Ji-Young Jeon

Effects of Ficus carica paste on loperamide-induced constipation in rats.

OBJECTIVE Constipation is one of the most common gastrointestinal complaints worldwide. This study examined the effects of fig (Ficus carica L.) paste for the treatment of loperamide-induced constipation in a rat model. METHODS Animals were divided into one normal control group and four experimental groups (0, 1, 6, and 30 g/kg). Loperamide (2 mg/kg, twice per day) was injected intraperitoneally to induce constipation in the four experimental groups. Fig paste was administered for 4 weeks to assess its anti-constipation effects. RESULTS Fecal pellet number, weight and water content were increased in the fig-treated groups as compared to the control group. Reductions in body weight and increased intestinal transit length were observed in the fig-treated groups. Fecal pellet number was reduced in the distal colons of the fig-treated rats. Exercise and ileum tension increased in the experimental groups as compared to the control group. According to histological analyses, the thickness of the distal colon and areas of crypt epithelial cells that produce mucin were increased in the fig-treated groups in a dose-dependent manner. CONCLUSION Constipation was decreased when fig fruit was fed to rats. Specifically, fecal number, weight, and water content, as well as histological parameters such as thickness and mucin areas in the distal colon were improved. Fig treatment may be a useful therapeutic and preventive strategy for chronic constipation.

Development and validation of an LC-MS/MS method for determination of compound K in human plasma and clinical application

A rapid, sensitive and selective analytical method was developed and validated for the determination of compound K, a major intestinal bacterial metabolite of ginsenosides in human plasma. Liquid-liquid extraction was used for sample preparation and analysis, followed by liquid chromatography tandem spectrometric analysis and an electrospray-ionization interface. Compound K was analyzed on a Phenomenex Luna C18 column (100×2.00 mm, 3 μm) with the mobile phase run isocratically with 10 mM ammonium acetate-methanol-acetonitrile (5:47.5:47.5, v/v/v) at a flow rate of 0.5 mL/min. The method was validated for accuracy (relative error <12.63%), precision (coefficient of variation <9.14%), linearity, and recovery. The assay was linear over the entire range of calibration standards i.e., a concentration range of 1 ng/mL to 1,000 ng/ mL (r2 >0.9968). The recoveries of compound K after liquid-liquid extraction at 1, 2, 400, and 800 ng/mL were 106.00±0.08%, 103.50±0.19%, 111.45±5.21%, and 89.62±34.46% for intra-day and 85.40±0.08%, 94.50±0.09%, 112.50±5.21%, and 95.87±34.46% for inter-day, respectively. The lower limit of quantification of the analytical method of compound K was 1 ng/ mL in human plasma. The developed method was successfully applied to a pharmacokinetic study of compound K after oral administration in ten of healthy human subjects.

Postprandial glucose-lowering effects of fermented red ginseng in subjects with impaired fasting glucose or type 2 diabetes: a randomized, double-blind, placebo-controlled clinical trial

BackgroundRed ginseng is prepared by steaming raw ginseng, a process believed to increase the pharmacological efficacy. Further bioconversion of red ginseng through fermentation is known to increase its intestinal absorption and bioactivity, and bioconversion diminishes the toxicity of red ginseng’s metabolite. This study was conducted to investigate the effects of daily supplementation with fermented red ginseng (FRG) on glycemic status in subjects with impaired fasting glucose or type 2 diabetes.MethodsThis study was a four-week long, randomized, double-blind, placebo-controlled trial. Forty-two subjects with impaired fasting glucose or type 2 diabetes were randomly allocated to two groups assigned to consume either the placebo or fermented red ginseng (FRG) three times per day for four weeks. Fasting and postprandial glucose profiles during meal tolerance tests were assessed before and after the intervention.ResultsFRG supplementation led to a significant reduction in postprandial glucose levels and led to an increase in postprandial insulin levels compared to the placebo group. There was a consistently significant improvement in the glucose area under the curve (AUC) in the FRG group. However, fasting glucose, insulin, and lipid profiles were not different from the placebo group.ConclusionDaily supplementation with FRG lowered postprandial glucose levels in subjects with impaired fasting glucose or type 2 diabetes.Trial registrationClinicalTrials.gov: NCT01826409

Effects of Ficus carica paste on constipation induced by a high-protein feed and movement restriction in beagles

Constipation is one of the most common functional digestive complaints worldwide. We investigated the laxative effects of figs (Ficus carica L) in a beagle model of constipation induced by high protein diet and movement restriction. The experiments were consecutively conducted over 9 weeks divided into 3 periods of 3 weeks each. All 15 beagles were subjected to a non-treatment (control) period, a constipation induction period, and a fig paste treatment period. We administered fig paste (12 g/kg daily, by gavage) for 3 weeks following a 3-week period of constipation induction in dogs. Segmental colonic transit time (CTT) was measured by counting radiopaque markers (Kolomark) using a radiograph performed every 6 h after feeding Kolomark capsules, until capsules were no longer observed. Fig paste significantly increased fecal quantity in constipated dogs, and segmental CTT was also reduced following fig paste administration. There were no significant differences in feed intake, water intake, body weight, or blood test results, between the constipation and fig paste administration periods. Our results demonstrate that fig is an effective treatment for constipation in beagles. Specifically, stool weight increased and segmental CTT decreased. Fig pastes may be useful as a complementary medicine in humans suffering from chronic constipation.

Effect of Red Ginseng on cytochrome P450 and P-glycoprotein activities in healthy volunteers

Background We evaluated the drug interaction profile of Red Ginseng (RG) with respect to the activities of major cytochrome P450 (CYP) enzymes and the drug transporter P-glycoprotein (P-gp) in healthy Korean volunteers. Methods This article describes an open-label, crossover study. CYP probe cocktail drugs, caffeine, losartan, dextromethorphan, omeprazole, midazolam, and fexofenadine were administered before and after RG supplementation for 2 wk. Plasma samples were collected, and tolerability was assessed. Pharmacokinetic parameters were calculated, and 90% confidence intervals (CIs) of the geometric mean ratios of the parameters were determined from logarithmically transformed data using analysis of variance after RG administration versus before RG administration. Results Fourteen healthy male participants were evaluated, none of whom were genetically defined as poor CYP2C9, 2C19, and CYP2D6 metabolizers based on genotyping. Before and after RG administration, the geometric least-square mean metabolic ratio (90% CI) was 0.870 (0.805–0.940) for caffeine to paraxanthine (CYP1A2), 0.871 (0.800–0.947) for losartan (CYP2C9) to EXP3174, 1.027 (0.938–1.123) for omeprazole (CYP2C19) to 5-hydroxyomeprazole, 1.373 (0.864–2.180) for dextromethorphan to dextrorphan (CYP2D6), and 0.824 (0.658–1.032) for midazolam (CYP3A4) to 1-hydroxymidazolam. The geometric mean ratio of the area under the curve of the last sampling time (AUClast) for fexofenadine (P-gp) was 0.963 (0.845–1.098). Administration of concentrated RG for 2 wk weakly inhibited CYP2C9 and CYP3A4 and weakly induced CYP2D6. However, no clinically significant drug interactions were observed between RG and CYP and P-gp probe substrates. Conclusion RG has no relevant potential to cause CYP enzyme- or P-gp-related interactions. Clinical trial registration number (ClinicalTrials.gov): NCT02056743.

Effect of fermented red ginseng on cytochrome P450 and P‐glycoprotein activity in healthy subjects, as evaluated using the cocktail approach

Aims We assessed the drug interaction profile of fermented red ginseng with respect to the activity of major cytochrome (CYP) P450 enzymes and of a drug transporter protein, P‐glycoprotein (P‐gp), in healthy volunteers. Methods This study was an open‐label crossover study. The CYP probe cocktail drugs caffeine, losartan, dextromethorphan, omeprazole, midazolam and fexofenadine were administered before and after 2 weeks of fermented red ginseng administration. Plasma samples were collected, and tolerability was assessed. Pharmacokinetic parameters were calculated, and the 90% confidence intervals (CIs) of the geometric mean ratios of the parameters were determined from logarithmically transformed data. Values were compared between before and after fermented red ginseng administration using analysis of variance (anova). Results Fifteen healthy male subjects were evaluated, none of whom were genetically defined as a poor CYP2C9, CYP2C19 or CYP2D6 metabolizer based on genotyping. Before and after fermented red ginseng administration, the geometric least‐square mean metabolic ratio (90% CI) was 0.901 (0.830–0.979) for caffeine (CYP1A2) to paraxanthine, 0.774 (0.720–0.831) for losartan (CYP2C9) to EXP3174, 1.052 (0.925–1.197) for omeprazole (CYP2C19) to 5‐hydroxyomeprazole, 1.150 (0.860–1.538) for dextromethorphan (CYP2D6) to dextrorphan, and 0.816 (0.673–0.990) for midazolam (CYP3A4) to 1‐hydroxymidazolam. The geometric mean ratio of the area under the curve of the last sampling time (AUClast) for fexofenadine (P‐gp) was 1.322 (1.112–1.571). Conclusion No significantly different drug interactions were observed between fermented red ginseng and the CYP probe substrates following the two‐week administration of concentrated fermented red ginseng. However, the inhibition of P‐gp was significantly different between fermented red ginseng and the CYP probe substrates. The use of fermented red ginseng requires close attention due to the potential for increased systemic exposure when it is used in combination with P‐gp substrate drugs.

Pharmacokinetics of a new orally soluble film formulation of sildenafil administered without water.

OBJECTIVE To compare the pharmacokinetic profiles and to assess bioequivalence of a newly developed orally soluble film formulation of sildenafil, taken without water, with those of a conventional formulation of sildenafil. METHODS This study was conducted in a population of healthy subjects as an open-label, randomized sequence, two-period, two-formulation, single-dose, crossover design. The subjects were randomly assigned to 1 of 2 sequences of the two formulations: an orally soluble film (OSF) of 50 mg sildenafil as the test drug and a film-coated tablet (FCT) of 50 mg sildenafil as the reference drug. Blood samples were collected at intervals from 0 to 24 hours after administration. Plasma concentrations of sildenafil and its active metabolite N-desmethyl sildenafil were analyzed using a liquid chromatography/tandem mass spectrometry method. RESULTS 48 healthy male subjects completed the study. The geometric mean (CV%) for Cmax in the OSF and FCT formulations were 267.21 (4.68%) ng/mL and 285.97 (5.32%) ng/mL, respectively. The geometric mean for AUClast in the OSF and FCT formulations were 664.48 (4.40%) ng x h/mL and 647.96 (4.63%) ng x h/mL, respectively. The geometric mean for AUCinf in the OSF and FCT formulations were 685.65 (4.37%) ng x h/mL and 666.28 (4.60%) ng x h/ mL, respectively. The 90% confidence intervals of the ratios of the geometric means of the Cmax, AUClast, and AUCinf were 0.844 - 1.030, 0.961 - 1.091, and 0.965 - 1.093, respectively. CONCLUSIONS The OSF sildenafil formulation exhibited no significant differences in its pharmacokinetics compared with those of the FCT formulation. Therefore this convenient OSF sildenafil formulation, which can be taken without the need for water or chewing, offers physicians a novel and attractive treatment option for men with erectile dysfunction. *These authors contributed equally to this work.

Effect of epigallocatechin-3-gallate, major ingredient of green tea, on the pharmacokinetics of rosuvastatin in healthy volunteers

Previous in vitro studies have demonstrated the inhibitory effect of green tea on drug transporters. Because rosuvastatin, a lipid-lowering drug widely used for the prevention of cardiovascular events, is a substrate for many drug transporters, there is a possibility that there is interaction between green tea and rosuvastatin. The aim of this study was to investigate the effect of green tea on the pharmacokinetics of rosuvastatin in healthy volunteers. An open-label, three-treatment, fixed-sequence study was conducted. On Day 1, 20 mg of rosuvastatin was given to all subjects. After a 3-day washout period, the subjects received 20 mg of rosuvastatin plus 300 mg of epigallocatechin-3-gallate (EGCG), a major ingredient of green tea (Day 4). After a 10-day pretreatment of EGCG up to Day 14, they received rosuvastatin (20 mg) plus EGCG (300 mg) once again (Day 15). Blood samples for the pharmacokinetic assessments were collected up to 8 hours after each dose of rosuvastatin. A total of 13 healthy volunteers were enrolled. Compared with the administration of rosuvastatin alone, the concomitant use at Day 4 significantly reduced the area under the concentration–time curve from time 0 to the last measurable time (AUClast) by 19% (geometric mean ratio 0.81, 90% confidence interval [CI] 0.67–0.97) and the peak plasma concentration (Cmax) by 15% (geometric mean ratio 0.85, 90% CI 0.70–1.04). AUClast or Cmax of rosuvastatin on Day 15 was not significantly different from that on Day 1. This study demonstrated that co-administration of EGCG reduces the systemic exposure of rosuvastatin by 19%, and pretreatment of EGCG can eliminate that effect of co-administration of EGCG.

Pharmacokinetic Comparison Study of a Combination Containing 500 mg of Naproxen and 20 mg of Esomeprazole: A Randomized, Single-dose, 2-way Crossover, Open-label Study in Healthy Korean Men

PURPOSE Nonsteroidal anti-inflammatory drugs have been used for analgesic, anti-inflammatory, and antithrombotic effects, but they carry a risk of major gastrointestinal damage. This risk can be greatly reduced by the coadministration of inhibitors of gastric acid secretion, such as proton pump inhibitors. This study was performed for the subsequent marketing of a combination drug that contained 500 mg of naproxen and 20 mg of esomeprazole in Korea. We evaluated the comparative bioavailability and tolerability of the test and reference formulations in healthy men. METHODS A total of 60 healthy men were enrolled in this single-dose, randomized, open-label, 2-period, 2-sequence, crossover study. During each period, men received a combination of 500 mg of naproxen and 20 mg of esomeprazole for test or reference, and between each period, there was a 1-week washout period. Blood samples were obtained 21 times throughout each period before dosing and 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 48, and 72 hours after oral administration. Plasma concentrations were determined using LC-MS/MS. The pharmacokinetic parameters, including Cmax, AUC0-t, AUC0-∞, and Tmax, were measured, and all treatment-emergent adverse events and their associations with the study medications were recorded throughout the entire study. FINDINGS A total of 59 men completed the study. No significant differences were found in the prevalence of AEs between the 2 formulations. In addition, there were no serious or unexpected AEs during the study. Both formulations had very similar Cmax, AUC, and t½ values, but the Tmax of naproxen appeared earlier in the test formulation than in the reference formulation and that of esomeprazole appeared later in the test formulation than in the reference formulation. IMPLICATIONS This study suggests that the test and reference formulations of a combination of 500 mg of naproxen and 20 mg of esomeprazole are bioequivalent in the extent of absorption and peak concentration. We anticipate that the test formulation will treat those who need relief from pain and inflammation and will decrease the risk of developing gastric ulcers. cris.nih.go.kr identifier: KCT0001117.

Pharmacokinetic properties and bioequivalence of candesartan cilexetil in Korean healthy volunteers.

Candesartan is a long-acting and selective nonpeptide AT1 subtype angiotensin II receptor antagonist. The aim of this study was to compare the pharmacokinetics and to evaluate the bioequivalence of two candesartan cilexetil 16 mg formulations. Forty healthy volunteers were randomly assigned into two groups. After a single dose of 16 mg candesartan cilexetil oral administration, blood samples were collected at specific time intervals from 0–36 h. The plasma concentrations of candesartan cilexetil were determined by LC-MS/MS. The pharmacokinetic parameters such as AUClast, AUCinf and Cmax were calculated and the 90% confidence intervals of the ratio (test/reference) pharmacokinetic parameters were obtained by analysis of variance on logarithmically transformed data. The mean for AUClast in the reference and the test drug were 1530.1 ± 434.6 and 1315.7 ± 368.6 ng·h/mL. The mean for AUCinf in the reference and the test drug were 1670.0 ± 454.5 and 1441.2 ± 397.8 ng·h/mL. The mean value for Cmax in the reference and the test drug was 142.6 ± 41.0 and 134.9 ± 41.4 ng/mL. The 90% confidence intervals for the AUClast, AUCinf and Cmax were in the range of log 0.81–log 0.91, log 0.81–log 0.91 and log 0.88–log1.01, respectively. No adverse events were reported by subjects or found on analysis of vital signs or laboratory tests. This single dose study found that the test and reference products met the regulatory criteria for bioequivalence in these health volunteers. Both formulations were safe and well tolerated in 16 mg of candesartan cilexetil hydrochloride.