Survey of prescriptions for triple whammy drug combinations with vitamin D as a possible fourth whammy.

BACKGROUND: Improper prescriptions can cause adverse reactions in patients with chronic kidney disease (CKD). MATERIALS AND METHODS: Hospital pharmacists investigated improper prescriptions, prerenal acute kidney injury (AKI) prescriptions, and adverse effects in AKI in 199 CKD patients at Kouseikai Hospital from July 2020 to June 2021, as well as combinations of "triple whammy" drugs (renin-angiotensin-system inhibitors, diuretics, and non-steroidal anti-inflammatory drugs) plus active vitamin D preparations. All participants (average age, 73.6 ± 16.2 years) were residents of Nagasaki City or its suburbs. RESULTS: Adverse reactions occurred in 38 of the 199 patients (19.1%). 13 patients had AKI, and 9 of these cases developed during the summer. A comparison of the 38 patients in the adverse reaction group and the 161 patients in the non-occurrence group showed that the former group was significantly older and had a lower body weight. In terms of renal function, estimated glomerular filtration rate (mL/min/1.73m2) was significantly lower, blood urea nitrogen/serum creatinine (BUN/S-Cr) was higher, dehydration was involved, and active vitamin D preparations were significantly more common in the adverse reaction group. CONCLUSION: Our findings suggest that concomitant prescription of active vitamin D in combination with the drugs that constitute the triple whammy should be avoided. The absence of hypercalcemia should be confirmed and adequate fluid intake should be encouraged to prevent prerenal nephropathy.

Role of Rho kinase and oxidative stress in cardiac fibrosis induced by aldosterone and salt in angiotensin type 1a receptor knockout mice.

Large clinical trials have shown that mineralocorticoid receptor (MR) antagonists improve cardiovascular or total mortality in patients with heart failure or myocardial infarction even though the patients were taking angiotensin-converting enzyme inhibitors or angiotensin II receptor (AT1R) antagonists. We previously reported that cardiac fibrosis induced by aldosterone and salt (Ald-NaCl) was exaggerated in AT1aR knockout mice (AT1aR-KOs). As the association of Rho kinase and oxidative stress was reported in Ald-NaCl-induced hypertension of rats, we investigated the effects of an MR antagonist (eplerenone) and a Rho kinase inhibitor (fasudil) on Ald-NaCl-induced cardiac fibrosis in AT1aR-KOs. AT1aR-KOs were administered aldosterone (0.15 microg/h) subcutaneously using an osmotic minipump and were provided with 1% NaCl drinking water for 4weeks. AT1aR-KOs receiving Ald-NaCl were treated with a low (30 mg/kg/day) or high (100mg/kg/day) dose of eplerenone or a fasudil (100mg/kg/day). Systolic blood pressure (SBP), left ventricular weight/body weight (LVW/BW), histological examination and cardiac gene expression were evaluated on day 28. Ald-NaCl treatment caused increases in SBP and LVW/BW in AT1aR-KOs, and eplerenone dose-dependently decreased SBP, LVW/BW and cardiac fibrosis. Fasudil decreased LVW/BW and cardiac fibrosis without affecting SBP. The expressions of connecting tissue growth factor (CTGF) and nicotinamide adenine dinucleotide phosphate (NADPH) components (p22phox, p47phox and p67phox) were increased in Ald-NaCl-treated AT1aR-KOs, and eplerenone or fasudil decreased the expression of CTGF and NADPH components. Phosphorylated ERM (a marker of the phosphorylation of Rho kinase) was increased in Ald-NaCl-treated AT1aR-KOs and was decreased by eplerenone. Nitrotyrosine and 4-hydroxy-2-nonenal, which indicate tissue damage via oxidative stress, were increased in AT1aR-KO and were apparently attenuated by eplerenone or fasudil. These results suggested that the Rho kinase pathway was activated to induce cardiac fibrosis by Ald-NaCl via MR in AT1aR-KOs. A Rho kinase inhibitor as well as eplerenone might be useful for cardiac damage by Ald-NaCl.