Glenn J. Gormley

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 5 alpha-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 of finasteride (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 less than 0.001), an increase of 1.6 ml per second (22 percent, P less than 0.001) in the maximal urinary-flow rate, and a 19 percent decrease in prostatic volume (P less than 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 efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia

BACKGROUND Men with benign prostatic hyperplasia can be treated with alpha 1-adrenergic-antagonist drugs that relax prostatic smooth muscle or with drugs that inhibit 5 alpha-reductase and therefore reduce tissue androgen concentrations. However, the effects of the two types of drugs have not been compared. METHODS We compared the safety and efficacy of placebo, terazosin (10 mg daily), finasteride (5 mg daily), and the combination of both drugs in 1229 men with benign prostatic hyperplasia. American Urological Association symptom scores and peak urinary-flow rates were determined at base line and periodically for one year. RESULTS The mean changes from base line in the symptom scores in the placebo, finasteride, terazosin, and combination-therapy groups at one year were decreases of 2.6, 3.2, 6.1, and 6.2 points, respectively (P<0.001 for the comparisons of both terazosin and combination therapy with finasteride and with placebo). The mean changes at one year in the peak urinary-flow rates were increases of 1.4, 1.6, 2.7, and 3.2 ml per second, respectively (P<0.001 for the comparisons of both terazosin and combination therapy with finasteride and with placebo). Finasteride had no more effect on either measure than placebo. In the placebo group, 1.6 percent of the men discontinued the study because of adverse effects, as did 4.8 to 7.8 percent of the men in the other three groups. CONCLUSIONS In men with benign prostatic hyperplasia, terazosin was effective therapy, whereas finasteride was not, and the combination of terazosin and finasteride was no more effective than terazosin alone.

Oral Montelukast Compared with Inhaled Salmeterol To Prevent Exercise-Induced Bronchoconstriction: A Randomized, Double-Blind Trial

Exercise-induced bronchoconstriction is common in patients with chronic asthma (1). Airway cooling or desiccation during exercise may trigger activation of mast cells and release of such mediators as histamine and cysteinyl leukotrienes, resulting in bronchospasm (1, 2). Cysteinyl leukotrienes (LTC4, LTD4, and LTE4), synthesized from arachidonic acid through the 5-lipoxygenase pathway, are potent bronchoconstrictors, with an effect greater than 1000 times that of histamine (3-5). Several researchers have demonstrated an increase in urinary concentrations of LTE4 after exercise (6, 7). Prophylaxis against exercise-induced bronchoconstriction with inhaled mast cell-stabilizing agents and short-acting -agonists must be administered 15 to 30 minutes before exercise. The long-acting inhaled -agonist salmeterol protects against exercise-induced bronchoconstriction for up to 12 hours, thus providing more flexibility in the dosing schedule for active patients with asthma (8, 9). However, in some patients, tolerance to salmeterol develops with long-term use, and the level of bronchoprotection diminishes by 6 to 9 hours (10-12). Montelukast sodium, a leukotriene receptor antagonist, is a potent oral medication for the treatment of asthma. The leukotriene receptor antagonists have demonstrated a significant bronchoprotective effect with exercise after one or two doses (13, 14). In patients with exercise-induced bronchoconstriction, short-term treatment with montelukast (Singulair, Merck & Co., Inc., Whitehouse Station, New Jersey) given once daily diminished the postexercise response, as described by the area under the FEV1 time curve (AUC0-60 min), by more than 50%, even at the end of the dosing interval (20 to 24 hours after administration) (15, 16). Furthermore, tolerance to the bronchoprotective effects of montelukast did not occur with long-term administration (17). We sought to test the hypothesis that the bronchoprotective effects of montelukast were greater than those of salmeterol in patients with chronic asthma who experienced exercise-induced bronchoconstriction. Methods Design We conducted a randomized, parallel-group study consisting of a 2-week, single-blind placebo baseline period followed by an 8-week, double-blind treatment period with montelukast sodium (10-mg tablet taken orally once in the evening) or inhaled salmeterol (50-g aerosol formulation [2 puffs] taken twice daily). Seventeen clinical study sites participated in the trial. To mask formulation differences, a double-dummy treatment regimen was used. Each patient received one tablet daily (active agent or matching placebo) or one inhaler twice daily (active agent or matching placebo) for both the single-blind and double-blind treatment periods. A computer-generated allocation schedule with a blocking factor of 4 was produced by the statistician. Each center was given a block of allocation numbers that were assigned sequentially to consecutive randomly assigned patients. Spirometric measurements were obtained before and after standardized exercise challenges at the beginning and end of the baseline period, within the first 3 days of the double-blind treatment period, and at weeks 4 and 8 of the treatment period. Additional measurements were physical examination, vital signs, electrocardiography, chest radiography, and laboratory tests (hematology, chemistry profile, and urinalysis). At each visit, all spontaneously reported adverse events were recorded. The protocol was approved by the institutional review board of each site, and written informed consent was obtained from each patient. Inclusion Criteria Male and female patients 15 to 45 years of age with a history of chronic asthma were enrolled. All patients had an FEV1 of at least 65% of the predicted value at rest and a decrease in FEV1 of at least 20% after a standardized exercise challenge on two occasions during the baseline period. All patients had been nonsmokers for at least 1 year and had a smoking history of less than 15 pack-years. Exclusion Criteria Persons who had upper respiratory infection or exacerbation of asthma requiring emergency care within the past month or were hospitalized for asthma in the past 3 months were excluded. Use of oral or inhaled corticosteroids, theophylline, cromolyn sodium, nedocromil, oral -agonist, and long-acting antihistamines was prohibited before and during the study. Use of inhaled albuterol for symptomatic relief of asthma and use of short-acting antihistamines were permitted. Evaluations A standard spirometer (Puritan-Bennett PB100/PB110, Puritan-Bennett, Wilmington, Massachusetts) was used to obtain all spirometric measurements according to American Thoracic Society standard criteria (18). Patients had to have discontinued use of inhaled short-acting -agonists for 6 hours before the visit. Exercise testing was done in the early afternoon near the trough of effect for both drugs according to a method described elsewhere (17). Measurements were obtained 20 and 5 minutes before exercise (prechallenge period). Exercise challenge was performed only if the average FEV1 in the prechallenge period was greater than 65% of predicted; otherwise, the test was rescheduled. Patients exercised on a treadmill while inhaling room temperature, compressed, dry air. During the first test, the speed and gradient of the treadmill were adjusted to achieve 80% to 90% of the patients age-predicted maximum heart rate. The settings were maintained for a total of 6 minutes; the same settings were used for future tests. This level of exercise has been used to quantify the level of bronchoconstriction associated with regular exercise (19). Serial spirometric measurements were obtained at 0, 5, 10, 15, 30, 45, and 60 minutes after exercise (postexercise period). Additional measurements were carried out at 15-minute intervals for up to 90 minutes if the patients FEV1 had not returned to within 5% of the prechallenge value by 60 minutes. If the patients FEV1 did not return to the prechallenge value by 90 minutes after exercise, a rescue dose of inhaled -agonist was administered at the discretion of the study investigator. Statistical Analysis An all-patients-treated analysis, which included patients with a baseline visit and at least one post-randomization visit, was performed. The change from baseline in the maximal percentage decrease in FEV1 after exercise at the end of 8 weeks of treatment was the primary end point. Analysis of variance was used to compare the two treatment groups. The analysis of variance model included terms for treatment, center, and the interaction of treatment and center. Ninety-five percent CIs for within-group means and the difference between groups were constructed to assess the magnitude of the treatment effect. Analysis of variance on the ranked data was used to analyze percentage inhibition for all end points. In the event of early termination of the exercise challenge because of administration of rescue medication, the largest percentage decrease in FEV1 achieved before administration of rescue medication was used in the analysis. Secondary end points were change from baseline for maximal percentage decrease in FEV1 at days 1 to 3 and week 4, the time required after maximal decrease in FEV1 to return within 5% of prechallenge values (time to recovery), and the AUC0-60 min at all visits. The mean of the 20- and 5-minute prechallenge measurements was used as the pre-exercise FEV1 value. If a patient required rescue with inhaled -agonist during the postexercise period, the last recorded FEV1 value was used and carried forward for all subsequent readings and 100 minutes was entered for the end point of time to recovery. The AUC0-60 min was calculated by using the trapezoidal method. If a patients FEV1 did not decrease below 95% of the prechallenge value, the time to recovery was assigned a value of zero. The persistence of effect over time was assessed by using a repeated-measures fixed-effects model with terms for center, treatment group, time, and the interaction of treatment group and time to calculate the rate of change over the treatment period. Persistence of effect was defined as a slope of zero. The magnitude of the slopes for each treatment group was estimated, and 95% CIs were calculated. An overall test of equal slopes between the treatment groups was examined, and a 95% CI on the difference in slopes between treatment groups was provided. The number and percentage of patients requiring rescue medication during or at the end of the exercise test were summarized by treatment group at each time point. In addition, the number and percentage of patients whose decrease in FEV1 from pre-exercise levels was less than 10%, 10% to 20%, 20% to 40%, and greater than 40% were summarized by treatment group for each visit. The overall incidence of adverse events and laboratory abnormalities was assessed by using the Fisher exact test, and within-group changes in the number of laboratory abnormalities were assessed by using the McNemar test. Descriptive statistics were provided by treatment group for patient demographic characteristics, clinical characteristics, and baseline profile. The study was designed with a sample size of 160 patients (80 patients per treatment group) to have 95% power (two-sided test at =0.05) to detect a 7% difference in the mean change in maximal percentage decrease in FEV1 between treatments. All statistical analyses were performed by using SAS software, version 6 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Source Funding for this trial was provided by Merck & Co., Inc., Whitehouse Station, New Jersey. Personnel from Merck U.S. Human Health, Clinical Development department played a significant role in the design, conduct, and analysis of the trial. The trial was conducted in accordance with guidelines for clinical trials of investigational agents established by U.S. regulatory authorities. Results Pati

Invasive versus conservative strategies in unstable angina and non\NQ-wave myocardial infarction following treatment with tirofiban: rationale and study design of the international TACTICS-TIMI 18 trial ☆

Abstract In the management of unstable angina and non–Q-wave acute myocardial infarction (AMI), there is considerable debate regarding the use of invasive strategy versus conservative strategy. The Thrombolysis In Myocardial Infarction (TIMI) III B trial found similar clinical outcomes for the 2 strategies, but the Veterans Administration Non–Q-Wave Infarction Strategies in-Hospital trial found a higher mortality with the invasive strategy. Both these trials were conducted before platelet glycoprotein IIb/IIIa inhibition and coronary stenting, both of which improve clinical outcome. Thus, there is a need to reexamine the question of which management strategy is optimal in the current era of platelet glycoprotein IIb/IIIa inhibition and new coronary interventions. The Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS-TIMI 18) trial is an international, multicenter, randomized trial that is evaluating the clinical efficacy of early invasive and early conservative treatment strategies in patients with unstable angina or non–Q-wave AMI treated with tirofiban, heparin, and aspirin. Patients are randomized to an invasive strategy, involving cardiac catheterization within 4 to 48 hours and revascularization with angioplasty or bypass surgery if feasible, versus a conservative strategy, where patients are referred for catheterization only for recurrent pain at rest or provokable ischemia. The primary end point is death, MI, or rehospitalization for acute coronary syndromes through a 6-month follow-up. The trial is also testing the “troponin hypothesis,” that baseline troponins T and I will be useful in selecting an optimal management strategy.

Treatment with finasteride following radical prostatectomy for prostate cancer.

OBJECTIVES The objective of this study was to evaluate the effect of finasteride (10 mg/d) or placebo on serum prostate-specific antigen (PSA) and recurrence rates in men with detectable PSA levels after radical prostatectomy. METHODS A total of 120 men, 48 to 89 years old, previously treated with radical prostatectomy for prostate cancer within the past 10 years, with serum PSA levels between 0.6 and 10.0 ng/mL, with no evidence of skeletal metastasis on bone scan, and with no previous androgen deprivation therapy, were treated with 10 mg finasteride or placebo in a double-blind fashion for 12 months. After the first year, all patients were treated with finasteride for an additional 12 months. Primary endpoints were serum PSA levels and recurrence rates defined as positive bone scan or positive biopsy. RESULTS Patients treated with finasteride had a delayed increase in serum PSA compared with placebo of approximately 9 months in the first year and 14 months by the end of the second year. Patients with baseline PSA levels less then 1.0 ng/mL had no significant increase in serum PSA during the 2 years of treatment. Fewer recurrences were observed in the finasteride group, but these differences were not statistically significant. Finasteride was well tolerated, and side effects were balanced between treatment groups. CONCLUSIONS The results of this study indicate that treatment with finasteride delays but does not prevent the rise in serum PSA observed in untreated patients with detectable PSA levels after radical prostatectomy. The reduction in local and distant recurrences in the finasteride group suggests that the effect on PSA reflects a direct effect on tumor growth without affecting the initial response to subsequent hormonal therapy. These data require confirmation by studies that are longer and larger, focused on demonstrating significant differences in progression rates and survival before the use of finasteride can be considered as an option for men with detectable PSA levels after radical prostatectomy.

Multicenter, randomized, double-blind, placebo controlled study to investigate the effect of finasteride (MK-906) on stage D prostate cancer.

A total of 28 untreated patients with asymptomatic, stage D prostate cancer was randomized in a double-blinded fashion to receive finasteride (10 mg. per day), a 5 alpha-reductase inhibitor or placebo. Patients were evaluated at 3-week intervals by rectal examination, and serum prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) levels, and at 6-week intervals by bone scan and transrectal ultrasound determinations of prostatic volume. Patients stopped the medication at week 6 at the discretion of the investigator when PSA levels increased from baseline. After 12 weeks all patients were reevaluated. Of the patients 13 received finasteride and 15 received placebo. The 2 groups did not differ statistically with respect to patient age, initial PSA and PAP level, or the extent of metastases on initial bone scan. A statistically significant decrease in the median percentage change from baseline in PSA at weeks 3 and 6 occurred in the finasteride group compared to the placebo group (-22.9% versus -2.9% and -15.1% versus +11.7%, respectively, p less than 0.05). Finasteride had no effect upon PAP, serum testosterone, prostatic volume or appearance of bone scans. A decrease in serum PSA in the finasteride treatment group suggests that finasteride exerts a minor effect in patients with prostate cancer. This effect does not approach that seen with medical or surgical castration yet because of the potency preserving feature and the lack of toxicity finasteride may warrant further study in the treatment of prostate cancer.

Alendronate Improves Bone Mineral Density in Elderly Women with Osteoporosis Residing in Long-Term Care Facilities: A Randomized, Double-Blind, Placebo-Controlled Trial

Context Although the prevalence of osteoporosis increases with advancing age, most therapeutic studies have focused on younger postmenopausal women. It is not known whether treatment is effective in elderly women. Contribution The efficacy and tolerability of alendronate in elderly female residents of long-term care facilities were tested in a 2-year randomized, double-blind, placebo-controlled study. Alendronate significantly increased bone mineral density and decreased bone turnover when compared with placebo in this elderly population. Side effects did not differ between treatment groups. Implications Elderly women with osteoporosis may benefit from alendronate therapy. The effect of this therapy on incidence of fractures or the optimum length of therapy cannot be determined from this study. The Editors Osteoporosis increases in prevalence with age and is very common in elderly women. The estimated prevalence of osteoporosis in community-dwelling elderly women aged 70 to 79 years is 55%; this rate increases to 73% among those older than 80 years of age (1). The prevalence in elderly female residents of long-term care facilities is even higher. One study (2) reported an 85% prevalence of osteoporosis at nursing home admission. A large survey of nursing home residents found a prevalence of 63.5% for women aged 65 to 74 years and 85.8% for women older than 85 years of age (3). Because most osteoporosis studies have focused on younger postmenopausal women and few studies have evaluated residents of long-term care facilities, we examined the efficacy and tolerability of alendronate for treating osteoporosis in elderly female residents of long-term care facilities. Methods This randomized, double-blind, placebo-controlled, 2-year study was conducted at 25 U.S. centers. Each center recruited ambulatory female residents 65 years of age or older who lived in local long-term care facilities, including skilled-care nursing homes and assisted-living centers, but not facilities that housed independent, community-dwelling elderly persons. Participants were required to have a bone mineral density (BMD) lower than a T-score of 2.0 at the posterioranterior lumbar spine or total hip. Women were excluded for the following: disorders of bone mineralization, 25-hydroxycholecalciferol level less than 25 nmol/L, untreated hyperthyroidism, recent major upper gastrointestinal mucosal erosive disease, or use of bone-active agents. The ethics committee for each site approved the study, and all patients gave informed consent. A total of 832 women consented to participate; the 327 women who met the inclusion and exclusion criteria were enrolled. Patients were randomly assigned (using a computer-generated allocation schedule) to receive alendronate, 10 mg/d (Fosamax, Merck & Co., Inc., Whitehouse Station, New Jersey), or matching placebo for 24 months. Patients also received vitamin D, 400 IU/d. Calcium carbonate (OsCal 500, SmithKlineBeecham Consumer Healthcare, Pittsburgh, Pennsylvania) was given to patients whose daily dietary calcium intake was less than 1500 mg. Bone mineral density of the hip and spine was measured by using dual-energy x-ray absorptiometry (Hologic, Waltham, Massachusetts) and was analyzed by a central quality assurance center (MDM, Waltham, Massachusetts). A central laboratory (Pacific Biometrics, Seattle, Washington) analyzed biochemical markers of bone formation (serum bone-specific alkaline phosphatase, measured by using Tandem-R Ostase kit, Hybritech, Inc., San Diego, California) and bone resorption (urinary N-telopeptide of type I collagen adjusted for urinary creatinine, measured by using Osteomark enzyme-linked immunoassay, Ostex International, Inc., Seattle, Washington). We also collected routine laboratory measures for safety (chemistry, hematology, and urinalysis) and information on the occurrence of clinical adverse experiences and clinical fractures. We used SAS software, version 6.12, for statistical analyses (SAS Institute, Inc., Cary, North Carolina). Baseline demographic characteristics of the two treatment groups were compared by using t-tests (for continuous data) and Fisher exact tests (for categorical data). Analysis of variance was used to compare BMD and biomarker end points between groups. Paired t-tests were used to compare outcomes against baseline values within treatment groups. An intention-to-treat approach was followed in the analyses of BMD end points (for missing data, the last postrandomization observation was carried forward to subsequent time points) and safety data. A per protocol approach was used for analysis of biomarkers. Sensitivity analyses were done separately for BMD and biomarker end points by using mixed models that accounted for the correlation between all available measurements of BMD (up to 12 for each participant) and biomarkers (up to 8 for each participant). Data points were not carried forward in these analyses. Treatment comparisons were made by using the appropriate contrasts from the interaction term for treatment test site visit (using the MIXED procedure [4]). Employees of Merck & Co., Inc., contributed to the protocol design, recruitment of investigators, and collection and analysis of data. Merck & Co., Inc., had committed to submitting the data for publication regardless of study outcome. Results Most patients were residents of continuing-care retirement communities (68%); others resided in retirement communities (12%), congregate-care facilities (8%), and other types of facilities (12%), including skilled-care nursing homes and residential-care facilities. The characteristics of each treatment group were similar at baseline. The mean age was 78.5 years (range, 65 to 91 years). Most patients (97%) were white. The mean BMD T-scores at the hip and spine ranged from 3.5 to 2.4. Fifty-five percent of patients had a history of fracture, 19% reported a history of upper gastrointestinal disorder at baseline, and 64% used either aspirin or a nonsteroidal anti-inflammatory drug during the study. Increases in BMD at all sites were significantly greater in the alendronate group than in the placebo group at all time points measured (Figure 1). Compared with placebo, alendronate produced significantly greater increases in BMD (24-month differences: posterioranterior spine, 4.4% [95% CI, 3.3% to 5.5%]; lateral lumbar spine, 5.7% [CI, 3.9% to 7.5%]; femoral neck, 3.4% [CI, 2.3% to 4.4%]; hip trochanter, 4.7% [CI, 3.4% to 6.0%]). The largest increases from baseline with alendronate occurred at the lateral lumbar spine (7.4% [CI, 6.1% to 8.7%]; absolute change, 0.039 g/cm2 [CI, 0.032 to 0.046 g/cm2]; P < 0.001) and the posterioranterior lumbar spine (6.3% [CI, 5.5% to 7.0%]; absolute change, 0.047 g/cm2 [CI, 0.042 to 0.053 g/cm2]; P < 0.001) at 24 months. Decreases in levels of bone-specific alkaline phosphatase and urinary N-telopeptide adjusted for urinary creatinine were significantly greater in alendronate recipients than in placebo recipients at all time points measured (P < 0.001) (Figure 2). The mixed-model analyses yielded similar results. Figure 1. Changes in bone mineral density ( BMD ). circles squares P P P P P Figure 2. Changes in biochemical markers of bone turnover. N circles squares P P P P P N More patients receiving placebo experienced a fracture during the study (11% of placebo recipients vs. 8% of alendronate recipients), but this finding was not statistically significant. Hip fracture occurred in 4 patients receiving placebo and 2 patients receiving alendronate. Overall, 13 fractures were reported in 13 patients receiving alendronate and 28 fractures were reported in 18 patients receiving placebo. In each group, the percentage of patients reporting any clinical adverse experience was the same (93%). The percentage of patients reporting any upper gastrointestinal adverse event did not significantly differ between groups (33% in the alendronate group vs. 35% in the placebo group), nor did the percentage of patients reporting serious upper gastrointestinal adverse events (0.6% for alendronate vs. 1.9% for placebo). Discussion In this study, alendronate significantly improved both hip and spine BMD in elderly female residents of long-term care facilities. These improvements were associated with the expected decreases in bone resorption. In addition, alendronate was generally well tolerated in this elderly cohort. Although several studies have documented improvements in BMD among community-dwelling postmenopausal women treated with alendronate, our study is the first to examine the efficacy of 10 mg of alendronate per day in elderly residents of long-term care facilities. Bone and colleagues (5) studied community-dwelling elderly women with osteoporosis (mean age, 71 years) and found a dose-related response of BMD with use of alendronate dosages as high as 5 mg/d. The improvements in BMD in our study indicate that even in elderly women, BMD significantly increases with alendronate. Furthermore, a woman who reaches age 65 years can on average expect to live to age 84, and women who survive to age 85 can expect to live to age 92 (6). Therefore, it would be clinically relevant and appropriate to treat these patients, even though they are elderly, with a medication that reduces fracture rates in 1 to 3 years. No bone loss occurred in the placebo group. This may have been due to adequate calcium intake and the use of vitamin D. Previous studies have shown that bone loss slows with calcium supplementation (7, 8) and that hip BMD increases and fracture rate decreases with use of vitamin D and calcium supplementation in elderly female residents of long-term care facilities (9). Our study showed that while use of calcium and vitamin D alone may help slow bone loss, additional therapy is required to substantially increase BMD. Establishing safety is important when any medication is given to elderly patients in long-term care settings. Previous clinical trials with

Long-term effects of finasteride on prostate tissue composition

OBJECTIVES To determine the long-term effects of finasteride treatment on prostate tissue composition; to relate these effects to clinical outcomes; and to test the hypothesis that finasteride exerts a selective or preferential action on the transition zone. METHODS Nineteen men with symptomatic benign prostatic hyperplasia (BPH) who completed a 6-month double-blind trial of finasteride were enrolled in a 24-month open-label extension study of drug responders. Magnetic resonance imaging and prostate biopsy for morphometric analysis were performed together 70 times: at baseline (n = 19), after treatment periods of intermediate duration (6 to 18 months, n = 32), and after long-term drug treatment (24 to 30 months, n = 19). At baseline, prostate volume averaged 51 cc, of which 57% was transition zone. RESULTS Decreases in symptom score, dihydrotestosterone and prostate-specific antigen levels, and prostate volume occurred at 6 months (P <0.01), stabilized, and were maintained without further long-term decreases. Prostate epithelium contracted progressively from baseline (19.2% tissue composition; 6.0-cc volume; 3.2 stroma/epithelial ratio) to intermediate (12.5%, 3.3 cc, and 5.6, respectively) to long-term treatment (6.4%, 2.0 cc, and 17.4, respectively, P <0.01 for all). Percent epithelial contraction was similar in the peripheral and transition zones (P = NS). The transition zone remained a relatively constant proportion (53% to 58%) of whole-prostate volume from baseline to long-term observation. CONCLUSIONS Long-term finasteride treatment (24 to 30 months) results in a marked involution of the prostate epithelium, which continues to progress for many months after clinical effects stabilize. The effect on the epithelium is similar in the peripheral and transition zones for both morphometric and volumetric changes. Progressive contraction of the prostate epithelium appears to constitute the underlying mechanism for sustained action of finasteride.

Clinical dose ranging studies with finasteride, a type 2 5α-reductase inhibitor, in men with male pattern hair loss

BACKGROUND Androgenetic alopecia is a common condition of adult men. Finasteride, a type 2 5alpha-reductase inhibitor, decreases the formation of dihydrotestosterone from testosterone. OBJECTIVE Two separate clinical studies were conducted to establish the optimal dose of finasteride in men with this condition. METHODS Men from 18 to 36 years of age with moderate vertex male pattern hair loss received finasteride 5, 1, 0.2, or 0.01 mg/day or placebo based on random assignment. Efficacy was determined by scalp hair counts, patient self-assessment, investigator assessment, and assessment of clinical photographs. Safety was assessed by clinical and laboratory measurements and by analysis of adverse experiences. RESULTS Efficacy was demonstrated for all end points for finasteride at doses of 0.2 mg/day or higher, with 1 and 5 mg demonstrating similar efficacy that was superior to lower doses. Efficacy of the 0.01 mg dose was similar to placebo. No significant safety issues were identified in the trials. CONCLUSION Finasteride 1 mg/day is the optimal dose for the treatment of men with male pattern hair loss and was subsequently identified for further clinical development.

Proscar: five-year experience

We assessed the long-term safety and efficacy of finasteride, an orally active 5 alpha-reductase inhibitor, in 2 previously reported groups of patients with symptomatic benign prostatic hyperplasia (BPH). Prostate volume was measured by magnetic resonance imaging, and the maximum urinary flow rate was assessed noninvasively. Symptoms were scored utilizing a patient self-administered symptom score questionnaire. Total symptom scores ranged from 0 (or asymptomatic) to 35 (severely symptomatic). After an initial double-blind period, the patients in study 1 were treated with 10 mg finasteride for 1 year and then switched to 5 mg finasteride for an additional 4 years, whereas patients in study 2 were treated with 5 mg finasteride for the entire 5 years. A total of 190 patients were randomized in the double-blind studies, 156 entered year 1 of the open extension and 70 patients completed 5 years of finasteride therapy. In both studies prostate volume was reduced from baseline by 30%, dihydrotestosterone was reduced by 72%, and the maximum urinary flow rate improved by approximately 1.5 ml/s. Prostate-specific antigen was decreased by approximately 50%. Finasteride was well tolerated; approximately 10% of patients reported sexual adverse experiences during the 5-year study period, which were considered drug related by the investigators. The incidence in reporting sexual adverse experiences did not increase with the increased duration of treatment: findings consistent with previous reports. In summary treatment of BPH with finasteride for 5 years inhibits the progression of the disease with an excellent safety profile and represents a low-risk medical option for the treatment of symptomatic BPH.