Doses Of Finasteride Research Articles

Pharmacokinetic-pharmacodynamic modeling approach for dose prediction of the optimal long-acting injectable formulation of finasteride

A controlled drug release formulation based on the subcutaneous injection of poly (lactic-co-glycolic acid) (PLGA) microspheres loaded with finasteride was prepared and evaluated for monthly delivery. After selection of biodegradable polymer and polymer-to-finasteride ratio, the formulation was characterized. Scanning electron microscopy (SEM) and laser-light particle size analysis were used to examine the morphology, surface structure, and particle size. High‑performance liquid chromatography (HPLC) was used to determine the drug loading, while liquid chromatography with tandem mass spectrometry (LC-MS/MS) was employed to analyze plasma finasteride concentrations. Results showed that the PLGA microspheres were spherical and of an appropriate size. The formulation stably releases the drug from the microspheres and the release sustained for a month without burst release, which was the desired duration. In vivo pharmacokinetic-pharmacodynamic (PK-PD) studies were conducted in beagle dogs through the administration of PROPECIA® (as a reference drug) per oral and subcutaneous injection of the long-acting injectable microsphere formulation (LAIF) loaded with five different doses of finasteride. From the acquired plasma data, PK-PD models for both PROPECIA®-administered group and LAIFs-injected groups were developed and validated. PK-PD profiles of both groups were predicted for up to one month. The predicted PK-PD profile of all LAIFs showed the achievability of monthly delivery and pharmacological effects without burst release, compared to the simulated PK-PD profile of PROPECIA®. According to the predicted PK-PD profiles, the formulation loaded with 16.8 mg of finasteride was determined to be the optimal dose. The data obtained from the PK-PD model could be used as the basis for the estimation of a first-in-human dose of the formulation.

Endocrine, prostatic vascular, and proapoptotic changes in dogs with benign prostatic hyperplasia treated medically or surgically

Benign prostatic hyperplasia (BPH) is a disorder related to hormone imbalance, local angiogenesis, and prostate growth, which can be treated surgically (orchiectomy) or medically (most commonly with finasteride). However, finasteride therapy is not completely established in dogs regarding local action and posology. This study aimed to evaluate the effect of different doses of finasteride and orchiectomy on hormonal profile, prostate apoptosis, blood flow, and biometry in dogs with BPH. Dogs were assigned to the following groups: untreated, 0.1 mg, 0.2 mg, and 0.5 mg/kg/d of finasteride and orchiectomy. All dogs were assessed monthly: day 0 (before treatment), day 30, and day 60 and subjected to prostate B-mode and Doppler ultrasonography and hormonal analysis (testosterone and dihydrotestosterone). After 60 d, prostatic biopsy was performed for histology and immunohistochemical evaluation for apoptosis (caspase-3). On day 60, percentage reduction of prostatic volume was greater in orchiectomized dogs than that in finasteride groups, which, conversely, was greater than untreated dogs. On day 60, 0.2-mg finasteride, 0.5-mg finasteride, and orchiectomy groups had higher prostatic blood flow than 0.1-mg finasteride and untreated groups. In addition, both 0.5-mg finasteride and orchiectomy groups had an increase in prostate artery resistance. Orchiectomy significantly decreased androgen concentrations at 30 d onward, differing from the remaining groups. The orchiectomy group had lower caspase-3 immunostaining, however, not different from untreated and 0.5-mg finasteride. In conclusion, 0.5 mg/kg finasteride promoted more effective prostate apoptosis and hemodynamic effects among medical treatments, whereas orchiectomy caused prostate atrophy and sharp endocrine changes in dogs with BPH.

The effects of Finasteride on the expression of Dazl, Tsga10, Sycp3, Prm2 genes during spermatogenesis in testes of NMRI mice.

In this study, the impact of Finasteride was assessed on the expression of four biomarkers of the spermatogenesis process, namely Dazl, Tsga10, Sycp3, and Prm2 using the Real-Time PCR technique. The experimental protocol was carried out on male NMRI mice for 35 days in which three animal groups received three different doses of Finasteride (1, 5, and 20 mg/body weight). The results showed that the expression levels of both Dazl and Prm2 genes were significantly decreased only at a dose of 20 mg/body weight, but at doses of 5 and 20 mg/body weight, the expression levels of Sycp3 and Tsga10 genes were significantly reduced. It seems that Finasteride, at a dose of 5 mg/body weight or higher, may have adverse effects on male spermatogenesis and fertility.

Letter to the Editors

I appreciate the careful reading and identification of potential limitations of our study by Drs. Kota and Mysore. They correctly note that the specific dose of finasteride (e.g., 1 or 5mg) was not identified for this study. The purpose of the study was to determine if exposure to ANY dose of

Long-term treatment with finasteride induces apoptosis and pathological changes in female mice.

Androgenetic alopecia is the most common type of alopecia, and it affects humans of both genders. Finasteride is a type II selective 5α-reductase inhibitor that is administered orally to treat androgenetic alopecia and benign prostatic hyperplasia in human males. However, its effect on the vital organs of females is unknown. This study was designed to investigate the effects of finasteride on the vital organs such as liver, kidney, and heart of female mice. To study the prospective effects of finasteride, female mice were orally administered two doses of finasteride (0.5 and 1.5 mg/kg) once daily for 35 days, and serum levels of various biochemical parameters and histopathology of various organs were examined. The results showed that serum levels of alkaline phosphatase were significantly increased by both high- and low-dose finasteride, whereas cholesterol was significantly increased by the high dose only. Creatine kinase was significantly increased by the high and low doses, whereas glucose was significantly decreased by both doses. Histopathological analysis and DNA damage assays showed that finasteride has adverse effects within both the short and the long periods in female mice. In addition, the proapoptotic genes Bax and caspase-3 were significantly increased by high dose finasteride, whereas the antiapoptotic gene Bcl-2 was significantly decreased by the low and high doses. In conclusion, finasteride is not currently approved for therapeutic use in females, and the findings in this study suggest caution in any future consideration of such use.

Repeated finasteride administration induces depression-like behavior in adult male rats.

The enzyme 5α-Reductase (5α-R) catalyzes the formation of dihydrotestosterone, which is involved in male pattern hair loss and benign prostatic hyperplasia. Finasteride inhibits 5α-R and is used to treat both these conditions. Several clinical studies show that chronic finasteride treatment induces persistent depression, suicidal thoughts, and cognitive impairment. The neural mechanisms underlying these effects of finasteride are not known and it is imperative that an animal model that mimics the clinical neuropsychiatric effects of finasteride is developed. Accordingly, we evaluated the behavioral effects of acute and repeated finasteride administration. Two months old male Wistar rats were administered with either vehicle (hydroxypropyl-β-cyclodextrin) or different doses of finasteride, subcutaneously, either acutely (30 min or 2 h) or for 1, 3, and 6 days (one dose per day). Behavioral despair and motivational behavior were evaluated in the forced swim test (FST) and splash test, respectively. FST and splash test were video-recorded and analyzed offline. Finasteride did not show any effects in the acute, one day or three days studies in the FST. However, repeated finasteride administration for 6 days significantly increased the immobility time. In the splash test, finasteride (100 mg/kg) administration increased the latency to groom and decreased the grooming duration implying lack of motivation in the three-day study. In the six-day study, latency to groom was significantly increased by the 100 mg/Kg dose. Further, a significant dose dependent decrease in the grooming duration was observed. In summary, our results indicate that repeated finasteride administration induces depression-like behavior in rats. This study provides the evidence that an animal model of finasteride-induced depression is feasible to investigate the cellular and molecular mechanisms, and the pharmacology underlying the neuropsychiatric effects of finasteride. Further, these results provide insights into the potential involvement of neurosteroids in depression and will lead to the development of novel therapeutics for its treatment.

A Review of the FAERS Data on 5-Alpha Reductase Inhibitors: Implications for Postfinasteride Syndrome

ObjectiveTo quantify reports made to the Food and Drug Administration Adverse Event Reporting System (FAERS), create a demographic of patient reports, and examine the cluster of symptoms to correlate consistency of postfinasteride syndrome (PFS) complaints. PFS is a provisional diagnosis encompassing a cluster of sexual, physical, and psychological and/or neurologic symptoms associated with 5-alpha reductase inhibitor use that emerge or continue after discontinuation of medication. Materials and MethodsFAERS dataset of 5-alpha reductase inhibitors from April 2011 to October 2014 was obtained. Each FAERS report had 16 categories for completion, but not every report was fully completed. Statistical analysis compared variables of interest between the 2 doses of finasteride (1 mg vs 5 mg). ResultsFrom FAERS, 2048 monotherapy cases were identified: 1581 of finasteride 1 mg, 240 of finasteride 5 mg, and 226 of unreported doses. Possibly related to labeling changes, from 2011 to 2014, there was a significant increase in adverse events (AEs) reported involving 1 mg dosing. Finasteride use was reported with many sexual AEs including diminished libido, erectile dysfunction, and ejaculatory complaints. Other common AEs included dermatologic, metabolic, and psychological and/or neurologic complaints. There were more AE reports with the 1 mg dose than the 5 mg dose. One case of dutasteride reported back pain, not generally attributed to PFS. ConclusionFAERS data suggests that finasteride exposure is reported with a diverse collection of symptoms, particularly in younger men on 1 mg dosage compared to older men on 5 mg. Many of these complaints fall well out of the realm of previously established AEs from long-term controlled studies.

The 5-alpha reductase inhibitor finasteride reduces dyskinesia in a rat model of Parkinson's disease

Levodopa-induced dyskinesia (LID) is a disabling motor complication occurring in Parkinson's disease patients (PD) after long-term l-DOPA treatment. Although its etiology remains unclear, there is accumulating evidence that LID relies on an excessive dopamine receptor transmission, particularly at the downstream signaling of D1 receptors. We previously reported that the pharmacological blockade of 5-alpha reductase (5AR), the rate limiting enzyme in neurosteroids synthesis, rescued a number of behavioral aberrations induced by D1 receptor-selective and non-selective agonists, without inducing extrapyramidal symptoms. Thus, the present study was designed to verify whether the 5AR inhibitor finasteride (FIN) may counteract the dyskinesias induced by dopaminergic agonists in 6-hydroxydopamine (6-OHDA)-lesioned rats. First, we assessed the acute and chronic effect of different doses of FIN (30–60mg/kg) on LID, in male 6-OHDA-lesioned dyskinetic rats. Thereafter, to fully characterize the therapeutic potential of FIN on LID and its impact on l-DOPA efficacy, we assessed abnormal involuntary movements and forelimb use in hemiparkinsonian male rats chronically injected with FIN (30–60mg/kg/24days) either prior to- or concomitant with l-DOPA administration. In addition, to investigate whether the impact of FIN on LID may be ascribed to a modulation of the D1- or D2/D3-receptor function, dyskinesias were assessed in l-DOPA-primed 6-OHDA-lesioned rats that received FIN in combination with selective direct dopaminergic agonists. Finally, we set to investigate whether FIN may produce similar effect in female hemiparkinsonian rats, as seen in males.The results indicated that FIN administrations significantly dampened LID in all tested treatment regimens, without interfering with the ability of l-DOPA to ameliorate forelimb use in the stepping test. The antidyskinetic effect appears to be due to modulation of both D1- and D2/D3-receptor function, as FIN also reduced abnormal involuntary movements induced by the selective D1 receptor agonist SKF-82958 and the D2/D3 receptor agonist ropinirole. Significant dampening of LID was also observed in female rats, although only at the higher tested dose.Clinical investigations are warranted to assess whether similar protection from dyskinesia is seen in PD patients.

The effect of finasteride on anxiety in rats

Introduction: The traditional neurobiological concept of the etiology of anxiety disorders is based on the monoamine hypothesis, which suggests that mood disorders are caused by a deficiency in serotonin or noradrenaline transmission at functionally important receptors in the brain. Recent studies have provided strong evidence that gamma-aminobutyric acid (GABA) is involved in the pathophysiology of the anxiety as well. By blocking 5α-reductase in the brain, finasteride (FIN) inhibits the synthesis of allopregnanolone (ALLO) and tetrahydrodeoxy-corticosterone (THDOC) in a dose-dependent manner and redirects progesterone to alternative metabolic pathways, the effects that change GABAergic transmission and affect the emotional state. Aim: The aim of this study was to investigate the effect of finasteride as GABAergic transmission modulator, on anxiety in rats. Materials and methods: Male Wistar rats were divided into the groups: 1. control treated with 2-hydroxypropyl-β-cyclodextrin; 2. finasteride-treated, FIN (150 mg/kg). Daily doses of FIN (50 mg/kg) were administered intraperitoneally during three days. The level of anxiety was measured 24 hours after the administration of the last dose of FIN using elevated plus maze and light-dark test. Results: In the elevated plus maze, the total time spent in the open arms was not significantly different in FIN compared to control group (p > 0.05). In addition, there was no significant difference in the number of crossings from one arm to the other via the central platform in FIN vs. control group (p > 0.05). In the light-dark test, the time that animals, from FIN group spent in the light part of the box, was significantly lower compared to the same parameter recorded in animals from the control group (p < 0.05). Conclusion: Finasteride exerts anxiogenic effects in rats, dominantly causing bright space anxiety-like behavior. Finasteride has no significant effect on the open space anxiety-like behavior.

A Population-Based Nested Case-Control Study in Taiwan: Use of 5α-Reductase Inhibitors Did Not Decrease Prostate Cancer Risk in Patients with Benign Prostate Hyperplasia

5α-Reductase inhibitors (5ARIs) are commonly used to treat benign prostate hyperplasia (BPH) by blocking the conversion of testosterone into the more potent dihydrotestosterone. This study explored a possible association between the use of the 5ARIs finasteride and dutasteride and the subsequent risk of prostate cancer or other cancers. We analyzed data from the Taiwanese National Health Insurance system. In a BPH cohort, we identified 1,489 patients with cancer and included them in our study group. For the control group, 3 patients without cancer were frequency matched with each BPH case for age, BPH diagnosis year, index year, and month. Information regarding past 5ARI use was obtained from the Taiwanese National Health Insurance Research Database (NHIRD). Multivariate logistic regression analysis was conducted, and odds ratio (OR) and 95% confidence interval (CI) were estimated. Finasteride use marginally increased the incidence of prostate and overall cancer at a level of statistical significance (prostate cancer: OR = 1.90; 95% CI: 1.00-3.59; overall cancer: OR = 1.51; 95% CI: 1.00-2.28). Dutasteride use significantly increased kidney cancer risk (OR = 9.68, 95% CI: 1.17-80.0). Dosage analysis showed that lower doses of finasteride were associated with higher overall and prostate cancer risks. The major limitation is the lack of important data in the NHIRD, such as prostate cancer histologic grades, smoking habits, alcohol consumption, body mass index, socioeconomic status, and family history of cancer. This population-based nested case-control study suggested that finasteride use may increase prostate and overall cancer risks for patients with BPH. The effects were more prominent for patients using lower doses of finasteride.

Effect of 1‐mg Dose of Finasteride on Spermatogenesis and Pregnancy

Effect of 1‐mg Dose of Finasteride on Spermatogenesis and Pregnancy

Abstract B97: Combination chemoprevention and underlying mechanisms of finasteride with NSAIDs using in vitro and in vivo models (Pten-/-) for prostate cancer

Abstract B97 Background The Prostate Cancer Prevention Trial (PCPT) in a total of 1,626 men demonstrated that finasteride, a 5α reductase inhibitor reduces prostate cancer risk by 24.8%, and however, it was associated with a risk of small increase in high-Gleason grade tumors. This suggests that although finasteride is a potential chemopreventive agent, prostate cancer risk factors are not limited its target. To enhance the efficacy of finasteride, earlier studies have successfully used the combination with flutamide for the treatment of advanced disease. Based on our successful attempts in testing the chemopreventive effects of NSAIDs in combination against prostate cancer, in this study, we tested the efficacy of finasteride with anti-inflammatory agents at low doses in preclinical models to synergistically decrease prostate cancer incidence. Methods To accomplish our goals, we examined the effects of finasteride individually and in combination with celecoxib or aspirin using in vitro and in vivo models. We used murine prostate cancer cells (CaP8) deleted for Pten-/- and human benign prostate hyperplastic epithelial cells (BPH1). The cells were pretreated for 24 h with testosterone before incubating with different doses of finasteride (15μM) or aspirin (40μM) or celecoxib (40μM) individually and in combination (half of each of the single dose) for 48 h. Effect on cell growth, cell cycle, apoptosis, molecular targets AR, AKT, Cyclin D1, COX-2 and serum PGE2 levels were analyzed with MTT, flow cytometry, Western blot and ELISA assays. To determine in vivo efficacy, four week old PTEN/KO mice (an immune-competent, orthotopic model) were administered (n=5/group) orally with finasteride (15mg/kg bw) or celecoxib (200 mg/kg bw) or aspirin (200 mg/kg bw) individually or in combinations with half of the single dose for a period of six weeks. Histopathological analysis of the DL prostate tissues was performed to determine the effect on the incidence of mPIN or adenocarcinoma stages. Specific immunohistochemical staining was performed to detect the molecular targets. Results Findings from MTT assays showed inhibition of CaP8 cell (Pten-/-) growth by 56% (P&amp;lt;0.001) with finasteride in combination with aspirin in contrast to the effect (32%) exerted by finasteride alone. A similar effect (53%) was observed in celecoxib treated cells. Cell cycle analysis revealed G1 arrest with a decline in the “S” phase in all the treatments. Human BPH1 cells showed a significant inhibitory effect (65%) with finasteride in combination with aspirin, in contrast to the effect (25%) with finasteride alone. Histological determination of tumor incidence of mPIN showed a decrease by 5 fold in the group of mice that received dietary administration of finasteride in combination with aspirin or celecoxib after six 6 weeks in contrast to the mice that received finastride or aspirin alone (P&amp;lt;0.001). Serum levels of PGE2 were reduced significantly in the finasteride and celecoxib combination group. Significance changes due to the treatment effect on tumor incidence and molecular targets will be discussed. Conclusion Finasteride in combination with anti-inflammatory agents, aspirin or celecoxib at low doses, synergistically prevents prostate cancer in preclinical models. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B97.

Prostate cancer update: 2007

PURPOSE OF REVIEW The present review highlights the year's most important developments in the risk assessment, diagnosis, and treatment of prostate cancer. RECENT FINDINGS Recent research has helped define the prognostic importance of incorporating tertiary Gleason 5 pattern into the Gleason sum as well as interpretation of prostate-specific antigen levels when patients are being treated with low doses of finasteride. More data have emerged on the benefits of active treatment in elderly men newly diagnosed with localized prostate cancer. Particular subgroups of high-risk postprostatectomy patients (low postsurgical prostate-specific antigen level, positive surgical margins) may benefit from adjuvant radiotherapy. For salvage radiotherapy, the first comprehensive nomogram has been developed. Further data is emerging on the cardiovascular risks associated with androgen deprivation therapy even when administered for shorter treatment durations in conjunction with definitive local therapy. In addition, androgen deprivation therapy may be associated with earlier incidence of fatal cardiovascular events. For advanced prostate cancer, the first prospective trial defining taxane-resistant prostate cancer is described. SUMMARY The data of the present year have important implications in the diagnosis and management of prostate cancer by urologists, radiation oncologists, and medical oncologists.

Studies on Neurosteroids XXV. Influence of a 5.ALPHA.-Reductase Inhibitor, Finasteride, on Rat Brain Neurosteroid Levels and Metabolism

In this study, we examined the influence of finasteride (FIN), a 5alpha-reductase inhibitor, on the brain levels and metabolism of neurosteroids [allopregnanolone (AP), 3alpha-dihydroprogesterone (3alpha-DHP), progesterone (PROG), 20alpha-dihydroprogesterone and 11-deoxycorticosterone (DOC)] in rats exposed to immobilization stress. For this purpose, the sensitive, reproducible and accurate liquid chromatography-electrospray ionization-tandem mass spectrometric (LC-ESI-MS/MS) methods that enable the quantification of trace amounts of brain neurosteroids were first developed. The animal study using these methods demonstrated that FIN dose-dependently inhibits the stress-induced elevation of the brain AP, a potent positive modulator of the gamma-aminobutyric acid (GABA) type A receptors, and a 10 mg/kg dose of FIN can almost completely deplete AP in the brains. The study also found that the 20alpha-reduction of PROG is enhanced when its 5alpha-reduction pathway is inhibited in the brains. No change was found in the brain levels of 3alpha-DHP, another GABAergic neurosteroid, and DOC by the administration of FIN.

Higher Dose of Finasteride Improves Female Hair Loss

Higher Dose of Finasteride Improves Female Hair Loss

Proscar and propecia--a therapeutic perspective.

The initial observation that the prostate could convert testosterone to dihydrotestosterone (DHT) (1), e.g. contained 5 -reductase activity, was the first of a long succession of pieces of evidence that DHT might be important in the pathogenesis of benign prostatic hyperplasia (BPH). In 1980 it was hypothesized that: “Treatment directed at inhibiting 5 reductase activity (and consequently dihydrotestosterone formation). . . might inhibit further prostatic growth and/or induce regression of the prostate without causing impotence or other manifestations of hypogonadism” (2). This hypothesis was consistent with observations in a group of patients with a genetic deficiency of 5 -reductase who had, among other phenotypic abnormalities, small prostates (3). A few years later it was demonstrated that the oral administration of a 5 -reductase inhibitor prevented the testosteronemotivated increase in prostate size and weight in castrated dogs (4). Although BPH in dogs is an imperfect model for BPH in humans, it is probable that this proof of principle served as the impetus for human studies, which demonstrated the convincing efficacy of this drug for BPH (5, 6) and led to its (finasteride 5 mg, Proscar) approval for use by the Federal Drug Administration. Two years after (1994) the approval of Proscar for BPH, a trial began to determine whether it could decrease the incidence of prostate cancer; the subjects were men 55 yr of age and older. The major result of the trial, a decrease in the incidence of low-grade prostate cancers accompanied by an absolute and relative increase in high-grade prostate cancers (Table 1), was surprising and led to discontinuation of the trial before its planned ending (7). The New England Journal of Medicine (NEJM) believed the results of the study to be of sufficient import to release them weeks before they appeared in print and to warrant the publication of both an accompanying editorial (8) and a perspective (9). The accompanying editorial by Scardino (8) concluded that Proscar probably should not be used for the prevention of prostate cancer, but that, based on his view of its risk to benefit ratio, it remained reasonable to use it for the treatment of BPH. Unlike Scardino, the authors of the article refrained from making specific recommendations on the use or nonuse of the drug. For a variety of reasons, the interpretation of the data is moderately contentious, as attested to by a series of letters in the NEJM (10–16) in October 2003, and a “News” article in the Journal of the National Cancer Institute (JNCI) (17) that swiftly followed the release of the results of the study. Although the issue of using Proscar to treat BPH has been addressed, there remains the question of how to advise patients who take Propecia (finasteride, 1 mg) for the treatment of baldness. This concern was not raised in the article itself, in the NEJM editorial, in the discussion in the JNCI, or in the correspondence in the October issue of the NEJM. This is a most significant oversight because the effects of 1 and 5 mg of finasteride result in more or less equal changes in serum DHT and testosterone (Refs. 18 and 19 and Fig. 1A), prostatic DHT and testosterone (Ref. 19 Fig. 1B), and scalp DHT (Refs. 18 and 20 and Fig. 1C). A subsequent study (21) confirmed the lack of difference in blood, but found a significantly greater fall in prostate DHT for the 5-mg than the 1-mg dose (placebo, 18.6 nmol/kg; 1 mg, 3.8 nmol/kg; 5 mg, 1.0 nmol/ kg; P 0.049 between the two doses of finasteride) after 6–8 wk of treatment. It is important to recall that these hormonal surrogates for clinical efficacy formed the most important basis for the early dose-ranging studies of this drug, which, in turn, led to the choice of the doses to be used in the large clinical trials addressing efficacy. The defining large trial (5) assessed efficacy in almost 900 men given placebo or 1 or 5 mg finasteride. At the end of 1 yr, 5 mg finasteride improved total urinary-symptom scores compared with placebo, whereas 1 mg did not. However, there was no difference between the doses in their effect on either prostate size or maximum urinary flow rate. Both were equally better than placebo. Thus, at least for purposes of this discussion, it is both conservative and reasonable to presume that the long-

Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial

Objectives To evaluate the efficacy and tolerability of the selective alpha 1-adrenergic antagonist doxazosin and the 5-alpha-reductase inhibitor finasteride, alone and in combination, for the symptomatic treatment of benign prostatic hyperplasia. Methods In a prospective, double-blind, placebo-controlled trial, 1095 men aged 50 to 80 years were randomized to treatment for 52 weeks with doxazosin, finasteride, the combination of doxazosin and finasteride, or placebo. The dose of finasteride (or its matched placebo) was 5 mg/day. Doxazosin (or its matched placebo) was initiated at 1 mg/day, and titrated up to a maximum of 8 mg/day over approximately 10 weeks according to the response of the maximal urinary flow rate (Qmax) and International Prostate Symptom Score (IPSS). The IPSS and Qmax were assessed at baseline and at weeks 10, 14, 26, 39, and 52 or at the endpoint. Results An intent-to-treat analysis of 1007 men showed doxazosin and doxazosin plus finasteride combination therapy produced statistically significant improvements in total IPSS and Qmax compared with placebo and finasteride alone ( P <0.05). Finasteride alone was not significantly different statistically from placebo with respect to total IPSS and Qmax. All treatments were generally well tolerated. Conclusions Doxazosin was effective in improving urinary symptoms and urinary flow rate in men with benign prostatic hyperplasia, and was more effective than finasteride alone or placebo. The addition of finasteride did not provide further benefit to that achieved with doxazosin alone.

The effect of finasteride in men with benign prostatic hyperplasia

Background. Benign prostatic hyperplasia is a progressive, androgen-dependent disease resulting in enlargement of the prostate gland and urinary obstruction. Preventing the conversion of testosterone to its tissue-active form, dihydrotestosterone, by inhibiting the enzyme 5α-reductase could decrease the action of androgens in their target tissues; in the prostate the result might be a decrease in prostatic hyperplasia and therefore in symptoms of urinary obstruction. Methods. In a double-blind study, we evaluated the effect of two doses offinasteride (1 mg and 5 mg) and placebo, each given once daily for 12 months, in 895 men with prostatic hyperplasia. Urinary symptoms, urinary flow, prostatic volume, and serum concentrations of dihydrotestosterone and prostate-specific antigen were determined periodically during the treatment period. Results. As compared with the men in the placebo group, the men treated with 5 mg of finasteride per day had a significant decrease in total urinary-symptom scores (P <0.001), an increase of 1.6 ml per second (22 percent, P <0.001) in the maximal urinary-flow rate, and a 19 percent decrease in prostatic volume (P <0.001). The men treated with 1 mg of finasteride per day did not have a significant decrease in total urinary-symptom scores, but had an increase of 1.4 ml per second (23 percent) in the maximal urinary-flow rate, and an 18 percent decrease in prostatic volume. The men given placebo had no changes in total urinary-symptom scores, an increase of 0.2 ml per second (8 percent) in the maximal urinary-flow rate, and a 3 percent decrease in prostatic volume. The frequency of adverse effects in the three groups was similar, except for a higher incidence of decreased libido, impotence, and ejaculatory disorders in the finasteride-treated groups. Conclusions. The treatment of benign prostatic hyperplasia with 5 mg of finasteride per day results in a significant decrease in symptoms of obstruction, an increase in urinary flow, and a decrease in prostatic volume, but at a slightly increased risk of sexual dysfunction.

The effects of finasteride on scalp skin and serum androgen levels in men with androgenetic alopecia

Data suggest that androgenetic alopecia is a process dependent on dihydrotestosterone (DHT) and type 2 5alpha-reductase. Finasteride is a type 2 5alpha-reductase inhibitor that has been shown to slow further hair loss and improve hair growth in men with androgenetic alopecia. We attempted to determine the effect of finasteride on scalp skin and serum androgens. Men with androgenetic alopecia (N = 249) underwent scalp biopsies before and after receiving 0.01, 0.05, 0.2, 1, or 5 mg daily of finasteride or placebo for 42 days. Scalp skin DHT levels declined significantly by 13.0% with placebo and by 14.9%, 61.6%, 56. 5%, 64.1%, and 69.4% with 0.01, 0.05, 0.2, 1, and 5 mg doses of finasteride, respectively. Serum DHT levels declined significantly (P <.001) by 49.5%, 68.6%, 71.4%, and 72.2% in the 0.05, 0.2, 1, and 5 mg finasteride treatment groups, respectively. In this study, doses of finasteride as low as 0.2 mg per day maximally decreased both scalp skin and serum DHT levels. These data support the rationale used to conduct clinical trials in men with male pattern hair loss at doses of finasteride between 0.2 and 5 mg.

Effects of APGW-AMID on [Ca] in rat pheochromocytoma PC12 cells

Levodopa-induced dyskinesia (LID) is a disabling motor complication occurring in Parkinson's disease patients (PD) after long-term l-DOPA treatment. Although its etiology remains unclear, there is accumulating evidence that LID relies on an excessive dopamine receptor transmission, particularly at the downstream signaling of D1 receptors. We previously reported that the pharmacological blockade of 5-alpha reductase (5AR), the rate limiting enzyme in neurosteroids synthesis, rescued a number of behavioral aberrations induced by D1 receptor-selective and non-selective agonists, without inducing extrapyramidal symptoms. Thus, the present study was designed to verify whether the 5AR inhibitor finasteride (FIN) may counteract the dyskinesias induced by dopaminergic agonists in 6-hydroxydopamine (6-OHDA)-lesioned rats. First, we assessed the acute and chronic effect of different doses of FIN (30–60 mg/kg) on LID, in male 6-OHDA-lesioned dyskinetic rats. Thereafter, to fully characterize the therapeutic potential of FIN on LID and its impact on l-DOPA efficacy, we assessed abnormal involuntary movements and forelimb use in hemiparkinsonian male rats chronically injected with FIN (30–60 mg/kg/24 days) either prior to- or concomitant with l-DOPA administration. In addition, to investigate whether the impact of FIN on LID may be ascribed to a modulation of the D1- or D2/D3-receptor function, dyskinesias were assessed in l-DOPA-primed 6-OHDA-lesioned rats that received FIN in combination with selective direct dopaminergic agonists. Finally, we set to investigate whether FIN may produce similar effect in female hemiparkinsonian rats, as seen in males.The results indicated that FIN administrations significantly dampened LID in all tested treatment regimens, without interfering with the ability of l-DOPA to ameliorate forelimb use in the stepping test. The antidyskinetic effect appears to be due to modulation of both D1- and D2/D3-receptor function, as FIN also reduced abnormal involuntary movements induced by the selective D1 receptor agonist SKF-82958 and the D2/D3 receptor agonist ropinirole. Significant dampening of LID was also observed in female rats, although only at the higher tested dose.Clinical investigations are warranted to assess whether similar protection from dyskinesia is seen in PD patients.