Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been attracting attention for cardiovascular as well as antidiabetic effects since the results of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME Trial) were reported. The hematocrit increases during treatment with SGLT2 inhibitors, which have a diuretic effect but do not cause sufficient hemoconcentration to increase the risk of cerebral infarction. Elevation of the hematocrit during SGLT2 inhibitor therapy is presumed to involve enhancement of erythropoiesis in addition to hemoconcentration. In patients with diabetes, the erythropoietin level increases after initiation of treatment with the SGLT2 inhibitor dapagliflozin and reaches a plateau in 2 -4 weeks. The reticulocyte count increases simultaneously, followed by elevation of hemoglobin and hematocrit. In patients with diabetes, the proximal tubules are overtaxed by excessive glucose reabsorption and the increased oxygen requirement causes tubulointerstitial hypoxia. Consequently, erythropoietin production is impaired because "neural crest-derived" fibroblasts surrounding the damaged renal tubules undergo transformation into dysfunctional fibroblasts. SGLT2 inhibitors reduce the workload of the proximal tubules and improve tubulointerstitial hypoxia, allowing fibroblasts to resume normal erythropoietin production. These drugs represent a new class of diuretics that have a renoprotective effect by improving tubulointerstitial hypoxia, which is the final common pathway to end-stage renal disease. In patients with diabetes, elevation of hematocrit may be a surrogate marker for recovery from reversible tubulointerstitial injury.
2-((1E,3E)-4-(6-( 11 C-methylamino)pyridin-3-yl)buta-1,3-dienyl) benzo [d]thiazol-6-ol ( 11 C-PBB3) is a clinically useful PET probe that we developed for in vivo imaging of tau pathology in the human brain. To ensure the availability of this probe among multiple PET facilities, in the present study we established protocols for the radiosynthesis and quality control of 11 C-PBB3 and for the characterization of its photoisomerization, biodistribution, and metabolism. Methods: 11 C-PBB3 was synthesized by reaction of the tert-butyldimethylsilyl desmethyl precursor (1) with 11 C-methyl iodide using potassium hydroxide as a base, followed by deprotection. Photoisomerization of 11 C-PBB3 under fluorescent light was determined. The biodistribution and metabolite analysis of 11 C-PBB3 was determined in mice using the dissection method. Results: 11 C-PBB3 was synthesized with 15.4% ± 2.8% radiochemical yield (decay-corrected, n 5 50) based on the cyclotron-produced 11 C-CO 2 and showed an averaged synthesis time of 35 min from the end of bombardment. The radiochemical purity and specific activity of 11 C-PBB3 were 98.0% ± 2.3% and 180.2 ± 44.3 GBq/μmol, respectively, at the end of synthesis (n 5 50). 11 C-PBB3 showed rapid photoisomerization, and its radiochemical purity decreased to approximately 50% at 10 min after exposure to fluorescent light. After the fluorescent light was switched off, 11 C-PBB3 retained more than 95% radiochemical purity over 60 min. A suitable brain uptake (1.92% injected dose/g tissue) of radioactivity was observed at 1 min after the probe injection, which was followed by rapid washout from the brain tissue. More than 70% of total radioactivity in the mouse brain homogenate at 5 min after injection represented the unchanged 11 C-PBB3, despite its rapid metabolism in the plasma. Conclusion: 11 C-PBB3 was produced with sufficient radioactivity and high quality, demonstrating its clinical utility. The present results of radiosynthesis, photoisomerization, biodistribution, and metabolite analysis could be helpful for the reliable production and application of 11 C-PBB3 in diverse PET facilities.
The "Japanese Clinical Guideline for Female Lower Urinary Tract Symptoms," published in Japan in November 2013, contains two algorithms (a primary and a specialized treatment algorithm) that are novel worldwide as they cover female lower urinary tract symptoms other than urinary incontinence. For primary treatment, necessary types of evaluation include querying the patient regarding symptoms and medical history, examining physical findings, and performing urinalysis. The types of evaluations that should be performed for select cases include evaluation with symptom/quality of life (QOL) questionnaires, urination records, residual urine measurement, urine cytology, urine culture, serum creatinine measurement, and ultrasonography. If the main symptoms are voiding/post-voiding, specialized treatment should be considered because multiple conditions may be involved. When storage difficulties are the main symptoms, the patient should be assessed using the primary algorithm. When conditions such as overactive bladder or stress incontinence are diagnosed and treatment is administered, but sufficient improvement is not achieved, the specialized algorithm should be considered. In case of specialized treatment, physiological re-evaluation, urinary tract/pelvic imaging evaluation, and urodynamic testing are conducted for conditions such as refractory overactive bladder and stress incontinence. There are two causes of voiding/post-voiding symptoms: lower urinary tract obstruction and detrusor underactivity. Lower urinary tract obstruction caused by pelvic organ prolapse may be improved by surgery.
Multidrug resistance-associated protein 1 (MRP1) acts as a defense mechanism by pumping xenobiotics and endogenous metabolites out of the brain. The currently available techniques for studying brain-to-blood efflux have significant limitations related to either their invasiveness or the qualitative assessment. Here, we describe an in vivo method, which overcomes these limitations for assessing MRP1 function, using positron emission tomography (PET) and a PET probe. 6-Bromo-7-[ 11 C]methylpurine was designed to readily enter the brain after intravenous administration and to be efficiently converted to its glutathione conjugate (MRP1 substrate) in situ. Dynamic PET scan provided the brain time-activity curve after injection of 6-bromo-7-[11 C]methylpurine into mice. The efflux rate of the substrate was kinetically estimated to be 1.4 h À1 with high precision. Moreover, knockout of Mrp1 gene caused approximately a 90% reduction of the efflux rate, compared with wildtype mice. In conclusion, our method allows noninvasive and quantitative assessment for MRP1 function in the living brain.
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