bxl628 has been researched along with Prostatic-Hyperplasia* in 9 studies
2 review(s) available for bxl628 and Prostatic-Hyperplasia
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Chronic inflammation in the pathogenesis of benign prostatic hyperplasia.
Benign prostatic hyperplasia (BPH) is a common disorder affecting 50-80% of the aged male population. Androgens and age have been traditionally considered the main determinants of prostate enlargement, but in the last years a potentially important role of chronic inflammation in BPH pathogenesis has emerged. Bacterial and non-infectious chronic prostatitis could represent inciting factors leading to tissue hyperproliferation, possibly via the recently demonstrated antigen-presenting capacity of prostatic stromal cells, enabling them to induce and sustain intraglandular immune responses. The prostate growth-promoting chemokine IL-8 could represent a direct link between chronic prostate inflammation and autocrine/paracrine stromal cell proliferation, in agreement with its marked secretion induced in BPH stromal cells by a combination of Th1 and Th17 cell-derived inflammatory cytokines. BPH stromal cells express the vitamin D receptor (VDR), which is up-regulated by exposure to inflammatory stimuli. The non-hypercalcaemic VDR agonist elocalcitol, shown to arrest BPH development by decreasing the intra-prostatic androgen signalling without directly interfering with systemic androgen action, exerts immunoregulatory and anti-inflammatory properties in different prostatic pathology characterized by growth and inflammation. The mechanism of action of VDR agonists supports an important role of chronic inflammation in BPH pathogenesis and strengthens the concept of these agents as a therapeutic option for pharmacological treatment of BPH. Topics: Androgens; Anti-Inflammatory Agents; Calcitriol; Chemokines; Chronic Disease; Cytokines; Humans; Inflammation; Interleukin-8; Male; Prostate; Prostatic Hyperplasia; Prostatitis; Receptors, Calcitriol; Signal Transduction; Stromal Cells | 2010 |
Emerging drug therapies for benign prostatic hyperplasia.
Benign prostatic hyperplasia (BPH) is the nonmalignant enlargement of the prostate gland caused by increases in number of both epithelial and stromal cells. Clinically, BPH leads to voiding dysfunction, which is most often referred to as lower urinary tract symptoms (LUTS). Historically, the only treatments for LUTS due to BPH were watchful waiting or surgery (transurethral or open prostatectomy). However, over the last 20 years medical therapy has taken a prominent role in the management of BPH. Current medical treatments for BPH include alpha-adrenergic receptor antagonists, inhibitors of the 5-alpha reductase enzyme and various phytotherapies. These agents are generally effective and safe; however, many patients are unable to tolerate the side effects or are refractory to medical management and require surgery. In light of this, many potential new therapies for the treatment of BPH are under development. Some represent a variation of current treatments, whereas others target novel molecular pathways within the prostate. The aim of this review is to examine current pharmacotherapies as well as to highlight emerging drugs that may improve our treatment of patients with LUTS secondary to BPH. Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; 5-alpha Reductase Inhibitors; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Antineoplastic Agents; Calcitriol; Cell Proliferation; Drug Therapy, Combination; Enzyme Inhibitors; Finasteride; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Indazoles; Male; Naphthalenes; Phytotherapy; Piperazines; Plant Extracts; Prostatic Hyperplasia; Randomized Controlled Trials as Topic; Receptors, Adrenergic, alpha-1; Serenoa | 2006 |
1 trial(s) available for bxl628 and Prostatic-Hyperplasia
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BXL628, a novel vitamin D3 analog arrests prostate growth in patients with benign prostatic hyperplasia: a randomized clinical trial.
To evaluate the effect of BXL628, a vitamin D3 analog, on prostate volume in patients with benign prostatic hyperplasia (BPH).. We conducted a phase II, double blind, randomized, placebo controlled, clinical study. Patients eligible were aged>or=50 years, had a diagnosis of BPH and a prostate volume>or=40 ml. Eligible patients were randomized and given either BXL628 150 mcg daily or placebo for 12 weeks. All randomized patients underwent at baseline and at the end of study pelvic MRI to measure prostatic volume, uroflowmetry (Qmax), American Urological Association Symptom Index (AUASI), serum PSA, testosterone, dihydrotestosterone and luteizing hormone.. A total of 119 patients were randomized: 57 patients to BXL628 and 62 to placebo. The percentage change of prostate volume at 12 week was -2.90 in the BXL628 group vs. +4.32 in the placebo group (p-value<0.0001). The estimated difference between treatments (BXL628 minus placebo) was -7.22% (95% confidence limit -9.27 to -5.18). Considering Qmax, mean change vs. baseline was -0.30 in BXL628 vs. +1.50 in the placebo group: this finding was not statistically significant. The mean change of the AUASI total score at final visit vs. baseline was -1.77 in the BXL628 group vs. -3.45 in the placebo group (p=not significant).. BXL628 was able to arrest prostate growth within 12 weeks in men aged>or=50 years with prostatic volume>or=40 ml. Its unprecedented mechanism of action may offer a new opportunity for the treatment of BPH. Topics: Aged; Aged, 80 and over; Calcitriol; Cell Division; Cholecalciferol; Double-Blind Method; Humans; Male; Middle Aged; Prostate; Prostatic Hyperplasia | 2006 |
6 other study(ies) available for bxl628 and Prostatic-Hyperplasia
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Human prostatic urethra expresses vitamin D receptor and responds to vitamin D receptor ligation.
Chronic inflammation is now considered a determinant of benign prostatic hyperplasia (BPH), promoting, together with the hormonal milieu, prostate overgrowth and lower urinary tract symptoms (LUTS). Prostatic urethra actively participates in determining progression of LUTS associated with BPH.. To investigate the expression of the vitamin D receptor (VDR) and the ability of the VDR agonist elocalcitol to reduce inflammatory responses in human prostatic urethra (hPU) cells.. Human prostatic urethra, prostate and bladder neck were obtained from patients affected by BPH. Immunohistochemical studies for VDR expression were performed in tissue samples, from which primary cell cultures were also derived. In hPU cells, proliferation and chemiotaxis were studied, along with Rho kinase (ROCK) activity (MYPT-1 phosphorylation) by western blot. Quantitative RT-PCR was performed for VDR, cyclooxygenase (COX-2), and interleukin (IL)-8 expression.. Urethra displays higher VDR expression compared to prostate and bladder neck tissues. The VDR agonist elocalcitol partially reverts COX-2 and IL-8 mRNA upregulation induced by a pro-inflammatory cytokine mixture (IL-17, interferon-γ, tumor necrosis factor-α) and inhibits cell migration in urethral cells. Elocalcitol prevents activation of ROCK, as previously demonstrated in bladder and prostate cell cultures.. Our results suggest that prostatic urethra is, within the lower urinary tract, a novel target for VDR agonists, as shown by the capacity of elocalcitol to inhibit ROCK activity and to limit inflammatory responses in human primary urethra cells. Topics: Aged; Calcitriol; Cell Culture Techniques; Cells, Cultured; Cytokines; Drug Evaluation, Preclinical; Gene Expression; Humans; Ligands; Male; Myocytes, Smooth Muscle; Prostate; Prostatic Hyperplasia; Receptors, Calcitriol; Urethra; Urinary Bladder | 2010 |
The vitamin D receptor agonist elocalcitol inhibits IL-8-dependent benign prostatic hyperplasia stromal cell proliferation and inflammatory response by targeting the RhoA/Rho kinase and NF-kappaB pathways.
Benign prostatic hyperplasia (BPH) is characterized by an important inflammatory component. Stimulation of human prostate stromal cells from BPH tissues with proinflammatory cytokines leads to secretion of IL-8, a chemokine involved in BPH pathogenesis. The vitamin D receptor (VDR) agonist elocalcitol can arrest prostate growth in BPH patients, but its mechanism of action in this pathology is still incompletely understood.. IL-8 levels were measured by real-time RT-PCR and ELISA. NF-kappaB translocation and COX-2 expression were evaluated by confocal microscopy. RhoA and Rho-kinase (ROCK) gene expression and functional activity were studied by real-time RT-PCR, immuno-kinase assays, Western blot analysis, confocal microscopy, and cell invasion.. Stimulation of BPH cells with IL-8 activates the calcium-sensitizing RhoA/ROCK pathway, as demonstrated by the increased membrane translocation of RhoA and by phosphorylation of the ROCK substrate myosin phosphatase target subunit 1 (MYPT-1). In agreement with these data, C3 exoenzyme, a selective RhoA inhibitor, inhibits IL-8-induced invasion of BPH cells. The VDR agonist elocalcitol significantly inhibits IL-8 production by BPH cells stimulated with inflammatory cytokines, and IL-8-induced proliferation of BPH cells. In addition, elocalcitol inhibits IL-8-induced membrane translocation of RhoA and MYPT-1 phosphorylation in BPH cells, and inhibits dose-dependently their IL-8-dependent invasion. The inhibition induced by elocalcitol of IL-8 production by BPH cells is accompanied by decreased COX-2 expression and PGE(2) production and by arrest of NF-kappaB p65 nuclear translocation, associated with inhibition of the RhoA/ROCK pathway.. These data provide a mechanistic explanation for the anti-proliferative and anti-inflammatory properties of elocalcitol in BPH cells. Topics: Calcitriol; Cell Proliferation; Cells, Cultured; Cyclooxygenase 2; Dinoprostone; Humans; Inflammation; Interferon-gamma; Interleukin-17; Interleukin-8; Male; NF-kappa B; Prostatic Hyperplasia; Receptors, Calcitriol; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Stromal Cells; Tumor Necrosis Factor-alpha | 2009 |
Elocalcitol, a vitamin D3 analog for the potential treatment of benign prostatic hyperplasia, overactive bladder and male infertility.
Elocalcitol, which had been under development by BioXell SpA, is a synthetic derivative of vitamin D3 that regulates cell proliferation and apoptosis via its binding to the vitamin D receptor. In preclinical studies, elocalcitol inhibited the androgen-dependent and androgen-independent proliferation of benign prostatic hyperplasia (BPH) cells more potently than finasteride, a 5alpha-reductase inhibitor. In a phase IIb trial in patients with BPH, treatment with elocalcitol resulted in a significantly reduced prostate volume compared with placebo; irritative urinary symptoms (frequency, urgency and nocturia) and urodynamic parameters were comparable to the alpha1-adrenoceptor antagonist tamsulosin. In a phase IIa trial in patients with prostatitis, elocalcitol significantly reduced levels of IL-8 in semen, suggesting improved quality and forward motility of sperm. However, phase IIb trial data from patients with overactive bladder (OAB) were less promising: elocalcitol failed to meet the primary endpoint despite demonstrating good efficacy in a phase IIa trial. Based largely on these disappointing data, BioXell decided to terminate all further clinical development of elocalcitol, including an uncompleted phase IIa trial in patients with male infertility. Given the novel mechanism of action, efficacy profile and improved tolerability of elocalcitol over existing classes of drugs, the compound could have potentially added to the armamentarium in the expanding therapeutic markets of BPH, OAB and male infertility. This possibility appears to have been negated by BioXell's recent decision to terminate all further development of elocalcitol. Topics: Animals; Apoptosis; Calcitriol; Cell Proliferation; Clinical Trials, Phase II as Topic; Female; Humans; Infertility, Male; Male; Prostatic Hyperplasia; Receptors, Calcitriol; Urinary Bladder, Overactive | 2009 |
Inhibition of prostate growth and inflammation by the vitamin D receptor agonist BXL-628 (elocalcitol).
The prostate is a target organ of vitamin D receptor (VDR) agonists and represents an extra-renal site of 1,25-dihydroxyvitamin D(3) synthesis, but its capacity to respond to VDR agonists has, so far, been almost exclusively probed for the treatment of prostate cancer. We have analyzed the capacity of VDR agonists to treat benign prostatic hyperplasia (BPH), a complex syndrome characterized by a static component related to prostate overgrowth, a dynamic one responsible for urinary irritative symptoms, and an inflammatory component. Preclinical data demonstrate that VDR agonists, and notably BXL-628 (elocalcitol), reduce the static component of BPH by inhibiting the activity of intra-prostatic growth factors downstream of the androgen receptor, and the dynamic component by targeting bladder cells. In addition, BXL-628 inhibits production of proinflammatory cytokines and chemokines by human BPH cells. These data have led to a proof-of-concept clinical study that has successfully shown arrest of prostate growth in BPH patients treated with BXL-628, with excellent safety. We have documented the anti-inflammatory effects of BXL-628 also in animal models of autoimmune prostatitis, observing a significant reduction of intra-prostatic cell infiltrate following administration of this VDR agonist, at normocalcemic doses, in mice with already established disease. These data extend the potential use of VDR agonists to novel indications that represent important unmet medical needs, and provide a sound rationale for further clinical testing. Topics: Animals; Calcitriol; Dogs; Humans; Inflammation; Male; Middle Aged; Molecular Structure; Organ Size; Prostate; Prostatic Hyperplasia; Receptors, Calcitriol | 2007 |
Human bladder as a novel target for vitamin D receptor ligands.
Human prostate is now considered a target for vitamin D receptor (VDR) ligands, such as BXL-628. Because BXL-628 inhibited prostate growth without interfering with androgen signaling, it represents a new option for benign prostate hyperplasia (BPH) therapy. However, BPH symptoms are related not only to prostate size, but also to compensatory bladder hypertrophy and eventual overactivity. We now report that human bladder expresses VDR (determined by real-time PCR immunohistochemistry and Western blot) and responds to VDR agonists, such as the natural ligand, calcitriol, and its synthetic and less hypercalcemic derivative, BXL-628. Experiments were conducted with stromal cells derived from human bladder neck obtained at surgery from BPH patients. BXL-628 counteracted keratinocyte growth factor (KGF) and androgen-induced cell proliferation and stimulated apoptosis with a parallel reduced expression of the survival oncoprotein Bcl-2. Prolonged serum starvation time-dependently pushed bladder stromal cells to express activated myofibroblast markers, such as desmin and smoothelin, without changing other contractile-related proteins and intermediate filaments, such as vimentin. Chronic exposure to BXL-628 prevented starvation-induced cell phenotype modification. Because hypertrophy and starvation-induced bladder remodeling are supposed to underlie bladder overactivity, it is possible that BXL-628 might be helpful in reducing not only cumbersome symptoms related to prostate overgrowth, but also those related to bladder irritation. Topics: Bone and Bones; Calcitriol; Cells, Cultured; Humans; Ligands; Male; Prostatic Hyperplasia; Receptor, Fibroblast Growth Factor, Type 2; Receptors, Calcitriol; Receptors, Fibroblast Growth Factor; Urinary Bladder | 2005 |
Inhibition of prostate cell growth by BXL-628, a calcitriol analogue selected for a phase II clinical trial in patients with benign prostate hyperplasia.
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.. Experiments with BXL-628 were carried out in human BPH cells and in the ventral prostate of intact and castrated rats.. BPH cell and rat prostate growth were evaluated along with morphological and biochemical hallmarks of apoptosis.. 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.. BXL-628 inhibited in vitro and in vivo prostate cell proliferation, and therefore might represent a novel, interesting option for the treatment of BPH. Topics: Animals; Calcitriol; Cell Division; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Humans; Male; Orchiectomy; Prostate; Prostatic Hyperplasia; Randomized Controlled Trials as Topic; Rats; Rats, Sprague-Dawley; Tumor Cells, Cultured | 2004 |