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PubMed2005

The clinical efficacy and tolerability of doxazosin standard and gastrointestinal therapeutic system for benign prostatic hyperplasia.

The therapeutic goal of treating benign prostatic hyperplasia (BPH) through early detection and effective therapy is to relieve the symptoms, improve patients' quality of life, decrease postvoid residual urine volume, and prevent the associated morbidity when the condition remains untreated. Alpha1-adrenoreceptor antagonists, e.g. doxazosin, terazosin, tamsulosin and alfuzosin, relax the bladder outlet to improve urinary flow, by reducing prostatic smooth muscle tone through the blockade of sympathetic adrenergic receptors. Doxazosin gastrointestinal therapeutic system (GITS) is a controlled-release formulation developed to enhance the pharmacokinetic profile of the drug while simultaneously minimizing possible adverse effects and reducing the need for dose titration. While both doxazosin standard and GITS are indicated for hypertension, they are also useful in the pharmacologically or naturally normotensive patient with BPH. In a cross-over trial comparing doxazosin GITS and tamsulosin, doxazosin gave a significantly greater improvement from baseline in symptoms. Results from recent trials (e.g. Medical Therapy of Prostatic Symptoms, MTOPS) showed that doxazosin was significantly more effective than the 5alpha-reductase inhibitor finasteride in relieving lower urinary tract symptoms, irrespective of prostate volume. The MTOPS trial showed clearly that over the long term, the combination of doxazosin and finasteride was more effective than either agent alone in significantly improving symptoms and reducing the clinical progression of BPH. Both doxazosin standard and GITS are well-tolerated, long-term therapies that are equally effective in younger and older men, and not associated with causing sexual dysfunction.

Adrenergic alpha-Antagonists↗
PubMed2007

Combinations of tomato and broccoli enhance antitumor activity in dunning r3327-h prostate adenocarcinomas.

The consumption of diets containing 5 to 10 servings of fruits and vegetables daily is the foundation of public health recommendations for cancer prevention, yet this concept has not been tested in experimental models of prostate cancer. We evaluated combinations of tomato and broccoli in the Dunning R3327-H prostate adenocarcinoma model. Male Copenhagen rats (n=206) were fed diets containing 10% tomato, 10% broccoli, 5% tomato plus 5% broccoli (5:5 combination), 10% tomato plus 10% broccoli (10:10 combination) powders, or lycopene (23 or 224 nmol/g diet) for approximately 22 weeks starting 1 month prior to receiving s.c. tumor implants. We compared the effects of diet to surgical castration (2 weeks before termination) or finasteride (5 mg/kg body weight orally, 6 d/wk). Castration reduced prostate weights, tumor areas, and tumor weight (62%, P<0.001), whereas finasteride reduced prostate weights (P<0.0001), but had no effect on tumor area or weight. Lycopene at 23 or 224 nmol/g of the diet insignificantly reduced tumor weights by 7% or 18%, respectively, whereas tomato reduced tumor weight by 34% (P<0.05). Broccoli decreased tumor weights by 42% (P<0.01) whereas the 10:10 combination caused a 52% decrease (P<0.001). Tumor growth reductions were associated with reduced proliferation and increased apoptosis, as quantified by proliferating cell nuclear antigen immunohistochemistry and the ApopTag assay. The combination of tomato and broccoli was more effective at slowing tumor growth than either tomato or broccoli alone and supports the public health recommendations to increase the intake of a variety of plant components.

Adenocarcinoma↗
PubMed1998

Tamsulosin: real life clinical experience in 19,365 patients.

OBJECTIVE: To compare the efficacy, global tolerability and blood pressure effects of tamsulosin (0.4 mg once daily) in subgroups of patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO). METHODS: Data from two open-label, observational studies (Study I: 9,507 patients treated for 4 weeks, Study II: 9,858 patients treated for 12 weeks) were analyzed to compare efficacy, global tolerability and effects on blood pressure in subgroups of patients. RESULTS: The efficacy of tamsulosin was largely unaffected by age or previous phytotherapy; in patients with severe symptoms, the efficacy was at least as large as in those with mild or moderate symptoms. More than 90% of patients reported a good or very good tolerability; in a multivariate analysis, this was slightly reduced in patients with concomitant disease but not affected by antihypertensive co-medication or baseline blood pressure. In patients without co-morbidity or co-medication, the tamsulosin-induced blood pressure reductions were similar to those previously reported for placebo treatment; mean additional blood pressure reductions in patients with concomitant disease or medication was not more than 2 mm Hg. Patients who had previously been treated with beta-sitosterol, other plant extracts or finasteride reported tamsulosin to be more effective than their previous treatment. Patients who had previously received beta-sitosterol or other plant extracts rated the global tolerability of tamsulosin to be similar to that of their previous treatment, while those who had previously received finasteride or other alpha 1-adrenoceptor antagonists rated the global tolerability of tamsulosin to be significantly better than that of their previous treatment. CONCLUSIONS: We conclude that tamsulosin is efficacious in all types of patients with LUTS suggestive of BPO. It is globally well tolerated and has marginal effects on blood pressure, including the vast majority of patients with cardiovascular comorbidity, diabetes or on antihypertensive comedication.

Adrenergic alpha-Antagonists↗
PubMed1999

Management of symptomatic BPH in the UK: who is treated and how?

OBJECTIVE: To review the contemporary management of symptomatic benign prostatic hyperplasia (BPH) in the United Kingdom (UK). METHODS: Information was obtained from published scientific articles, IMS market analysis data and surveys among primary care practitioners and urologists. RESULTS: A survey in Stirling (Scotland) identified the number of men aged 40-79 years with symptomatic BPH defined as a prostate size >20 g with urinary symptoms (total symptom score >/=11) and/or a maximum urinary flow rate <15 ml/s. It appeared that 25% of men had symptomatic BPH. Approximately 2.5 million men fall in this category in the UK currently and the number is expected to grow by almost 50% by the year 2025. Although not every man with symptomatic BPH is bothered by his LUTS and will therefore seek medical advice, many men with mainly filling symptoms and greater symptom severity do visit their physician, especially now more medical treatment options are available. Due to the low number of urologists in the UK, general practitioners (GPs) have traditionally been more involved in the diagnosis and management of symptomatic BPH than in other countries. The contribution of GPs and nurses in managing this condition will probably increase even more when the National Health Services (NHS) reform with GPs and nurses co-operating in primary care groups (PCGs) which are responsible for the total healthcare budget is fully implemented. Although urologists will have to define their role in this new system, this trend will probably help them to cope with the increasing numbers of elderly males seeking medical advice for LUT problems in the next millennium and to reduce already existing out-patient and surgical waiting lists. First results suggest that two thirds of patients attending shared care prostate clinics have uncomplicated LUTS related to BPH and can initially be managed at primary care level. The number of consultations and prescriptions for medical therapy for symptomatic BPH has increased considerably during the 1990s whereas the number of surgical procedures performed on an annual basis has remained stable at around 40,000 cases/year accounting for 70 million Euro/year. Of the two medical treatment approaches approved for the treatment of symptomatic BPH in the UK, the sales for alpha(1)-adrenoceptor antagonists have increased steadily during the latter part of the 1990s whereas that for finasteride has remained flat. In 1998, alpha(1)-adrenoceptor antagonists had 64% market share and finasteride 36% from a total market of 53 million Euro. CONCLUSIONS: In the UK, challenges for the future management of symptomatic BPH will be the increased number of patients, further enhancement of efficient co-operation between PCGs and urologists and evaluation of most appropriate management of this condition from a disease progression and cost-effectiveness point of view. Copyrightz1999S. KargerAG,Basel

Forecasting↗
PubMed2000

How do symptoms indicative of BPH progress in real life practice? The UK experience.

OBJECTIVE: Lower urinary tract symptoms (LUTS) are usually, but not exclusively associated with benign prostatic hyperplasia (BPH). Using a population identified from the UK General Practice Research Database (GPRD), we describe the changes in the management of LUTS/BPH and assess the effectiveness of medical therapy between 1992 and 1998. METHODS: 61,364 men with LUTS/BPH and without a record of prostatic cancer were identified on the database. 14,195 were treated with an alpha1-blocker or finasteride. Treatment failure was defined as prostatic surgery, catheterisation or a switch in medical therapy. RESULTS: LUTS/BPH incidence increased linearly from the age of 45 to 85 years (r2 = 0.992) and prevalence increased from 3.5% to 35% for men in their late 40s and 80s respectively. Prostatectomy rates increased linearly from the age of 50 to 80 years (r2 = 0.984). Between 1992 and 1998, total treated-patient time had increased 3-fold, patients have been medically treated earlier and have increasingly been prescribed the LUTS/BPH-specific treatments finasteride, tamsulosin and alfuzosin in comparison to older treatments (indoramin, prazosin). In parallel, there has been a progressive increase in the interval between first diagnosis and prostatic surgery, and this interval is significantly longer for medically treated patients than those receiving no medical therapy. The intervals between the start and failure of medical therapy were significantly shorter for patients receiving indoramin and prazosin than for those receiving specific LUTS/BPH treatments. CONCLUSIONS: Between 1992 and 1998 there has been a significant lengthening of the period between first diagnosis of LUTS/BPH and surgery. This postponement of surgery is associated with earlier treatment and the increased use of specific LUTS/BPH treatments that appear more effective than older products in delaying treatment failure.

Aged↗
PubMed2001

Lower urinary tract symptoms suggestive of benign prostatic obstruction--Triumph: the role of general practice databases.

The Triumph project aims to document the current management of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) in general practice and to assess the effectiveness of the initial treatment options used. The first phase of the project will consider existing data sources in primary care. A patient's medical record will contain most, if not all, clinically relevant information, and databases combining the records from a network of computerised general practices can provide longitudinal data for complete populations, linking prescribing records to clinical information on disease progression and outcomes for individual patients. Database research can provide rapid information and offers the ability to conduct studies on a scale that would previously have been prohibited by both time and expense. Within the Triumph project, the THALES, General Practice Research Database (GPRD) and Integrated Primary Care Information (IPCI) databases are, or will be, used to examine the current management of LUTS/BPH in France, the UK and the Netherlands respectively. Preliminary results from the UK General Practice Research Database (GPRD) showed that LUTS/BPH incidence increased linearly from the ages of 45 to 85 years (r(2) = 0.992) and prevalence increased from 3.5% to 35% for men in their late 40s and 80s respectively. With treatment failure defined as a change to another medical therapy, catheterisation or prostatic surgery, and accounting for age and year variation, patients receiving the older alpha(1)-blockers (indoramin and prazosin) appeared to fail significantly earlier than those receiving finasteride. There was no significant difference between finasteride and the newer alpha(1)-blockers (tamsulosin, alfuzosin, terazosin and doxazosin). Patterns of changes between products from the THALES database in France were broadly similar to those seen in the UK.

Databases, Factual↗
PubMed1994

Future implications for the management of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a growing medical problem in terms of morbidity, mortality, and health care costs. Renewed research has highlighted the lack of standardized parameters available with which to define and evaluate BPH and its treatment. The many treatments available, ranging from surgery to watchful waiting, point to the complex pathophysiology of BPH and the subjectivity of the treatment decisions. Workup of patients with micturition disorders, coupled with use of the International Prostate Symptom Score evaluation, permits the development of criteria for evaluating treatment efficacy and acceptable treatment options. Based on double-blind, placebo-controlled trials, a-blockers and finasteride have been accepted as treatment options. The former produce relaxation of the smooth muscle by inhibiting adrenergically induced increases in intracellular calcium. The latter blocks the 5a-reductase system, which effectively stops the conversion of testosterone to dihydrotestosterone. a-Blockers improve symptoms and flow immediately while finasteride diminishes the prostate volume, specifically of glandular tissue, leading to improved symptoms and flow. All other medical and nonmedical treatments require further evaluation by randomized, prospective trials to determine their safety profile and efficacy.

Humans↗
PubMed1999

Gender differences in hypertension in spontaneously hypertensive rats: role of androgens and androgen receptor.

Males are at greater risk of cardiovascular and renal disease than are females. For example, male spontaneously hypertensive rats (SHR) have higher blood pressures than females. Androgens have been strongly implicated in the hypertension of male SHR, because castration attenuates the hypertension. This study determined whether the androgen receptor plays a role in hypertension in male SHR and whether testosterone alone can cause the hypertension or whether conversion to dihydrotestosterone is necessary. Male SHR, aged 10 weeks, were given the androgen receptor antagonist flutamide (8 mg/kg SC; n=8) or the 5alpha-reductase inhibitor finasteride (30 mg x kg(-1) x d(-1) SC; n=11) daily for 5 to 6 weeks. Control rats (n=10) received vehicle (20% benzyl benzoate or ethanol in castor oil). After 5 to 6 weeks, blood pressure (mean arterial pressure) and glomerular filtration rate were measured. Long-term flutamide treatment caused a reduction in mean arterial pressure (control 178+/-5 mm Hg; flutamide 159+/-3 mm Hg; P<0.01), but finasteride had no effect (180+/-5 mm Hg). There were no differences in glomerular filtration rate among the groups. These data indicate that hypertension in male SHR is mediated via the androgen receptor and does not require conversion of testosterone to dihydrotestosterone.

Androgens↗
PubMed1999

Inhibition of androgen synthesis in human testicular and prostatic microsomes and in male rats by novel steroidal compounds.

The C(17,20)-lyase and 5alpha-reductase are key enzymes in the biosynthesis of androgens. The effects of novel steroidal compounds were evaluated as inhibitors against both human C(17,20)-lyase and 5alpha-reductase in vitro. The concentrations of testosterone (T) and dihydrotestosterone (DHT) in the prostate, testis and serum and changes in the tissue weights were also determined in rats treated with the novel inhibitors. L-12 and L-26 showed potent inhibition of human testicular C(17,20)-lyase with IC50 values of 50 and 25 nM, respectively. L-12, L-38, and I-47 showed moderate inhibition of human testicular C(17,20)-lyase with IC50 values of 75, 108, and 70 nM, respectively similar to ketoconazole (78 nM). Interestingly, L-6, L-26, and L-38 also showed some inhibitory activity against 5alpha-reductase with IC50 values of 75, 125, and 377 nM, respectively. Finasteride, an inhibitor of 5alpha-reductase had an IC50 value of 33 nM. However, ketoconazole did not inhibit 5alpha-reductase nor did finasteride inhibit C(17,20)-lyase. Treatment of normal male rats with several of these novel inhibitors (50 mg/kg x day, s.c., for 14 consecutive days) caused about 45-91% decrease in serum, testicular and prostatic T concentration. Similarly, serum and prostatic DHT concentration were significantly decreased in rats treated with these novel compounds by 50-90% compared with controls. Surgical castration caused almost complete elimination of circulating T and DHT concentration in rat tissues. L-6 and L-12 were the most effective and reduced the wet weight of the prostate by 50%. Although future improvements in their bioavailability are necessary, these novel steroidal compounds show promise as potential agents for reducing T and DHT levels in patients with androgen dependent diseases.

Androgens↗
PubMed2001

New progesterone esters as 5alpha-reductase inhibitors.

The pharmacological activity of four new progesterone derivatives: 4-bromo-17alpha-(p-fluorobenzoyloxy)-4-pregnene-3,20-dione (7), 4-bromo-17alpha-(p-bromobenzoyloxy)-4-pregnene-3,20-dione (8), 4-bromo-17alpha-(p-chlorobenzoyloxy)-pregnene-3,20-dione (9) and 4-bromo-17alpha-(p-toluoyloxy)-4-pregnene-3,20-dione (10) was determined. These compounds were evaluated as 5alpha-reductase inhibitors on gonadectomized hamster seminal vesicles and flank organs. The pharmacological data of this study indicate that compounds 7 and 9 having at C-17 p-fluorobenzoyloxy and p-chlorobenzoyloxy ester functions respectively showed the highest antiandrogenic effect as measured by the reduction of the weight of the seminal vesicles. In the flank organ model, the same compounds 7 and 9 exhibited a smaller diameter, 1.8 and 1.0 mm, respectively, than the commercially available finasteride 3 (2.3 mm), thus indicating a higher inhibitory effect on 5alpha-reductase enzyme. Steroid 7 showed a higher inhibitory activity on the conversion of T to DHT (Fig. 3) than the presently used finasteride, thus indicating a higher antiandrogenic effect. The nonsubstituted benzoyloxy ester (compound 15) showed a lower antiandrogenic activity as measured in the seminal vesicles model than the p-substituted benzoyloxy compounds.

5-alpha Reductase Inhibitors↗
PubMed2001

Evaluation of new pregnane derivatives as 5alpha-reductase inhibitor.

The objective of this study was to synthesize several new pregnane derivatives and evaluate them as antiandrogens. From the commercially available 16-dehydropregnenolone acetate (7), two new steroidal compounds were synthesized: 17alpha-hydroxy-17beta-methyl-16beta-phenyl-D-homoandrosta-1,4,6-triene-3,20-dione (18) and 17alpha-acetoxy-17beta-methyl-16beta-phenyl-D-homoandrosta-1,4,6-triene-3,20-dione (19). The 5alpha-reductase inhibitory effect of the new compounds 18 and 19 together with the previously synthesized intermediates 7, 8, 13, 16, and 17 was determined in three different models: gonadectomized hamster flank organs diameter size, incorporation of [1,2-(14)C]sodium acetate into lipids in flank organs and conversion of [3H]testosterone (T) to [3H]dihydrotestosterone (DHT) by Penicillium crustosum. The evaluation of these steroids was carried out with three different controls: one group was treated with vehicle, the second with T and the third group with T plus finasteride. The pharmacological results from this work demonstrated that T significantly increases the diameter of the pigmented spot on the flank organs (p<0.05) as well as the incorporation of labeled sodium acetate into lipids in gonadectomized hamster flank organs (from 0.125 to 0.255 nmol per gland). In this study we also observed that broth of Penicillium crustosum converted [3H]T to [3H]DHT in a manner comparable to that of the flank organs. All experiments indicated that finasteride as well as steroids 7, 8, 13, 16-19 reduced significantly the conversion of T to DHT in P. crustosum. These compounds also decrease the size of the pigmented spot in the flank organs as well as reducing the incorporation of radiolabeled sodium acetate into lipids; T and the control sample (treated with vehicle only) were used for comparison. Apparently the presence of the 4,6-diene-3,20-dione moiety and also the C-17 ester group produce a higher inhibitory effect on the parameters used. PPThe data from this study indicated also that the three models used for the pharmacological evaluation exhibited comparable results.

5-alpha Reductase Inhibitors↗
PubMed2005

Dutasteride: a novel dual inhibitor of 5alpha-reductase for benign prostatic hyperplasia.

Dutasteride is a new dual 5alpha-reductase inhibitor for the treatment of benign prostatic hyperplasia. It differs from finasteride as it inhibits both isoenzymes of 5alpha-reductase and results in near-complete suppression of serum dihydro-testosterone. Similar to finasteride, it reduces serum prostatic specific antigen by approximately 50% at 6months and total prostate volume by 25% in 2years. Randomised, placebo-controlled trials conducted over 2years have shown the efficacy of dutasteride in symptomatic relief, improvements in quality of life and peak urinary flow rate, and reduction of acute urinary retention events and the need for surgery. The main side effects are erectile dysfunction, decreased libido, gynaecomastia and ejaculation disorders. However, long-term usage for > 4years did not reveal increased new onset of sexual side effects. In addition, the combination of dutasteride and tamsulosin is well-tolerated and has the added advantage of rapid symptomatic relief. Finally, dutasteride has been shown to possess tumour regression properties invitro and its role in chemoprevention of prostate cancer will be confirmed in the ongoing Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2004

Inhibition of prostate cell growth by BXL-628, a calcitriol analogue selected for a phase II clinical trial in patients with benign prostate hyperplasia.

OBJECTIVE: Calcitriol analogues might represent an interesting new therapy for benign prostate hyperplasia (BPH). We here report the preclinical characterization of BXL-628, an analogue selected for an ongoing double-blind, randomized, placebo-controlled phase II trial in BPH. DESIGN: Experiments with BXL-628 were carried out in human BPH cells and in the ventral prostate of intact and castrated rats. METHODS: BPH cell and rat prostate growth were evaluated along with morphological and biochemical hallmarks of apoptosis. RESULTS: BXL-628 inhibited human BPH cell proliferation and induced apoptosis even in the presence of androgens or growth factors. It also decreased prostate growth to an extent similar to finasteride, inducing DNA fragmentation and apoptosis, both in intact and in testosterone-supplemented castrated rats. Accordingly, BXL-628, like finasteride, increased the expression of clusterin, a prostatic atrophy marker. However, BXL-628 did not inhibit 5 alpha-reductase 1 and 2, did not bind to the androgen receptor (AR) in BPH homogenates and did not affect AR-coupled luciferase activity. In addition, BXL-628 did not affect rat pituitary and testis activity or calcemia. CONCLUSIONS: BXL-628 inhibited in vitro and in vivo prostate cell proliferation, and therefore might represent a novel, interesting option for the treatment of BPH.

Animals↗
PubMed2001

Changing therapeutic regimens in benign prostatic hyperplasia. Clinical and economic considerations.

About one-quarter of men aged 50 years and older experience voiding problems due to benign prostatic hyperplasia (BPH). Until about 10 years ago, surgery (particularly transurethral resection of the prostate) was the only effective treatment for symptomatic BPH. Over the last decade, several new treatments have been introduced. These include different types of medication (alpha-blockers and finasteride), thermotherapy, laser prostatectomy, needle ablation and vaporisation methods. The diffusion of these less invasive treatment modalities has resulted not only in a decrease in the age-adjusted surgery rates, but also in an increase of the total number of men treated for BPH. A large number of studies on clinical benefits and risks reveal that the conventional types of surgery remain the most effective treatments, whereas new interventional therapies require a shorter hospital stay and result in fewer short term complications. The efficacy of medication is lower than that of interventional treatments. Adverse effects include dizziness and orthostatic hypotension (alpha-blockers) and decreased sexual function (finasteride), but are generally mild. There is some evidence that medication and minimally invasive treatments may preclude eventual surgical treatment, but the precise effect is difficult to estimate because of differences in the study populations and the relatively short study periods. As a result of the dynamic nature of BPH treatment and the lack of long term data, the cost effects of the introduction of the various new treatments are also difficult to assess. Given the aging of the population and the growing percentage of patients with BPH for whom any type of treatment can be considered, a considerable increase of total costs can be expected. Long term prospective studies are necessary to gain insight into the most cost-effective treatment for different patient groups.

Costs and Cost Analysis↗
PubMedDate not supplied

Management of hirsutism.

This review reports our own experience with, and literature studies of, the pharmacological management of hirsutism in women with hyperandrogenism (polycystic ovary syndrome) or with normal serum androgen levels and regular ovulatory menstrual cycles (idiopathic hirsutism). Treatment consists of suppressing ovarian or adrenal androgen secretion, or blocking androgen actions in the skin. The major drugs used are gonadotropin-releasing hormone (GnRH) agonists, combined oral contraceptives (COCs), and steroidal (cyproterone acetate and spironolactone) or nonsteroidal (flutamide and finasteride) antiandrogens. GnRH agonists, suppressing the pituitary, decrease androgen and estradiol secretion and improve severe hirsutism. To avoid estrogen deficiency problems, 'add back' therapy with estrogen-progestogen or COCs is advisable. This method of treatment is complicated and expensive, limiting its use to severe forms of ovarian hyperandrogenism with hyperinsulinemia. The third-generation COCs, containing new progestogens or cyproterone, have very restricted effectiveness in the short term (6 cycles), but their long term use (> 12 cycles) cures mild-to-moderate hirsutism and improves severe hirsutism. As well as suppressing gonadotropins and ovarian androgen steroidogenesis, these formulations decrease free testosterone levels and may also decrease adrenal androgen production. In women being treated with antiandrogens, COCs are important to provide control of the menstrual cycle and contraception. Cyproterone, a progestational agent, inhibits gonadotropin secretion and blocks androgen action. It is used in COCs or in a reverse sequential regimen. In the latter, it is very effective in the short term treatment of hirsutism. Spironolactone blocks androgen receptors. Its effectiveness in hirsutism is dosage-dependent: low dosages are less active than other antiandrogens, whereas high dosages (200 mg/day) are very effective at the cost of several adverse effects (particularly dysfunctional uterine bleeding), but the concomitant use of a COC may prevent these. Flutamide is a pure antiandrogen that blocks androgen receptors and inhibits hair growth. It is very effective in treating hirsutism within 6 to 12 months. Dry skin is very frequent during treatment with flutamide, and hepatotoxicity is possible at high dosages. Finasteride, a 5 alpha-reductase type 2 inhibitor, is the least effective antiandrogen, but a dosage of 5 mg/day decreases hirsutism without adverse effects. Pregnancy must be avoided during therapy with antiandrogens because of the possible risk of abnormal development of a male fetus. Antiandrogens, especially flutamide (250 to 500 mg/day) and cyproterone (12.5 to 50 mg/day in a reverse sequential regimen), alone or in association with COCs, seem to be the most effective agents for the treatment of hirsutism.

Adolescent↗
PubMed1999

Steroidal antiandrogens and 5alpha-reductase inhibitors.

The purpose of this work is to synthesize a pregnane derivative with a high antiandrogenic effect or a high inhibitory activity for the enzyme 5 alpha-reductase type 2. Benign prostatic hyperplasia and prostate cancer are androgen dependent diseases which afflict a large percentage of the male population. Dihydrotestosterone 3, a 5 alpha-reductase metabolite of testosterone 2 has been implicated as a causative factor in the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of steroid 5 alpha-reductase enzyme. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new drugs. The advent of finasteride 22 "figure 5" a 5 alpha-reductase inhibitor, has greatly alleviated the symptoms associated with benign prostatic hyperplasia. On the other hand, the discovery of cyproterone acetate 4 "figure 2" alone or in combination with the antiandrogens flutamide 14 "figure 3" or bicalutamide 21 has greatly reduced the misery of prostate cancer. Prostate cancer kills about 40,000 men in the USA and approximately 400,000 prostatectomies are performed each year. In our laboratory we have recently synthesized ten new progesterone derivatives 17 alpha-acyloyloxy-6-halo (chloro, bromo) 16 beta-methyl-4, 6-pregnadiene-3, 20-diones (54a-54e and 55a-55e), "figure 10". These steroids were evaluated as antiandrogens and exhibited a much higher activity than the commercially available cyproterone acetate 4. The same compounds were also evaluated as 5 alpha-reductase inhibitors and showed a slightly higher inhibitory activity than that of finasteride 22, the drug of choice today for the treatment of benign prostatic hyperplasia In another study we synthesized several new 4-halo (bromo and chloro) 17 alpha-benzoyloxy and also 4-halo-17 alpha-acetoxy progesterone derivatives (58-63) "figure 13". These compounds were prepared from the commercially available 17 alpha-acetoxy progesterone 56. The pharmacological evaluation of these steroids "figure 14" indicated that the 17 alpha-benzoyloxy derivatives (4-chloro and bromo) 62 and 63 were very potent antiandrogens. On the other hand, the 4-halo (bromo and chloro) 17 alpha-acetoxy (58, 59) and the 17 alpha-benzoyloxy-4-chloro analog 63 showed a very high inhibitory activity for the enzyme 5 alpha-reductase type 2 "figure 15".

Adrenergic Antagonists↗
PubMed1999

Current management of androgenetic alopecia in men.

Androgenetic alopecia (AGA) is a common dermatological condition affecting both men and women. Until recently there has been little interest in AGA as a clinical condition, largely due to the lack of any genuinely effective treatment for it. A number of "remedies" exist, such as vitamin supplements, which are not generally harmful but which have no proven efficacy in promoting hair growth or preventing further hair loss. Hair systems and surgery provide camouflage for the symptoms but do not effect a cure. By far the most promising approaches to the treatment of AGA are drug therapies, such as minoxidil and finasteride. Finasteride, an inhibitor of the type II 5alpha-reductase that converts testosterone to dihydrotestosterone, has been shown to prevent further hair loss, and promotes new hair growth in the majority of the men taking part in clinical trials. Tailored drug approaches like this offer the greatest hope for the successful future treatment of AGA.

Alopecia↗
PubMed2000

The mechanism of adverse events associated with terazosin: an analysis of the Veterans Affairs cooperative study.

PURPOSE: We determined the mechanism of adverse events associated with alpha1-blockers for treating benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: We randomized 1,229 men with clinical BPH at 31 Veterans Affairs medical centers into equal treatment groups, including those who received placebo, terazosin, finasteride, and combined terazosin and finasteride therapy, respectively. Adverse events were captured at all study visits during our 1-year study. Our current review of adverse events is limited to patients randomized to the placebo and terazosin groups. We compared the incidence of orthostatic blood pressure change, postural symptoms and orthostatic hypotension in men who were normotensive and hypertensive at baseline, respectively. We also determined the association of changes in systolic blood pressure with the incidence of treatment related adverse events. RESULTS: The treatment related rates of dizziness, asthenia, postural hypotension and syncope were 19%, 6%, 6% and 1%, respectively. Of these adverse events only postural hypotension was associated with orthostatic blood pressure changes. The incidence of asthenia, dizziness and postural hypotension was not significantly greater in patients with a systolic blood pressure decrease of 5 or greater and less than 5 mm. Hg, respectively. CONCLUSIONS: Dizziness and asthenia are not associated with changes in blood pressure, suggesting that these treatment related adverse events associated with alpha1-blockers are not related to vascular events. Designing a subtype selective alpha1 antagonist that has less effect on blood pressure may not result in marked improvement in tolerability over commercially available alpha1-blockers.

Adrenergic alpha-Antagonists↗