A Phase I, Open-Label, Sequential, Single-Dose Clinical Trial to Evaluate the Pharmacokinetic, Pharmacodynamic, and Safety of IVL3001, a Finasteride-Based Novel Long-Acting Injection for Androgenetic Alopecia.

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.

Anxiety-, and depression-like behavior following short-term finasteride administration is associated with impaired synaptic plasticity and cognitive behavior in male rats.

Finasteride, a 5α-Reductase inhibitor, is used to treat male pattern baldness and benign prostatic hyperplasia. Several clinical studies show that chronic finasteride treatment induces persistent depression, suicidal thoughts and cognitive impairment and these symptoms are persistent even after its withdrawal. Previous results from our lab showed that repeated administration of finasteride for six days induces depression-like behavior. However, whether short-term finasteride administration induces anxiety-like behavior and memory impairment and alters synaptic plasticity are not known, which formed the basis of this study. Finasteride was administered to 2-2.5 months old male Wistar rats for six days and subjected to behavioral evaluation, biochemical estimation and synaptic plasticity assessment. Anxiety-like behavior was evaluated in the elevated plus maze (EPM), open field test (OFT), light/dark test (LDT), and novelty suppressed feeding test (NSFT), and learning and memory using novel object recognition test (NORT) and novel object location test (NOLT) and depression-like behavior in the sucrose preference test (SPT). Synaptic plasticity in the hippocampal Schaffer collateral-CA1 was evaluated using slice field potential recordings. Plasma corticosterone levels were estimated using ELISA. Finasteride administration induced anxiety-like behavior in the EPM, OFT, LDT and NSFT, and depression-like behavior in the SPT. Further, finasteride induced hippocampal dependent spatial learning and memory impairment in the NOLT. In addition, finasteride decreased basal synaptic plasticity and long-term potentiation (LTP) in the hippocampus. A trend of increased plasma corticosterone levels was observed following repeated finasteride administration. These results indicate the potential role of corticosterone and synaptic plasticity in finasteride-induced effects and further studies will pave way for the development of novel neurosteroid-based therapeutics in neuropsychiatric diseases.

Repeated finasteride administration promotes synaptic plasticity and produces antidepressant- and anxiolytic-like effects in female rats.

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.

Medications Mostly Associated With Ejaculatory Disorders: Assessment of the Eudra-Vigilance and Food and Drug Administration Pharmacovigilance Databases Entries.

OBJECTIVE: To identify which medications are mostly associated with ejaculatory disorders through a disproportionality analysis. METHODS: The Food and Drug Administration Adverse Event Reporting System (FDA-FAERS) and the Eudra-Vigilance (EV) database were queried to identify medications more commonly associated to ejaculatory disorders from September 10, 2012 to June 1, 2023. Proportional Reported Ratios (PRRs) were computed for all the selected drugs. RESULTS: Overall, 7404 reports of ejaculatory disorders reports were identified, and of these, 6854 cases (92.6%) were attributed to ten specific medications. On FDA-FAERS and EV databases, Paroxetine and Tamsulosin were the main responsible of delayed ejaculation (103/448 events, 23.0%) and retrograde ejaculation (366/1033 events, 35.4%), respectively. Finasteride was mostly related to painful ejaculation and ejaculation failure, with 150 events (7.8%) and 735 events (38.4%) respectively. Within the group of high-risk medications, Sildenafil presented higher risk of ejaculatory disorders than Tadalafil (PRR=5.85 (95%CI 5.09-6.78), P < .01). CONCLUSION: Ten drugs were recognized to display significant reporting levels of ejaculatory disorders. Among them, Finasteride and Sildenafil were responsible for the most reports in FDA-FAERS and in EV databases, respectively. Physicians should thoroughly counsel patients treated with these drugs about the risk of ejaculatory disorders. Further integration into clinical trials is needed to enhance the applicability and significance of these results.

Exploring rat corpus cavernosum alterations induced by finasteride treatment and withdrawal.

Despite its efficacy for treating androgenetic alopecia, finasteride, an inhibitor of 5α-reductase (i.e., the enzyme converting testosterone, T, into dihydrotestosterone, DHT), is associated with several side effects including sexual dysfunction (e.g., erectile dysfunction). These side effects may persist after drug suspension, inducing the so-called post-finasteride syndrome (PFS). The effects of subchronic treatment with finasteride (i.e., 20 days) and its withdrawal (i.e., 1 month) in rat corpus cavernosum have been explored here. Data obtained show that the treatment was able to decrease the levels of the enzyme 5α-reductase type II in the rat corpus cavernosum with increased T and decreased DHT levels. This local change in T metabolism was linked to mechanisms associated with erectile dysfunction. Indeed, by targeted metabolomics, we reported a decrease in the nitric oxide synthase (NOS) activity, measured by the citrulline/arginine ratio and confirmed by the decrease in NO2 levels, and a decrease in ornithine transcarbamylase (OTC) activity, measured by citrulline/ornithine ratio. Interestingly, the T levels are negatively correlated with NOS activity, while those of DHT are positively correlated with OTC activity. Finasteride treatment also induced alterations in the levels of other molecules involved in the control of penile erection, such as norepinephrine and its metabolite, epinephrine. Indeed, plasma levels of norepinephrine and epinephrine were significantly increased and decreased, respectively, suggesting an impairment of these mediators. Interestingly, these modifications were restored by suspension of the drug. Altogether, the results reported here indicate that finasteride treatment, but not its withdrawal, affects T metabolism in the rat corpus cavernosum, and this alteration was linked to mechanisms associated with erectile dysfunction. Data here reported could also suggest that the PFS sexual side effects are more related to dysfunction in a sexual central control rather than peripheral compromised condition.

Efficacy of the association of topical minoxidil and topical finasteride compared to their use in monotherapy in men with androgenetic alopecia: A prospective, randomized, controlled, assessor blinded, 3-arm, pilot trial.

PURPOSE: Topical minoxidil (MNX) 2%-5% and oral finasteride (F) 1 mg/day are the only two pharmacological treatments authorized for androgenetic alopecia (AGA). Recently, a 2.2 mg/mL topical formulation of F was developed to minimize the systemic adverse effects associated with the oral formula. MNX and F act through different mechanisms; therefore, their association could improve clinical efficacy. To evaluate the efficacy of the association of 5% MNX and 0.25% topical F compared to their use in monotherapy, a 6-month, prospective, randomized, assessor-blinded trial was conducted. PATIENTS AND METHODS: Forty-two males, mean age 24 ± 3 years, with AGA (I-VII of Norwood-Hamilton Grading Scale), treatment naive or free from any therapy for at least 6 months, were enrolled and randomly assigned to three arm treatment groups (2:1:1): group A (n = 19, the subjects applied 5% MNX in the morning and F spray in the evening), group B (n = 12, the subjects applied F spray in the evening), and group C (n = 11, the subjects applied 5% MNX twice daily). The efficacy of treatments was evaluated at baseline and after 3 and 6 months using a global photography score (GPAS; from -3 to +3) and trichoscopy evaluation and assessed by an investigator unaware of treatment allocation. At baseline and after treatments, the serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone sulfate (DHEA-S), and testosterone were also evaluated. RESULTS: All treatments resulted in an increase in hair density compared to baseline. However, this improvement was significant only for group A (MNX + F), both at three (+56 density/cm2 , p < 0.05) and six (+81 density/cm2 , p < 0.001) months. The mean change from baseline in hair density was higher for group A compared to other groups and statistically different compared to group B (F) (p < 0.01), both after 3 and 6 months. Group A showed a global photographic assessment score (GPAS) significantly higher compared to group B (p < 0.001) and group C (p < 0.05) both at 3 and 6 months (2.0 ± 0.7 vs. 0.6 ± 0.8 and 1.3 ± 0.6; respectively). A significantly greater percentage of subjects in Group A achieved a GPAS score of ≥2 in comparison with Groups B and C both after 3 and 6 months (79% vs. 8% and 41%, respectively). No significant differences were observed in mean hair diameter and hormonal levels between the three groups. Good tolerability was observed in all treated groups. CONCLUSION: The association of 5% MNX lotion and 0.25% F in spray formulation in patients with AGA showed a significantly higher clinical and instrumental efficacy compared to the monotherapies, with comparable tolerability and safety profile.

Medical Treatment for Androgenetic Alopecia.

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.

Post-Finasteride Syndrome And Post-Ssri Sexual Dysfunction: Two Clinical Conditions Apparently Distant, But Very Close.

Post-finasteride syndrome and post-SSRI sexual dysfunction, are two poorly explored clinical conditions in which men treated for androgenetic alopecia with finasteride or for depression with SSRI antidepressants show persistent side effects despite drug suspension (e.g., sexual dysfunction, psychological complaints, sleep disorders). Because of some similarities in the symptoms, common pathological mechanisms are proposed here. Indeed, as discussed, clinical studies and preclinical data obtained so far suggest an important role for brain modulators (i.e., neuroactive steroids), neurotransmitters (i.e., serotonin, and cathecolamines), and gut microbiota in the context of the gut-brain axis. In particular, the observed interconnections of these signals in these two clinical conditions may suggest similar etiopathogenetic mechanisms, such as the involvement of the enzyme converting norepinephrine into epinephrine (i.e., phenylethanolamine N-methyltransferase). However, despite the current efforts, more work is still needed to advance the understanding of these clinical conditions in terms of diagnostic markers and therapeutic strategies.

The efficacy of the combination of topical minoxidil and oral spironolactone compared with the combination of topical minoxidil and oral finasteride in women with androgenic alopecia, female and male hair loss patterns: A blinded randomized clinical trial.

INTRODUCTION: Androgenic alopecia (AGA) is the most common cause of hair loss in women, affecting their quality of life. The present study was conducted with the aim of comparing the combined effect of topical minoxidil and oral spironolactone with the combined effect of topical minoxidil and oral finasteride in women with AGA, female and male hair loss patterns. METHOD: This clinical study was performed on 60 women suffering from AGA. The patients were divided into two groups receiving spironolactone 100 mg/day and finasteride 5 mg/day. In addition, a 2% minoxidil solution was used in all patients in addition to treatment with finasteride or spironolactone. At 2 months after initiation and at the end of treatment, patients were evaluated using the Ludwig/Norwood-Hamilton scale and the degree of physician and patient satisfaction. RESULTS: After 2 months, hair density, hair thickness, and hair loss had improved in both groups; however, statistically, there was no significant difference between the two groups with respect to these parameters (p > 0.05). After 4 months, a significant difference was found between the two groups in terms of treatment response (physician satisfaction), hair density, and hair loss severity. So that, the drugs used were ineffective in 6.7% of cases in the minoxidil-spironolactone group and in 16.7% of cases in the minoxidil-finasteride group. In addition, 43.3% of cases in the minoxidil-spironolactone group and 53% in the minoxidil-finasteride group responded well to treatment. The treatment effect was excellent in 56.7% and 0% of the mentioned groups, respectively, and the mentioned difference was statistically significant (p: 0.01). The response to treatment in female pattern hair loss (FPHL) was not statistically significant (p: 0.52), but there was a significant difference in the response to both treatments in male pattern hair loss (MPHL; p: 0.007). In terms of patient satisfaction, minoxidil-spironolactone treatment was significantly better than minoxidil-finasteride regarding hair density and severity of hair loss (p: 0.01). Finally, in terms of treatment complications, the patients in two groups did not have any serious adverse effects. CONCLUSION: The combination of minoxidil and spironolactone could be considered a more effective treatment than the combination of minoxidil and finasteride in women with AGA, FPHL, and MPHL.

Cognitive dysfunction following finasteride use: a disproportionality analysis of the global pharmacovigilance database.

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.

Active pharmaceutical ingredient-ionic liquids assisted follicular co-delivery of ferulic acid and finasteride for enhancing targeted anti-alopecia.

Androgenetic alopecia (AGA) is the primary hair loss with impairing patients' quality of life. Finasteride (FIN) is an SRD5A2 inhibitor for AGA treatment, but oral FIN causes systemic adverse effects. Topical FIN delivery is anticipated to overcome this problem. Ferulic acid (FA) is a natural phenolic acid with vascular remodeling and anti-inflammatory effects. Herein, an active pharmaceutical ingredient ionic liquid (API IL) based on choline and FA (CF-IL) is for the first time constructed to load FIN for fabricating FIN CF-IL. CF-IL aims to act as carriers and cargos and enhance hair follicle (HF) co-delivery of FA and FIN for synergistic anti-alopecia. Thermal and spectroscopic analysis combined with quantum chemistry calculations and molecular dynamics confirm the formation of CF-IL. The CF-IL simultaneously increases the solubility of FA (∼648-fold) and FIN (∼686-fold), enhances the permeation and retention of FIN and FA through the follicular pathway, and promotes cellular uptake. FIN CFIL regulates the abnormal mRNA expressions in dihydrotestosterone-irritated hDPCs, and promotes hair regrowth in AGA mice in a combined manner with FIN and FA. These findings suggest that FA-based API IL is a promising approach for percutaneously co-delivering FA and FIN to HF, providing an enhanced targeting treatment for AGA.

Dissolving microneedles for alopecia treatment.

Alopecia is a treatable benign disease, however, approximately 15-30% of women and 50% of men suffer from alopecia, which greatly affects patient's self-esteem and quality of life. Currently, commercial products for alopecia treatment include topical minoxidil solution, oral finasteride tablets and oral baricitinib tablets. However, the barrier of stratum corneum, systemic adverse effects and poor cure rate limit the application of commercial products. Therefore, researchers investigated the mechanism of alopecia, and developed new drugs that could target lactate dehydrogenase-related pathways, remove excessive reactive oxygen in hair follicles, and reduce the escape of hair follicle stem cells, thus injecting new strength into the treatment of alopecia. Moreover, starting from improving drug stratum corneum penetration and reducing side effects, researchers have developed hair loss treatment strategies based on dissolved microneedles (MNs), such as drug powders/microparticles, nanoparticles, biomimetic cell membranes, phototherapy and magnetically responsive soluble microneedles, which show exciting alopecia treatment effects. However, there are still some challenges in the practical application of the current alopecia treatment strategy with soluble microneedles, and further studies are needed to accelerate its clinical translation.

Evaluation of the therapeutic effects of AGA drugs by measuring finasteride, dutasteride, and dihydrotestosterone in hair.

BACKGROUND: Androgenetic alopecia (AGA) is treated by 5α-reductase inhibitors (5ARI) such as finasteride and dutasteride, which are widely used as therapeutic agents. However, their pharmacokinetics in target organs (scalp and hair follicles) have not yet been investigated. PURPOSE: To confirm the effective action of finasteride and dutasteride in the hair follicle tissues, we developed a method to measure these concentrations in hair. RESULTS: Compared to the non-detection (N.D.) group, the dihydrotestosterone (DHT) concentrations decreased significantly in both the finasteride and dutasteride groups. The dutasteride group showed significantly lower DHT concentrations among all groups. CONCLUSIONS: Measurement of finasteride, dutasteride, and DHT concentrations in hair would aid in evaluating the drug pharmacokinetics and its therapeutic effects on AGA patients.

Suicidal risk associated with finasteride versus dutasteride among men treated for benign prostatic hyperplasia: nationwide cohort study.

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.

A systematic review of clinical trials using single or combination therapy of oral or topical finasteride for women in reproductive age and postmenopausal women with hormonal and nonhormonal androgenetic alopecia.

Female pattern hair loss (FPHL) is a hereditary form of hair loss in women and the most common patterned progressive hair loss in female patients with androgenetic alopecia (AGA). One of the best methods for treating hair loss in women is the finasteride treatment. This systematic review includes a summary of the pharmacology of finasteride and the effect of the drug on women, especially those in the menopausal age group, and is aimed at elucidating methods of preventing systematic side effects. A search of all published literature from 1999 to 2020 has been conducted with the use of PubMed/MEDLINE, Embase, PsycINFO, TRIP Cochrane, as well as Cochrane Skin databases. A total of 380 articles were found, of which 260 articles were removed and 87 review studies were excluded. Lastly, full texts of 33 original articles were reviewed and 14 articles that met the inclusion criteria were selected. Ten out of the 14 articles reported a high rate of alopecia recovery in women taking finasteride. Based on the results, it can be stated that 5 mg of oral finasteride per day could be an effective and safe treatment in normoandrogenic women with FPHL, especially when used in combination with other drugs, such as topical estradiol and minoxidil. We also found that topical finasteride is more effective than other topical formulas for treating hair loss.