[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.

Congestive hepatopathy and acute pancreatitis as severe complications of mixed connective tissue disease.

Mixed connective tissue disease (MCTD) causes multiple organ dysfunctions, such as joint swelling, pulmonary fibrosis and hypertension, and serositis, but hepatopancreatic complications are rare. Here, we report a case of young man who exhibited acute severe liver dysfunction. He also had impaired cardiac function: both ventriculi were hypokinetic, but pulmonary hypertension and pericarditis were not observed. Since his liver and cardiac function markedly improved after commencing furosemide and carperitide, we considered congestive hepatopathy due to MCTD and accompanying heart failure. Heart failure and congestive hepatopathy recurred and he was treated with diuretics and prednisolone, but he passed away by co-occurrence of acute hemorrhagic pancreatitis. Necropsy revealed chronic hepatic congestion but not accompanying autoimmune hepatitis and hepatic vasculitis. We should consider congestive hepatopathy and hemorrhagic pancreatitis as serious complications of MCTD.

Clinical Survey of Decreased Blood Flow Rate in Continuous Renal Replacement Therapy: A Retrospective Observational Study.

BACKGROUND: Continuous renal replacement therapy (CRRT) is an essential procedure for patients with acute kidney injury in intensive care. It is important to maintain an adequate blood flow rate during CRRT. Several previous studies have reported the relationships between blood flow rate and filter lifespan, or circuit life, in CRRT. Here, we aim at elucidating the incidence and factors associated with a decreased blood flow rate in CRRT. METHODS: This is a retrospective observational study. From January 2014 to June 2017, 119 patients who underwent CRRT in the intensive care unit were enrolled. The definition of a decreased blood flow rate included situations in which the medical staff needed to decrease the blood flow volume. We statistically analyzed the association of the decreased blood flow rate with patients' clinical characteristics. RESULTS: Of 119 patients, 52 required a decreased blood flow rate during CRRT. Almost half of the cases occurred within one day of starting CRRT. None of the clinical factors (age, sex, height, sequential organ failure assessment (SOFA) score, catheter position, systemic infection, albumin, hemoglobin, and activating coagulation time) were significantly associated with decreased blood flow rate. CONCLUSIONS: A decreased blood flow rate often occurs during CRRT. Clinical factors significantly associated with the occurrence of the decreased blood flow rate were not detected in the current study. Further investigation regarding the occurrence of a decreased blood flow is warranted.

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.

A Case of Heparin-Induced Thrombocytopenia That Developed in the Therapeutic Course of Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) causes thrombocytopenia via an immunological mechanism, resulting in severe organ injury due to arterial-venous thrombosis. HIT often develops in hemodialysis patients owing to heparin use. Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic vasculitis, and cases of AAV complicated with HIT are rare. In addition, it mostly occurs in patients undergoing hemodialysis. CASE PRESENTATION: An 87-year-old woman presented with rapidly progressive renal failure and severe leg edema. She was diagnosed with AAV and treated with glucocorticoid and heparin calcium to prevent deep vein thrombosis. Eight days after the start of heparin calcium, her platelet count decreased and the anti-platelet factor 4-heparin complex antibody was strongly positive (>5.0 U/mL; the cutoff point of the anti-platelet factor 4-heparin complex antibody evaluated by the latex turbidity assay is 1.0 U/mL). She was diagnosed with HIT and treated with argatroban. Subsequently, her platelet counts increased gradually. CONCLUSION: We encountered a case of HIT that developed prior to the induction of hemodialysis in the clinical course of AAV. When AAV clinical course presents thrombocytopenia, the possibility of HIT should be considered.

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.

Absorption, disposition, metabolism and excretion of [14C]mizagliflozin, a novel selective SGLT1 inhibitor, in rats.

The pharmacokinetic and metabolite profiles of mizagliflozin, a novel selective sodium glucose co-transporter 1 inhibitor designed to act only in the intestine, were investigated in rats. Mizagliflozin administrated intravenously (0.3 mg/kg) and orally (3 mg/kg) declined with a short half-life (0.23 and 1.14 h, respectively). The absolute bioavailability was only 0.02%. Following intravenous administration of [14 C]mizagliflozin (0.3 mg/kg), radioactivity in plasma was also rapidly declined. Up to 24 h after oral administration of [14 C]mizagliflozin (1 mg/kg), radioactivity was recovered in the faeces (98.4%) and in the urine (0.8%). No remarkable accumulation of radioactivity in tissues was observed using tissue dissection technique and whole body autoradiography. Orally dosed [14 C]mizagliflozin was mostly metabolised to its aglycone, KP232, in the intestine. In the plasma, KP232 and its glucuronide were predominant. KP232 glucuronide was also prominent in the bile and was recovered as KP232 in the faeces possibly because of the deconjugation by gut microflora. Mizagliflozin was observed neither in the urine nor the faeces. These findings suggest that orally administered mizagliflozin is poorly absorbed, contributing to low systemic exposure; if absorbed, mizagliflozin is rapidly cleared from circulation.

Onset of Takotsubo Syndrome during the Clinical Course of Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis: A Case Report.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic vasculitis resulting in severe organ injuries. ANCA is a disease-labeled antibody of AAV, and myeloperoxidase (MPO) and proteinase 3 are the main targeted antigens of ANCA. Takotsubo syndrome, a transient cardiac dysfunction caused by emotional or physical stress, is characterized by ST-segment elevation and negative T waves in electrocardiogram, transient left ventricular asynergy, and absence of obstructive coronary disease. To the best of our knowledge, only two cases of coexistence of AAV and takotsubo syndrome have been reported. Herein, we report the case of AAV complicated with takotsubo syndrome. A 78-year-old Japanese woman presented with severe renal dysfunction, which was diagnosed as MPO-ANCA-associated systemic vasculitis. Despite the treatment with cyclophosphamide and glucocorticoid, the patient presented with severe respiratory failure due to alveolar hemorrhage and heart failure. Electrocardiography indicated newly developed T wave inversions. Echocardiography demonstrated severe left ventricular dysfunction with hypokinesis of the apical area. Moreover, coronary angiography revealed no noticeable stenotic or obstructive lesions. These findings indicate the onset of takotsubo syndrome. After immunosuppressive therapy, systemic vasculitis and takotsubo syndrome were improved. Although a coexisting case of AAV and takotsubo syndrome is rare, we have to consider the possible complication of takotsubo syndrome in case of presenting acute heart failure. Considering the present case and the previously reported coexisting cases of takotsubo syndrome and AAV, we propose that female sex, initiation of glucocorticoid therapy, and high titer of MPO-ANCA are potential risk factors of developing takotsubo syndrome.

One-year outcomes of fixed treatment of intravitreal aflibercept for exudative age-related macular degeneration and the factor of visual prognosis.

The aim of this study was to investigate the efficacy of periodic intravitreal aflibercept (IVA) in exudative age-related macular degeneration, and to explore the predictive factors for visual outcome.This is a prospective interventional case series.Fifty-two eyes of 52 treatment-naïve age-related-macula-degeneration patients were enrolled. All participants received IVA bimonthly following 3 monthly loading dose. The primary endpoint was change in best corrected visual acuity (BCVA) and central retinal thickness (CRT), and the secondary outcomes included changes in subfoveal choroidal thickness (SCT), macular atrophy (MA), and retinal average sensitivity (AS) determined by microperimetry at 12 months compared with baseline. The predictive factors for the change of BCVA were examined.Of 52 enrolled patients, 4 patients were drop out. Remaining 48 patients were examined. Mean logMAR BCVA significantly improved from 0.42 ±â€Š0.37 at baseline to 0.29 ±â€Š0.34 at 12 months (P = .008). Mean CRT and SCT significant reduced from 285.6 ±â€Š135.2 µm, 247.9 ±â€Š96.7 µm at baseline to 233.4 ±â€Š98.0 µm, 208.1 ±â€Š94.6 µm at 12 months, respectively (P < .001). At 12 months, 35 eyes of 48 eyes (72.3%) were archived dry macula. MA occurred in 7 eyes of 35 eyes with dry macula at 12 months (20.0%). AS was significant improved (P = .027) between baseline (median: 15.7 dB) and 12 months (median: 19.5 dB). The BCVA of the cases with MA involved fovea was significant worse. Age was significantly predicted for the BCVA at 12 months.IVA administered over 1 year improved BCVA, AS, and morphological findings, and the predictive factors for BCVA were age and MA-involved fovea.

Elevated plasma aldosterone levels are associated with a reduction in retinal ganglion cell survival.

OBJECTIVE: The purpose of this article is to investigate the relationship between the plasma concentration of aldosterone and changes in the number of retinal ganglion cells (RGCs) after systemic administration of aldosterone. METHODS: An osmotic minipump that was subcutaneously implanted into the midscapular region of rats administered 40, 80 or 160 µg/kg/day aldosterone or vehicle. Enzyme immunoassay kits were used to measure the plasma aldosterone concentrations two weeks after the systemic administration of aldosterone or vehicle. Six weeks after these systemic administrations, the number of RGCs was measured. RESULTS: The plasma aldosterone concentrations at two weeks after systemic administration of vehicle or 160 µg/kg/day aldosterone were 238 ± 17 pg/ml and 1750 ± 151 pg/ml (748.5% ± 183.2%), respectively. There was a significant decrease in the number of RGCs in the central retina of the rats after the administration of either 80 or 160 µg/kg/day aldosterone. In the peripheral retina, however, there was a significant decrease in the number of RGCs in 40, 80 or 160 µg/kg/day aldosterone. There was a significant correlation between the number of RGCs and plasma aldosterone concentration. CONCLUSIONS: After systemic administration of aldosterone, there was a negative correlation between the plasma aldosterone concentration and the number of RGCs.

Clinical Features of Central Serous Chorioretinopathy With Type 1 Choroidal Neovascularization.

PURPOSE: To evaluate the type 1 choroidal neovascularization (CNV) incidence and associated factors in eyes with central serous chorioretinopathy (CSC). DESIGN: Retrospective case series. METHODS: Records of 363 eyes (324 patients) with CSC were reviewed. Age, sex, CSC type, choroidal vascular hyperpermeability (CVH), best-corrected visual acuity (BCVA), subfoveal choroidal thickness (SCT), and systemic hypertension (HT) were assessed and compared between subjects with and without neovascular CSC. RESULTS: We identified 219 and 144 eyes with chronic and acute CSC, respectively. The mean participant age was 55.2 ± 12.0 years, and 58 (15.6%) eyes had neovascular CSC. Age (no CNV: 54.8 ± 12.1 years, CNV: 57.3 ± 10.9 years; P = .118) and SCT (no CNV: 388.0 ± 104.5 µm, CNV: 377.4 ± 108.9 µm; P = .487) were comparable between eyes with and without CNV. However, BCVA (logarithm of the minimum angle of resolution) was significantly worse in subjects with CNV (0.28 ± 0.33 [20/38] vs 0.15 ± 0.29 [20/28]; P = .014). Neovascular CSC occurred more often in women (72 [23.6%] vs 20 [34.5%], P = .099) and in cases of chronic CSC (171 [56.1%] vs 48 [82.8%], P < .001), CVH (205 [67.2%] vs 58 [100%], P < .001), and HT (91 [29.8%] vs 24 [41.4%], P = .092). Chronic CSC (P = .001), female sex (P = .075), and poor BCVA (P = .091) were associated with neovascular CSC (multiple regression). CONCLUSIONS: Chronic CSC, female sex, CVH, and poor BCVA are risk factors for CNV in eyes with CSC.

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.

A Case of Rapid Progressive Kidney Dysfunction with Severely Calcified Stenotic Aorta.

Coral reef aorta is rare type of atherosclerotic diseases with severe calcification in the visceral part of the aorta. We present a case of coral reef aorta with severe abdominal aortic stenosis in a 67-year-old man. The patient presented with hypertension, claudication, and rapid progression of renal dysfunction over several months. Angiography revealed a severely stenotic suprarenal abdominal aorta resulting in renal ischemia and dysfunction. In addition, his right kidney was completely atrophied. After open surgical repair of the stenotic aorta including renal artery reconstruction, renal function did not improve. There was stenotic anastomosis to the renal artery. After endovascular therapy to the stenotic anastomosis, renal function dramatically improved. Stenotic coral reef aorta may be the cause of kidney dysfunction. In addition, surgical complication of stenotic anastomosis may be successfully treated by endovascular therapy.

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.

PA21, a novel phosphate binder, improves renal osteodystrophy in rats with chronic renal failure.

The effects of PA21, a novel iron-based and non-calcium-based phosphate binder, on hyperphosphatemia and its accompanying bone abnormality in chronic kidney disease-mineral and bone disorder (CKD-MBD) were evaluated. Rats with adenine-induced chronic renal failure (CRF) were prepared by feeding them an adenine-containing diet for four weeks. They were also freely fed a diet that contained PA21 (0.5, 1.5, and 5%), sevelamer hydrochloride (0.6 and 2%) or lanthanum carbonate hydrate (0.6 and 2%) for four weeks. Blood biochemical parameters were measured and bone histomorphometry was performed for femurs, which were isolated after drug treatment. Serum phosphorus and parathyroid hormone (PTH) levels were higher in the CRF rats. Administration of phosphate binders for four weeks decreased serum phosphorus and PTH levels in a dose-dependent manner and there were significant decreases in the AUC0-28 day of these parameters in 5% PA21, 2% sevelamer hydrochloride, and 2% lanthanum carbonate hydrate groups compared with that in the CRF control group. Moreover, osteoid volume improved significantly in 5% of the PA21 group, and fibrosis volume and cortical porosity were ameliorated in 5% PA21, 2% sevelamer hydrochloride, and 2% lanthanum carbonate hydrate groups. These results suggest that PA21 is effective against hyperphosphatemia, secondary hyperparathyroidism, and bone abnormalities in CKD-MBD as sevelamer hydrochloride and lanthanum carbonate hydrate are, and that PA21 is a new potential alternative to phosphate binders.