piperidines and Prostatic-Hyperplasia

Metabolic syndrome (MetS) is a combination of metabolic disorders that can predispose individuals to benign prostatic hyperplasia (BPH). The inhibition of the cannabinoid 1 (CB1) receptor has been used to treat metabolic disorders in animal models. This study reports the use of a peripherally restricted CB1 antagonist (AM6545) and a neutral CB1 antagonist (AM4113) to improve MetS-related BPH in rats. Animals were divided into three control groups to receive either a normal rodent diet, AM6545, or AM4113. MetS was induced in the fourth, fifth, and sixth groups using a concentrated fructose solution and high-salt diet delivered as food pellets for eight weeks. The fifth and sixth groups were further given AM6545 or AM4113 for additional four weeks. Body and prostate weights were measured and prostate sections were stained with hematoxylin eosin. Cyclin D1, markers of oxidative stress and inflammation, and levels of the endocannabinoids were recorded. BPH in rats with MetS was confirmed through increased prostate weight and index, as well as histopathology. Treatment with either AM6545 or AM4113 significantly decreased prostate weight, improved prostate histology, and reduced cyclin D1 expression compared with the MetS group. Groups treated with CB1 antagonists experienced reduced lipid peroxidation, recovered glutathione depletion, restored catalase activity, and had lower inflammatory markers interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α). MetS rats treated with either AM6545 or AM4113 showed reduced concentrations of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the prostate compared with the MetS group. In conclusion, the CB1 antagonists AM6545 and AM4113 protect against MetS-induced BPH through their anti-proliferative, antioxidant, and anti-inflammatory effects.

Topics: Animals; Cannabinoid Receptor Antagonists; Cyclin D1; Humans; Male; Metabolic Syndrome; Piperidines; Prostatic Hyperplasia; Rats; Receptor, Cannabinoid, CB1

In the early stages, prostate cancer is androgen‑ dependent; therefore, medical castration has shown significant results during the initial stages of this pathology. Despite this early effect, advanced prostate cancer is resilient to such treatment. Recent evidence shows that derivatives of Cannabis sativa and its analogs may exert a protective effect against different types of oncologic pathologies. The purpose of the present study was to detect the presence of cannabinoid receptors (CB1 and CB2) on cancer cells with a prostatic origin and to evaluate the effect of the in vitro use of synthetic analogs. In order to do this, we used a commercial cell line and primary cultures derived from prostate cancer and benign prostatic hyperplasia. The presence of the CB1 and CB2 receptors was determined by immunohistochemistry where we showed a higher expression of these receptors in later stages of the disease (samples with a high Gleason score). Later, treatments were conducted using anandamide, 2-arachidonoyl glycerol and a synthetic analog of anandamide, methanandamide. Using the MTT assay, we proved that the treatments produced a cell growth inhibitory effect on all the different prostate cancer cultures. This effect was demonstrated to be dose-dependent. The use of a specific CB1 receptor blocker (SR141716) confirmed that this effect was produced primarily from the activation of the CB1 receptor. In order to understand the MTT assay results, we determined cell cycle distribution by flow cytometry, which showed no variation at the different cell cycle stages in all the cultures after treatment. Treatment with endocannabinoids resulted in an increase in the percentage of apoptotic cells as determined by Annexin V assays and caused an increase in the levels of activated caspase-3 and a reduction in the levels of Bcl-2 confirming that the reduction in cell viability noted in the MTT assay was caused by the activation of the apoptotic pathway. Finally, we observed that endocannabinoid treatment activated the Erk pathway and at the same time, produced a decrease in the activation levels of the Akt pathway. Based on these results, we suggest that endocannabinoids may be a beneficial option for the treatment of prostate cancer that has become nonresponsive to common therapies.

Topics: Adenocarcinoma; Apoptosis; Arachidonic Acids; Cell Cycle; Drug Screening Assays, Antitumor; Endocannabinoids; Glycerides; Humans; Male; MAP Kinase Signaling System; Neoplasm Proteins; Piperidines; Polyunsaturated Alkamides; Prostatic Hyperplasia; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Signal Transduction; Tumor Cells, Cultured

To investigate whether 7-[2-[4-(2-chlorophenyl) piperazinyl] ethyl]-1,3-di-methylxanthine (KMUP-1) inhibits the effects of testosterone on the development of benign prostatic hyperplasia and sensitizes prostate contraction.. A benign prostatic hyperplasia animal model was established by subcutaneous injections of testosterone (3 mg/kg/day, s.c.) for 4 weeks in adult male Sprague-Dawley rats. Animals were divided into six groups: control, testosterone, testosterone with KMUP-1 (2.5, 5 mg/kg/day), sildenafil (5 mg/kg/day) or doxazosin (5 mg/kg/day). After 4 weeks, the animals were killed, and prostate tissues were prepared for isometric tension measurement and western blotting analysis. KMUP-1, Y27632, zaprinast, doxazosin or tamsulosin were used at various concentrations to determine the contractility sensitized by phenylephrine (10 μmol/L).. KMUP-1 inhibited testosterone-induced phosphorylation of extracellular signal-regulated phosphorylated protein kinase and mitogen-activated protein kinase kinase and Rho kinase-II activation. Sildenafil and doxazosin significantly decreased benign prostatic hyperplasia-induced mitogen-activated protein kinase kinase and Rho kinase-II activation. The decreased expressions of soluble guanylate cyclase α1 was reversed by KMUP-1, doxazosin and sildenafil. Soluble guanylate cyclase β1 and protein kinase G were increased by KMUP-1, doxazosin, and sildenafil in the testosterone-treated benign prostatic hyperplasia group. Phosphodiesterase-5A was increased by testosterone and inhibited by KMUP-1 (5 mg/kg/day) or sildenafil (5 mg/kg/day). KMUP-1 inhibited phenylephrine-sensitized prostate contraction of rats treated with testosterone.. Mitogen-activated protein kinase 1/extracellular regulated protein kinases kinase, soluble guanylate cyclase/cyclic guanosine monophosphate, protein kinase/protein kinase G and Rho kinase-II are related to prostate smooth muscle tone and proliferation induced by testosterone. KMUP-1 inhibits testosterone-induced prostate hyper-contractility and mitogen-activated protein kinase 1/extracellular regulated protein kinases kinase-phosphorylation, and it inactivates Rho kinase-II by cyclic guanosine monophosphate, protein kinase and α1A-adenergic blockade. Thus, KMUP-1 might be a beneficial pharmacotherapy for benign prostatic hyperplasia.

Topics: Animals; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Guanylate Cyclase; Male; MAP Kinase Signaling System; Piperidines; Prostatic Hyperplasia; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; rho-Associated Kinases; Soluble Guanylyl Cyclase; Xanthines

Topics: Animals; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Guanylate Cyclase; Male; MAP Kinase Signaling System; Piperidines; Prostatic Hyperplasia; Receptors, Cytoplasmic and Nuclear; rho-Associated Kinases; Soluble Guanylyl Cyclase; Xanthines

The existing drugs for benign prostatic hyperplasia (BPH) are partially effective with undesirable side-effects; hence new agents acting by different mechanism(s) are required as supplements. Modulation of estrogen receptor signaling using selective estrogen receptor modulators (SERMs) offers an alternative approach for BPH management. Using human BPH-derived stromal cells and tissue explants in culture we evaluated two SERMs, DL-2-[4-(2-piperidinoethoxy)phenyl]-3-phenyl-2 H-1-benzopyran (BP) and Ormeloxifene (Orm) in comparison to Tamoxifen (Tam) and 4-hydroxytamoxifen (OHT). BP, OHT and Tam were more effective than Orm in reducing stromal cell proliferation of human BPH. BP was either equipotent or more effective than OHT and Tam in increasing estrogen receptor(ER)-ß, TGFß1, Fas and FasL, and in decreasing ER-α, AR, EGF-R and IGF-I expressions in BPH stromal cells. BP, Tam and Orm (1.0 mg/Kg) reduced rat prostate weights by almost same extent as Finasteride (Fin, 5.0 mg/Kg); however combination treatment (SERM+Fin) was more effective. BP was exceptionally efficient in reducing IGF-1 and cleaving PARP while combination treatments more effectively increased bax:bcl-2 ratio. Fin reduced acinar diameter and prostatic DHT level but increased testosterone, estradiol (E(2)) and E(2)/T+DHT ratio. SERMs, especially BP, reduced epithelial cell height drastically without significantly altering steroid hormone levels and E(2)/T+DHT ratio. Combination treatment reduced both acinar diameter and epithelial cell height with modest increase in E(2), T and E(2)/T+DHT. The study reveals the potential of SERMs per se for BPH management, and more effectively in combination with a 5α-reductase inhibitor. BP appears promising for further evaluation as a drug candidate for BPH and prostate cancer.

Topics: 5-alpha Reductase Inhibitors; Animals; Apoptosis; Aromatase; Benzopyrans; Cell Proliferation; Cell Survival; Cells, Cultured; Dihydrotestosterone; Dose-Response Relationship, Drug; Drug Therapy, Combination; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Finasteride; Gene Expression Regulation; Humans; Male; Piperidines; Prostate; Prostatic Hyperplasia; Rats; Rats, Sprague-Dawley; Receptors, Androgen; RNA, Messenger; Selective Estrogen Receptor Modulators; Signal Transduction; Stromal Cells; Tamoxifen; Testosterone; Tissue Culture Techniques

A 67-year-old man with neurally mediated syncope (NMS) complicated by prostatic hypertrophy responded well to combined therapy with pirmenol and midodrine. In 2003, syncope occurred while the patient was driving a car. Results of head-up tilt-table testing (HUT) suggested a mixed type of NMS. Oral administration of disopyramide provided severe urinary obstruction. Pirmenol treatment was not associated with syncope during ordinary HUT, but nausea, sweating, and syncope occurred during HUT with provocative administration of isosorbide dinitrate. Combined therapy with pirmenol and midodrine avoided syncope during HUT, and has prevented attacks since discharge from the hospital.

Topics: Aged; Anti-Arrhythmia Agents; Humans; Male; Midodrine; Piperidines; Prostatic Hyperplasia; Syncope, Vasovagal; Tilt-Table Test; Vasoconstrictor Agents

We synthesized some quinazoline-based compounds, such as FH-71 (ethyl 4-(3-(4-(2-methoxyphenyl)piperazinyl)aminoquinazolin-2-carboxylate), EW-65 (4-(3-(4-(2-methoxyphenyl)piperazinyl)propyl)aminoquinazolin-2-carboxamide) and EW-154 (2-(4-(4-(2-methoxyphenyl)piperazinyl)butyl)amino-4-cyclohexylamino-quinazolin), and then characterized their pharmacological properties in several tissues. All of these compounds produced potent inhibition of phenylephrine but not high K(+) or U46619 (11 alpha,9 alpha-epoxymethano-15S-hydroxy-prosta-5Z,13E-dienoic acid)-induced contractions in rat aorta, suggesting alpha(1)-adrenoceptor antagonist properties. With rat vasa deferentia and spleens as the functional alpha(1A)- and alpha(1B)-adrenoceptor models, respectively, FH-71 exhibited greater antagonistic potency in rat vas deferens, EW-154 in rat spleen, and EW-65 had similar effects in both tissues. The potency ratios of terazosin, FH-71, EW-65 and EW-154 against phenylephrine-induced contractions in rat vas deferens/spleen were 1, 19.04, 0.39 and 0.09, respectively. The results suggest that FH-71 is a selective alpha(1A)-adrenoceptor antagonist, whereas EW-154 exhibits more antagonistic selectivity against alpha(1B)-adrenoceptors. FH-71 also showed a greater potency than EW-65 and EW-154 against phenylephrine-induced contraction in human hyperplastic prostate. The pA(2) values were 8.34, 7.44 and 7.05, respectively. Furthermore, FH-71 and EW-65 were not cytotoxic whereas EW-154 (all in 10 microM) had a massive toxic effect (more than 80%) in human prostatic smooth muscle cells. These data show FH-71 to be a potent and selective alpha(1A)-adrenoceptor antagonist with activity in human hyperplastic prostate.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Aorta; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; Male; Piperazines; Piperidines; Prostatic Hyperplasia; Quinazolines; Rats; Receptors, Adrenergic, alpha-1; Spleen; Vas Deferens

Two series of compounds were recently reported as novel alpha1a-selective adrenoceptor antagonists. In the first series, a dihydropyrimidone moiety is attached to a 4-phenyl piperidine containing side chain, while in the second, it is linked to a 4-substituted phenyl piperazine containing side chain. These compounds having potential for the treatment of benign prostatic hyperplasia, a urological disorder in the older age male population, were subjected to a quantitative structure-activity relationship study. The analysis has helped to ascertain the role of different substituents in explaining the observed binding potencies of these analogues. In the first category of compounds, three sites R1, R2, and X were varied and from the quantitative structure-activity relationship, it emerged that X- and R1-substituents having respectively, the high values of field and resonance effects may lead to more potent alpha1a-antagonists. The substituent of R2, being either CH3 or C2H5, does not add to improve the activity and thus the site, at present, becomes redundant. This site may, however, be explored for some additional substituents in future. In the second series of compounds, the phenyl ring, linked to a piperazine moiety at the end of a side chain, was substituted with various groups onto different positions. From derived significant correlations, it appeared the less polar and/or bulky substituents at the meta- and para-positions and a more hydrophobic substituent at the para-position are advantageous.

Topics: Adrenergic Agonists; Adrenergic alpha-1 Receptor Antagonists; Binding Sites; Humans; Male; Piperazines; Piperidines; Prostatic Hyperplasia; Pyrimidinones; Quantitative Structure-Activity Relationship

The 4-oxospiro[benzopyran-2,4'-piperidine] ring system is contained within potent class III antiarrhythmic agents. We highlight how these agents can be chemically transformed into a new class of potent (< 1 nM) and selective (> 25-fold) alpha 1a-receptor subtype adrenergic antagonists.

Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Anti-Arrhythmia Agents; Benzopyrans; Humans; Male; Piperidines; Prostatic Hyperplasia; Rats; Spiro Compounds

A number of novel dihydropyridine derivatives based upon 1, 4-dihydro-3-(methoxycarbonyl)-2, 6-dimethyl-4-(4-nitrophenyl)-5-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (4) have been synthesized and tested at cloned human alpha adrenoceptors as well as the rat L-type calcium channel. Within this compound series, 5-(aminocarbonyl)-1,4-dihydro-2, 6-dimethyl-4-(4-nitrophenyl)-3-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (19) displayed good binding affinity and selectivity for the alpha1a adrenoceptor (pKi = 8.73) and potently inhibited (pA2 = 9.23) phenylephrine-induced contraction of the human prostate.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Aged; Aged, 80 and over; Animals; Brain; Calcium Channels; Humans; In Vitro Techniques; Male; Middle Aged; Muscle Contraction; Muscle, Smooth; Phenylephrine; Piperidines; Prostate; Prostatic Hyperplasia; Pyridines; Rats; Receptors, Adrenergic, alpha-1

We report the synthesis and evaluation of novel alpha1a adrenoceptor subtype-selective antagonists. Systematic modification of the lipophilic 4,4-diphenylpiperidinyl moiety of the dihydropyridine derivatives 1 and 2 provided several highly selective and potent alpha1a antagonists. From this series, we identified the 4-(methoxycarbonyl)-4-phenylpiperidine analogue SNAP 5540 (-) [(-)-63] for further characterization. When examined in an isolated human prostate tissue assay, this compound was found to have a Ki of 2.8 nM, in agreement with the cloned human receptor binding data (Ki = 2.42 nM). Further evaluation of the compound in isolated dog prostate tissue showed a Ki of 3.6 nM and confirmed it to be a potent antagonist (Kb = 1.6 nM). In vivo, this compound effectively blocked the phenylephrine-stimulated increase in intraurethral pressure (IUP) in mongrel dogs, at doses which did not significantly affect the arterial pressure (diastolic blood pressure, DBP), with a DBP Kb/IUP Kb ratio of 16. In addition, (-)-63 also showed greater than 40 000-fold selectivity over the rat L-type calcium channel and 200-fold selectivity over several G protein-coupled receptors, including histamine and serotonin subtypes. These findings prove that alpha1a adrenoceptor-subtype selective antagonists such as (-)-63 may be developed as uroselective agents for an improved treatment of BPH over nonselective alpha1 antagonists such as prazosin and terazosin, with fewer side effects.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Binding, Competitive; Blood Pressure; Cell Line; Dihydropyridines; Dogs; Drug Evaluation, Preclinical; Humans; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Piperidines; Prostate; Prostatic Hyperplasia; Rats; Receptors, Adrenergic, alpha-1; Recombinant Proteins; Stereoisomerism; Structure-Activity Relationship

Mouse prostatic hyperplasia has been induced experimentally by implanting fetal urogenital sinus tissue into the prostate gland of syngeneic mice. We compared the effects of castration and steroid antagonist administration on the growth of the prostate gland during both the early (15 days) and late (30 days) phases of prostatic enlargement. Castration at the time of induction of prostatic hyperplasia is by far the most effective method of inhibiting prostatic overgrowth. A comparison of castration for 7 days with the short-term (7 days) administration of steroid antagonists showed that during the early phase of prostatic enlargement castration is more effective than antiandrogen, which is more effective than 5 alpha-reductase inhibitors. In the late phase of mouse prostatic enlargement, castration for 7 days is less effective than treatment with either antiandrogen or a 5 alpha-reductase inhibitor. Our data indicate that treatment with a combination of an antiestrogen (keoxifene) with a 5 alpha-reductase inhibitor (in particular, 6-methylene progesterone) is the most effective combination for reducing prostatic overgrowth. The antiestrogen (keoxifene) treatment alone was ineffective in both the early and late phases of prostatic overgrowth.

Topics: 5-alpha Reductase Inhibitors; Androgen Antagonists; Animals; Azasteroids; Dihydrotestosterone; DNA; Drug Therapy, Combination; Estrogen Antagonists; Female; Male; Mice; Mice, Inbred BALB C; Orchiectomy; Piperidines; Progesterone; Prostatic Hyperplasia; Raloxifene Hydrochloride; Urogenital System

Ten male patients with prostatism, median age 63 years (range 50 to 70 years) were given an intravenous injection of a new serotonin antagonist, ketanserin, at a dose of 10 mg., and were investigated urodynamically before and after injection. A statistically significant increase in maximum and mean flow rates and a statistically significant decrease in urethral pressure profile measurements was observed. Supine CO2 cystometry showed no significant decrease in volumes of first sensation and bladder capacity. No subjective side effects were registered, but we observed a statistically significant decrease in mean blood pressure of 6.5 mm. Hg (range 5 to 14 mm. Hg). The mechanism behind the beneficial effect of ketanserin on micturition in prostatism is not yet known, but the results could explain an alpha blocking effect of the drug.

Topics: Aged; Blood Pressure; Humans; Ketanserin; Male; Middle Aged; Piperidines; Pressure; Prostatic Hyperplasia; Serotonin Antagonists; Urethra; Urinary Bladder; Urodynamics

The result of our examinations was that instillagel has a desinfecting effect in the urethra. This result is mathematically secured by means of the 2 I-test and highly significant. 95% of the preoperatively infected urethras were germ-free immediately after operation. This effect could not be proved in nifucin-gel-medicain as well as in urocomb. Using these lubricants all preoperatively infected urethras were also infected immediately after operation.

Topics: Anti-Infective Agents, Urinary; Bacterial Infections; Chlorhexidine; Drug Combinations; Electrosurgery; Humans; Lidocaine; Lubrication; Male; Nitrofurazone; Piperidines; Postoperative Complications; Propiophenones; Prostatic Hyperplasia; Prostatic Neoplasms; Tetracaine; Urethra; Urinary Bladder Neoplasms; Urinary Tract Infections

96 patients with benign hyperplasia of the prostate and dysuric complaints in stage I and beginning stage II were treated conservatively and medicamentously up to 12 months. In the collective of patients subdivided into 4 groups the conservative therapy was carried out in 3 groups with different phyto-preparations and in one group with gestonorone capromate. The voiding of the bladder was examined by means of uroflowmetry in intervals of four weeks before and after therapy. A clear success of the effect appeared only in the group of patients treated with gestonorone capromate. With phyto-preparations uroflowmetrically no significant effect on the disturbed voiding of the bladder could be established. The conservative treatment of the benign hyperplasia of the prostate should be carried out under uroflowmetrical control, in order not to miss the time of a necessary operative intervention.

Topics: Aged; Alkaloids; Follow-Up Studies; Gestonorone Caproate; Humans; Kymography; Male; Middle Aged; Nortropanes; Piperidines; Plant Extracts; Prostatic Hyperplasia; Pyrrolidines; Sitosterols; Urine

Topics: Benzilates; Female; Glaucoma; Humans; Male; Muscles; Piperidines; Prostatic Hyperplasia; Urinary Bladder Diseases