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Caffeine consumption is a risk factor for chronic daily headache, but few studies have addressed relationships between pediatric patient caffeine levels and headache severity. We examined associations between serum and urine caffeine levels and headache severity in childhood and adolescence migraine cases.Levels of caffeine and caffeine metabolites in serum and urine samples were determined by LC-MS/MS. Wilcoxon rank-sum test was used for comparisons of age, sleep time, headache severity, caffeine consumption, and caffeine detection. Spearman's rank correlation coefficient (ρ) was calculated for associations. Correlations with ρ≥ 0.3 and differences with p 0.05 were considered statistically significant.Of the 40 patients studied, 34 declared caffeine consumption and 6 declared no caffeine consumption. These two groups did not differ significantly in any of the above clinical parameters. LC-MS/MS analysis of both serum and urine samples revealed 9 caffeine-negative (level0.0625 μM) and 31 caffeine-positive cases. HIT-6 score was higher (p= 0.033) for the caffeine-positive vs. caffeine-negative group. Caffeine was detected by LC-MS/MS in serum and/or urine for 3 of the 6 patients who declared no caffeine consumption. No significant correlations were observed among age, sleep times, headache severity score, or levels of caffeine and caffeine metabolites.31 of 40 (77.5%) cases of childhood/ adolescence migraine showed serum and urine caffeine-positivity based on LC-MS/MS. HIT-6 score, a measure of headache severity, was significantly higher for caffeine-positive vs. -negative cases. Symptoms of childhood/ adolescence migraine were exacerbated by caffeine consumption.

Menkes disease is a rare hereditary disease in which systemic deficiency of copper due to mutation of the ATP7A gene causes severe neurodegenerative disorders. The present parenteral drugs have limited efficacy, so there is a need for an efficacious drug that can be administered orally. This study focused on glyoxal-bis (N(4)-methylthiosemicarbazonato)-copper(II (CuGTSM), which has shown efficacy in macular mice, a murine model of Menkes disease, and examined its pharmacokinetics. In addition, nanosized CuGTSM (nCuGTSM) was prepared, and the effects of nanosizing on CuGTSM pharmacokinetics were investigated. CuGTSM or nCuGTSM (10 mg/kg) was administered orally to male macular mice or C3H/HeNCrl mice (control), and plasma was obtained by serial blood sampling. Plasma concentrations of CuGTSM and GTSM were measured by LC-MS/MS and pharmacokinetic parameters were calculated. When CuGTSM was administered orally, CuGTSM and GTSM were both detected in the plasma of both mouse strains. When nCuGTSM was administered, the Cmax was markedly higher, and the mean residence time was longer than when CuGTSM was administered for both CuGTSM and GTSM in both mouse strains. With macular mice, the AUC ratio (GTSM/CuGTSM) was markedly higher and the plasma CuGTSM concentration was lower than with C3H/HeNCrl mice when either CuGTSM or nCuGTSM was administered. Absorption of orally administered CuGTSM was confirmed in macular mice, and the nano-formulation improved the absorption and retention of CuGTSM in the body. However, the plasma concentration of CuGTSM was lower in macular mice than in control mice, suggesting easier dissociation of CuGTSM.

In vitro–in vivo extrapolation (IVIVE) using human liver microsomes has been widely used to predict metabolic clearance, but some of the factors used in the process of prediction show variability f...

Ceftriaxone (CTRX) is a third-generation cephalosporin commonly used to treat infections such as community-acquired pneumonia and urinary tract infections caused by mainly Gram-negative bacteria and some Gram-positive bacteria. Here, we report a case of a patient on hemodialysis who had chorea-like symptoms with high blood concentration of CTRX. A 74-year-old Japanese woman receiving hemodialysis was admitted with obstructive cholangitis and was started on CTRX therapy at a dose of 2 g every 24 hours. On the 6th day after starting administration of CTRX, chorea-like symptoms appeared. We suspected that her symptoms were caused by a high blood concentration of CTRX. We performed a series of blood sampling to determine the concentration of CTRX at different time points before and after discontinuing CTRX administration. CTRX concentrations were higher than those expected in healthy adults, and her chorea-like symptoms had disappeared from the second day of discontinuation of CTRX. The association between CTRX blood concentration and chorea-like symptoms is unclear. However, measuring a series of plasma or serum concentrations from symptom onset to disappearance suggested that chorea-like symptoms appeared when the concentration exceeded approximately 450 μg/mL. Care should be taken when administering CTRX to patients with cholestasis undergoing hemodialysis, as blood CTRX levels may rise unexpectedly and result in complications.

We have previously shown that two enteral nutrition formulas suppressed gastric lesions induced by the oral administration of indomethacin (IND) in mice. However, the mechanism of their protective effect is unknown. In this study, the effect of the two enteral nutrition formulas on gastric lesions induced by subcutaneous IND injection was investigated, with the objective of exploring the possibility that they may interact directly with IND in the gastrointestinal tract. Ten-week-old, male, ICR mice were fasted, then orally given either purified water, Mermed® One, or 2-fold diluted Terumeal® 2.0α as enteral nutrition formula (25 mL/kg). IND was injected subcutaneously at 20 mg/kg after 30 min, and the stomach was removed 6 h later and fixed in formalin. The number and area of lesions in the stomachs of mice given enteral nutrition formula was reduced to 56–89% and 34–61%, respectively, compared with the mice given purified water. The time courses of plasma IND concentrations were comparable among the three groups. These results suggested that the effect of these enteral nutrition formulas on gastric lesions did not originate from their direct interaction with IND in the gastrointestinal tract or their effect on the disposition of IND.

Creatinine is excreted into urine by glomerular filtration and renal tubular secretion through drug transporters such as organic anion transporter 2 (OAT2), organic cation transporter 2 (OCT2), OCT3, multidrug and toxin extrusion protein 1 (MATE1), and MATE2-K. We aimed to investigate whether our method for estimating percentage changes in serum creatinine concentration (SCr) and creatinine clearance (CLcre) from the baseline is applicable for studying renal transporter inhibitors. We tested 14 compounds (cimetidine, cobicistat, dolutegravir, dronedarone, DX-619, famotidine, INCB039110, nizatidine, ondansetron, pyrimethamine, rabeprazole, ranolazine, trimethoprim, and vandetanib), which were reported to cause reversible changes in SCr and/or CLcre in healthy subjects excluding elderly. Percentage changes were estimated from the relative contributions of the forementioned transporters to CLcre and competitive inhibition by these compounds at their maximum plasma unbound concentrations. For 7 and 9 out of these compounds, changes in SCr and/or CLcre were estimated within 2- and 3-fold of observed values, respectively. Less than 10% changes in SCr and/or CLcre caused by cobicistat, dolutegravir, and rabeprazole were reproduced as such by our method. These findings suggest that our method can be used to estimate changes in SCr and CLcre caused by competitive inhibitions of renal drug transporters.

Fish oil supplements are good sources of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, which are important in the prevention and treatment of hypertriglyceridemia. The purpose of this study was to examine the content of EPA and DHA, oxidation markers and mercury of fish oil supplements marketed in Brasilia, Brazil. Fatty acid contents were determined by gas chromatography using internal (C23:0) and external methyl ester standards. For this analysis, samples were prepared by alkali-catalyzed methylation with boron trifluoride (14% in methanol). Mercury was determined by direct vapor detection method. Oxidation markers were evaluated by measuring peroxide value (PV), anisidine value (AV) and by calculating TOTOX. The adequacy of EPA and DHA ranged from 75.9 to 105.1% and from 88.9 to 137.4%, respectively, compared to the information in the label. Mercury concentration was above limit of quantification levels, between 11 and 15 mg/kg in 14.4% of the products. Twenty percent of the products exceeded recommended levels of PV and TOTOX. Despite the high percentage of adequacy of the parameters analyzed, about 2/3 of the products showed some inadequacies according to the law. These data deserve concern due to the potential side effects of oxidized and contaminated fish oils to their proclaimed health benefits. This survey shows the relevance of constant monitoring of fish oil quality, considering current legislation and scientific advance. DOI: http://dx.doi.org/10.17807/orbital.v11i3.1390

A chemoselective demethylation method for various methoxypyridine derivatives has been developed. Treatment of 4-methoxypyridine with L-selectride in THF for 2 h at reflux temperature afforded 4-hydroxypyridine in good yield; no reaction to anisole occurred. The utility of our method was demonstrated by the efficient synthesis of the metabolic substances of the antiulcer agent omeprazole. Chemoselective demethylation at the site of 3,5-dimethyl-4-methoxypyridine in the presence of 4-methoxybenzimidazole was achieved.

Rilpivirine is a non-nucleoside reverse transcriptase inhibitor, used for the treatment of human immunodeficiency virus type-1 infection. An open label study was conducted to investigate the pharmacokinetics (PK) and safety of a single oral dose of rilpivirine 25 mg in Japanese healthy adult subjects. No adverse events were reported. The mean Cmax (144.3 ng/mL) and AUCinf (4542 ng h/mL) in Japanese subjects were approximately 30 % higher than those reported from a similar study in Caucasian healthy subjects, whereas the median tmax and mean t1/2 values were comparable between studies. A simple physiologically based PK model was developed to characterize the rilpivirine PK profile. The model adequately described rilpivirine PK profiles, and well-predicted drug-drug interactions. With exploration using the model, body size and CYP3A4 abundance were identified as factors which explained the observed inter-ethnic difference in rilpivirine exposure. The inter-ethnic difference in rilpivirine exposure was however considered not clinically relevant, since inter-individual variabilities of those intrinsic factors are larger than inter-ethnic ones; and the observed AUCinf in Japanese subjects was within the range of AUCtau associated with efficacy and safety in Phase 3 studies. This study results support the use of rilpivirine without dose modification specific to Japanese patients.

This paper proposes a method for estimating lighting environments from an AR marker coupled with the structural color patterns inherent to a compact disc (CD) form-factor. To achieve photometric consistency, these patterns are used as input to a Conditional Generative Adversarial Network (CGAN), which allows us to efficiently and quickly generate estimations of an environment map. We construct a dataset from pairs of images of the structural color pattern and environment map captured in multiple scenes, and the CGAN is then trained with this dataset. Experiments show that we can generate visually accurate reconstructions with this method for certain scenes, and that the environment map can be estimated in real time.

Fatty acid synthase (FASN) is a key enzyme in fatty acid biosynthesis that is usually over-expressed in patients with breast cancer, but its relationship with the patient's dietary habit is not clear. A higher intake of n-3 polyunsaturated fatty acids is related to reduced breast carcinogenesis in vitro and in vivo. The aim of this study was to clinically investigate the association between serum FASN levels and fatty acid intake in women newly diagnosed with breast cancer.In a case-control cross-sectional study, with 18 breast cancer patients and 29 controls, we evaluated nutritional status, dietary intake, and serum FASN levels. Statistical analyses were carried out with parametric and non-parametric tests, according to the sample's normality distribution.The mean age of breast cancer group (n = 18) and control group (n = 29) was 46.8 ± 9.7 y and 44.4. ± 8.6 y, respectively. Mean serum concentration of FASN in breast cancer group was significantly higher (132.51 ± 95.05 ng/mL) than in control group (36.88 ± 20.87 ng/mL) (p 0.0001). Among breast cancer group, serum FASN levels of premenopausal women were significantly higher than those of postmenopausal women (p = 0.026). There was no significant difference between the early and late disease stages in regard to serum FASN levels in breast cancer group. Mean nutrient intake was similar and n-3 docosahexaenoic acid intake was low in both groups. We observed no association regarding fatty acid intake and serum FASN levels.These data suggest that dietary n-3 fatty acid has no association with serum FASN levels among newly diagnosed breast cancer patients.

To investigate the perception of hunger and satiety and its association with nutrient intake in women who regain weight in the postoperative period after bariatric surgery. Cross-sectional study of adult women divided into three groups: weight regain (n = 20), stable weight (n = 20) (both at least 24 months after Roux-en-Y gastric bypass surgery), and non-operated obesity (n = 20). A visual analogue scale measured hunger/satiety perception while fasting, immediately after finishing a test meal, and 180 min after finishing the test meal. The incremental area above or under the curve was calculated. Food intake was analyzed by 3 days of food recall and adjusted for intraindividual variation. To make between-group comparisons, Mann-Whitney, ANOVA, Kruskal-Wallis, and independent-samples T tests and Pearson’s correlation were used. There were no between-group differences in incremental areas of hunger/satiety, but protein intake was significantly lower among patients who regained weight compared with those who had stable body weight (0.99 ± 0.23 g/kg body weight vs. 1.17 ± 0.21 g/kg body weight, p = 0.047). In the group that regained weight, satiety was correlated positively with usual dietary protein density (r = 0.541; p = 0.017) and negatively with usual carbohydrate intake (r = − 0.663; p = 0.002). Women who regained weight presented similar perceptions of hunger/satiety to those of patients without weight regain and with non-operated obesity. In patients who regained weight postoperatively, satiety perception was correlated positively with usual dietary protein density and inversely with usual carbohydrate intake.

The antidiabetic drugs glibenclamide, repaglinide, and nateglinide are well-known substrates for hepatic uptake transporters of the organic anion transporting polypeptide (OATP) family and metabolizing enzymes of the cytochrome P450 (CYP) 2C subfamily. The systemic exposure of these drugs varies substantially among individuals, impacted by genetic polymorphisms of transporters and metabolizing enzymes as well as drug-drug interactions. The use of the conventional in vitro-in vivo extrapolation (IVIVE) method was found to underestimate their hepatic intrinsic clearance (CLint,all); the clinically observed CLint,all values were ≥10-fold higher than the predicted values from in vitro data. In order to improve the accuracy in predicting CLint,all of these drugs, the following modifications were implemented; i) the extended clearance concept was applied during IVIVE processes, ii) albumin was added to metabolic assays using human liver microsomes (to minimize the impact of intrinsic inhibitors on kinetic parameters for CYP2C-mediated metabolism) and to hepatic uptake assays (to accommodate the enhanced hepatic uptake observed with albumin-bound drugs), and iii) differing rates of efflux and influx via diffusion were used. The IVIVE method with these modifications yielded the predicted CLint,all values from in vitro data in closer agreement with the CLint,all values observed in vivo; the fold differences between the predicted and observed CLint,all values reduced from 13-15 to 5.9-6.7. Our current approach offers an improvement in the prediction of CLint,all and further investigations are warranted to enhance the prediction accuracy of IVIVE.

During new drug development, clinical drug interaction studies are carried out in accordance with the mechanism of potential drug interactions evaluated by in vitro studies. The obtained information should be provided efficiently to medical experts through package inserts and various information materials after the drug's launch. A recently updated Japanese guideline presents general procedures that are considered scientifically valid at the present moment. In this review, we aim to highlight the viewpoints of the Japanese guideline and enumerate drugs that were involved or are anticipated to be involved in evident pharmacokinetic drug interactions and classify them by their clearance pathway and potential intensity based on systematic reviews of the literature. The classification would be informative for designing clinical studies during the development stage, and the appropriate management of drug interactions in clinical practice.

We have previously reported that the microsomal activities of CYP2C8 and CYP3A4 largely depend on the buffer condition used in in vitro metabolic studies, with different patterns observed between the 2 isozymes. In the present study, therefore, the possibility of buffer condition dependence of the fraction metabolized by CYP2C8 (fm2C8) for repaglinide, a dual substrate of CYP2C8 and CYP3A4, was estimated using human liver microsomes under various buffer conditions. Montelukast and ketoconazole showed a potent and concentration-dependent inhibition of CYP2C8-mediated paclitaxel 6α-hydroxylation and CYP3A4-mediated triazolam α-hydroxylation, respectively, without dependence on the buffer condition. Repaglinide depletion was inhibited by both inhibitors, but the degree of inhibition depended on buffer conditions. Based on these results, the contribution of CYP2C8 in repaglinide metabolism was estimated to be larger than that of CYP3A4 under each buffer condition, and the fm2C8 value of 0.760, estimated in 50 mM phosphate buffer, was the closest to the value (0.801) estimated in our previous modeling analysis based on its concentration increase in a clinical drug interaction study. Researchers should be aware of the possibility of buffer condition affecting the estimated contribution of enzyme(s) in drug metabolism processes involving multiple enzymes.

Aims Vonoprazan, a new class of potassium-competitive proton pump inhibitors has been found to attenuate the antiplatelet function of clopidogrel in a recent clinical study, despite weak in vitro activity against CYP2C19. To elucidate the mechanism of this interaction, the present study investigated the effects of esomeprazole and vonoprazan on the pharmacokinetics of proguanil, a CYP2C19 substrate. Methods Seven healthy male volunteers (CYP2C19 extensive metabolizers) received a single oral administration of 100 mg proguanil/250 mg atovaquone (control phase), oral esomeprazole (20 mg) for 5 days followed by proguanil/atovaquone (esomeprazole phase) and oral vonoprazan (20 mg) for 5 days followed by proguanil/atovaquone (vonoprazan phase). Concentrations of proguanil and its metabolite, cycloguanil, in plasma and urine in each phase were determined using liquid chromatography-tandem mass spectrometry. Results Coadministration with proton pump inhibitors resulted in increase and decrease in the area under the plasma concentration-time curve (AUC) of proguanil and cycloguanil, respectively, significantly reducing their AUC ratio (cycloguanil/proguanil) to 0.317-fold (95% confidence interval [CI] 0.256-0.379) and 0.507-fold (95% CI 0.409-0.605) in esomeprazole phase and vonoprazan phase, respectively. Esomeprazole and vonoprazan also significantly reduced the apparent formation clearance (cumulative amount of cycloguanil in urine divided by AUC of proguanil) to 0.324-fold (95% CI 0.212-0.436) and 0.433-fold (95% CI 0.355-0.511), respectively, without significant changes in renal clearance of proguanil and cycloguanil. Conclusions Although further studies are needed, both esomeprazole and vonoprazan potentially inhibit CYP2C19 at clinical doses, suggesting caution in the coadministration of these drugs with CYP2C19 substrates.

Omega 3-docosahexaenoic acid (DHA) and vitamin E Delta-tocotrienol (Delta-T3) are extensively studied as protective nutrients against cancer development. Little is known about the biological mechanisms targeted by these bioactive molecules on lipid droplet (LD) biogenesis, an important breast cancer aggressiveness marker, and the occurrence of lipophagy in breast cancer cells. The aim of this study was to investigate the effect of DHA, Delta-T3 and DHA plus Delta-T3 co-treatment in LD biogenesis and lipophagy process in triple negative breast cancer cell line MDA-MB-231. Cells were treated with 50 &mu, M DHA and/or 5 &mu, M Delta-T3. Our results demonstrated that DHA can trigger an increase in LD biogenesis and co-treatment with Delta-T3 was able to reduce this LD biogenesis. In addition, we showed that a higher cytoplasmic LD content is associated with a higher breast cancer cells malignance and proliferation. Reduction of cytoplasmic LD content by silencing ADRP (adipose differentiation-related protein), a structural LD protein, also decreased cell proliferation in MDA-MB-231 cells. Treatment with DHA and Delta-T3 alone or co-treatment did not reduce cell viability. Moreover, we showed here that DHA can trigger lipophagy in MDA-MB-231 cells and DHA plus Delta-T3 co-treatment was able to enhance this lipophagy process. Our findings demonstrated that co-treatment with DHA plus Delta-T3 in MDA-MB-231 cells could reduce LD biogenesis and potentiate lipophagy in these cells, possibly having a positive impact to inhibit breast cancer malignancy. Therefore, suitable doses of DHA and Delta-T3 vitamin E isoform supplementation can be a prominent tool in therapeutic treatments against breast cancer.

Bariatric surgery has been shown to be an effective treatment for obesity. Changes in energy expenditure, especially through diet-induced thermogenesis (DIT), have been identified as one of the mechanisms to explain this success. However, not all patients are able to maintain healthy postoperative weight loss. Therefore, a question arises: In the weight regain after bariatric surgery, are these changes in energy metabolism still active?To investigate if weight regain after Roux-en-Y gastric bypass (RYGB) surgery is associated with a lower diet-induced thermogenesis in the late postoperative period.A cross-sectional study with the participants chosen from among the patients from a private practice.This was a cross-sectional study where 3 groups of female patients were evaluated: (1) 20 patients with a RYGB postoperative time period of at least 2 years, who kept a healthy weight after surgery (loss of at least 50% of excess weight; Healthy group); (2) 19 patients with clinically severe obesity (BMI40 kg/m(2), without co-morbidities and35 kg/m(2), with co-morbidities; Pre group); (3) 18 patients who experienced weight regain after RYGB (Regain group). The 3 groups were submitted to indirect calorimetry to measure resting metabolic rate (RMR), respiratory quotient (RQ), and DIT. Immediately after the RMR measurement, a mixed meal of regular consistency was offered. Ten minutes after the food intake began, energy expenditure measurements were initiated continuing throughout the following 3 postprandial hours. Body composition was evaluated using multifrequency bioelectrical impedance. In subgroups of the studied population, glucose and insulin levels were measured at baseline and at 30, 60, 90, 120, and 180 minutes after feeding. The mean area under the curve (AUC) between the 3 groups and measurements at baseline were compared using the analysis of variance (ANOVA).The Healthy group had the highest weight adjusted RMR value compared with both the Pre and Regain group (23.03±3.02 kcal/kg; 16.18±2.94 kcal/kg; 17.11±3.28 kcal/kg, respectively; P.0001). The Regain and Pre groups showed no difference for this variable. The weight-adjusted DIT (AUC 0-180 min) was about 42% and 34% higher in the Healthy group compared with the Pre and Regain groups, respectively (P.0001). Lean body mass (kg) showed a positive correlation with the AUC of weight-adjusted DIT in the 3 groups. Multiple regression revealed that lean body mass was the only variable related to weight adjusted DIT, independent of group and other selected variables.Weight-adjusted DIT in the Regain group was smaller compared with the Healthy group, and with no difference compared with the Pre group. The lean body mass seems to have a positive association with diet-induced thermogenesis.

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The purpose of this study was to predict the drug-drug interactions (DDIs) via CYP3A4 by estimating the extent of hepatic CYP3A4 inhibition based on a physiologically based pharmacokinetic (PBPK) model of both substrate and inhibitor and the increase in the intestinal availability (Fg ) due to the enzyme inhibition. For the DDIs resulting from reversible inhibition of CYP3A4, the prediction using in vivo Ki values estimated from other clinical DDI studies and predicted in vivo Ki values calculated using the correlation between the log P and the in vivo Ki /in vitro Ki ratio was more accurate than that using in vitro Ki values. Incorporating inhibition of both intestinal and hepatic metabolism resulted in better prediction than that obtained considering inhibition in the liver alone, and all the DDIs (AUC increase by the inhibitor) were predicted within 2-fold accuracy when in vivo Ki values were used. In addition, Fg values were successfully back-calculated from the clinical DDI data based on the present model. In conclusion, the present PBPK model incorporating the in vivo Ki values was found to be useful for quantitative prediction of clinical DDIs and for estimation of the Fg values for CYP3A4 substrates for which intravenous data were not available.

Summary Background & aims Standardized phase angle (SPA) is a value derived from bioelectrical impedance phase angle analysis and has been recognized as marker of nutritional risk and clinical status of cancer patients. This study aimed to evaluate the changes in SPA during radiation therapy of cancer patients and identify possible nutritional and clinical determinants of these changes. Methods Nutritional assessment was performed before the initiation and at the end of the radiotherapy. It included anthropometrics and bioelectrical impedance analysis. A generalized linear mixed model was used to evaluate the effects of selected independent variables on the changes in standardized phase angle. Results A total of 104 patients entered the study and those with complete information were included in the analysis ( n = 62). Most patients (61%) were at clinical stage I and II, the most prevalent irradiation site was the pelvis (39%) and 98% were well nourished or overweight. According to the regression analysis, changes in body weight and irradiation at head and neck/upper abdomen and thorax were associated with standardized phase angle modifications during radiotherapy. Clinical stage and radiation dose were not associated with changes in standardized phase angle. Compared to baseline values, for every 1 kg weight reduction during the radiation therapy, the standardized phase angle also decreased by 0.107 ( p Conclusions In well nourished or overweight patients, weight loss during radiation therapy is closely associated with decrease in standard phase angle.

The implication of inflammation in pathophysiology of several type of cancers has been under intense investigation. Omega-3 fatty acids can modulate inflammation and present anticancer effects, promoting cancer cell death. Pyroptosis is an inflammation related cell death and so far, the function of docosahexaenoic acid (DHA) in pyroptosis cell death has not been described. This study investigated the role of DHA in triggering pyroptosis activation in breast cancer cells. MDA-MB-231 breast cancer cells were supplemented with DHA and inflammation cell death was analyzed. DHA-treated breast cancer cells triggered increased caspase-1and gasdermin D activation, enhanced IL-1β secretion, translocated HMGB1 towards the cytoplasm, and membrane pore formation when compared to untreated cells, suggesting DHA induces pyroptosis programmed cell death in breast cancer cells. Moreover, caspase-1 inhibitor (YVAD) could protect breast cancer cells from DHA-induced pyroptotic cell death. In addition, membrane pore formation showed to be a lysosomal damage and ROS formation-depended event in breast cancer cells. DHA triggered pyroptosis cell death in MDA-MB-231by activating several pyroptosis markers in these cells. This is the first study that shows the effect of DHA triggering pyroptosis programmed cell death in breast cancer cells and it could improve the understanding of the omega-3 supplementation during breast cancer treatment.

Preoperative bariatric patients can follow very low calorie diets (VLCD), reducing surgical risks. However, possible advantages of a liquid diet over one of normal consistency are controversial. This study investigated the effect of a liquid VLCD compared with one of normal consistency considering visceral fat (VF) loss and metabolic profile in preoperative clinically severe obese patients.This was a randomized, open-labeled, controlled clinical trial. Patients were divided into 2 groups: liquid diet and normal diet. Data were collected at baseline and 7 and 14 days after intervention. Information gathered was analyzed for loss of weight and VF, biochemical data, anthropometric data, and energy intake.Fifty-seven patients consumed the liquid diet and 47 consumed the normal consistency diet. The liquid diet group lost significantly more weight (P.0290) and VF (P.0410) than the normal diet group. An inverse correlation occurred between VF loss and surgical time among the liquid diet group (r2=-.1302, P=.001). Additionally, there was a positive correlation between the percentage of excess weight loss and ketonuria (P=.0070). No between-group difference occurred regarding calorie intake.Patients that consumed a liquid diet presented a positive effect on reducing VF and greater weight loss than the normal diet group. Both VLCDs presented benefits offering a protective effect during the preoperative stage.

Serum creatinine (SCr) levels rise during trimethoprim therapy for infectious diseases. This study aimed to investigate whether the elevation of SCr can be quantitatively explained using a physiologically-based pharmacokinetic (PBPK) model incorporating inhibition by trimethoprim on tubular secretion of creatinine via renal transporters such as organic cation transporter 2 (OCT2), OCT3, multidrug and toxin extrusion protein 1 (MATE1), and MATE2-K. Firstly, pharmacokinetic parameters in the PBPK model of trimethoprim were determined to reproduce the blood concentration profile after a single intravenous and oral administration of trimethoprim in healthy subjects. The model was verified with datasets of both cumulative urinary excretions after a single administration and the blood concentration profile after repeated oral administration. The pharmacokinetic model of creatinine consisted of the creatinine synthesis rate, distribution volume, and creatinine clearance (CLcre), including tubular secretion via each transporter. When combining the models for trimethoprim and creatinine, the predicted increments in SCr from baseline were 29.0%, 39.5%, and 25.8% at trimethoprim dosages of 5 mg/kg (b.i.d.), 5 mg/kg (q.i.d.), and 200 mg (b.i.d.), respectively, which were comparable with the observed values. The present model analysis enabled us to quantitatively explain increments in SCr during trimethoprim treatment by its inhibition of renal transporters.

This study developed learning materials to support the acquisition of skills for elderly care. Our aim is to establish a method that develops human resources for elderly care using ICT and develop learning materials for caregivers. We developed learning materials that increase the awareness of novice caregivers based on comparisons of their care with the care of experts by overlapping the movements of novices and experts in 3DCG movies. Evaluation and feedback from a nurse, a physical therapist, an orthopedist, and a nursing school teacher confirmed that 3DCG movies and overlapping techniques can provide useful educational benefits.

1. Blood levels of S-warfarin have been reported to be increased by concomitant administration of metronidazole (MTZ), an antiprotozoal imidazole derivative. 2. To elucidate the mechanism of this interaction and to identify other possible drug-drug interactions, we conducted an in vitro study with the human hepatoma HepaRG cells and cryopreserved human hepatocytes on the ability of MTZ to reduce the expression of cytochrome P450 (CYP) as well as nuclear receptors that regulate the expression of these enzymes. 3. HepaRG cells and cryopreserved human hepatocytes were treated with MTZ (20 to 500 µM) and were then analyzed by real-time RT-PCR to determine mRNA levels of drug-metabolizing enzymes and nuclear receptors. 4. In both cells, the expressions of CYP2C8, CYP2C9, CYP3A4 and constitutive androstane receptor (CAR) were decreased by MTZ treatment. Particularly, in HepaRG cells, their mRNA levels were decreased by MTZ treatment in a concentration-dependent manner. 5. Our findings suggest that the interaction between MTZ and S-warfarin may be due to the MTZ-induced down-regulation of CYP2C9, the primary enzyme responsible for S-warfarin hydroxylation, and CAR, which regulates CYP2C9 expression. We also found that MTZ use may alter the disposition of drugs metabolized by the CYP isozymes investigated.

We investigated the effects of enteral nutrition formula on non-steroidal anti-inflammatory drug (NSAID)-induced gastric lesions in mice. Male ICR mice aged 7&ndash, 9 weeks old were fasted, then orally given either purified water, Mermed&reg, One, or 2-fold diluted Terumeal&reg, 2.0&alpha, as enteral nutrition (25 or 50 mL/kg each). Indomethacin (IND) was orally administered at 20 mg/kg after 30 min, and the stomach was removed 6 h later and fixed in formalin. The number and area of lesions in the stomachs of the mice given enteral nutrition showed a significant, dose-dependent decrease compared to the purified water-treated group, and no significant difference was seen between the two enteral nutrition-treated groups. Comparable time courses of plasma IND concentrations suggest that enteral nutrition does not inhibit gastrointestinal absorption of IND. Our findings indicate that administering enteral nutrition could inhibit the onset of NSAID-induced gastric ulcers.

Post-bariatric surgery may compromise nutritional status due to energy and protein intake restriction. Systematic review was performed to synthesize evidence on the amount of protein intake and its association with lean mass and serum proteins during at least 6 months following Roux-en-Y gastric bypass or sleeve gastrectomy. Twelve studies (n = 739) were identified in the search. Protein intake below 60 g/day and significant lean mass loss were observed in majority of these studies. Of the four studies that measured association between protein intake and lean mass retention, only two supported this hypothesis. There is insufficient evidence of the effect of dietary protein on serum protein levels. Further studies are needed to better estimate the protein intake that supports a healthy nutritional status in this population.

This study developed learning materials to support the acquisition of skills for elderly care. Our aim is to establish a method that develops human resources for elderly care using ICT and develop learning materials for caregivers. We developed learning materials that increase the awareness of novice caregivers based on comparisons of their care with the care of experts by overlapping the movements of novices and experts in 3DCG movies. Evaluation and feedback from a nurse, a physical therapist, an orthopedist, and a nursing school teacher confirmed that 3DCG movies and overlapping techniques can provide useful educational benefits.

Near-infrared (NIR) spectroscopy combined with chemometrics has been utilized in predictions of natural medicine content without destroying samples. Suppositories (oren powdered extract content 0, 0.5, 1.0, 2.5, 10, 12.5, and 15%) were produced by mixing oren powdered extract with macrogol mixture consisting of 1 part macrogol 1500 and 2.5 parts macrogol 4000 at 54°C, and pouring the melt mixture into a plastic container. NIR spectra of the 10 prepared samples were recorded 10 times, and a total of 100 spectra were randomly divided into two data sets, one for calibration and the other for validation. The calibration model for the oren content of the suppository was calculated based on NIR spectra using a partial least-squares regression analysis after pre-treatment (smoothing and the multiplicative scatter correction). The relationship between the actual and predicted values for calibration and validation models had a straight line with correlation coefficients of 0.9936 and 0.9898, respectively. The regression vector result of the calibration model indicates that the peaks at 6945, 5747, and 5160 cm(-1) in the regression vector were consistent with those in oren powder extracts. NIR spectroscopy combined with chemometrics offers promise as a method of predicting the oren powder content in suppositories without destroying the samples.

The objective of this study was to provide support for a body weight-tiered dosing regimen by characterizing abatacept pharmacokinetics (PK) and the relationship between exposure and the ACR20 (American College of Rheumatology criteria for 20% improvement) response in Japanese patients with rheumatoid arthritis (RA). A population PK model was developed using NONMEM with 2,535 samples from 344 Japanese RA patients in two clinical trials. The exposure-response relationship was characterized using a Generalized Estimating Equation (GEE) logistic regression model, with time-varying actual trough concentrations and ACR20 responder rates over 6 months in a randomized, placebo-controlled phase 2 trial for stable methotrexate. Abatacept exposure was well characterized using a linear, two-compartment model, in which body weight and the empirically calculated glomerular filtration rate were significant covariates for clearance. The ACR20 response model was developed by examining the quasi-likelihood information criterion, and the cumulative logit in the final model was specified by the log-transformed trough concentration. The predicted ACR20 responder rate was consistent with the actual values in the clinical trial and this model revealed trough concentrations higher than the recommended body weight-tiered dose are unlikely to result in substantial increases in clinical efficacy. Considering that ACR20 is a longitudinal binary variable and the response to RA treatment is delayed, the GEE model was useful for predicting the probability of an ACR20 response. In conclusion, the same dosing regimen as non-Japanese patients is recommended because a body weight-tiered dosing regimen achieves similar exposures across the wide range of body weight.

Obesity is a major cause of metabolic syndrome and is due to an increase in the number and hypertrophy of adipocytes. Accordingly, inhibition of the differentiation and proliferation of adipocytes may be used in the treatment and prevention of metabolic syndrome. This study investigated the effects of 50 commonly used Kampo medicines on the differentiation of 3T3-L1 preadipocytes to search for a drug with an antiobesity effect. Kampo medicines were screened, and the strongest differentiation-inhibitory effect was noted with Orengedokuto. To explore the active ingredients in Orengedokuto, the effects of four crude drug components of Orengedokuto were investigated. It was found that the differentiation-inhibitory effect of Orengedokuto was accounted for by Coptidis rhizome and Phellodendri cortex. Furthermore, berberine, a principal ingredient common to Coptidis rhizome and Phellodendri cortex, showed a differentiation-inhibitory effect. The effect of berberine involves an inhibition of the mRNA and protein expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα). Moreover, berberine inhibited lipid accumulation in adipocytes. These findings suggest that an antiobesity effect could be a new indication for Orengedokuto and that its active ingredient is berberine, with a mechanism involving the inhibition of PPARγ and C/EBPα expression.