Performance comparison of first-order conditional estimation with interaction and Bayesian estimation methods for estimating the population parameters and its distribution from data sets with a low number of subjects.

BACKGROUND: Exploratory preclinical, as well as clinical trials, may involve a small number of patients, making it difficult to calculate and analyze the pharmacokinetic (PK) parameters, especially if the PK parameters show very high inter-individual variability (IIV). In this study, the performance of a classical first-order conditional estimation with interaction (FOCE-I) and expectation maximization (EM)-based Markov chain Monte Carlo Bayesian (BAYES) estimation methods were compared for estimating the population parameters and its distribution from data sets having a low number of subjects. METHODS: In this study, 100 data sets were simulated with eight sampling points for each subject and with six different levels of IIV (5%, 10%, 20%, 30%, 50%, and 80%) in their PK parameter distribution. A stochastic simulation and estimation (SSE) study was performed to simultaneously simulate data sets and estimate the parameters using four different methods: FOCE-I only, BAYES(C) (FOCE-I and BAYES composite method), BAYES(F) (BAYES with all true initial parameters and fixed ω 2 ), and BAYES only. Relative root mean squared error (rRMSE) and relative estimation error (REE) were used to analyze the differences between true and estimated values. A case study was performed with a clinical data of theophylline available in NONMEM distribution media. NONMEM software assisted by Pirana, PsN, and Xpose was used to estimate population PK parameters, and R program was used to analyze and plot the results. RESULTS: The rRMSE and REE values of all parameter (fixed effect and random effect) estimates showed that all four methods performed equally at the lower IIV levels, while the FOCE-I method performed better than other EM-based methods at higher IIV levels (greater than 30%). In general, estimates of random-effect parameters showed significant bias and imprecision, irrespective of the estimation method used and the level of IIV. Similar performance of the estimation methods was observed with theophylline dataset. CONCLUSIONS: The classical FOCE-I method appeared to estimate the PK parameters more reliably than the BAYES method when using a simple model and data containing only a few subjects. EM-based estimation methods can be considered for adapting to the specific needs of a modeling project at later steps of modeling.

Development of QTc prolongation model incorporating circadian rhythm using harmonic model.

1. QT prolongation is one of the major safety tests used in the development of a new drug. The ICH guidelines for the evaluation of QT prolongation recommend the use of the in vitro hERG assay and the in vivo telemetry test. However, QT intervals change under normal conditions due to circadian rhythm and can affect the results of the tests. In this study, we developed a PK/PD model to describe the QT interval after the administration of astemizole allowing for the normal changes by circadian rhythm. 2. The typical PK parameters of absorption rate constant (ka), volume of distribution (Vc and Vm), metabolism (km), and elimination rate constant (kel and kel-m) were 0.49 h(-1), 4950 L, 20 L, 0.0127 h(-1), 0.0095 h(-1), and 0.95 h(-1), respectively. The final PK/PD model was the biophase model with the modified harmonic model. The typical PK/PD parameters, base QTc interval (QT0), amplitude (T1, T3), period of QTc interval changing (T2, T4), and EC50 were 233 ms, 3.31, 1.5, -9.24 h, 1.85 h, and 0.81 ng/ml, respectively. 3. The PK/PD model to explain the changes of the QT interval that allows normal changes in the circadian rhythm after the administration of astemizole was developed successfully. This final model can be applied to the development of a human model.

Simultaneous determination of 7-O-succinyl macrolactin A and its active major metabolite, macrolactin A in dog plasma using high-performance liquid chromatography with UV detection.

We developed a method for the simultaneous quantification of 7-O-succinyl macrolactin A and its active metabolite, macrolactin A, in dog plasma. After protein precipitation with acetonitrile including flufenamic acid as an internal standard, 7-O-succinyl macrolactin A, macrolactin A, and flufenamic acid were chromatographed on a reverse-phase C18 analytical column. The mobile phase, consisting of 20 mM acetate buffer and acetonitrile, was eluted using a gradient program at 1 mL/min, and the UV absorbance was measured at 230 nm. The retention times of 7-O-succinyl macrolactin A, flufenamic acid, and macrolactin A were 3.4, 4.8, and 6.9 min, respectively. The coefficient of variation in the assay precision for both substances was less than 6%, and the accuracy ranged from 96 to 105%. This method was used to measure the concentrations of 7-O-succinyl macrolactin A and macrolactin A in dog plasma following an intravenous administration of a single dose (25 mg/kg) of 7-O-succinyl macrolactin A salt.

Development of a pharmacokinetic/pharmacodynamic/disease progression model in NC/Nga mice for development of novel anti-atopic dermatitis drugs.

1. JHL45, a novel immune modulator against atopic dermatitis (AD), was synthesized from decursin isolated from Angelica gigas. The goal is to evaluate the lead compound using quantitative modeling approaches to novel anti-AD drug development. 2. We tested the anti-inflammatory effect of JHL45 by in vitro screening, characterized its in vitro pharmacokinetic (PK) properties. The dose-dependent efficacy of JHL45 was developed using a pharmacokinetics/pharmacodynamics/disease progression (PK/PD/DIS) model in NC/Nga mice. 3. JHL45 has drug-like properties and pharmacological effects when administered orally to treat atopic dermatitis. The developed PK/PD/DIS model described well the rapid metabolism of JHL45, double-peak phenomenon in the PK of decursinol and inhibition of IgE generation by compounds in NC/Nga mice. Also, a quantitative model was developed and used to elucidate the complex interactions between serum IgE concentration and atopic dermatitis symptoms. 4. Our findings indicate that JHL45 has good physicochemical properties and powerful pharmacological effects when administered orally for treatment of AD in rodents.

Development of a population pharmacokinetic model to describe olmesartan medoxomil/ hydrochlorothiazide (20/12.5 mg) FDC tablet in male healthy South Korean subjects.

AIM: The objective of the present study was to develop population pharmacokinetic models for olmesartan medoxomil and hydrochlorothiazide and to investigate the influence of demographic factors on these population pharmacokinetics. METHODS: Plasma concentrations of olmesartan medoxomil and hydrochlorothiazide were measured in 41 healthy volunteers enrolled in our bioequivalence study by LC-MS/MS following oral administration of an olmesartan medoxomil/hydrochlorothiazide (20/12.5 mg) fixed-dose combination tablet. This data and covariates were subjected to nonlinear mixed-effect modeling analysis using the NONMEM software. Evaluation featured a visual predicted check and bootstrapping. RESULTS: The distributions of olmesartan medoxomil and hydrochlorothiazide were best fitted using a two-compartment model with no lag time and first-order elimination. When analyzing hydrochlorothiazide kinetics, we found that TCHO and CL/F were correlated, while. HB and Ka influenced olmesartan medoxomil modeling. All evaluations indicated that the pharmacokinetic profiles of olmesartan medoxomil and hydrochlorothiazide were adequately described using our PPK model. CONCLUSIONS: This study indicates that demographic factors influence the inter-individual variability in the disposition of the combination drug, and it might be more useful to apply it to the PK of olmesartan medoxomil/hydrochlorothiazide (20/12.5 mg) FDC tablets administered to patients with hypertension. *These two authors contributed equally to this work.

A simple pharmacokinetic model of alendronate developed using plasma concentration and urine excretion data from healthy men.

The study of pharmacokinetics of alendronate has been hampered by difficulties in accurately and reproducibly determining their concentrations in serum and urine. Thus, pharmacokinetic characteristics of alendronate have been described in many reports based on urinary excretion data; and plasma pharmacokinetics and the simultaneous pharmacokinetic models of alendronate in plasma and urine are not available. The aims of this study were to measure alendronate concentration in plasma and excretion in urine concurrently and to develop compartmental pharmacokinetic model using urine data. In open-label, single-dose pharmacokinetic study, 10 healthy male volunteers received oral dose of alendronate (70 mg tablet). Blood and urine alendronate concentrations were determined using validated high-performance liquid chromatography method. Non-compartmental analysis was performed using WinNonlin program (Pharsight Inc., Apex, NC). A one-compartment pharmacokinetic model was applied to describe pharmacokinetics of alendronate. A peak plasma alendronate concentration of 33.10 ± 14.32 ng/mL was attained after 1.00 ± 0.16 h. The cumulative amount of alendronate excreted in urine and peak excretion rate were 731.28 ± 654.57 µg and 314.68 ± 395.43 µg/h, respectively. The model, which included first-order absorption rate for oral dosing, showed good fit to alendronate data obtained from plasma and urine. The absorption rate constant was 2.68 ± 0.95 h(-1). The elimination rate constants Kurine and Knon-ur were 0.005 ± 0.004 h(-1) and 0.42 ± 0.08 h(-1), respectively. The pharmacokinetics of alendronate in plasma and urine of healthy men can be predicted using one-compartment model, and thus the behavior of drug in plasma can be estimated from urinary excretion data.

Iodine intake from brown seaweed and the related nutritional risk assessment in Koreans.

BACKGROUND/OBJECTIVES: Although iodine is essential for thyroid hormone production and controls many metabolic processes, there are few reports on the iodine intake of the population because of the scarcity of information on the iodine content in food. This study estimated the iodine intake of Koreans from brown seaweed, the major source of iodine in nature. SUBJECTS/METHODS: The dietary intake data from the recent Korea National Health and Nutrition Examination Survey (2016-2021) and the iodine content in brown seaweed were used for the estimation. Nationwide brown seaweed samples were collected and prepared using the representative preparation/cooking methods in the Koreans' diet before iodine analysis by alkaline digestion followed by inductively coupled plasma mass spectrometry. RESULTS: The mean (± SE) iodine intake from sea mustard was 96.01 ± 2.36 µg/day in the Korean population. Although the iodine content in kelp was approximately seven times higher than that in sea mustard, the mean iodine intake from kelp (except broth) was similar to that of sea mustard, 115.58 ± 7.71 µg/day, whereas that from kelp broth was 347.57 ± 10.03 µg/day. The overall mean iodine intake from brown seaweed was 559.16 ± 13.15 µg/day, well over the Recommended Nutrient Intake of iodine for Koreans. Nevertheless, the median intake was zero because only 37.6% of the population consumed brown seaweed on the survey date, suggesting that Koreans do not consume brown seaweed daily. CONCLUSION: The distribution of the usual intake of iodine from brown seaweed in Koreans would be much tighter, resulting in a lower proportion of people exceeding the tolerable upper intake levels and possibly a lower mean intake than this study presented. Further study evaluating the iodine nutriture of Koreans based on the usual intake is warranted. Nevertheless, this study adds to the few reports on the iodine nutriture of Koreans.

Effect of food intake on the pharmacokinetics of sarpogrelate and its active metabolite following oral administration to beagle dogs.

1. The objectives of this study were to develop a pharmacokinetic model for sarpogrelate and its metabolite M-1 and to identify the effect of food on sarpogrelate and M-1 pharmacokinetics in beagle dogs. 2. A single 100 mg oral dose of sarpogrelate was administered to fasted and fed beagle dogs and the plasma concentrations of sarpogrelate and M-1 were measured simultaneously by liquid chromatography tandem mass spectrometry. The resultant data were analyzed by modeling approaches using ADAPT5. 3. The plasma concentration time course of sarpogrelate and M-1 were described using a parent-metabolite compartment model with first-order absorption and elimination. The systemic exposure of sarpogrelate and its metabolite after the administration of a single 100 mg oral dose was significantly decreased under the fed condition compared to that under the fasting condition. Modeling approaches have sufficiently explained the food effect of sarpogrelate, i.e. an increased Vc and decreased Ka, in fed dogs. The food effect of sarpogrelate was due to its pH-dependent dissolution. 4. These findings suggest that food intake affects both the rate and extent of absorption of sarpogrelate, and that the pharmacological effect of sarpogrelate can differ significantly according to food intake.

Quantitative determination of duloxetine and its metabolite in rat plasma by HPLC-MS/MS.

The major metabolite of duloxetine is a glucuronide conjugate of 4-hydroxy duloxetine (4-HD). However, interestingly, there have been no reports determining concentrations of 4-HD and no fully validated method has been established for measuring duloxetine and 4-HD in rat plasma. We developed a method for the simultaneous quantification of duloxetine and its metabolite in rat plasma using high-performance liquid chromatography tandem mass spectrometry. Duloxetine and 4-HD were analyzed on a reverse-phase C18 analytical column after protein precipitation of the plasma sample with methanol, using carbamazepine as an internal standard. The isocratic mobile phase of 5 mm ammonium acetate-methanol (4:6, v/v) was eluted at 0.4 mL/min. Quantification was performed on a triple-quadrupole mass spectrometer using electrospray ionization, and the ion transition monitored in selective reaction monitoring mode. The coefficient of variation for assay precision was <18.0%, and the accuracy was 84.0-118.0%. This method was successfully used to measure the concentrations of duloxetine and its metabolite in plasma following the oral administration of a single 40 mg/kg dose in rats.

Biopharmaceutical characterization of decursin and their derivatives for drug discovery.

Angelica gigas Nakai and its components are known to have neuroprotective, antiplatelet, and anticancer activities. The present study evaluated the in vitro and in vivo biopharmaceutical characterization of Angelica gigas component substances, including decursin (the main substance), decursinol angelate (decursin isomer), JH714 (ether form of decursin) and epoxide decursin (epoxide form of decursin). Decursin, decursinol angelate and JH714 exhibited acceptable metabolic stability (>50%) in liver microsomes from human and higher bound fraction (>90%) in human plasma operating ultrafiltration. Decursin and decursinol angelate in CYP1A2 and CYP2C19 indicated less than 50% CYP activity, suggesting inhibition of the CYP isoforms using Vivid® CYP screening kit. JH714 only showed an apparent permeability coefficient of <10 × 10⁻6 cm/s in MDCK cells, suggesting that it is poorly absorbed. Blood brain barrier permeability was examined after oral administration to male Sprague-Dawley (SD) rats, and pharmacokinetic studies were performed after oral and intravenous administration of 10 mg/kg compounds. Decursin, decursinol angelate and JH714 showed ratios of compound concentration in brain with respect to plasma (Cbrain/Cplasma) of >1.5, suggesting good brain/plasma ratio at 0.5, 1, 3, and 5 h. In contrast, Cbrain/Cplasma was <0.5 for epoxide decursin. For all test compounds, >1.5% of the dose remained in GI tract after 8 h, and the excretion rate in urine was <0.5% which suggests that gastro intestinal tract may be major site of disposition following oral administration. Finally, these results may be useful for the design of dosage regimens of decursin and its derivatives.

Pharmacokinetic analysis of doxifluridine and its metabolites, 5-fluorouracil and 5-fluorouridine, after oral administration in beagle dogs.

Doxifluridine (5'-deoxy-5-fluorouridine, 5'-dFUR) is a fluoropyrimidine derivative that is activated preferentially in malignant cells by thymidine phosphorylase to form 5-fluorouracil (5-FU). The purpose of this study was to investigate the pharmacokinetic properties of doxifluridine and its two major metabolites, 5-FU, and 5-fluorouridine (5-FUrd), in beagle dogs following a single oral administration of 200 mg doxifluridine capsule (Furtulon(®)). After the administration of 200 mg of Furtulon to 23 beagle dogs, the plasma concentrations of doxifluridine, 5-FU, and 5-FUrd were measured simultaneously, using LC-MS/MS. The parent-metabolite compartment model with first-order absorption and Michaelis-Menten kinetics described the pharmacokinetics of doxifluridine, 5-FU, and 5-FUrd. Michaelis-Menten kinetics sufficiently explained the generation and elimination processes of 5-FU and 5-FUrd. The studies described here are the first to evaluate the relationship between pharmacokinetics of doxifluridine and its metabolites in dogs, and these findings will help in understanding the toxicity mechanism of doxifluridine.

Population PK/PD analysis of metformin using the signal transduction model.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Metformin, a biguanide glucose lowering agent, is commonly used to manage type 2 diabetes. The molecular mechanisms of metformin have not been fully identified, but turnover of biomarkers such as glucose and signalling pathways or translocation of glucose transporters are closely related to the glucose-lowering effects of metformin. The PK/PD of metformin have been investigated in healthy humans and patients with type 2 diabetes mellitus and modelling has been performed using an indirect response model. WHAT THIS STUDY ADDS: The purpose of this investigation was to develop a population PK/PD model for metformin using a signal transduction model in healthy humans and predict the PK/PD profile in patients with type 2 diabetes. The aim was to compare a previous model (a biophase model) with the signal transduction model, and use a more appropriate model to follow the actions of metformin. Additionally, our developed model was appropriate to predict the time course of plasma metformin and fasting plasma glucose (FPG) concentrations in patients with type 2 diabetes. To our knowledge, this is the first published population PK/PD analysis using the signal transduction model for metformin. AIMS To develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model for metformin (500 mg) using the signal transduction model in healthy humans and to predict the PK/PD profile in patients with type 2 diabetes. METHODS: Following the oral administration of 500 mg metformin to healthy humans, plasma concentrations of metformin were measured using LC-MS/MS. A sequential modelling approach using NONMEM VI was used to facilitate data analysis. Monte Carlo simulation was performed to predict the antihyperglycaemic effect in patients with type 2 diabetes. RESULTS: Forty-two healthy humans were included in the study. Population mean estimates (relative standard error, RSE) of apparent clearance, apparent volume of distribution and the absorption rate constant were 52.6 l h(-1) (4.18%), 113 l (56.6%) and 0.41 h(-1) , respectively. Covariate analyses revealed that creatinine clearance (CL(CR) ) significantly influenced metformin: CL/F= 52.6 × (CL(cr) /106.5)(0.782) . The signal transduction model was applied to describe the antihyperglycaemic effect of metformin. The population means for efficacy, potency, transit time and the Hill coefficient were estimated to be 19.8 (3.17%), 3.68 µg ml(-1) (3.89%), 0.5 h (2.89%) and 0.547 (9.05%), respectively. The developed model was used to predict the antihyperglycaemic effect in patients with type 2 diabetes. The predicted plasma glucose concentration value was similar to previous values. CONCLUSIONS: The population signal transduction model was developed and evaluated for metformin use in healthy volunteers. Model evaluation by non-parametric bootstrap analysis suggested that the proposed model was robust and parameter values were estimated with good precision.

Physicochemical characterization and toxicity of decursin and their derivatives from Angelica gigas.

Angelica gigas NAKAI is used to treat dysmenorrhea, amenorrhea, menopause, abdominal pain, injuries, migraine, and arthritis. The present study provided a physicochemical and toxicological characterization of compounds in A. gigas NAKAI (decursin, decursinol angelate, diketone decursin, ether decursin, epoxide decursin and oxim decursin). Diketone decursin (173.16 µg/mL) and epoxide decursin (122.12 µg/mL) exhibited >100 µg/mL kinetic solubility after applying nephelometry, suggesting a highly soluble compound. The Student's t-test revealed significant differences in the pKa ranges of the compounds by automatic titration from capillary electrophoresis (p<0.05). Diketone decursin, epoxide decursin and oxim decursin might be formulated into an oral dosage form (log P: 0-3) by an automatic titration analysis. A parallel artificial membrane permeability assay demonstrated permeability coefficients of <10 x 10⁻6 cm/s for all of the compounds, suggesting poor permeability. Ether decursin exhibited a toxic effect after being applied to mouse (NIH 3T3, EC50: 57.9 µM) and human (HT-29, EC50: 36.1 µM; Hep-G2, EC50: 4.92 µM) cells. Additionally, epoxide and oxim decursin were toxic through acute oral toxicity (four and three deaths of Institute of Cancer Research (ICR) mice) and mutation toxicity testing by applying Salmonella typhimurium cells with and without S9. Although diketone decursin exhibited less permeability, it is potentially valuable pharmacological compound that should be investigated.

Determination of daumone in mouse plasma by HPLC/MS-MS.

Daumone, a pheromone secreted by Caenorhabditis elegans, is an essential regulator of chemosensory processes in development and aging. A quantification method using HPLC/MS-MS was developed for the determination of daumone in mouse plasma. After simple protein precipitation with acetonitrile including methaqualone (an internal standard), the analytes were chromatographed on a reversed-phase column and detected by liquid chromatography/tandem mass spectrometry with electrospray ionization. The accuracy and precision of the assay were in accordance with FDA regulations for validation of bioanalytical methods. This method was applied to measure the plasma daumone concentrations following a 5-week repeated oral administration of daumone in mice.

Pharmacokinetic characterization of decursinol derived from Angelica gigas Nakai in rats.

Decursinol is a major coumarin derived from the roots of Angelica gigas and has various pharmacological effects against inflammation, angiogenesis, nociceptive pain and Alzheimer's disease. In vitro and in vivo studies were conducted to characterize the metabolism and pharmacokinetics of decursinol. Decursinol exhibited high stability to oxidative and glucuronic metabolism in human and rat liver microsomes. In Caco-2 cell monolayers, decursinol showed high permeability (>14 × 10(-6) cm/s) at all tested concentrations in the absorptive direction, which saturated at 100 µM. Secretion increased in a concentration-dependent manner, with an efflux ratio of more than 2 at 50 µM, indicating the participation of an active efflux transporter such as P-glycoprotein, multidrug resistance protein 2 or breast cancer resistance protein. The fraction of decursinol not bound to plasma proteins was 25-26% in the rat and 9-18% in humans. In human plasma, but not rat plasma, the percentage of unbound decursinol was concentration dependent. Following intravenous administration in rats, non-linear elimination of decursinol was observed with K(m) and V(max) values of 2.1 µg/mL and 2.5 mg·h(-1)·kg(-1), respectively. Following oral administration, decursinol exhibited high oral bioavailability (>45%) and rapid absorption (T(max), 0.4-0.9 h) over the dose range studied. In addition, dose-dependent absorption and elimination were observed at 20 mg/kg.

Influence of dissolved oxygen concentration on the pharmacokinetics of alcohol in humans.

BACKGROUND: Ethanol oxidation by the microsomal ethanol oxidizing system requires oxygen for alcohol metabolism, and a higher oxygen uptake increases the rate of ethanol oxidation. We investigated the effect of dissolved oxygen on the pharmacokinetics of alcohol in healthy humans (n = 49). The concentrations of dissolved oxygen were 8, 20, and 25 ppm in alcoholic drinks of 240 and 360 ml (19.5% v/v). METHODS: Blood alcohol concentrations (BACs) were determined by converting breath alcohol concentrations. Breath samples were collected every 30 min when the BAC was higher than 0.015%, 20 min at BAC < or =0.015%, 10 min at BAC < or =0.010%, and 5 min at BAC < or =0.006%. RESULTS: The high dissolved oxygen groups (20, 25 ppm) descended to 0.000% and 0.050% BAC faster than the normal dissolved oxygen groups (8 ppm; p < 0.05). In analyzing pharmacokinetic parameters, AUC(inf) and K(el) of the high oxygen groups were lower than in the normal oxygen group, while C(max) and T(max) were not significantly affected. In a Monte Carlo simulation, the lognormal distribution of mean values of AUC(inf) and t(1/2) was expected to be reduced in the high oxygen group compared to the normal oxygen group. CONCLUSIONS: In conclusion, elevated dissolved oxygen concentrations in alcoholic drinks accelerate the metabolism and elimination of alcohol. Thus, enhanced dissolved oxygen concentrations in alcohol may have a role to play in reducing alcohol-related side effects and accidents.

Quantitative determination of sparfloxacin in rat plasma by liquid chromatography/tandem mass spectrometry.

Sparfloxacin, a fluoroquinolone antibiotic, is used for the treatment of bacterial infection. A quantification method using mass spectrometry was developed for the determination of sparfloxacin in rat plasma. After simple protein precipitation with acetonitrile, the analytes were chromatographed on a reversed-phase C18 column and detected by liquid chromatography/tandem mass spectrometry with electrospray ionization. The accuracy and precision of the assay were in accordance with FDA regulations for validation of bioanalytical methods. This method was applied to measure the plasma sparfloxacin concentrations after a single oral administration of sparfloxacin in rats.

Melanin-concentrating hormone-1 receptor binding activity of pheophorbides isolated from Morus alba leaves.

The time-resolved fluorescence technique based on melanin-concentrating hormone (MCH) receptor subtype-1 (MCH-1 receptor) binding assay was adopted to carry out a bioassay-guided fractionation of the methanol extract of Morus alba leaves. This fractionation and purification led to the isolation of two compounds identified as pheophorbide a methyl ester and 13(2)(S)-hydroxypheophorbide a methyl ester. These active pheophorbides exhibited potent inhibitory activity in binding of europium-labeled MCH to the human recombinant MCH-1 receptor (IC(50) value; 4.03 and 0.33 microM, respectively). Besides binding activity, the pheophorbides inhibited MCH-mediated extracellular signal-regulated kinase (ERK) phosphorylation in Chinese hamster ovary cells expressing human MCH-1 receptor. These results suggest that pheophorbide a methyl ester and 13(2)(S)-hydroxypheophorbide a methyl ester act as modulators of MCH-1 receptor and MCH-mediated ERK signaling.

Progress on sodium reduction in South Korea.

INTRODUCTION: High dietary sodium is a leading contributor to hypertension, and hypertension is the leading underlying cause of death globally. There is a robust body of evidence supporting the health benefits of sodium reduction. Sodium intake in South Korea is high, with about half the population consuming >4000 mg/day, twice the recommended upper limit. METHODS: In 2012, South Korea implemented its National Plan to Reduce Sodium Intake, with a goal of reducing population sodium consumption by 20%, to 3900 mg/day, by 2020. The plan included five key components: (1) a consumer awareness campaign designed to change food consumption behaviours; (2) increased availability of low-sodium foods at schools and worksites; (3) increased availability of low-sodium meals in restaurants; (4) voluntary reformulation of processed foods to lower sodium content; and (5) development of low-sodium recipes for food prepared at home. Monitoring and evaluation included tracking sodium intake and sources of dietary sodium using the Korea National Health and Nutrition Examination Survey. RESULTS: By 2014, South Korea had reduced dietary sodium consumption among adults by 23.7% compared to a survey conducted in 2010 prior to implementation of a nationwide salt reduction campaign that used this comprehensive, multipronged approach. The reductions in sodium intake were accompanied by reductions in population blood pressure and hypertension prevalence. Although causal associations between the sodium reduction programme and reduced sodium intake cannot be made, the declines occurred with the introduction of the programme. CONCLUSION: Multicomponent interventions have great potential to reduce population sodium intake. Lessons learnt from South Korea could be applied to other countries and are likely very relevant to other Asian countries with similar food sources and consumption profiles.

Effect of food on systemic exposure to niflumic acid following postprandial administration of talniflumate.

PURPOSE: Talniflumate was designed as a prodrug of niflumic acid, a potent analgesic and anti-inflammatory drug, which is widely prescribed for treating rheumatoid diseases. The prandial effect on talniflumate absorption remains unclear; therefore, this study investigated the effect of food on the systemic exposure to niflumic acid in healthy volunteers. METHODS: Volunteers received a single 740-mg dose of talniflumate 30 min after consuming a high-fat breakfast, a low-fat breakfast, or no food (fasting condition). Plasma concentrations of both talniflumate and niflumic acid were measured using validated high-performance liquid chromatography coupled to tandem mass spectrometry. RESULTS: The maximum concentration of niflumic acid was 224 +/- 193 ng/ml at approximately 2.7 h in the fasted condition compared with 886 +/- 417 ng/ml (p < 0.05) at 1.8 h and 1,159 +/- 508 ng/ml (p < 0.01) at 2.2 h with the low- and high-fat meals, respectively. The mean area under the curve from zero to infinity (AUC(inf)) values after the low- and high-fat meals were four- and fivefold, respectively, the value while fasting (p < 0.05). CONCLUSIONS: It is strongly recommended that talniflumate be taken after a meal to increase systemic exposure to its active metabolite. Our results suggest a reduction in the daily dosage of talniflumate when taken with food.