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Journal of Pharmaceutical and... Nov 2021Dutasteride is a specific and selective inhibitor of both 5α-reductase isoforms used mainly in benign prostatic hyperplasia and lower urinary tract symptoms. Although...
Dutasteride is a specific and selective inhibitor of both 5α-reductase isoforms used mainly in benign prostatic hyperplasia and lower urinary tract symptoms. Although the drug is extensively metabolized in humans, data on the concentrations of its main metabolites are lacking. There is also a lack of data on dutasteride stability in frozen plasma samples. Our method was used to determine dutasteride and its active metabolites: 4'-hydroxydutasteride, 6β-hydroxydutasteride, and 1,2-dihydrodutasteride in plasma after a single administration of 0.5 mg of dutasteride. We also assessed the long-term stability (two years in the freezer) of dutasteride in clinical samples. The developed method covered the range of 0.1-3.5 ng/mL for dutasteride and 0.08-1.2 ng/mL for 1,2-dihydrodutasteride, 4'-hydroxydutasteride, 6β-hydroxydutasteride. It was proved to be reliable as it met all validation criteria required by the European Medicine Agency for bioanalytical methods. 4'-hydroxydutasteride and 1,2-dihydrodutasteride concentrations in plasma were higher than 6β-hydroxydutasteride. Dutasteride was stable in the freezer for up to 2 years in clinical samples. Thus within 1014 days of storage (below - 65 °C), samples can be reanalyzed without the risk of unreliable results.
Topics: 5-alpha Reductase Inhibitors; Azasteroids; Chromatography, Liquid; Dutasteride; Humans; Male; Pharmaceutical Preparations; Prostatic Hyperplasia; Tandem Mass Spectrometry
PubMed: 34562803
DOI: 10.1016/j.jpba.2021.114362 -
The Canadian Journal of Hospital... 2017Finasteride and dutasteride are competitive inhibitors of 5α-reductase enzymes and are commonly used to treat symptomatic benign prostatic hyperplasia (BPH). (Review)
Review
BACKGROUND
Finasteride and dutasteride are competitive inhibitors of 5α-reductase enzymes and are commonly used to treat symptomatic benign prostatic hyperplasia (BPH).
OBJECTIVE
To compare the efficacy and safety of finasteride and dutasteride in terms of clinically important outcomes.
DATA SOURCES
A literature search was performed using the search terms "prostatic hyperplasia", "prostatic hypertrophy", "dutasteride", "finasteride", "quality of life", "adverse drug reaction", and "mortality". The Embase, PubMed, Cochrane Central Register of Controlled Trials, International Pharmaceutical Abstracts, Cumulative Index to Nursing and Allied Health Literature, and Latin American and Caribbean Health Sciences Literature databases were searched from inception to December 2015.
STUDY SELECTION AND DATA EXTRACTION
Randomized controlled trials, quasi-randomized trials, and systematic reviews comparing finasteride with dutasteride, either as monotherapy or in combination with α-blockers, for treatment of men with BPH were included. The outcomes of interest included need for prostate-related surgery, episodes of acute urinary retention, withdrawals due to adverse events, number of patients experiencing serious adverse events, mortality, and sexual dysfunction.
DATA SYNTHESIS
Four studies involving a total of 1879 patients were included in the analysis. There were no significant differences in any of the clinically important outcomes examined: for prostate-related surgery, odds ratio (OR) 2.01 (95% confidence interval [CI] 0.18-22.24); for episodes of acute urinary retention, OR 1.47 (95% CI 0.68-3.19); for number of withdrawals due to adverse events, OR 1.10 (95% CI 0.68-1.75); for total number of patients experiencing adverse events, OR 0.94 (95% CI 0.78-1.14); for number of patients experiencing serious adverse events, OR 1.31 (95% CI 0.87-1.97); and for sexual dysfunction, OR 0.83 (95% CI 0.64-1.08).
CONCLUSION
There is insufficient evidence to suggest that either finasteride or dutasteride offers an advantage in efficacy or safety over the other, in terms of clinically important outcomes.
PubMed: 28487578
DOI: 10.4212/cjhp.v70i2.1643 -
Neuropharmacology Dec 2021The main neuropathological feature of Parkinson's disease (PD) is degeneration of dopamine (DA) neurons in the substantia nigra (SN); PD prevalence is higher in men,...
The main neuropathological feature of Parkinson's disease (PD) is degeneration of dopamine (DA) neurons in the substantia nigra (SN); PD prevalence is higher in men, suggesting a role of sex hormones in neuroprotection. This study sought the effects of sex hormones in the brain in a mouse model of PD and modulation of steroid metabolism/synthesis with the 5α-reductase inhibitor dutasteride shown to protect 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) male mice. Male and female mice were gonadectomized (GDX) or SHAM operated. They were treated with vehicle or dutasteride (5 mg/kg) for 10 days and administered a low dose of MPTP (5.5 mg/kg) or saline on the 5th day to model early PD; brains were collected thereafter. Striatal measures of the active metabolite 1-methyl-4-phenylpyridinium (MPP) contents showed no difference supporting an effect of the experimental conditions investigated. In SHAM MPTP male mice loss of striatal DA and metabolites, DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) specific binding in the striatum and SN was prevented by dutasteride treatment; these changes were inversely correlated with glial fibrillary acidic protein (GFAP, an astrogliosis marker) levels. In SHAM female mice MPTP treatment had little or no effect on striatal and SN DA markers and GFAP levels whereas GDX male and female mice showed a similar loss of striatal DA markers and increase of GFAP. No effect of dutasteride treatment was observed in GDX male and female mice. In conclusion, sex differences in mice MPTP toxicity and response to dutasteride were observed that were lost upon gonadectomy implicating neuroinflammation.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Castration; Corpus Striatum; Disease Models, Animal; Dopamine; Dutasteride; Female; Glial Fibrillary Acidic Protein; Humans; Male; Mice, Inbred C57BL; Parkinson Disease; Sex Characteristics; Substantia Nigra; Mice
PubMed: 34555366
DOI: 10.1016/j.neuropharm.2021.108784 -
Urologia Sep 2014The 5alpha-reductase inhibitors (5ARIs) represent a valid therapeutic option in the long-term treatment of benign prostatic hyperplasia (BPH). One of the most debated... (Review)
Review
OBJECTIVE
The 5alpha-reductase inhibitors (5ARIs) represent a valid therapeutic option in the long-term treatment of benign prostatic hyperplasia (BPH). One of the most debated topics is the interpretation of the variation of the serum PSA during treatment with 5ARIs. The objective of this review was to analyze the change in serum PSA levels over time and to evaluate its sensitivity and specificity in the screening for prostate cancer (CaP) during treatment.
METHODS
An extensive search using PubMed and Scopus was performed including the following key words: "5ARI", "finasteride", "dutasteride", "prostate cancer", "benign prostatic hyperplasia", "PSA", "kinetics", "PSA derivatives".
RESULTS
The reduction of serum PSA during treatment with 5ARIs can be observed up to 48 months after the beginning of the therapy. This category of drugs seems to improve the diagnostic performance of PSA in screening CaP. On the other hand, there is a reduction of the diagnosis of indolent cancers. Any increase in PSA from nadir should be considered suspicious for malignancy. However, if the choice of a biopsy depended only on an increase of the values of serum PSA, a variable percentage of potentially aggressive tumors could not be diagnosed. Therefore, it is important to consider in the clinical and diagnostic follow-up other factors such as digital rectal examination, age, family history of CaP and imaging techniques.
CONCLUSIONS
5-ARIs have a positive impact on the specificity of PSA but they must not be the only tool that can identify CaPs with poor prognosis.
Topics: 5-alpha Reductase Inhibitors; Dutasteride; Finasteride; Humans; Male; Prostate-Specific Antigen; Prostatic Hyperplasia
PubMed: 24803356
DOI: 10.5301/urologia.5000068 -
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 -
Scientific Reports Mar 2023Finasteride, a 5α-reductase inhibitor used in benign prostatic hyperplasia and androgenetic alopecia, has been associated with an increased suicidal risk, whereas it is...
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.
Topics: Male; Humans; Aged; Dutasteride; Finasteride; Prostatic Hyperplasia; Cohort Studies; Suicidal Ideation; Oxidoreductases
PubMed: 37002313
DOI: 10.1038/s41598-023-32356-3 -
Veterinary Sciences Sep 2022A 5-year-old recently castrated male Doberman dog presented for prolonged erection of one week's duration with associated pain and dysuria. This was the fourth episode...
A 5-year-old recently castrated male Doberman dog presented for prolonged erection of one week's duration with associated pain and dysuria. This was the fourth episode within a year. Each episode was associated with an unusual event, which was stressful for the dog. Castration performed two months prior to the final episode did not prevent recurrence. Due to tissue necrosis, penile amputation and urethrostomy had to be performed. The dog recovered fully. Prolonged erection that persists beyond or that is unrelated to sexual stimulation is called "priapism". This term refers to the Greek god Priapus, a god of fertility, memorialized in sculptures for his giant phallus. In humans, depending on the mechanism involved, priapism is classified as nonischemic or ischemic. Because prognosis and treatment are different, priapism must be determined to be nonischemic or ischemic. Nonischemic priapism is a rare condition observed when an increase in penile arterial blood flow overwhelms the capacity of venous drainage; it is often associated with penile trauma, and does not require medical intervention. Ischemic priapism is associated with decreased venous return. In humans, ischemic priapism accounts for 95% of cases, the majority of which are idiopathic. Ischemic priapism is a urological emergency; simple conservative measures such as aspiration of blood from the corpora cavernosa and intracavernosal injection of an adrenergic agent are often successful. Stuttering priapism, also called recurrent or intermittent priapism, is a particular form of ischemic priapism reported in humans that is characterized by repetitive episodes of prolonged erections. Management consists of treating each new episode as an episode of acute ischemic priapism, and preventing recurrence with oral medications such as dutasteride and/or baclofen, gabapentin, or tadalafil. To the authors' knowledge, this case is the first report of stuttering priapism in a dog.
PubMed: 36288131
DOI: 10.3390/vetsci9100518 -
Expert Opinion on Drug Safety Nov 2018Alopecia is often a cause of great concern to patients for cosmetic and psychologic reasons. The aim of treating non-scarring alopecias is to reduce hair loss and, to... (Review)
Review
Alopecia is often a cause of great concern to patients for cosmetic and psychologic reasons. The aim of treating non-scarring alopecias is to reduce hair loss and, to some extent, enhance hair regrowth. However, therapies for scarring alopecias are limited and aiming to halt disease progression. Nonetheless, available modalities of treatment come with numerous side effects. Areas covered: Many new treatments for non-scarring alopecias have been introduced in recent years. This review summarizes the safety concerns when using novel therapeutic modalities such as JAK inhibitors, hair transplantation, mesotherapy, oral minoxidil, platelet-rich plasma, microneedling, and 5α-reductase inhibitors for treating hair loss. A broad literature search was performed using PubMed and Google Scholar in April 2018 to compile published articles that reported the adverse effects of new therapeutic modalities for alopecia. Expert opinion: Although emerging therapeutic modalities for alopecia have demonstrated efficacy in hair regrowth and treating established disease, their safety profiles vary widely. When considering the new treatments for alopecia, physicians should weigh the potential benefits and risks of each treatment or combination treatment to ensure safe and successful outcomes.
Topics: Alopecia; Cicatrix; Disease Progression; Drug Design; Hair; Humans; Platelet-Rich Plasma
PubMed: 30318935
DOI: 10.1080/14740338.2018.1533549 -
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 -
Journal of Translational Medicine Feb 2023The incidence of bladder cancer (BCa) is approximately four times higher in men than in women. To develop effective BCa treatments, there is an urgent need to understand...
BACKGROUND
The incidence of bladder cancer (BCa) is approximately four times higher in men than in women. To develop effective BCa treatments, there is an urgent need to understand the differences in the BCa control mechanisms based on gender. Our recent clinical study showed that androgen suppression therapy using 5α-reductase inhibitors and androgen deprivation therapy affects BCa progression, but the underlying mechanisms are still unknown.
METHODS
mRNA expression levels of the androgen receptor (AR) and SLC39A9 (membrane AR) in T24 and J82 BCa cells were evaluated by reverse transcription-PCR (RT-PCR). The effect of dutasteride, a 5α-reductase inhibitor, in BCa progression was determined in cells transfected with control and AR-overexpressing plasmids. In addition, cell viability and migration assays, RT-PCR, and western blot analysis were performed to analyze the effect of dutasteride on BCa in the presence of testosterone. Finally, steroidal 5α-reductase 1 (SRD5A1), one of the dutasteride target genes, was silenced in T24 and J82 BCa cells using control and shRNA-containing plasmids, and the oncogenic role of SRD5A1 was evaluated.
RESULTS
Dutasteride treatment led to significant inhibition of the testosterone-induced increase dependent on AR and SLC39A9 in cell viability and migration of T24 and J82 BCa cells and induced alterations in the expression level of cancer progression proteins, such as metalloproteases, p21, BCL-2, NF-KB, and WNT in AR-negative BCa. Furthermore, the bioinformatic analysis showed that mRNA expression levels of SRD5A1 were significantly higher in BCa tissues than in normal paired tissues. A positive correlation between SRD5A1 expression and poor patient survival was observed in patients with BCa. Also, Dutasteride treatment reduced cell proliferation and migration via blocking the SRD5A1 in BCa.
CONCLUSIONS
Dutasteride inhibited testosterone-induced BCa progression dependent on SLC39A9 in AR-negative BCa and repressed oncogenic signaling pathways, including those of metalloproteases, p21, BCL-2, NF-KB, and WNT. Our results also suggest that SRD5A1 plays a pro-oncogenic role in BCa. This work provides potential therapeutic targets for the treatment of BCa.
Topics: Humans; 5-alpha Reductase Inhibitors; Androgen Antagonists; Androgens; Azasteroids; Dutasteride; Hyperplasia; NF-kappa B; Oxidoreductases; Prostate; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Testosterone; Urinary Bladder Neoplasms; Cell Line, Tumor
PubMed: 36800968
DOI: 10.1186/s12967-023-03972-4