Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We attempted to determine the effects of the combination of a 5-alpha reductase inhibitor and an antiandrogen on rat ventral prostate and seminal vesicle weight. We also attempted to determine whether the prostatic cell death gene TRPM-2 would be expressed using this combination of drugs. Adult male Sprague-Dawley rats were randomly assigned to 7 groups of 15 animals. Four groups served as controls: an intact group sacrificed at the initiation of the trial (group 1), a castrate control group (group 2), an intact control group (group 3), and a group treated with the combination of an LHRH agonist plus antiandrogen (group 7). Three other groups were treated with daily subcutaneous injections of 5 alpha reductase inhibitor (group 5), a nonsteroidal pure antiandrogen (group 4) or both (group 6). After 5 days of treatment 5 animals in each group were sacrificed and prostatic tissue was assayed for the androgen repressed prostatic cell death gene TRPM-2. At 30 days (35 days for group 7) the remaining animals were sacrificed and their ventral prostates, seminal vesicles, and testes (except group 3) were weighed. The combination group (group 6) had a significantly lower prostate weight than either of the monotherapy groups (4, 5), or intact control groups, was equivalent to group 7 but was significantly heavier than the castrate group 2. The seminal vesicle weights of the combination group 6 were significantly lower than the monotherapy groups (4, 5), intact control group, castrate group (3) and was equivalent to group 7. Only castration was able to induce expression of the cell death gene TRPM-2. In this model, the combination of 5 alpha reductase inhibitor and an antiandrogen is as effective a mode of androgen ablation as combination therapy of LHRH agonist plus antiandrogen. Clinically, this combination may translate into adequate androgen blockade without impotence or other side effects of testosterone deprivation. Clinical trials appear warranted to assess this hypothesis.
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PMID:Sequential androgen blockade: a biological study in the inhibition of prostatic growth. 133 49

Pharmacologic strategies for the treatment of BPH are at present directed toward relaxing prostate smooth muscle and reducing prostate volume. Historically, the primary limitation of pharmacotherapy for BPH has been that the symptomatic improvement achieved was overshadowed by the morbidity of treatment. However, the morbidity has been markedly diminished based on a more precise understanding of the embryology, physiology, and pharmacology of the prostate. The origins and pharmacologic properties of the smooth musculature of the prostate and bladder are unique. Therefore, drugs such as alpha blockers may relax the prostate selectively without altering bladder function. Although phenoxybenzamine, a nonselective alpha blocker, relieves infravesical obstruction secondary to BPH, the severity of the adverse reactions limits the use of this drug. The contractile properties of the prostate smooth muscle are mediated by alpha-1 adrenoceptors. The effectiveness of phenoxybenzamine and selective alpha-1 blockers such as prazosin and terazosin are similar. The side effects of the selective alpha-1 blockers are negligible. Androgen suppression, which lowers testosterone, produces intolerable side effects such as gynecomastia, erectile dysfunction, and impaired libido. The androgen dependency of the prostate provides the rationale for using 5 alpha-reductase inhibitors for the treatment of BPH. Reduction of prostate volume can be achieved by blocking the action or synthesis of dihydrotestosterone without impotence, gynecomastia, and hot flashes. These recent advances in pharmacotherapy for BPH are based on understanding of the fundamental developmental properties of the prostate.
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PMID:Embryologic development of the prostate. Insights into the etiology and treatment of benign prostatic hyperplasia. 169 77

Luteinizing hormone-releasing hormone (LHRH) agonist, when administered in a continuous, nonpulsatile manner, causes desensitization of the LHRH receptor complex on the gonadotroph cells in the anterior pituitary gland. Biosynthesis and secretion of luteinizing hormone cease, and testicular androgenic production is inhibited. When used in this capacity, LHRH agonists can be an effective treatment for benign prostatic hyperplasia. After 4 to 6 months of therapy, prostatic volume decreases by 25% to 30%, voiding symptoms improve significantly in approximately 25% to 33% of patients, and the peak urinary flow rate increases substantially (more than 15 ml/second) in approximately 25% to 33% of patients. During the first month of treatment, serum luteinizing hormone, follicle-stimulating hormone, testosterone, dihydrotestosterone, 17 beta-estradiol, and prostate-specific antigen decline to low values and remain low throughout treatment. Prostatic 5 alpha-reductase activity and androgen receptor content also decrease with treatment. Side effects are significant: impotence, decreased libido, and hot flushes are the most common. Because the effect of LHRH agonist therapy on the serum testosterone concentration is reversible, treatment of benign prostatic hyperplasia with an LHRH agonist must be considered life-long therapy. Thus, this therapy should be reserved for patients who are impotent or who are poor surgical risks.
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PMID:LHRH agonists. A nonsurgical treatment for benign prostatic hyperplasia. 172 94

Endocrine management is the best palliative management available for patients with carcinoma of the prostate. It is based on androgen withdrawal by castration or other means. Endocrine management was introduced into clinical medicine by Huggins and his associates in the early 1940s on the basis of careful clinical and experimental research establishing the biological effects of androgen withdrawal in animal systems and in humans. It was believed for a long time that endocrine treatment would prolong life. This, however, in spite of extensive clinical research, remains unproven. The possibility that the life span of prostate cancer patients is determined by the hormone independent cell populations within virtually all prostate cancers still remains a possibility. Endocrine treatment has, however, been shown to have a significant impact on symptoms related to prostate cancer, especially on bone pain, urethral and ureteral obstruction. It has also been shown to prolong time to progression and to death from prostate cancer. Although castration and the application of exogenous oestrogens with the purpose of interfering with pituitary testicular feedback have been standard treatment of prostate cancer for more than 30 years, new treatment methods have recently become available. Luteinizing hormone releasing hormone agonists allow suppression of plasma testosterone to castration levels without exerting the side effects associated with oestrogens (eg cardiovascular incidents, gynaecomastia). Also, the application of pure or steroidal anti-androgens allows direct counteraction of circulating androgens at the target cell. The possibility that initial suppression of adrenal androgen production, which contributes about 10% of circulating androgens in males, may be more beneficial than suppression of testicular androgens alone has been subject to intense clinical research recently. Simultaneous suppression of testicular and adrenal androgens in primary management of prostate cancer is called total androgen blockade or total androgen suppression. Up to now, however, no convincing advantages of total androgen suppression regimens above castration have been shown. Total androgen suppression seems to produce significantly better survival when compared with daily injections of LHRH alone. The use of pure anti-androgens or of 5 alpha-reductase inhibitors could potentially prevent the most significant side effect of all androgen withdrawal regimens, loss of libido and impotence. However, neither the use of pure anti-androgens as monotherapy nor the use of 5 alpha-reductase inhibitors as monotherapy has been shown to produce clinical results that are equal to castration.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Endocrine therapy: where do we stand and where are we going? 184 51

Alpha-1-protease inhibitor (alpha-1-PI) is the major regulator of extracellular leukocyte elastase activity and can be rendered impotent against elastase by oxidation of a critical methionine, residue 358. Alpha-1-PI was isolated from rat plasma by affinity chromatography on Sepharose-bound anhydrochymotrypsin, DEAE-cellulose anion-exchange, and Sephadex G-150 gel filtration. The product was radiolabeled using non-oxidative conditions with Bolton-Hunter reagent, and an aliquot subsequently oxidized with N-chlorosuccinimide. Turnover studies in rats indicated that both native and oxidized alpha-1-PI had half-lives of 170 min. Using partially purified human neutrophil methionine sulfoxide-peptide reductase (Met(O)PR), it was demonstrated that oxidized product could be converted back "in vitro" to an active inhibitor of elastase. To assess whether oxidized alpha-1-PI underwent reduction "in vivo," methionine-oxidized rat inhibitor was injected into the rats, aliquots of plasma samples were withdrawan and passed through a Sepharose-bound anhydrochymotrypsin affinity resin, and bound functional alpha-1-PI was eluted with 0.1 M chymostatin. Radioactive counting of bound and unbound fractions indicated that reduction does not occur in vivo and suggested that, at least under homeostatic conditions, the Met(O)PR is confined to intracellular sites where it does not have access to the circulating protein.
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PMID:Studies on the turnover of methionine oxidized alpha-1-protease inhibitor in rats. 349 3

In order to learn whether a direct relationship exists between cellular uptake and cytotoxicity of Adriamycin, we have compared the temperature dependencies of these two processes in L1210 cells. We find that the equilibrium concentration of drug taken inside the cells varies smoothly with temperature between 37 degrees C and 0 degree C. Even at 0 degree C, however, there is still measurable uptake of the drug into cells. The cytotoxicity index (cloning in soft agar), on the other hand, does not parallel the uptake temperature dependence. Cytotoxicity rapidly diminishes as the temperature of drug exposure is lowered; at all temperatures below about 20 degrees C, Adriamycin is not active. In contrast, other cytotoxic anticancer drugs like mitomycin C, bleomycin, and ARK 73-21 (a platinum analogue) retain cytotoxic potency at low temperatures. The inability of Adriamycin to kill cells at low temperature persists even at very high drug concentrations where substantial quantities of drug enter the cells. The low temperature impotence is not a result of inoperative enzymes which could metabolize Adriamycin to an alkylating species or electron donor to oxygen, since NADH and NADPH dependent reductase activities show linear Arrhenius behavior with no indication of low temperature inactivity. Using purified L1210 plasma membranes with bound Adriamycin as a fluorescence polarization probe, we find evidence of a phase change in the cell surface occurring at the same temperature as the loss of biological activity (approximately equal to 20 degrees C). We conclude that Adriamycin induced cytotoxicity is not dictated solely by uptake, in apparent contradiction with mechanisms requiring an intracellular target. Moreover, the loss of cytotoxicity below 20 degrees C appears to be linked to a structural change in the cell surface membrane, supporting a role other than transport for this membrane in transducing Adriamycin action.
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PMID:Temperature dependence studies of adriamycin uptake and cytotoxicity. 360 49

Finasteride is a synthetic 4-azasteroid that is a specific competitive inhibitor of 5 alpha-reductase, an intracellular enzyme that converts testosterone to dihydrotestosterone (DHT). It has no binding affinity for androgen receptor sites and itself possesses no androgenic, antiandrogenic, or other steroid hormone-related properties. It is well absorbed after oral administration, with absolute bioavailability in humans of 63% (range 34-108%). The mean time to maximum concentration is 1-2 hours, and it is approximately 90% plasma protein bound. The elimination half-life averages 6-8 hours. The agent is metabolized to a series of five metabolites, of which two are active and possess less than 20% of the 5 alpha-reductase activity of finasteride. Little is known about potential drug interactions, although they appear to be minimal and not clinically relevant. The drug is indicated for the treatment of symptomatic benign prostatic hyperplasia. Its efficacy in regression of prostate gland enlargement is rapid and predictable, although correlation with subsequent improvement in urinary flow and symptoms is highly variable. Dosages of 0.5-100 mg/day regress prostate enlargement; the recommended dosage is 5 mg once/day. Finasteride may hold promise for other DHT-mediated disorders such as acne, facial hirsutism, frontal lobe alopecia, and prostate cancer, but its use in these conditions remains investigational. The frequency of adverse drug events is low, with the most common side effects being impotence, decreased libido, and decreased volume of ejaculate. No reports of intentional overdose have been reported, and dosages of up to 80 mg/day for 3 months have been taken without adverse effect.
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PMID:Finasteride: the first 5 alpha-reductase inhibitor. 768 28

Finasteride is a novel therapeutic agent that selectively inhibits the enzyme 5 alpha-reductase, thereby reducing prostatic dihydrotestosterone (DHT) levels and prostate size. In men with symptomatic benign prostatic hyperplasia (BPH), these effects have been associated with improvements in peak urinary flow rate and urological symptoms; withdrawal from therapy, however, results in regrowth of the adenoma and long term therapy is therefore necessary. Although the magnitude of clinical improvement seen with finasteride has been perceived to be modest [especially when compared with that associated with transurethral resection of the prostate (TURP)], it has been maintained in the medium term (up to 2 years) and thus may represent significant reversal of disease progression. Such beneficial effects, however, may not become apparent until completion of at least 6 months of therapy. Furthermore, since clinical studies have been unable to proactively identify a responsive subgroup, a trial period of 6 or possibly 12 months is necessary to assess patient responsiveness. Despite these potential shortcomings, the benefits of therapy appear to outweigh the risks. Indeed, finasteride is well tolerated; most adverse events have been related to sexual dysfunction (decreased libido, ejaculation disorders and impotence) and occurred in only a small proportion (about 2 to 3%) of patients. Moreover, although there has been concern that finasteride might mask the detection of prostate cancer through its decremental effects on serum prostate specific antigen (PSA) levels, careful monitoring in clinical trials appears to have avoided this problem. Thorough pretreatment assessment and periodic follow-up examinations for malignancy are therefore required in clinical practice. The role of finasteride in the treatment of patients with BPH is still emerging and will no doubt gain in clarity with further planned investigations. TURP (or other invasive procedures such as the insertion of prostatic stents in patients unsuitable for resection), continues to be the mainstay of therapy for those patients with severe symptomatic BPH. However, available data support a first line role for finasteride in the treatment of patients with uncomplicated symptomatic BPH. Within this setting, finasteride appears to offer a needed additional treatment option for those patients in whom surgery is not indicated, and may be of special benefit to the considerable proportion of patients who opt not to undergo prostatectomy.
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PMID:Finasteride. A review of its potential in the treatment of benign prostatic hyperplasia. 769 5

There is now substantial evidence that coeliac sprue is associated with infertility both in men and women. In women it can also lead to delayed menarche, amenorrhoea, early menopause, recurrent abortions, and a reduced pregnancy rate. In men it can cause hypogonadism, immature secondary sex characteristics and reduce semen quality. The real mechanism by which coeliac sprue produces these changes is unclear, but factors such as malnutrition, iron, folate and zinc deficiencies have all been implicated. In addition in men gonadal dysfunction is believed to be due to reduced conversion of testosterone to dihydrotestosterone caused by low levels of 5 alpha-reductase in coeliac sprue. This leads to derangement of the hypothalamic-pituitary axis. Hyperprolactinaemia is seen in 25% of coeliac patients, which causes impotence and loss of libido. Gluten withdrawal and correction of deficient dietary elements can lead to a return of fertility both in men and women.
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PMID:Infertility, obstetric and gynaecological problems in coeliac sprue. 798 65

The effects of depot medroxyprogesterone (DMPA), a 5 alpha-reductase, luteinizing-hormone release and human androgen receptor adhesion inhibitor, were assessed in 80 patients with benign prostatic hyperplasia (BPH) in a double-blind, placebo-controlled study. Patients were randomized to DMPA 150 mg single-dose intramuscular injection or placebo in a similar fashion. The following changes were seen with DMPA after 3 months (duration of DMPA effect): (1) serum testosterone reached castration levels within 3 days as compared to no changes in the placebo group; (2) the prostate volume was reduced by 25% compared to a 3% decrease with placebo (p < 0.001); (3) maximum urinary-flow rates increased by 3.7 ml/s compared to placebo (p < 0.001); (4) total urinary symptom scores decreased by 4.9 points compared to a nonsignificant decrease with placebo (p < 0.005). There was a 2.5-point decrease in irritative symptoms (urinary frequency, nocturia and urgency) as compared to a nonsignificant decrease with placebo (p < 0.005). After 3 months, the urinary symptoms and urodynamic changes were reversed but significantly greater than the baseline values (p < 0.001). The prostates showed regrowth to the initial sizes within 18-36 weeks. DMPA was better tolerated, except for a higher incidence of impotence, decreased libido and ejaculatory disorders, than in the placebo group. The quality of life is improved with DMPA since it did not produce hot flashes. It was concluded that single-dose DMPA 150 mg is a safe and effective treatment for prostatic obstruction where potency is a secondary consideration.
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PMID:Depot medroxyprogesterone in the management of benign prostatic hyperplasia. 853 77


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