[Sustaining molecular response with very low dose ponatinib and further response after hemodialysis initiation in a patient with chronic myeloid leukemia].

A 46-year-old man was diagnosed with chronic myeloid leukemia (CML) in chronic phase. He was treated with imatinib, nilotinib, and dasatinib, but failed to achieve a complete cytogenetic response (CCyR). After tyrosine kinase inhibitor therapy, F317L BCR-ABL1 kinase domain mutation was detected. At age 66, the patient started ponatinib (PON) at 45 mg/day, and achieved CCyR within three months. Subsequently, PON was tapered to 15 mg once weekly due to arterial-occlusive events. PON was discontinued after a 3-year deep molecular response (≥ MR4.5). However, the patient lost MR4.0 within two months, and PON (15 mg once weekly) was restarted. He achieved MR4.0 again within one month, and then a deeper molecular response (MR5.0) after starting dialysis therapy at the same PON dose. The trough value of PON (15 mg once weekly) was 5.8 ng/ml, which suppressed F317L mutation in the CML clone. Currently, the patient is 77 years old and is sustaining MR5.0. Chronic renal failure may cause hyperabsorption and metabolic retardation in patients receiving PON. Initiation of hemodialysis may improve homeostasis resulting in enhanced anti-tumor immunity against CML.

Comparison of the factors associated with the short-term prognosis between elderly and non-elderly patients with anti-neutrophil cytoplasmic antibody-associated vasculitis: a retrospective observational study.

OBJECTIVES: The difference in factors associated with the prognosis between elderly and non-elderly patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is uncertain. We aimed to elucidate the clinical factors associated with the short-term prognosis (within 6 months from the start of the treatment) and investigate the differences in the associated factors between elderly and non-elderly individuals. METHODS: We performed a dual centre retrospective observational study of patients newly treated with AAV (eosinophilic granulomatous with polyangiitis was excluded). The primary outcome was all-cause death, and the secondary outcome was end-stage renal disease (ESRD) and infectious complications within 6 months after the start of treatment. We analysed factors associated with these outcomes using logistic regression analyses. RESULTS: Of the 79 patients, patients aged ≥75 years were defined as elderly (n=41), whereas those aged <75 years were de¬fined as non-elderly (n=38). In elderly patients, age was significantly associated with all-cause mortality. In the non-elderly patients, the geriatric nutritional risk index was significantly associated with all-cause death. The estimated glomerular filtration rate (eGFR) before the start of treatment was significantly associated with ESRD in elderly and non-elderly patients. In elderly patients, the Birmingham vasculitis score 3, eGFR, methylprednisolone pulse use, and cyclophosphamide use were significantly associated with infectious complications. Factors other than the serum albumin level were not significantly associated with infectious complications in the non-elderly population. CONCLUSIONS: The factors associated with all-cause death and infectious complications differed between elderly and non-elderly patients. Awareness of these differences may contribute to better management of AAV.

Relationship Between Immunosuppressive Therapy and the Development of Infectious Complications Among Patients with Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis: A Single-center, Retrospective Observational Study.

Introduction Infectious complications are the leading cause of death in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). However, the relationship between initial immunosuppressive therapy and the development of infectious complications and the details of infectious complications among patients with AAV are uncertain. We thus aimed to determine the association between initial immunosuppressive therapy and infectious complications. Material and methods Forty-seven patients with newly diagnosed AAV were enrolled in this retrospective observational study (patients with eosinophilic granulomatous polyangiitis were excluded). We statistically determined the association between types of initial immunosuppressive therapy (methylprednisolone pulse and/or cyclophosphamide therapy) and the development of infectious complications. In addition, we investigated the causes and timing of the onset of infectious complications. Results Twenty-one (21; 44.7%) patients required antibiotic, antimycotic, or antiviral therapy because of the development of infectious complications. Multiple logistic regression analyses adjusted for age and sex revealed that methylprednisolone pulse and cyclophosphamide therapy were significantly associated with the development of infectious complications (odds ratio (OR) 4.85, 95% confidence interval (CI) 1.09-21.5, p = 0.038; OR 5.32, 95% CI 1.28-22.2, p = 0.022, respectively). Bacterial pneumonia and sepsis occurred in 10 (47.6%) and 6 (28.6%) patients, respectively. Almost half of these infectious complications, including fungal infection, developed within six months from the start of initial treatment. Conclusion Among patients with AAV, methylprednisolone pulse and cyclophosphamide therapy may increase the risk of developing infectious complications, such as pneumonia and sepsis, including fungal infection, particularly within six months from the initiation of treatment.

Nephrotic Syndrome due to Focal Segmental Glomerulosclerosis Complicating Sjögren's Syndrome: A Case Report and Literature Review.

BACKGROUND: Renal tubular acidosis and tubulointerstitial nephritis constitute the primary renal complications associated with Sjögren's syndrome (SjS), and glomerulonephritis and nephrotic syndrome are rare. CASE PRESENTATION: A 79-year-old Japanese woman presented with bilateral leg edema and weight gain and was diagnosed with nephrotic syndrome. In addition, she reported a 5-year history of dryness of mouth and was diagnosed with SjS. Renal biopsy revealed segmental glomerulosclerosis, with some specimens showing collapse of the glomerular capillary loops, proliferation of glomerular epithelial cells, and sclerotic lesions at the tubular poles, without spike formation, double contour lesions, or any other changes of the glomerular basement membrane. Immunofluorescence staining showed no immune complex (immunoglobulin IgG, IgA, or IgM) or complement (C3) deposition in the glomerular capillary walls. Based on these findings, she was diagnosed with focal segmental glomerulosclerosis (FSGS). The administration of steroid and cyclosporine achieved complete remission of nephrotic syndrome. CONCLUSION: Although glomerular diseases are rare, a variety of glomerular lesions including FSGS are reported in patients with SjS. Therefore, renal biopsy is warranted in patients with SjS presenting with severe urinary abnormalities.

MACULAR ATROPHY FINDINGS BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY COMPARED WITH FUNDUS AUTOFLUORESCENCE IN TREATED EXUDATIVE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To compare the areas of choriocapillaris (CC) nonperfusion and macular atrophy (MA) in treated exudative age-related macular degeneration. METHODS: This was a prospective, observational, cross-sectional study. Forty-four eyes exhibiting MA (42 patients with age-related macular degeneration), with a dry macula, underwent fundus autofluorescence and optical coherence tomography angiography. The area of MA detected by fundus autofluorescence and CC nonperfusion detected by optical coherence tomography angiography was measured using image analysis software. The rates of concordance between the MA and CC nonperfusion areas were calculated. We qualitatively and quantitatively compared the areas of MA and CC nonperfusion in age-related macular degeneration eyes. RESULTS: The mean areas of MA and CC nonperfusion were 5.95 ± 4.50 mm and 10.66 ± 7.05 mm, respectively (paired t-test, P < 0.001). In 39 eyes (88.6%), the CC nonperfusion area was larger than the MA area, and the mean CC nonperfusion area was significantly larger than the mean MA area. Fundus autofluorescence matching optical coherence tomography angiography showed that the CC nonperfusion area was almost included in the MA area. The mean concordance rate for the MA area inside the CC nonperfusion area was 87.7 ± 13.9%. CONCLUSION: The MA and CC nonperfusion areas markedly overlapped. The area of CC nonperfusion correlated with the MA area. Choroidal ischemia might be involved in the pathogenesis of MA in treated age-related macular degeneration.

Anti-Vascular Endothelial Growth Factor Therapy for Macular Edema following Central Retinal Vein Occlusion: 1 Initial Injection versus 3 Monthly Injections.

PURPOSE: To compare the 12-month efficacy of 1 initial intravitreal injection of an anti-vascular endothelial growth factor (VEGF) agent followed by pro re nata (PRN) dosing with that of 3 initial monthly injections followed by PRN dosing in patients with macular edema (ME) after central retinal vein occlusion (CRVO). METHODS: Twenty-nine eyes received 1 initial injection (1+PRN group) and 20 received 3 monthly injections (3+PRN group). RESULTS: At month 12, changes in logMAR visual acuity from baseline were -0.172 ± 0.372 and -0.142 ± 0.317 in the 1+PRN and 3+PRN groups, respectively; the difference was not significant (p = 0.769). The number of anti-VEGF injections administered in the 3+PRN group (5.9 ± 2.1) was significantly greater than that in the 1+PRN group (4.1 ± 2.8; p = 0.022). CONCLUSION: When used for ME after CRVO, a 1+PRN regimen achieved 12-month outcomes similar to those of a 3+PRN regimen with fewer injections.

CLINICAL FEATURES OF TREATED AND UNTREATED TYPE 1 IDIOPATHIC MACULAR TELANGIECTASIA WITHOUT THE OCCURRENCE OF SECONDARY CHOROIDAL NEOVASCULARIZATION FOLLOWED FOR 2 YEARS IN JAPANESE PATIENTS.

PURPOSE: To evaluate the clinical features of Type 1 idiopathic macular telangiectasia (IMT) followed up for 2 years. METHODS: Forty-nine patients with unilateral Type 1 IMT were examined. Thirty-one IMT eyes were treated with direct laser photocoagulation and/or intravitreal bevacizumab; the remaining 18 eyes, with good vision or slight macular edema, were untreated. Changes in best-corrected visual acuity and central retinal thickness between baseline and 24 months after the initial visit were examined. RESULTS: Of 49 eyes, nine were treated with direct laser photocoagulation, 12 with laser photocoagulation and intravitreal bevacizumab, 10 with intravitreal bevacizumab monotherapy, whereas 18 did not receive any treatment. The mean logarithm of the minimum angle of resolution best-corrected visual acuity was 0.20 ± 0.19 (median, 20/29) and 0.13 ± 0.22 (median, 20/25) at baseline and 24 months, respectively (P = 0.023). The mean central retinal thickness was 375.0 ± 94.5 µm and 315.3 ± 78.5 µm at baseline and 24 months, respectively (P < 0.001). Retinal vein occlusion and retinal macroaneurysm occurred in six eyes and one eye, respectively, during follow-up. CONCLUSION: Treatment with laser photocoagulation and/or intravitreal bevacizumab may be effective for Type 1 IMT, 36.7% of IMT eyes required no treatment over a 2-year follow-up, and other retinal vascular events were not uncommon.

Coexistence of Anti-Glomerular Basement Membrane Glomerulonephritis and Membranous Nephropathy in a Female Patient with Preserved Renal Function.

Renal prognosis for anti-glomerular basement membrane (GBM) glomerulonephritis is poor. The greater the amount of anti-GBM antibody binding the antigen (type IV collagen of the glomerular basement membrane), the greater the number of crescents that develop in glomeruli, resulting in progression of renal impairment. Immunofluorescence staining reveals linear IgG depositions on glomerular capillary walls. Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in middle-aged to elderly patients. Immune complex is deposited in the sub-epithelial space of the glomerulus resulting in the development of a membranous lesion. Immunofluorescence staining reveals granular IgG depositions on glomerular capillary walls. Coexisting anti-GBM glomerulonephritis and MN are rare and, here we report a case of coexisting anti-GBM glomerulonephritis and MN with preserved renal function. There are some cases of coexisting anti-GBM glomerulonephritis and MN do not show severely decreased renal function. A 76-year-old Japanese woman presented with nephrotic syndrome, microscopic hematuria, and was positive for anti-GBM antibody. Kidney biopsy revealed linear and granular IgG depositions in glomerular capillary walls, crescent formations, and electron-dense deposits in the sub-epithelial space. She was diagnosed with anti-GBM glomerulonephritis and MN. Steroid and cyclosporine therapy achieved complete remission, and kidney function was preserved. In conclusion, coexisting anti-GBM glomerulonephritis and MN can have preserved renal function. IgG subclass of deposited anti-GBM antibody may be associated with the severity of anti-GBM glomerulonephritis. In addition, in the case of nephrotic syndrome with hematuria, we should consider the possibility of coexisting anti-GBM glomerulonephritis and MN.

Alpha1A-adrenoceptor antagonist improves underactive bladder associated with diabetic cystopathy via bladder blood flow in rats.

BACKGROUND: Patients with diabetes experience lower urinary tract symptoms. Cystopathy may evolve into underactive bladder (UAB), depending on the degree and duration of the symptoms. In the present study, we aimed to investigate the effects of silodosin, an alpha1A-adrenoceptor (AR) antagonist, on UAB in a rat model of diabetes mellitus (DM). METHODS: Female Sprague-Dawley rats (6 weeks old) were administered streptozotocin (STZ) (50 mg/kg, i.v.) to establish a DM model. One week after STZ administration, vehicle or silodosin (0.3 or 1 mg/kg/day) was delivered subcutaneously through an osmotic pump. Nine weeks after STZ administration (8 weeks after drug treatment), a catheter was implanted into the bladder under urethane anesthesia. After the measurement of emptied bladder blood flow (BBF), saline was continuously infused into the bladder and intravesical pressure and micturition volume were measured. In another experiment, the bladder was isolated and nerve markers were quantified. RESULTS: A cystometrogram showed that bladder capacity (BC), residual volume (RV), and bladder extension (BC/bladder weight) increased by 7.43, 10.47, and 3.59 times, respectively, in vehicle rats in comparison with normal rats. These findings suggested the occurrence of UAB-like symptoms in this model. Silodosin (1 mg/kg/day) inhibited the increase in BC and RV by 49.0% and 46.8%, respectively, and caused a decrease in BBF of approximately 25.5% (when the difference between normal and vehicle was set as 100%) in STZ rats. The nerve marker expression levels tended to be decreased in the bladders of STZ rats and these effects were ameliorated by silodosin. CONCLUSIONS: The STZ rats showed increased bladder extension and RV, symptoms that were suggestive of UAB, and these symptoms were ameliorated by silodosin. These results suggested that the alpha1A-AR antagonist would be useful for the prevention or treatment of UAB.

The effect of vitreomacular and cataract surgery on oxygen saturation in retinal vessels.

PURPOSE: To evaluate the effects of vitreomacular and cataract surgery on retinal oximetry in vitreomacular disease. PATIENTS AND METHODS: Thirty-eight eyes with epiretinal membrane (ERM) and 15 with idiopathic macular hole (MH) underwent 25 gauge pars plana vitrectomy combined with cataract surgery and intraocular lens implantation. Retinal oximetry was performed using the Oxymap T1 before, 1 month, and 6 months after surgery. Oxymap T1 simultaneously captures monochrome images of the fundus at two different wavelengths of light. Built-in Oxymap Analyzer software measures the oxygen saturation and vessel diameter. RESULTS: Mean arterial oxygen saturation significantly increased from 96.8%±6.2% to 100.2%±5.8% at 1 month and to 99.6%±5.8% at 6 months after surgery (P<0.01). Mean venous oxygen saturation also significantly increased from 54.6%±7.5% to 61.2%±6.4% at 1 month and to 62.6%±5.9% at 6 months after surgery (P<0.01). Mean arteriovenous (A-V) difference decreased from 42.2%±6.6% to 39.0%±7.8% at 1 month and to 37.0%±6.9% at 6 months after surgery (P<0.01). The ERM and MH groups showed similar changes in retinal oxygen saturation. However, there were no significant changes in the caliber of major retinal vessels after surgery (from 125.2±15.2 µm to 124.0±15.4 µm in artery, from 168.7±14.6 µm to 169.8±14.6 µm in vein). CONCLUSION: Oxymap T1 was able to measure the increase in oxygen saturation in retinal arteries and veins, which led to a decrease in the A-V difference in oxygen saturation after vitrectomy combined with cataract surgery.

Effect of rovatirelin, a novel thyrotropin-releasing hormone analog, on the central noradrenergic system.

Rovatirelin ([1-[-[(4S,5S)-(5-methyl-2-oxo oxazolidin-4-yl) carbonyl]-3-(thiazol-4-yl)-l-alanyl]-(2R)-2-methylpyrrolidine) is a novel synthetic agent that mimics the actions of thyrotropin-releasing hormone (TRH). The aim of this study was to investigate the electrophysiological and pharmacological effects of rovatirelin on the central noradrenergic system and to compare the results with those of another TRH mimetic agent, taltirelin, which is approved for the treatment of spinocerebellar degeneration (SCD) in Japan. Rovatirelin binds to the human TRH receptor with higher affinity (Ki=702nM) than taltirelin (Ki=3877nM). Rovatirelin increased the spontaneous firing of action potentials in the acutely isolated noradrenergic neurons of rat locus coeruleus (LC). The facilitatory action of rovatirelin on the firing rate in the LC neurons was inhibited by the TRH receptor antagonist, chlordiazepoxide. Reduction of the extracellular pH increased the spontaneous firing of LC neurons and rovatirelin failed to increase the firing frequency further, indicating an involvement of acid-sensitive K+ channels in the rovatirelin action. In in vivo studies, oral administration of rovatirelin increased both c-Fos expression in the LC and extracellular levels of noradrenaline (NA) in the medial prefrontal cortex (mPFC) of rats. Furthermore, rovatirelin increased locomotor activity. The increase in NA level and locomotor activity by rovatirelin was more potent and longer acting than those by taltirelin. These results indicate that rovatirelin exerts a central nervous system (CNS)-mediated action through the central noradrenergic system, which is more potent than taltirelin. Thus, rovatirelin may have an orally effective therapeutic potential in patients with SCD.

Effect of silodosin, a selective α(1A)-adrenoceptor antagonist, on voiding behavior and bladder blood flow in a rat model of bladder outlet obstruction.

This study was performed to investigate the effects of silodosin (selective α1A-adrenoceptor antagonist) on bladder blood flow (BBF) and bladder function in a rat model of bladder outlet obstruction (BOO) and to determine the expression of α1-adrenoceptor subtype mRNA in human and rat bladder microvessels. BOO was produced by partial ligature of the proximal urethra, which was maintained for 2 weeks. The BOO rats received either silodosin at a rate of 0.3mg/kg/day or vehicle subcutaneously via an osmotic pump for 2 weeks after BOO surgery. A metabolic cage study was performed in conscious animals. BBF was measured using a Laser Speckle Blood Flow Imager. Urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nerve growth factor (NGF) were measured. Immunohistological examinations of nerve distribution and NGF expression in the rat bladder were conducted. The expression of each α1-adrenoceptor subtype mRNA in human and rat bladder microvessels was determined by in situ hybridization. Silodosin ameliorated the increase in voiding frequency and decrease in mean voided volume in BOO rats in the metabolic cage study. Silodosin also abrogated the decrease in BBF in BOO rats. The levels of 8-OHdG and NGF in BOO rats were significantly decreased by administration of silodosin. Silodosin prevented the decrease in nerve distribution and increase in NGF expression. Human and rat bladder microvessels showed expression of all α1-adrenoceptor subtype mRNAs. The results presented here suggest that silodosin improves voiding behavior in rat models with BOO by inducing recovery of BBF.

Effect of switching therapy to pegaptanib in eyes with the persistent cases of exudative age-related macular degeneration.

Purpose of this study was to evaluate the efficacy of switching to pegaptanib monotherapy for persistent cases of exudative age-related macular degeneration (AMD).Out of 296 eyes of 296 patients treated with ranibizumab or ranibizumab combined with photodynamic therapy (PDT), 50 eyes of 50 AMD patients were found to be resistant to these treatments. Over a 12-month period, intravitreal pegaptanib (IVP) 0.3 mg was administered at intervals of 6 weeks until the exudation disappeared prospectively. All patients were examined with the following tests: best-corrected visual acuity (BCVA) and central retinal thickness (CRT), determined at the initial visit, before the first IVP (baseline), and at 12 months. The factors responsible for achieving dry macula with IVP were examined statistically.The rate of persistent cases with intravitreal ranibizumab (IVR) and/or PDT was 17.0%. The mean number of IVPs administered was 5.4 (range, 2-9). Logarithm of the minimal angle of resolution BCVA at 12 months was stable or improved by ≥ 0.3 in 49 eyes (98.0%), with a significant improvement noted between the baseline and final BCVA (P=0.01, paired t test). The CRT (mean ± standard deviation) was 446.9 ± 150.6 µm at the initial visit, 414.5 ± 146.5 µm at baseline, and 318.7 ± 99.0 µm at 12 months. There was a significant decrease in the mean CRT between the measurements at baseline and at 12 months after the first IVP (P=0.002, Bonferroni correction). At 12 months, the exudative change was completely resolved in 27 eyes (54.0%) and reduced in 21 eyes (42.0%). The number of previous IVR treatments was significantly correlated with dry macula at 12 months.After switching therapy to pegaptanib in persistent cases of AMD, most patients maintained or improved their BCVA and exhibited a positive treatment response at 12 months.

Hypoxia enhances the induction of human amniotic mesenchymal side population cells into vascular endothelial lineage.

Human amniotic mesenchymal side population (hAM-SP) cells have pluripotency and weak immunogenicity, and have promising roles in the field GAPDH of regenerative medicine. The aim of the present study was to determine whether hypoxic conditions induce the differentiation of hAM-SP cells into the vascular endothelial lineage. Mesenchymal cells were isolated from enzyme-treated amniotic membranes and stained with Hoechst 33342. The hAM-SP cells were negatively sorted by FACS and cultured in induction medium containing vascular endothelial growth factor (VEGF) under normoxic (20% O2) or hypoxic (1% O2) conditions for 1 or 2 weeks. The expression of endothelial markers such as kinase domain region (KDR), fms-like tyrosine kinase (Flt)-1, von Willebrand factor (vWF), vascular endothelial (VE)-cadherin and human vascular cell adhesion molecule (VCAM) at the gene and protein level was evaluated by real-time PCR and fluorescent immunostaining, respectively. The gene expression of KDR, Flt-1, VE-cadherin and vWF peaked after 2 weeks of culture. The protein expression of KDR and VE-cadherin was also enhanced after 2 weeks of culture under hypoxic conditions. To confirm the involvement of hypoxia-inducible factor (HIF) in the induction under hypoxic conditions, the expression of genes which are known to be upregulated by HIF was analyzed by DNA microarray. The expression of these genes increased under hypoxic conditions. hAM-SP cells cultured under hypoxic conditions differentiated into the vascular endothelial lineage, probably due to upregulation of the gene expression associated with angiogenesis through activation of the HIF system.

Effects of silodosin and tamsulosin on the urethra and cardiovascular system in young and old dogs with benign prostatic hyperplasia.

We examined whether the effects (efficacy on the urethra and hypotension) of silodosin (alpha(1A)-adrenoceptor antagonist) and tamsulosin (alpha(1A+1D)-adrenoceptor antagonist) in dogs with benign prostatic hyperplasia altered with age. We used young and old dogs, diagnosed as having benign prostatic hyperplasia by veterinarian's palpation. Under anesthesia, the increase in intraurethral pressure evoked by hypogastric nerve stimulation was measured, together with the level of systemic mean blood pressure. Each drug was administered intravenously in progressively increasing doses. At the end of the experiment, the prostate was isolated from each dog, then weighed and investigated pathologically to confirm benign prostatic hyperplasia. The wet weight of the prostate was greater in old dogs with benign prostatic hyperplasia than in young dogs with benign prostatic hyperplasia. By light microscopy, hyperplasia in the prostatic epithelium was confirmed in both groups. Silodosin (0.3-300 microg/kg) dose-dependently inhibited the hypogastric nerve stimulation-induced increase in intraurethral pressure (without significant hypotensive effects) in both young and old dogs with benign prostatic hyperplasia. Tamsulosin (0.3-300 microg/kg) also dose-dependently inhibited the intraurethral pressure increase in both groups, but it had a hypotensive effect that was significantly greater in old than in young dogs with benign prostatic hyperplasia. In conclusion, as regards the effect of silodosin on intraurethral pressure, potency was similar between young and old dogs with benign prostatic hyperplasia, and it was without significant hypotensive effects. We therefore suggest that silodosin might be a good medication for lower urinary tract symptoms in patients with benign prostatic hyperplasia in all age groups.

Uroselectivity in male dogs of silodosin (KMD-3213), a novel drug for the obstructive component of benign prostatic hyperplasia.

AIMS: Our main aim was to compare the prostatic selectivity of silodosin with that of other alpha(1)-adrenoceptor (AR) antagonists. METHODS: We examined uroselectivities in two sets of experiments namely, in vitro and in vivo functional studies using male dogs. In the in vitro study, after evaluating the inhibitory effects of silodosin on noradrenaline (NA)-induced contractions in the isolated prostate and isolated carotid artery using the Magnus method, we calculated prostatic selectivity. In the in vivo study, we examined the effects of drugs on the hypogastric nerve stimulation (HNS)-induced increase in intraurethral pressure (IUP) and on blood pressure. The uroselectivity of silodosin was compared with those of tamsulosin and naftopidil. RESULTS: In vitro, all drugs antagonized NA-induced contraction in both prostate and carotid artery. The prostatic selectivity of silodosin (79.4) was much higher than those of tamsulosin (1.78), naftopidil (0.55), BMY 7378 (0.115), and prazosin (0.01). In vivo, intravenously (i.v.) administered silodosin dose-dependently inhibited the HNS-induced increase in IUP with much less hypotensive effect than either tamsulosin or naftopidil, the uroselectivity (ED(15)/ID(50)) of silodosin (237) being significantly higher than those of tamsulosin (1.21) and naftopidil (2.65). CONCLUSIONS: Our results clearly demonstrate that silodosin is a potent and highly selective alpha(1A)-AR antagonist. A selective alpha(1A)-AR antagonist such as silodosin may have good potential as a less-hypotensive drug for the treatment of urinary dysfunction in benign prostatic hyperplasia patients.

A selective alpha1A-adrenoceptor antagonist inhibits detrusor overactivity in a rat model of benign prostatic hyperplasia.

PURPOSE: Alpha(1)-adrenoceptor antagonists relax the obstructed prostatic urethra and suppress the irritative symptoms frequently observed in patients with benign prostatic hyperplasia. We investigated the effects of 3 alpha(1)-adrenoceptor antagonists on urodynamics in rats with hormone induced benign prostatic hyperplasia to determine which alpha(1)-adrenoceptor subtype selective antagonists would suppress irritative symptoms. MATERIALS AND METHODS: Rats were treated with testosterone and 17beta-estradiol by weekly intramuscular injections. After 4 weeks a pressure flow study was done and the effects of the alpha(1)-adrenoceptor antagonists KMD-3213 silodosin, tamsulosin and prazosin on urodynamics were compared. We especially investigated the involvement of the bladder and prostatic urethra to clarify the mechanism of detrusor overactivity expression. RESULTS: Hormone treatment induced benign prostatic hyperplasia and resulted in detrusor overactivity, as determined by cystometry. Baseline perfusion urethral pressure and the phenylephrine induced increase in it were significantly higher in rats with vs without benign prostatic hyperplasia. Cystometry in hormone treated female rats did not show detrusor overactivity. KMD-3213 decreased detrusor overactivity, similar to other alpha(1)-adrenoceptor antagonists. CONCLUSIONS: These results suggest that an excessive response to sympathetic nerve stimulation, which is mainly mediated via alpha(1A)-adrenoceptor, in the hypertrophied prostate gives rise to detrusor overactivity. Furthermore, the alpha(1A)-adrenoceptor selective antagonist KMD-3213 would be suitable for improving irritative symptoms in patients with benign prostatic hyperplasia.

[Effect of silodosin on intraurethral pressure increase induced by hypogastric nerve stimulation in dogs with benign prostatic hyperplasia].

We compared the urethral and cardiovascular effects of silodosin (selective alpha(1A)-adrenoceptor antagonist), a novel medication for benign prostatic hyperplasia (BPH), with those of tamsulosin (selective alpha(1A)/alpha(1D)-adrenoceptor antagonist) and naftopidil (selective alpha(1D)-adrenoceptor antagonist). We evaluated the effects of these three drugs on the increase in intraurethral pressure (IUP) induced by electrical stimulation of the hypogastric nerve in anesthetized dogs with spontaneous BPH. All three drugs dose-dependently reduced both the increase in IUP and the mean blood pressure (MBP). The rank order of potencies was tamsulosin>silodosin>naftopidil for the reductions in both IUP and MBP. However, the uroselectivity (ED(15) value for hypotensive effect/ID(50) value for reduction in IUP) of silodosin (uroselectivity, 19.8) was about 21 and 4 times higher than that of tamsulosin (0.939) and naftopidil (4.94), respectively. These data suggest that silodosin might be one of the most useful medications for dysuria in BPH patients.

Cardiovascular effects of KUR-1246, a new tetrahydronaphthalen derivative beta2-adrenoceptor agonist and a selective uterine relaxant.

The aim of this study was to assess the cardiovascular effects of KUR-1246 (CAS 194785-31-4, (-)-bis(2-{[(2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl) phenyl] ethyl}amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy}-N,N-dimethylacetamide)monosulfate), a new beta2-adrenoceptor agonist tocolytic agent. In conscious dogs, the intravenous administration of KUR-1246 at 0.1 and 1 microg/kg had no effects on blood pressure, heart rate or femoral artery blood flow. KUR-1246 at 10 and 100 microg/kg significantly decreased blood pressure and increased heart rate. In the electrocardiograms, KUR-1246 did not affect QT intervals or QTc. In addition, the cardiac effects of KUR-1246 were evaluated in in vitro electrophysiological studies. KUR-1246 at 10 micromol/L did not affect action potential parameters (the maximal upstroke velocity, resting membrane potential, action potential amplitude and action potential durations) in isolated papillary muscles of guinea pigs or in the human ether-a-go-go related gene (HERG) tail current recorded from stably transfected human embryonic kidney (HEK) 293 cells. On the basis of these results, the effects of KUR-1246 in conscious dogs on the cardiovascular system appear to be limited to changes in blood pressure and heart rate. Therefore, KUR-1246 is unlikely to provoke ventricular arrhythmias by delaying the ventricular repolarization.