Evaluation of miR-122 to Predict High Dose Acetaminophen-Induced Liver Injury in Mice: The Combination Uses of 5-Fluorouracil

Administration of high doses of acetaminophen (APAP) is known to cause drug-induced liver injury (DILI) in humans. Therefore, the detection or prediction of these side-effects at an early stage using appropriate biomarkers is the need of the hour. Micro RNA (miR)-122 is expected to be a novel biomarker for liver injury. However, more evidence is required in various alternate situations such as its use in combination as APAP is often used along with anticancer drugs. In the present study, we aimed to evaluate the functions of miR-122 as a biomarker for liver injury in comparison with alanine aminotransferase (ALT) in a mice model with the APAP-induced liver injury (AILI). Consequently, there was a dose-dependent increase in miR-122 after administration of APAP intraperitoneally. Similar observations were made for ALT activity. Additionally, the expression of miR-122 increased in a more rapid manner compared to ALT activity. However, there was a variation in the miR-122 expression. Further, we investigated the drug-drug interaction between APAP and 5-fluorouracil using miR-122 and ALT in mice. As a result, the degree of AILI was not changed by the use of 5-fluorouracil in combination with APAP in mice

Glucagon-like peptide-1 receptor agonists as an effective therapeutic agent for diabetes mellitus and obesity in patients with schizophrenia under treatment with second-generation antipsychotics

Objectives: Cases of schizophrenia are commonly complicated with obesity and diabetes mellitus partially caused by excessive eating associated with the use of second-generation antipsychotics (SGAs). We aimed to study the efficacy of glucagon-like peptide-1 in patients with schizophrenia under treatment with SGAs. Methods: Diabetic patients with schizophrenia were included if their HbA1c levels increased more than 1% and/or their weight increased more than 3 kg after treatment with SGAs. Patients who developed diabetes after treatment with SGAs were also included. The participants were treated with GLP-1 receptor agonists for one year, and their changes in weight and HbA1c and any adverse events were evaluated. Results: Seven patients were treated with GLP-1 receptor agonists; their mean age was 46.1 yrs old (range; 26 to 59), mean body weight was 85.3 kg (65.5 to 96.8), and mean BMI was 33.8 (27 to 38.7). Five of them showed improvement in their HbA1c levels of 1.2% (0.1 to 3.4, p=0.089) with a weight loss of 3.7 kg (-9.6 to +3.5, p=0.14) on average. The adverse effects observed were all gastrointestinal, but were not severe enough to cause termination of the GLP-1 receptor agonist treatment. The GLP-1 receptor agonist was not effective in one patient, and another patient terminated the treatment in a few months. Conclusions: Although the number of patients studied was small, GLP-1 receptor agonists seem to be effective for treating diabetes and bringing about weight loss in patients with schizophrenia under treatment with SGAs

Effect of pH and Additives on the Compatibility between Vancomycin and Furosemide Injections

The physicochemical compatibility between injections of different agents is very important. An injection of the antibiotic vancomycin (VCM) is acidic and its standard pH range is 2.5-4.5. In clinical treatments, VCM injections are often used with LasixR (furosemide) injections. The LasixR injection is alkaline and its standard pH range is 8.6-9.6. Therefore, mixing VCM injections with LasixR injections may cause compatibility problems. We evaluated the effect of pH on the compatibility between VCM (original and two generic) and LasixR injections. Compatibility was not observed in non-pH-adjusted VCM with LasixR injections, but white crystals appeared when VCM injections adjusted to pH 2.5 experimentally were mixed with a LasixR injection, suggesting that the acidic condition of VCM injections cause compatibility. However, the residual rates of VCM did not change after 24 h in all mixtures. We analyzed the crystals by mass spectrometry and 1H-NMR, and identified them to comprise furosemide

Uremic Toxins Enhance Statin-Induced Cytotoxicity in Differentiated Human Rhabdomyosarcoma Cells

The risk of myopathy and rhabdomyolysis is considerably increased in statin users with end-stage renal failure (ESRF). Uremic toxins, which accumulate in patients with ESRF, exert cytotoxic effects that are mediated by various mechanisms. Therefore, accumulation of uremic toxins might increase statin-induced cytotoxicity. The purpose of this study was to determine the effect of four uremic toxins—hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionate, indole-3-acetic acid, and 3-indoxyl sulfate—on statin-induced myopathy. Differentiated rhabdomyosarcoma cells were pre-treated with the uremic toxins for seven days, and then the cells were treated with pravastatin or simvastatin. Cell viability and apoptosis were assessed by viability assays and flow cytometry. Pre-treatment with uremic toxins increased statin- but not cisplatin-induced cytotoxicity (p < 0.05 vs. untreated). In addition, the pre-treatment increased statin-induced apoptosis, which is one of the cytotoxic factors (p < 0.05 vs. untreated). However, mevalonate, farnesol, and geranylgeraniol reversed the effects of uremic toxins and lowered statin-induced cytotoxicity (p < 0.05 vs. untreated). These results demonstrate that uremic toxins enhance statin-induced apoptosis and cytotoxicity. The mechanism underlying this effect might be associated with small G-protein geranylgeranylation. In conclusion, the increased severity of statin-induced rhabdomyolysis in patients with ESRF is likely due to the accumulation of uremic toxins

Evaluation of Trace Elements in Augmentation of Statin-Induced Cytotoxicity in Uremic Serum-Exposed Human Rhabdomyosarcoma Cells

Patients with end-stage kidney disease (ESKD) are at higher risk for rhabdomyolysis induced by statin than patients with normal kidney function. Previously, we showed that this increase in the severity of statin-induced rhabdomyolysis was partly due to uremic toxins. However, changes in the quantity of various trace elements in ESKD patients likely contribute as well. The purpose of this study is to determine the effect of trace elements on statin-induced toxicity in rhabdomyosarcoma cells exposed to uremic serum (US cells) for a long time. Cell viability, apoptosis, mRNA expression, and intracellular trace elements were assessed by viability assays, flow cytometry, real-time RT-PCR, and ICP-MS, respectively. US cells exhibited greater simvastatin-induced cytotoxicity than cells long-time exposed with normal serum (NS cells) (non-overlapping 95% confidence intervals). Intracellular levels of Mg, Mn, Cu, and Zn were significantly less in US cells compared to that in NS cells (p < 0.05 or 0.01). Pre-treatment with TPEN increased simvastatin-induced cytotoxicity and eliminated the distinction between both cells of simvastatin-induced cytotoxicity. These results suggest that Zn deficiencies may be involved in the increased risk for muscle complaints in ESKD patients. In conclusion, the increased severity of statin-induced rhabdomyolysis in ESKD patients may be partly due to trace elements deficiencies