonists (eg, alfuzosin, doxazosin, tamsulosin, terazosin) remain the cornerstone of therapy for LUTS/BPH. In addition, 5-alpha-reductase inhibitors (ie, dutasteride, finasteride) have been associated with improvements in LUTS/BPH in men with larger prostates, especially when used in combination with a1-AR antagonists. Although all these drugs have been shown to be beneficial for the treatment of BPH, there are differences in side-effect profiles. When selecting an appropriate course of therapy, these side effects and any impact they may have on existing comorbid conditions must be considered.
Topics: 5-alpha Reductase Inhibitors; Adrenergic alpha-Antagonists; Adult; Age Distribution; Aged; Aged, 80 and over; Cardiovascular Diseases; Comorbidity; Diabetes Complications; Enzyme Inhibitors; Erectile Dysfunction; Global Health; Humans; Male; Metabolic Syndrome; Middle Aged; Prevalence; Prostatic Hyperplasia; Risk Factors
PubMed: 16613526
DOI: No ID Found -
Neural Plasticity 2012Spinal and bulbar muscular atrophy (SBMA) is the first member identified among polyglutamine diseases characterized by slowly progressive muscle weakness and atrophy of... (Review)
Review
Spinal and bulbar muscular atrophy (SBMA) is the first member identified among polyglutamine diseases characterized by slowly progressive muscle weakness and atrophy of the bulbar, facial, and limb muscles pathologically associated with motor neuron loss in the spinal cord and brainstem. Androgen receptor (AR), a disease-causing protein of SBMA, is a well-characterized ligand-activated transcription factor, and androgen binding induces nuclear translocation, conformational change and recruitment of coregulators for transactivation of AR target genes. Some therapeutic strategies for SBMA are based on these native functions of AR. Since ligand-induced nuclear translocation of mutant AR has been shown to be a critical step in motor neuron degeneration in SBMA, androgen deprivation therapies using leuprorelin and dutasteride have been developed and translated into clinical trials. Although the results of these trials are inconclusive, renewed clinical trials with more sophisticated design might prove the effectiveness of hormonal intervention in the near future. Furthermore, based on the normal function of AR, therapies targeted for conformational changes of AR including amino-terminal (N) and carboxy-terminal (C) (N/C) interaction and transcriptional coregulators might be promising. Other treatments targeted for mitochondrial function, ubiquitin-proteasome system (UPS), and autophagy could be applicable for all types of polyglutamine diseases.
Topics: Androgen Antagonists; Animals; Bulbo-Spinal Atrophy, X-Linked; Genetic Therapy; Hormone Antagonists; Humans; Ligands; Receptors, Androgen; Treatment Outcome
PubMed: 22720173
DOI: 10.1155/2012/369284 -
European Urology Focus Jan 2023It is unclear how cumulative multivariable effects of clinically relevant covariates impact response to pharmacological treatments for lower urinary tract symptoms...
BACKGROUND
It is unclear how cumulative multivariable effects of clinically relevant covariates impact response to pharmacological treatments for lower urinary tract symptoms (LUTS)/benign prostatic enlargement (BPE).
OBJECTIVE
To develop models to predict treatment response in terms of International Prostate Symptom Score (IPSS) and the risk of acute urinary retention (AUR) or BPE-related surgery, based on large data sets and using as predictors baseline characteristics that commonly define the risk of disease progression.
DESIGN, SETTING, AND PARTICIPANTS
A total of 9167 patients with LUTS/BPE at risk of progression in three placebo-controlled dutasteride trials and one comparing dutasteride, tamsulosin, and dutasteride + tamsulosin combination therapy (CT) were included in the analysis to predict response to placebo up to 24 mo and active treatment up to 48 mo.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Predictors included age, IPSS, total prostate volume (PV), maximum urinary flow rate (Q), prostate-specific antigen, postvoid residual urine (PVR), α-blocker usage within 12 mo, and randomised treatment. A generalised least-squares model was developed for longitudinal IPSS and a Cox proportional-hazards model for time to first AUR/surgery.
RESULTS AND LIMITATIONS
The vast majority of patients benefit from dutasteride or CT when compared with tamsulosin alone. The predicted IPSS improvement with dutasteride or CT increased with greater PV and severity of symptoms at baseline. The tamsulosin effect was lower with greater baseline PV and tended to decrease over time. Predicted AUR/surgery risk was greater with tamsulosin versus CT or dutasteride; this risk increased with larger PV, higher PVR, and lower Q (all at baseline). An educational interactive web-based tool facilitates visualisation of the results (www.bphtool.com). Limitations include: the placebo and active-treatment predictions are from different studies, the lack of similar studies for external validation, and the focus on a population at risk of progression from the 4-yr CombAT study.
CONCLUSIONS
Predictive modelling based on large data sets and visualisation of the risk for individual profiles can improve our understanding of how risk factors for disease progression interact and affect response to different treatments, reinforcing the importance of an individualised approach for LUTS/BPE management.
PATIENT SUMMARY
We used data from previous studies to develop statistical models for predicting how men with lower urinary tract symptoms or benign prostate enlargement and at risk of disease complications respond to certain treatments according to their individual characteristics.
Topics: Male; Humans; Dutasteride; Tamsulosin; Azasteroids; Sulfonamides; Treatment Outcome; Drug Therapy, Combination; Prostatic Hyperplasia; Urinary Retention; Lower Urinary Tract Symptoms; Disease Progression
PubMed: 35985933
DOI: 10.1016/j.euf.2022.07.004 -
The American Journal of Managed Care Feb 2007The purpose of this manuscript is to provide clinicians, health plan decision makers, and policy makers with highlights of key findings pertaining to our current... (Review)
Review
The purpose of this manuscript is to provide clinicians, health plan decision makers, and policy makers with highlights of key findings pertaining to our current understanding of the condition of enlarged prostate (EP) from a managed care perspective. This includes a brief discussion regarding the prevalence and economic burden of EP, followed by a review of clinical characteristics and pathophysiology, with the final section on treatment approaches with a focus on pharmacologic options. This supplement is not intended to be a comprehensive review of EP, because many review articles on this subject are available elsewhere. This manuscript does, however, serve to introduce 3 additional manuscripts contained within this supplement. The first article provides the readers with a real-world comparison of dutasteride and finasteride relative to acute urinary retention and surgery attenuation rates. The second article investigates differences in discontinuation rates of alpha blockers when used in combination with dutasteride or finasteride. The last article addresses the cost implications associated with dutasteride and finasteride therapy. All 3 articles represent data from a naturalistic, managed care population. This supplement is intended to assist managed care formulary decision makers in evaluating key clinical and economic data which could help to differentiate dutasteride and finasteride. Although the information presented does not prove superiority of either product, it will answer some important questions and raise some important issues beyond ingredient cost.
Topics: Aged; Enzyme Inhibitors; Forecasting; Health Care Costs; Humans; Male; Managed Care Programs; Middle Aged; Prostatectomy; Prostatic Hyperplasia; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Treatment Outcome; United States; Urinary Retention
PubMed: 17295599
DOI: No ID Found -
Acta Cirurgica Brasileira 2021To investigate whether renal modifications occur following treatment with dutasteride or finasteride.
PURPOSE
To investigate whether renal modifications occur following treatment with dutasteride or finasteride.
METHODS
Twenty-four male rats were divided into three groups: control (that received distilled water), dutasteride (0.5 mg/kg/day), and finasteride (5 mg/kg/day) groups. All administrations were given by gavage for 40 consecutive days. After inducing euthanasia, blood was collected for urea and creatinine analyses, and both the kidneys were collected for stereological analyses of kidney morphology.
RESULTS
Serum urea and creatinine levels were increased in both the finasteride and the dutasteride groups compared with those in the control group. In addition, kidney weight, kidney volume, cortical volume, glomerular volumetric density, and mean glomerular volume were reduced in both treatment groups. Finally, the number of glomeruli per kidney was reduced by 26.8% in the finasteride group and by 51.6% in the dutasteride group compared with that in the control group.
CONCLUSIONS
The 5-ARIs finasteride and dutasteride promoted morphological and functional damages in rat kidneys. In addition, rats in the dutasteride group showed more severe renal modifications than those in the finasteride group.
Topics: 5-alpha Reductase Inhibitors; Animals; Dutasteride; Finasteride; Kidney; Male; Rats
PubMed: 34550196
DOI: 10.1590/ACB360703 -
The Lancet. Neurology Feb 2011Spinal and bulbar muscular atrophy (SBMA) is caused by polyglutamine expansion in the androgen receptor, which results in ligand-dependent toxicity. Animal models have a... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
BACKGROUND
Spinal and bulbar muscular atrophy (SBMA) is caused by polyglutamine expansion in the androgen receptor, which results in ligand-dependent toxicity. Animal models have a neuromuscular deficit that is mitigated by androgen-reducing treatment. We aimed to assess the efficacy and safety of the 5α-reductase inhibitor dutasteride in patients with SBMA, and to identify outcome measures for use in future studies of the disease.
METHODS
We undertook a randomised, double-blind, placebo-controlled, single-site clinical trial in ambulatory, symptomatic men with genetically confirmed SBMA. Participants were assigned by random number table to receive dutasteride (0·5 mg per day) or placebo orally for 24 months. Patients and investigators were masked to treatment allocation. The primary outcome measure was quantitative muscle assessment (QMA). The final efficacy analysis included all patients who were compliant with study treatment at 24 months. This trial was registered with ClinicalTrials.gov, NCT00303446.
FINDINGS
50 men were randomly assigned to treatment groups (25 dutasteride, 25 placebo), and 44 were included in the efficacy analysis (21 dutasteride, 23 placebo). At 24 months, the placebo group showed a decrease of 4·5% (-0·30 kg/kg) from baseline in weight-scaled muscle strength as indicated by QMA, and the dutasteride group had an increase in strength of 1·3% (0·14 kg/kg); the difference between groups (5·8%, 95% CI -5·9 to 17·6; p=0·28) was not significant. Prespecified secondary outcome measures of creatine kinase, muscle strength and function, motor nerve conduction, activities of daily living, and erectile function did not show a significant difference between the study groups in change from baseline. Quality of life, as measured by the physical component summary of the Medical Outcomes Study 36-item Short Form version 2, favoured dutasteride (change in score from baseline: placebo, -3·6%, vs dutasteride, 2·1%; p=0·01), whereas the mental component summary favoured placebo (3·3%vs -3·2%; p=0·03). The dutasteride group had fewer patients reporting falls than did the placebo group (9 vs 16; p=0·048); there were no other significant differences in reported adverse events.
INTERPRETATION
Our study did not show a significant effect of dutasteride on the progression of muscle weakness in SBMA, although there were secondary indications of both positive and negative effects compared with placebo. A longer trial duration or larger number of patients might be needed to show an effect on disease progression. Performance testing, QMA, and quality of life measures were identified as potentially useful endpoints for future therapeutic trials.
Topics: Accidental Falls; Adult; Aged; Azasteroids; Bulbo-Spinal Atrophy, X-Linked; Disease Progression; Double-Blind Method; Dutasteride; Follow-Up Studies; Fractures, Bone; Humans; Male; Middle Aged; Treatment Outcome
PubMed: 21216197
DOI: 10.1016/S1474-4422(10)70321-5