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What is known and objective Cisplatin-based chemotherapy is a first-line treatment for advanced or metastatic urinary tract urothelial carcinoma (UC). Accurate assessment of renal function is indispensable for determining cisplatin dosing to enhance the safety and effectiveness of cisplatin. The objective of this study was to assess serum cystatin C (sCys C) levels in patients with urothelial carcinoma and to explore its clinical value as a serum marker of glomerular filtration rate (GFR). Methods This study retrospectively enrolled 18 UC patients treated with a combination of gemcitabine and cisplatin between April 2018 and November 2020. We calculated the estimated GFR (eGFR) based on serum creatinine (sCr) or sCys C and estimated Cr clearance (eCCr) based on sCr. The correlation, bias, accuracy and creatinine height index between eGFR or eCCr and measured GFR (mGFR) based on Cr clearance were calculated from urinary Cr and sCr. Results and discussion Estimated GFR based on sCys C correlated most strongly with mGFR. Moreover, the bias, mean error, mean absolute error and root mean square error were significantly lower in eGFRs based on sCyc C than in eGFRs based on sCr and eCCr. The correlation between eGFR based on sCys C/mGFR and creatinine height index was weaker than that between eGFR based on sCr/mGFR and creatinine height index, suggesting that sCys C was less affected by muscle mass. What is new and conclusion In UC patients, eGFR based on sCys C reflected renal function more accurately than eGFR based on sCr, suggesting that sCys C may be useful for assessing renal function in clinical practice.

Recently, the concept of psychonephrology was developed and has been recognized as a field of study that focuses on nephrology and mental health fields, such as psychiatry and psychosomatic medicine. Indeed, patients with chronic kidney disease frequently suffer from mental problems as the disease stage progresses. Most psychotropic drugs are hepatically metabolized, but some are unmetabolized and eliminated renally. However, renal disease may affect the pharmacokinetics of many psychotropic drugs, as the decreased renal function not only delays the urinary excretion of the drug and its metabolites but also alters various pharmacokinetic factors, such as protein-binding, enterohepatic circulation, and activity of drug-metabolizing enzymes. Therefore, when prescribing drug therapy for patients with both renal disease and mental issues, we should consider reducing the dosage of psychotropic drugs that are eliminated mainly via the kidney and also carefully monitor the blood drug concentrations of other drugs with a high extrarenal clearance, such as those that are largely metabolized in the liver. Furthermore, we should carefully consider the dialyzability of each psychotropic drug, as the dialyzability impacts the drug clearance in patients with end-stage renal failure undergoing dialysis. Therapeutic drug monitoring (TDM) may be a useful tool for adjusting the dosage of psychotropic drugs appropriately in patients with renal disease. We herein review the pharmacokinetic considerations for psychotropic drugs in patients with renal disease as well as those undergoing dialysis and offer new insight concerning TDM in the field of psychonephrology.

The aim of this study was to investigate the beneficial effects of sacran, a sulfated polysaccharide, on renal damage and intestinal microflora, in 5/6 nephrectomy rats as a model for chronic kidney disease (CKD). 5/6 Nephrectomy rats were divided into sacran treated and non-treated groups and examined for lethality after 4 weeks. The 5/6 nephrectomy rats were also divided into three groups: sacran treated, non-treated and AST-120 treated groups, and treated orally in a concentration-dependent manner for 4 weeks. Renal function was estimated by biochemical and histopathological analyses. Metagenomic analysis of feces from each group after 4 weeks was also performed and changes in intestinal microflora were compared. The administration of sacran to CKD rats at ≥19 mg/d increased their survival. In addition, the sacran-treated group improved CKD-related parameters in a concentration-dependent manner, and the inhibitory effect of 40 mg/d of sacran was comparable to that of AST-120. The changes in the intestinal microflora of the sacran treated group were positively correlated with an increase in the number of Lactobacillus species, which are known to be rich in beneficial bacteria, and the increment of this beneficial bacteria was negatively correlated with the concentration of indoxyl sulfate, a uremic toxin, in plasma. These results strongly suggest that the oral administration of sacran could contribute to the stabilization of intestinal microflora in CKD rats and to the reduction of oxidative stress as well as the inhibition of progression of CKD.

Chronic kidney disease (CKD) patients with secondary hyperparathyroidism (SHPT) have an increased risk of cardiovascular disease (CVD). Cinacalcet is a calcimimetic that permits impaired endothelial functions to be recovered via inhibiting parathyroid hormone (PTH) production in SHPT patients. However, the underlying mechanism for its action remains unknown. The purpose of this study was to examine the effect of cinacalcet on the redox state of human serum albumin (HSA), a reliable marker for assessing endothelial oxidative damage in SHPT patients who were receiving hemodialysis. Cinacalcet was administered to six SHPT patients for a period of 8 weeks. After 4 weeks of treatment, cinacalcet significantly decreased the oxidized albumin ratio which is a ratio of reduced and oxidized forms of HSA via increasing reduced form of HSA. Moreover, the radical scavenging abilities of HSA that was isolated from SHPT patients were increased by cinacalcet, suggesting the recovery of the impaired vascular anti-oxidant ability. Interestingly, the oxidized albumin ratio in SHPT patients was significantly higher than that in hemodialysis patients. In addition, the changes of intact PTH levels were significantly correlated with the oxidized albumin ratio. It therefore appears that PTH may induce oxidative stress in SHPT patients. In fact, an active analogue of PTH increased the production of reactive oxygen species in human endothelial cells. Thus, cinacalcet exhibits anti-oxidative activity through its pharmacological action. Additionally, cinacalcet itself showed radical scavenging activity. In conclusion, cinacalcet improves the redox status of HSA by inhibiting PTH production and partially by its radical scavenging action.

Serum creatinine (SCr) levels depend on muscle mass and are therefore elevated in people with high muscle mass, potentially leading to underestimation of kidney function in this population. Although recent therapeutic guidelines have shown measurement of serum cystatin C (ScysC) to be useful, this method has not been validated in people with high muscle mass. We conducted this study to investigate methods for more accurately estimating kidney function in people with high muscle mass. Linear regression analysis was used to assess the correlation of endogenous creatinine clearance (24-hour CLcr) and 24-hour CLcr × 0.715 (i.e., modified glomerular filtration rate (GFR)); with estimated kidney function from SCr and ScysC in 15 healthy young adult men with high muscle mass. A significant but weak positive correlation was observed between 24-hour CLcr and estimated CLcr by the Cockcroft and Gault formula (CG CLcr; R2 = 0.371, p = 0.016). The estimated GFR calculated from ScysC (eGFRcys) was significantly higher than CLcr × 0.715, but the two were not correlated (R2 = 0.125, p = 0.197). However, when CG CLcr and eGFRcr were adjusted by muscle mass parameters, the correlation between measured and estimated values improved. Further improvement was seen when participants with a fat mass greater than 25% were excluded (R2 = 0.623, p = 0.004; R2 = 0.510, p = 0.014; n = 11 for both). The results of our study suggest that currently used formulas for estimating kidney function, including eGFRcys, may not be appropriate for people with high muscle mass, but use of muscle mass parameters may improve predictivity. .

Objectives Grapefruit (Citrus paradisi) juice enhances the oral bioavailability of drugs that are metabolized by intestinal cytochrome P450 3A4 (CYP3A4). Patients are advised to avoid drinking grapefruit juice to prevent this drug–grapefruit juice interaction. The aim of this study was to investigate whether processing grapefruit juice with cyclodextrins (CDs) would result in preventing or inhibiting this interaction. Methods Grapefruit juice and the major furanocoumarins found in grapefruit, bergamottin (BG) and 6′, 7′-dihydroxy bergamottin (DHBG) were mixed with α, β and γCDs. The effects of these processed juice samples and furanocoumarins on CYP3A activity were compared with the corresponding values for unprocessed juices and furanocoumarins. Interactions between CDs and these furanocoumarins were also investigated by phase solubility and 1H NMR studies. Key findings The inhibition of CYP3A by grapefruit juice was significantly attenuated by processing particularly with γCD. Similar attenuation effects by γCD were observed in the cases of BG and DHBG. Furthermore, BG and DHBG were suggested to be strongly encapsulated in the cavity of γCD. Conclusion The encapsulation of BG and DHBG by γCD and the resulting attenuation of the inhibition of CYP3A activity by grapefruit juice may be applicable to juice processing for preventing drug-grapefruit juice interactions.

Non-steroidal anti-inflammatory medications are associated with renal impairment. However, there is little information on whether these medications affect postoperative renal function compared with acetaminophen. The objective of this study was to compare the effects of acetaminophen and loxoprofen, used as postoperative analgesic, effect on postoperative analgesia using propensity score matching analysis. We retrospectively enrolled 328 patients treated with loxoprofen or acetaminophen after open radical prostatectomy between October 2017 and February 2020. We analyzed postoperative pain intensity, the incidence rate of acute kidney injury, drug-induced liver injury, and rate of elevation in serum creatinine after open radical prostatectomy. Eighty-one matched pairs of patients treated with loxoprofen or acetaminophen were selected using propensity score matching analysis. The postoperative numerical rating scale was significantly higher in the acetaminophen group than in the loxoprofen group on postoperative day 5. The use of patient-controlled anesthesia and rescue analgesics was significantly higher in the acetaminophen group than in the loxoprofen group. The loxoprofen group had a significantly higher postoperative increase in serum creatinine than the acetaminophen group on postoperative days 5 and 8. The incidence of acute kidney injury was 4.9% in the loxoprofen group and 0% in the acetaminophen group, while the incidence of drug-induced liver injury was 0% in both groups. Acetaminophen appears to be safer than loxoprofen in terms of effects on renal function. Nevertheless, the number of acetaminophen doses and the dose per dose may need to be increased for patients with significant postoperative pain.

Creatinine (Cr) levels are strongly affected by muscle mass, and the estimated glomerular filtration rate (eGFR), a measure based on serum creatinine (SCr), is often overestimated in patients with sarcopenia. To evaluate the coefficient of determination (R2) between eGFR and the actual measured value, we performed a linear regression analysis of a modified GFR (mGFR: measured Cr clearance × 0.715) and various renal function estimates adjusted for muscle mass in 19 patients with sarcopenia. The eGFR values based on SCr (eGFRcr) were higher than those based on mGFR, although a high R2 (0.704; p < 0.001) was found between these values. There was no deviation between eGFR based on serum cystatin C (eGFRcys) and mGFR, although the R2 value 0.691 was equivalent to that of eGFRcr. In the equation used to calculate eGFRcr not adjusted for body surface area (mL/min), muscle mass parameters obtained from bioelectrical impedance analysis were used instead of actual body weight to recalculate the eGFRcr. The R2 between this eGFRcr and mGFR did not improve, although there was less deviation. However, assuming that all patients were female by using female coefficients for all patients, the R2 between eGFRcr-fcc (eGFRcr with female coefficient correction) and mGFR improved and was the highest (0.808) on substitution of appendicular skeletal muscle mass. The correlation between eGFRcr-fcc and mGFR improved over eGFRcys when muscle mass was substituted for body weight in the equation used to estimate eGFR in patients with sarcopenia and sex differences were removed.

Background Constipation is frequently observed in patients with chronic kidney disease (CKD). Lactulose is expected to improve the intestinal environment by stimulating bowel movements as a disaccharide laxative and prebiotic. We studied the effect of lactulose on renal function in adenine-induced CKD rats and monitored uremic toxins and gut microbiota. Methods Wistar/ST male rats (10-week-old) were fed 0.75% adenine-containing diet for 3 weeks to induce CKD. Then, they were divided into three groups and fed as follows: control, normal diet; and 3.0- and 7.5-Lac, 3.0% and 7.5% lactulose-containing diets, respectively, for 4 weeks. Normal diet group was fed normal diet for 7 weeks. The rats were observed for parameters including renal function, uremic toxins, and gut microbiota. Results The control group showed significantly higher serum creatinine (sCr) and blood urea nitrogen (BUN) 3 weeks after adenine feeding than at baseline, with a 8.5-fold increase in serum indoxyl sulfate (IS). After switching to 4 weeks of normal diet following adenine feeding, the sCr and BUN in control group remained high with a further increase in serum IS. In addition, tubulointerstitial fibrosis area was increased in control group. On the other hand, 3.0- and 7.5-Lac groups improved sCr and BUN levels, and suppressed tubulointerstitial fibrosis, suggesting preventing of CKD progression by lactulose. Lac groups also lowered level of serum IS and proportions of gut microbiota producing IS precursor. Conclusion Lactulose modifies gut microbiota and ameliorates CKD progression by suppressing uremic toxin production.

A female in her late 50s experienced dyspnea and was transported by an ambulance. Her hemoglobin score was low, and CT imaging showed a giant tumor in her stomach. The tumor perforated her liver and invaded the abdominal wall and duodenum around the Treitz ligament. She required surgery because of the massive hemorrhage due to the tumor. Total gastrectomy with lateral segmentectomy of the liver and resection of the duodenum and the ileum around the Treitz ligament were performed. At 1.5 months after surgery, chemotherapy for malignant lymphoma was successfully initiated.

It is important to calculate the drug removal by hemodialysis (HD) for drug dosing regimens in HD patients. However, there are limited and inconsistent information about the dialyzability of drugs by HD. Therefore, the aim of our study is to evaluate drug removal by utilizing a rat model of HD (HD rat) and to extrapolate this result to the drug removal rate in HD patients. HD rats received bilateral nephrectomy and HD for 2 h. The dialysis removal of 6 drugs was evaluated in HD rats. Dialysis efficiency, plasma protein binding rate (PBR) and distribution volume (Vd) of drugs were also measured. Furthermore, we examined the correlation between the dialyzability of drug in HD rats and humans and constructed the prediction formula of the drug dialyzability in HD patients. The clearance of urea and creatinine and normalized dialysis dose in HD rats were 0.83 ± 0.07 mL/min, 0.70 ± 0.08 mL/min, and 0.13 ± 0.06, respectively. The drug dialyzability in HD rats was similar to reported clinical data except for doripenem. A higher correlation was observed between drug dialyzability in reported clinical data and HD rats which were adjusted for PBR (r2 = 0.936; p < 0.001) compared to unadjusted (r2 = 0.812; p = 0.009). Therefore, we constructed the prediction formula of the drug dialyzability in HD patients by utilizing the HD rat model and PBR. This study is useful for evaluating the dialyzability of high-risk drugs in a clinical setting and might provide appropriate preclinical dialyzability data for new drug.

Background and Aims High-dose methotrexate (MTX) chemotherapy is used to treat a variety of malignancies, including lymphoma, lymphoid leukemia, and sarcomas. Since MTX binds to proteins at a binding ratio of 50%, and nearly 90% of MTX in the blood is excreted via the kidneys, impaired kidney function would cause accumulation of MTX and result in complications. We encountered 4 patients who developed acute renal failure following high-dose MTX administration, but recovered after several modalities of blood purification therapies at our hospital. To clarify which blood purification method might be the most effective to remove accumulated MTX, we retrospectively investigated the removal rate of MTX by different modalities of blood purification therapy. Four patients (3 males and 1 female) who developed acute renal failure immediately after the start of administration of high-dose MTX therapy received blood purification therapies, including hemodialysis (HD), hemodiafiltration (HDF), plasma exchange (HD + PE), direct hemoperfusion (DHP), or any combination of the above, from January 2010 to December 2015. Methods Case 1: Patient (female, 57 years old, weight 54 kg) received HD (9times) followed by HDF (5 times) for 4 h each using a cellulose triacetate (CTA) membrane. Case 2: Patient (male, 56 years old, weight 90.7 kg) received HD (8 times) with 2different membranes (polyethersulfone and polyarylate blended polymer (PEPA); CTA; polymethyl methacrylate (PMMA)) for 4 h each. Case 3: Patient (male, 79 years old, weight 56 kg) received HD (3 times) followed by HDF (6times), HD + PE (once) for 4 h each. Case 4: Patient (male, 23 years old, weight 104.6kg) received HDF using CTA (3 times) membranes, followed by HD + PE, HD + DHP (3 times) and DHP (once) for 4 h each. We retrospectively investigated the blood level of MTX before and after each of the blood purification therapies and compared the removal rate of MTX by the different modalities. Results and discussion The average dose of MTX prescribed was 1.1 g/m2 (0.9-3.8). The blood levels of MTX reduced from 29.4 μM (9.8-57.8) to 0.06 μM (0.02-0.09) after several treatment sessions, and improvement of the renal function was observed in all cases. The highest removal rate was observed with HD + DHP (61.7%, n = 3), followed by DHP (50.0%, n = 1), HDF (44.1%, n = 19), HD (34.6%, n = 23) and HD + PE (30.3%, n = 2). As for the most effective membrane used for HD, the highest removal ratio was observed with PEPA (69.6%, n = 3), followed by PMMA (36.5%, n = 3) and CTA (28.2% %, n = 17). In regard to the most effective modality for removing accumulated MTX from the blood, high removal efficiencies were observed for HD + DHP and DHP. Therefore, it appears that use of these modalities would be the most desirable, as these appear to be highly capable of effectively removing accumulated MTX. Higher removal rates were observed with the use of the PEPA membranes than with that of the CTA and PMMA membrane, probably due to the better adsorption capacities of PEPA membrane. From these results, we conclude that HD or HDF with a high-adsorption characteristics (PEPA) combined with DHP might be the most effective method for removing accumulated MTX from the blood, as well as controlling water removal and correcting electrolyte concentrations. Conclusion Improvement of the renal function was observed after several sessions of blood purification therapy in all patients who developed acute renal failure after high-dose MTX therapy. The removal efficiency of MTX was sufficiently high when HD + DHP, HDF or HD was performed, especially with the use of a membrane with high adsorption characteristics.

Nonalcoholic steatohepatitis (NASH), a more advanced form of nonalcoholic fatty liver disease (NAFLD), is associated with increased cardiovascular and liver-related mortality. Stroke-prone spontaneously hypertensive rats (SHRSP5/Dmcr) that are fed a high-fat and high-cholesterol diet develop hepatic lesions that are similar to those observed in human NASH pathology. We investigated the hepatic protective and antioxidant effects of surface-deacetylated chitin nanofibers (SDACNFs) that were administered to SHRSP5/Dmcr rats for 8 weeks. The administration of SDACNFs (80 mg/kg/day) resulted in a significant decrease in hepatic injury, oxidative stress, compared with the non-treatment. The SDACNFs also caused a reduction in the population of harmful members of the Morganella and Prevotella genus, and increased the abundance of the Blautia genus, a useful bacterium in gut microbiota. We therefore conclude that SDACNF exerts anti-hepatic and antioxidative effects not only by adsorbing lipid substances but also by reforming the community of intestinal microflora in the intestinal tract.

Acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) is the most popular analgesic/antipyretic agent in the world. APAP has been regarded as a safer drug compared with non-steroidal anti-inflammatory drugs (NSAIDs) particularly in terms of lower risks of renal dysfunction, gastrointestinal injury, and asthma/bronchospasm induction, even in high-risk patients such as the elderly, children, and pregnant women. On the other hand, the recent increasing use of APAP has raised concerns about its toxicity. In this article, we review recent pharmacological and toxicological findings about APAP from basic, clinical, and epidemiological studies, including spontaneous drug adverse events reporting system, especially focusing on drug-induced asthma and pre-and post-natal closure of ductus arteriosus. Hepatotoxicity is the greatest fault of APAP and the most frequent cause of drug-induced acute liver failure in Western countries. However, its precise mechanism remains unclear and no effective cure beyond N-acetylcysteine has been developed. Recent animal and cellular studies have demonstrated that some cellular events, such as c-jun N-terminal kinase (JNK) pathway activation, endoplasmic reticulum (ER) stress, and mitochondrial oxidative stress may play important roles in the development of hepatitis. Herein, the molecular mechanisms of APAP hepatotoxicity are summarized. We also discuss the not-so-familiar "dark side" of APAP as an otherwise safe analgesic/antipyretic drug.

Oxidative stress induced by hyperuricemia is closely associated with the renin-angiotensin system, as well as the onset and progression of cardiovascular disease (CVD) and chronic kidney disease (CKD). It is therefore important to reduce oxidative stress to treat hyperuricemia. We previously found that benzbromarone, a uricosuric agent, has a direct free radical scavenging effectin vitro. The antioxidant effects of benzbromarone were evaluatedin vivovia oral administration of benzbromarone for 4 weeks to model rats with angiotensin II- and salt-induced hypertension. Benzbromarone did not alter plasma uric acid levels or blood pressure but significantly reduced the levels of advanced oxidation protein products, which are oxidative stress markers. Furthermore, dihydroethidium staining of the kidney revealed a reduction in oxidative stress after benzbromarone administration. These results suggest that benzbromarone has a direct antioxidant effectin vivoand great potential to prevent CVD and CKD.

A high dietary intake of phosphorus is considered to be a significant health threat for hemodialysis (HD) patients. Prescription medications, which might be a major source of phosphorus, is largely unrecognized in Japan. However, the amount of phosphorus indicated on the package label, is not quantified. In this study, the phosphorus content of 22 of the most widely prescribed medications that are used in conjunction with HD therapy were examined and differences between branded and generic prescription medications were compared. All samples were selected from medications that are typically prescribed for HD patients. The samples were ground prior to analysis. Phosphorus was measured using the Wako L-Type Phosphate method. All instruments used in the study were calibrated according to the manufacturers' specifications. Amlodipine (15 mg/tablet) and paroxetine (30.0 mg/tablet) were found to contain higher contents of phosphorus than the medications tested. Differences in phosphorus content between branded and generic drugs was also determined. The phosphorus content of all generic paroxetine preparations was significantly lower than the values for identical branded medications. On the other hand, the phosphorus content of several generic amlodipine preparations were significantly different from those of similar, branded preparations. Specific information regarding the phosphorus content of prescribed medications used by HD patient needs to be made available to the dialysis community.

The interplay between oxidative stress, inflammation, and tissue fibrosis leads to the progression of chronic kidney disease (CKD). Edoxaban, an activated blood coagulation factor Xa (FXa) inhibitor, ameliorates kidney disease by suppressing inflammation and tissue fibrosis in animal models. Interestingly, rivaroxaban, another FXa inhibitor, suppresses oxidative stress induced by FXa. Thus, FXa inhibitors could be multitargeted drugs for the three aforementioned risk factors for the progression of CKD. However, the exact mechanism responsible for eliciting the antioxidant effect of FXa inhibitors remains unclear. In this study, the antioxidant effect of edoxaban was evaluated. First, the intracellular antioxidant properties of edoxaban were evaluated using human proximal tubular cells (HK-2 cells). Next, direct radical scavenging activity was measured using the electron spin resonance and fluorescence analysis methods. Results show that edoxaban exhibited antioxidant effects on oxidative stress induced by FXa, indoxyl sulfate, and angiotensin II in HK-2 cells, as well as the FXa inhibitory activity, was involved in part of the antioxidant mechanism. Moreover, edoxaban exerted its antioxidative effect through its structure-specific direct radical scavenging activity. Edoxaban exerts antioxidant effects by inhibiting FXa and through direct radical-scavenging activity, and thus, may serve as multitargeted drugs for the three primary risk factors associated with progression of CKD.

IntroductionPatients with chronic kidney disease (CKD) depend on advice from healthcare professionals to avoid using unsuitable over-the-counter (OTC) drugs. Recently, qualified, registered nonpharmacist salespersons became licensed to sell OTC drugs in Japan. However, registered salespersons' knowledge and awareness of precautions regarding unsuitable OTC drugs for use in patients with CKD are unclear.ObjectivesThis study aimed to clarify the awareness, knowledge, and implementation of precautions by registered salespersons regarding OTC drugs used by patients with CKD. Additionally, we evaluated the change of registered salespersons' knowledge and awareness of this topic generated by a pharmacist intervention.MethodsA questionnaire survey and pharmacist intervention were applied to 175 registered salespersons. The intervention comprised a 50-minute lecture imparted by a pharmacist who was trained in nephrology. The knowledge, awareness, and implementation of precautions by participants with respect to nonsteroidal anti-inflammatory drugs (NSAIDs) and antacids were evaluated before and after the intervention.ResultsApproximately half of the registered salespersons reported previous experience with selling OTC drugs that were inappropriate for patients with CKD (NSAIDs, 48.0%; antacids, 39.7%). Few participants recognized the need to check renal function when selling those drugs to such patients (NSAIDs, 25.7%; antacids, 47.5%). The registered salespersons' awareness and knowledge were significantly higher after the intervention than before it.ConclusionThe results indicate that before the intervention, the registered salespersons had low levels of awareness and knowledge regarding OTC drug use in patients with CKD despite having prior experience selling unsuitable OTC drugs. However, the pharmacist intervention improved the registered salespersons' awareness and knowledge. The educational program for registered salespersons might be necessary to prevent inappropriate OTC drug use by patients with CKD.

The concomitant use of herb and prescription medications is increasing globally. Herb-drug interactions are therefore a clinically important problem. Yokukansan (YKS), a Japanese traditional herbal medicine, is one of the most frequently used herbal medicines. It is effective for treating the behavioral and psychological symptoms of dementia. We investigated the potential effects of YKS on drug-metabolizing enzyme activities in humans. An open-label repeat-dose study was conducted in 26 healthy Japanese male volunteers (age: 22.7±2.3 years) with no history of smoking. An 8-h urine sample was collected after a 150-mg dose of caffeine and a 30-mg dose of dextromethorphan before and after the administration of YKS (2.5 g, twice a day for 1 week). The activities of cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A, xanthine oxidase (XO) and N-acetyltransferase 2 (NAT2) were assessed based on the urinary metabolic indices of caffeine and dextromethorphan, and the urinary excretion ratio of 6β-hydroxycortisol to cortisol. There were no statistically significant differences in the activities of the examined enzymes before or after the 7-d administration of YKS. Although further studies assessing the influence of YKS on the pharmacokinetics and pharmacodynamics of the substrates of the drug-metabolizing enzymes are needed to verify the present results, YKS is unlikely that a pharmacokinetic interaction will occur with concomitantly administered medications that are predominantly metabolized by the CYP1A2, CYP2D6, CYP3A, XO and NAT2.

Patients on dialysis are frequently administered high doses of potassium binders such as calcium polystyrene sulfonate (CPS) and sodium polystyrene sulfonate (SPS), which exacerbate constipation. Here, we compare the degree of constipation induced by CPS and SPS using a loperamide-induced constipation model to identify the safer potassium binder. Constipation model was created by twice-daily intraperitoneal administration (ip) of loperamide hydrochloride (Lop, 1 mg/kg body weight) in rats for 3 days. Rats were assigned to a control group, Lop group, Lop + CPS group or Lop + SPS group, and a crossover comparative study was performed. Defecation status (number of feces, feces wet weight, fecal water content and gastrointestinal transit time (GTT)) was evaluated. In the Lop + CPS group, GTT was significantly longer, and fecal water content was reduced. In the Lop + SPS group&mdash, although the fecal water content and GTT were unaffected&mdash, the number of fecal pellets and the fecal wet weight improved. Thus, SPS was less likely to cause constipation exacerbation than CPS. Considering the high frequency of constipation in dialysis patients with hyperkalemia, preferentially administering SPS over CPS may prevent constipation exacerbation.

The primary cause of death of hemodialysis (HD) patients is cardiovascular disease, and increased oxidative stress has been proposed to be involved in the disease pathogenesis. In this study, we examined the effect of olmesartan on oxidative stress induced by angiotensin II, lipopolysaccharide, indoxyl sulfate, advanced oxidation protein products (AOPP) or hydrogen peroxide (H2O2), which are known to be present at higher concentrations in the blood of HD patients, using human umbilical vein endothelial cells (HUVECs). Oxidative stress was evaluated by measuring the mean fluorescence intensity of CM-H2DCFCA, an ROS-sensitive fluorescent dye, in HUVECs. HUVECs were incubated with each of the above compounds in the presence or absence of olmesartan. Moreover, these oxidant-stimulated cells were also treated with the reactive oxygen species (ROS) inhibitor N-acetyl-cysteine (NAC), NADPH oxidase inhibitor diphenylene iodonium (DPI) or PKC inhibitor calphostin C. In addition, we investigated the effects of olmesartan on cytotoxicity and vascular endothelial growth factor (VEGF) secretion, which is involved in vascular inflammation in HUVECs induced by AOPP or H2O2. The treatment of these oxidant-stimulated cells with olmesartan resulted in a significant reduction in intracellular ROS production to an extent that was nearly equivalent to that of NAC, DPI or calphostin C. Furthermore, olmesartan reduced the cytotoxicity and VEGF secretion induced by AOPP or H2O2. These results demonstrated that the antioxidant activity of olmesartan might contribute to both its vasculoprotective and anti-hypertensive effects.

Uric acid exerts an important antioxidant effect against external oxidative stress under physiological conditions. However, uric acid itself can increase oxidative stress via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation in adipocytes and vascular cells. Uric acid transporter 1 is involved in the generation of this oxidative stress. Furthermore, uric acid locally activates the renin-angiotensin system, thus producing angiotensin II and subsequently increasing intracellular oxidative stress. Benzbromarone has been reported to suppress uric acid reabsorption via uric acid transporter 1 inhibition in renal tubular cells. In this study we evaluated the in vitro antioxidant effect of benzbromarone from several perspectives. First, the direct radical-trapping capacity of benzbromarone was measured by chemiluminescence assay and electron paramagnetic resonance spectroscopy. Second, the intracellular antioxidant activity of benzbromarone in hyperuricemia was evaluated using endothelial cells. In light of these results, benzbromarone is hypothesized directly to scavenge the superoxide anion radical. In addition, benzbromarone inhibited reactive oxygen species production that was induced by angiotensin II or uric acid in endothelial cells. These findings suggest that benzbromarone possesses the ability directly to scavenge radicals and may act as an antioxidant against uric acid and angiotensin II-induced oxidative stresses in endothelial cells at therapeutically achievable levels in blood.

Background/Aims: We have so far demonstrated the renoprotective effect of camostat mesilate (CM) in 5/6 nephrectomized rats at least partly through its antioxidant effect. However, precise mechanisms were not fully clarified. Therefore, we now examined the renoprotective and antioxidant mechanisms of CM by using the adenine-induced chronic kidney disease (CKD) rat model. Methods: In protocol 1, we analyzed the effect of CM on CKD. Rats were fed on a 0.75% adenine diet for 3 weeks to induce CKD followed by the experimental period with vehicle, CM, or hydralazine (HYD) treatment for 5 weeks. In protocol 2, we examined the safety of CM and HYD on the normal rats. In addition, we explored free radical scavenging activities of CM and its metabolites in vitro using electron paramagnetic resonance (EPR) spectroscopy. Results: CM, but not HYD, significantly reduced the serum creatinine levels, although both treatments showed similar reduction in the blood pressure. CM decreased mRNA expression and protein levels of fibrotic markers, the severity of renal fibrosis, the accumulation of oxidative stress, and the expression of NADPH oxidase components in the kidney. In the protocol 2, there were no statistically significant differences in general parameters except for the systolic blood pressure in HYD group. EPR study revealed that CM and its metabolites have potent hydroxyl radical scavenging activities in vitro. Conclusion: Our findings indicate that CM significantly ameliorates the progression of CKD partly through its antioxidant effect independently from its blood pressure-lowering effect. Our results suggest the possibility that CM could be a new therapeutic agent that could arrest the progression of CKD.

The present study sought to derive a simple formula for predicting the drug removal rates during hemodialysis. We examined the relationship between drug removal rates during hemodialysis and the molecular weights or pharmacokinetic parameters of injectable drugs (N = 90) obtained from pharmaceutical interview forms in Japan. Stepwise multiple regression analysis with the removal rate by hemodialysis as the objective variable adjusted for molecular weight or pharmacokinetic parameters as explanatory variables, showed that the logarithm of molecular weight (B = -18.87), the protein binding rate (B = -0.40), and the fraction of the unchanged drug excreted into the urine/volume of distribution (B = 0.05) were significantly and independently associated with drug removal rate by hemodialysis (α = 90.78, adjusted R

Acetaminophen, a common analgesic/antipyretic, is a frequent cause of acute liver failure in Western countries. The development of an effective cure against acetaminophen hepatotoxicity is crucial. Ethyl pyruvate, an ethyl ester derivative of pyruvic acid, has been identified as a possible candidate against acetaminophen hepatotoxicity in animal experiments. However, the mode of the hepatoprotective action of ethyl pyruvate remains unclear. We examined the hepatoprotective effect of ethyl pyruvate against hepatocyte injury and oxidative stress in a mouse model of acetaminophen hepatotoxicity. In addition, to examine whether ethyl pyruvate has direct hepatocellular protection against acetaminophen hepatotoxicity to counteract the influence of inflammatory cells, such as macrophages, we examined the effects of ethyl pyruvate on cellular injury induced by N-acetyl-p-benzoquinone imine, a toxic metabolite of acetaminophen, in a human hepatocyte cell line, HepG2 cells. Treatment with ethyl pyruvate significantly prevented increases in serum transaminase levels and hepatic centrilobular necrosis induced with an acetaminophen overdose in mice in a dose-dependent manner. Although hepatic DNA fragmentation induced by acetaminophen was also attenuated with ethyl pyruvate, nitrotyrosine formation was not inhibited. Ehyl pyruvate significantly attenuated mitochondria dehydrogenase inactivity induced by N-acetyl-p-benzoquinone imine in HepG2 cells. The attenuating effect was also observed in a rat hepatocyte cell line. Increases in annexin V and propidium iodide-stained cells induced by N-acetyl-p-benzoquinone imine were prevented with ethyl pyruvate in HepG2 cells. Pyruvic acid, a parent compound of ethyl pyruvate, tended to attenuate these changes. The results indicate that ethyl pyruvate has direct hepatocellular protection against N-acetyl-p-benzoquinone imine induced injury observed in acetaminophen overdose. The in vivo and in vitro results suggest that ethyl pyruvate attenuates acetaminophen-induced liver injury via, at least in part, its cellular protective potential.

Sustained-release olmesartan tablets (OLM) were prepared by the simple, direct compression of composites of anionic sulfobutyl ether-&beta, cyclodextrin (SBE-&beta, CD) and cationic spray-dried chitosan (SD-CS), and were evaluated for use as a sustained release preparation for the treatment of hypertension. An investigation of the interaction between OLM and SBE-&beta, CD by the solubility method indicated that the phase diagram of the OLM/SBE-&beta, CD system was the AL type, indicating the formation of a 1:1 inclusion complex. The release of OLM from tablets composed of the SD-CS/SBE-&beta, CD composite was slow in media at both pH 1.2 and at 6.8. The in vitro slow release characteristics of the SD-CS/SBE-&beta, CD composite were reflected in the in vivo absorption of the drug after normal rats were given an oral administration of the preparation. Furthermore, the SD-CS/SBE-&beta, CD composite continuously increased the antihypertensive effect of OLM in hypertensive rats, compared with that of the drug itself. These results suggest that a simple mixing of SD-CS and SBE-&beta, CD can be potentially useful for the controlled release of a drug for the continuous treatments of hypertension.

Background This study was conducted to clarify whether respiratory stimulants used to treat apnea of prematurity (AOP) attenuate or aggravate hypoxia-induced neuronal damage. Methods A human neuroblastoma cell line, SH-SY5Y cells, and hippocampal slice cultures from rat pups were exposed to hypoxia to induce cell injury. The effects of respiratory stimulants on cell injury were evaluated. Results Theophylline and doxapram did not have any effects against cell injury induced by hypoxia in SH-SY5Y cells and hippocampal slice cultures of rat pups, while caffeine protected these cells and the slice cultures from hypoxia. The protective effects of caffeine in SH-SY5Y cells disappeared with co-treatment by the adenosine A2A receptor agonist, CGS21680, and were mimicked by the adenosine A2AR antagonist, SCH58261. Meanwhile, co-treatment with phosphatidylinositol 3-kinase/AKT pathway inhibitors did not affect the protective effects of caffeine. Hydroxy radical scavenging activity of caffeine were not observed at the concentrations that produced cytoprotective activity, and radical scavengers did not have any effects on the cell injury induced by hypoxia in SH-SY5Y cells. Conclusions Caffeine significantly attenuated cell injury induced by hypoxia in SH-SY5Y cells and hippocampal slice cultures of rat pups, at least partly through A2AR antagonism. Caffeine can protect neuronal cells from injury induced by hypoxemia, and may be a beneficial treatment for AOP with neuroprotective potential.

Aims Acetaminophen is a safe antipyretic and analgesic drug within the clinically recommended dosage range, but overdose can cause fatal liver and or kidney damage. Most of the nonsteroidal anti-inflammatory drugs (NSAIDs) exert their analgesic effect via inhibition of cyclooxygenase, which also results in a reduction of renal blood flow. Therefore, the use of NSAIDs in pain treatment for chronic kidney disease (CKD) patients is of particular concern. Acetaminophen lacks the anti-inflammatory and anti-coagulatory properties of the NSAIDs. In this study, we investigate whether acetaminophen has an impact on the progression of renal failure. Main methods Acetaminophen (150 mg/kg/day or 750 mg/kg/day) or indomethacin (5 mg/kg/day) was orally administered to adenine-induced chronic renal failure model rats for 4 weeks. The plasma concentrations of acetaminophen and its metabolites were measured during the treatment period; renal function and oxidative stress in the rats were also monitored. Key findings Indomethacin significantly decreased the survival rate of renal failure model rats. In contrast, both low (150 mg/kg) and high (750 mg/kg) doses of acetaminophen improved the survival rate. The progression of renal failure was attenuated by acetaminophen (750 mg/kg) after administration for 2 weeks. The metabolites of acetaminophen were found to accumulate in plasma. Plasma glutathione concentration had significantly recovered after acetaminophen administration. Significance Acetaminophen has no effect on the progression of renal damage in adenine-induced renal failure model rats. This result is in part due to acetaminophen's antioxidant activity. These results suggest that acetaminophen is a suitable analgesic agent for treating CKD patients.

The interaction between arbekacin and the hemodialysis membrane is unclear. The aim of this study was to evaluate the adsorption of arbekacin (ABK) onto hemodialysis membranes and to establish a simpler system for evaluating the adsorption properties of the drug. First, small cut pieces of polysulfone or sulfonated polyacrylonitrile (AN69) hollow fiber membranes were stirred in a solution of ABK for the qualitative assessment. Then, we designed the experimental system that was approximately 1/100 of the actual size using a small dialyzer “mini-module” of our original design for the polysulfone or AN69. We circulated ABK solution in this system for the quantitative assessment. Finally, we administered ABK in subjects undergoing hemodialysis as a clinical trial to evaluate the adsorption of ABK onto polysulfone or AN69. In the qualitative assessment, the rates of ABK adsorption onto polysulfone and AN69 were 6.2 ± 2.9 and 49.8 ± 1.8 %, respectively. In the quantitative assessment, although there was almost no change in the circulating ABK concentration with the use of polysulfone, there was about 68 % decrease in the circulating ABK concentration with the use of AN69. In the clinical trial, clearance by the dialyzer using AN69 was high at 10 min after starting dialysis, despite the sieving coefficient being 0. However, reduction of ABK clearance was observed with time; the removal rate of ABK at the completion of the dialysis using polysulfone or AN69 was about 67 %, with no difference between the two membranes. The main limitation of this study was the small sample size in the clinical trial. These findings suggest that ABK is adsorbed onto AN69. Furthermore, the present adsorption experiment with a mini-module was considered useful as an evaluation system because it was easy to handle, using less solvent and drugs compared with a previous report, and it reflected the results of the clinical trial.

A ferric citrate formulation for treating hyperphosphatemia is a new therapeutic that not only suppresses the accumulation of phosphorus in patients with chronic kidney disease-mineral bone disorders (CKD-MBD), but also ameliorates anemia caused by iron deficiency. In contrast, it has been demonstrated that intravenous iron injection markedly increases oxidative stress. This study was designed to investigate the effect of a ferric citrate formulation on oxidative stress in CKD-MBD patients receiving hemodialysis therapy. Fifteen CKD-MBD patients undergoing dialysis were enrolled in this study. The patients were orally administered a ferric citrate formulation for 6 months. Their plasma phosphorus concentrations remained unchanged with the switch from other phosphorus adsorbents to the ferric citrate formulation. In addition, the ferric citrate formulation generally allowed for dose reduction of an erythropoiesis stimulating agent with an increased hematopoietic effect. The average values of plasma ferritin level increased after the introduction of a ferric citrate formulation, but did not exceed 100 (ng/mL). Interestingly, oxidative stress markers did not increase significantly, and anti-oxidative capacity was not significantly decreased at 6 months after the drug administration. Similarly, no change was observed in any inflammation markers. The ferric citrate formulation induces negligible oxidative stress in CKD-MBD patients receiving dialysis under the present clinical condition.

3-Carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), a furan fatty acid uremic toxin (UT) and a substrate for organic ion transporters, contributes to the accumulation of CMPF in renal tubular cells. Although oxidative stress induced by UTs has been proposed as a mechanism of its toxicity in chronic kidney disease, little information is available regarding the redox property of CMPF and its relation to renal cell damage. The findings herein show that CMPF enhances the production of reactive oxygen species (ROS) in HK-2 cells in the presence of angiotensin II (A-II), an inducer of O(2)(·-). When iron is also present, CMPF and A-II induce the Fenton reaction, resulting in a further increase in ROS production. Such CMPF-induced oxidative stress increases TGF-β1 secretion in HK-2 cells, and a positive correlation between CMPF-induced ROS production and the secretion of active TGF-β1 was observed. CMPF caused a reduction in cell viability which was negatively correlated with intracellular ROS production. These negative effects of CMPF in HK-2 cells were completely suppressed by probenecid, an inhibitor of organic anion transport. Interestingly, in vitro ROS assays indicate that CMPF directly interacts with superoxide anion radicals (O(2)(·-)) and peroxy radicals (LOO) to produce CMPF radicals. The subsequent interaction of CMPF radicals with dissolved oxygen leads to the overproduction of O(2)(·-). Based on these findings, we conclude that CMPF, which accumulates in the renal cells, appears to play a prominent role as a pro-oxidant which subsequently leads to renal cellular damage via the overproduction of O(2)(·-).