Discovery of novel aminobenzisoxazole derivatives as orally available factor IXa inhibitors.

Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated.

Urinary phosphorus excretion per creatinine clearance as a prognostic marker for progression of chronic kidney disease: a retrospective cohort study.

BACKGROUND: Whether phosphate itself has nephrotoxicity in patients with chronic kidney disease (CKD) is controversial, although phosphate excretion into urine may cause tubular damage in rat models. To evaluate actual phosphate load on each nephron, we examined the association between 24-h urinary phosphorus excretion per creatinine clearance (24-h U-P/CCr), a newly proposed index that is a surrogate for nephron load, and CKD progression in patients with CKD. METHODS: We conducted a single-center, retrospective cohort study. To avoid potential confounders for protein intake, only patients on our educational program for CKD with a fixed diet regimen and aged 20 years or older were included. The observation period was 3 years. Primary outcomes were CKD progression defined as a composite of end-stage kidney disease (ESKD) or 50 % reduction of estimated glomerular filtration rate. Patients were stratified by quartiles of 24-h U-P/CCr levels as Quartiles 1-4. The association was examined in three models: unadjusted (Model 1), adjusted for risk factors for CKD progression (Model 2), and factors that affect renal phosphate handling (Model 3). RESULTS: A total of 191 patients met the eligibility criteria. Patients with higher 24-h U-P/CCr showed a higher risk for the composite outcomes. The hazard ratios [95 % confidence interval] for 24-h U-P/CCr levels in Quartile 2, 3, and 4, respectively, versus Quartile 1 were 2.56 (1.15-6.24), 7.53 (3.63-17.62), and 12.17 (5.82-28.64) in Model 1; 1.66 (0.63-4.97), 3.57 (1.25-11.71), and 5.34 (1.41-22.32) in Model 2; and 3.07 (0.97-11.85), 7.52 (2.13-32.69), and 7.89 (1.74-44.33) in Model 3. CONCLUSIONS: Our study showed that higher phosphorus excretion per creatinine clearance was associated with CKD progression.

Effect of chitosan chewing gum on reducing serum phosphorus in hemodialysis patients: a multi-center, randomized, double-blind, placebo-controlled trial.

BACKGROUND: HS219 (40 mg chitosan-loaded chewing gum) is designed to bind salivary phosphorus as an add-on to available phosphorus binders. We performed a randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of HS219 in hemodialysis (HD) patients with hyperphosphatemia as an add-on to phosphorus binders. METHODS: Sixty-eight HD patients who were maintained on calcium carbonate (n=33) or sevelamer hydrochloride (n=35) were enrolled. The primary end point was a change in serum phosphorus levels. Secondary end points included changes in levels of salivary phosphorus, serum calcium, parathyroid hormone (PTH), and intact fibroblast growth factor (iFGF) 23. RESULTS: Sixty-three patients chewed either HS219 (n=35) or placebo (n=28) for 30 min, three times a day, for 3 weeks. HS219 was well tolerated and safe. However, HS219 was not superior to placebo with additional reduction of serum phosphorus with respect to phosphorus binders at the end of the chewing period. There were no significant effects of HS219 on reduction of salivary phosphorus, serum calcium, iPTH, or iFGF23 levels. CONCLUSIONS: The chitosan-loaded chewing gum HS219 does not affect serum and salivary phosphorus levels in Japanese HD patients with hyperphosphatemia. Our findings do not support previous findings that 20 mg of chitosan-loaded chewing gum reduces serum and salivary phosphorus levels. TRIAL REGISTRATION: [corrected] ClinicalTrials.gov NCT01039428, 24 December, 2009.

Does a proton pump inhibitor cause hypokalemia?

Proton pump inhibitors (PPIs) act only in the stomach, although the proton pump, H(+),K(+)-ATPase exists and contributes to H(+) and K(+) homeostasis in the kidney. We encountered two hypokalemic cases receiving omeprazole. These cases were women ages 69 and 80 years old. Their serum potassium levels decreased with accelerated urinary potassium excretion with the use of omeprazole, and recovered by potassium-supplement and the discontinuation of omeprazole. Because inhibitory effects of PPIs on H(+),K(+)-ATPase are exerted only in acidic condition, hypokalemia is not generally introduced by PPIs alone. However, in extreme alkalosis or impaired K(+)-recycling system, PPIs may cause hypokalemia unrelated to hypomagnesemia.

Pseudoaldosteronism caused by combined administration of cilostazol and glycyrrhizin.

We report a case of obvious pseudoaldosteronism which occurred after the additional administration of cilostazol against arteriosclerosis obliterans (ASO) for bilateral legs in a 65 year-old man patient who had safely received glycyrrhizin for the previous ten years. Serum potassium level of the patient had been kept above 4 mEq/L until initiating cilostazol in November, 2006, then gradually decreased to 2.5 mEq/L for the following seven months. Both plasma renin activity and aldosterone were suppressed under co-administration of the angiotensin converting enzyme inhibitor, imidapril and the angiotensin II receptor blocker, olmesartan, both of which had been prescribed for longer than a year. Urinary potassium excretion was accelerated even in the critical level of hypokalemia. Because other drugs and supplements had not been changed at least for a year, pseudoaldosteronism caused by the combination of glycyrrhizin and another triggering factor, possibly cilostazol was highly suspected. By discontinuation of glycyrrhizin, potassium supplement, and the additional administration of the aldosterone blocker, spironolactone, the serum potassium level returned to the normal level two weeks later, even though cilostazol had been continued to avoid progression in his ASO. This is the first report of a case exhibiting pseudoaldosteronism induced by the interaction of glycyrrhizin with cilostazol, not by glycyrrhizin alone.