Effects of food and ethnicity on the pharmacokinetics of venadaparib, a next-generation PARP inhibitor, in healthy Korean, Caucasian, and Chinese male subjects.

AIM: Venadaparib is a next-generation poly(ADP-ribose) polymerase inhibitor under development for treating gastric cancer. This study aimed to evaluate the effects of food and ethnicity on the pharmacokinetics (PKs) and safety of venadaparib after a single oral administration in healthy Korean, Caucasian, and Chinese male subjects. METHODS: In this randomized, open-label, single-dose, two-sequence, two-period, and crossover study, Korean and Caucasian subjects received venadaparib 80 mg in each period (fasted or fed state) with a seven-day washout. In an open-label, single-dose study, Chinese subjects received venadaparib 80 mg only in the fasted state. Serial blood samples were collected up to 72 h post-dosing. RESULTS: Twelve subjects from each ethnic group completed the study. The geometric mean ratios (90% confidence intervals) of the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the last measurable time point (AUClast) of venadaparib for the fed to fasted state were 0.82 (0.7457-0.9094) and 1.02 (0.9088-1.1339) in Koreans, and 0.77 (0.6871-0.8609) and 0.96 (0.9017-1.0186) in Caucasians, respectively. No statistically significant differences were observed in Cmax (P-value = 0.45) or AUClast (P-value = 0.30) among the three ethnic groups. A single venadaparib dose was well-tolerated. CONCLUSION: The overall systemic exposure of venadaparib was not affected by the high-fat meal, despite delayed absorption with a decreased Cmax in the fed state. The PK profiles were comparable among the Korean, Caucasian, and Chinese subjects. A single venadaparib 80 mg dose was safe and well-tolerated in both fasted and fed states.

In vitro and in vivo reduction of post-prandial blood glucose levels by ethyl alcohol and water Zingiber mioga extracts through the inhibition of carbohydrate hydrolyzing enzymes.

BACKGROUND: Type 2 diabetes is a serious problem for developed and developing countries. Prevention of prediabetes progression to type 2 diabetes with the use of natural products appears to be a cost-effective solution. Zingiber mioga has been used as a traditional food in Asia. Recent research has reported the potential health benefits of Zingiber mioga, but the blood glucose reducing effect has not been yet evaluated. METHODS: In this study Zingiber mioga extracts (water and ethanol) were investigated for their anti-hyperglycemic and antioxidant potential using both in vitro and animal models. The in vitro study evaluated the total phenolic content, the oxygen radical absorbance capacity (ORAC) and the inhibitory effect against carbohydrate hydrolyzing enzymes (porcine pancreatic α-amylase and rat intestinal sucrase and maltase) of both Zingiber mioga extracts. Also, the extracts were evaluated for their in vivo post-prandial blood glucose reducing effect using SD rat and db/db mice models. RESULTS: Our findings suggest that the ethanol extract of Zingiber mioga (ZME) exhibited the higher sucrase and maltase inhibitory activity (IC50, 3.50 and 3.13 mg/mL) and moderate α-amylase inhibitory activity (IC50, >10 mg/mL). Additionally, ZME exhibited potent peroxyl radical scavenging linked antioxidant activity (0.53/TE 1 µM). The in vivo study using SD rat and db/db mice models also showed that ZME reduces postprandial increases of blood glucose level after an oral administration of sucrose by possibly acting as an intestinal α-glucosidase inhibitor (ZME 0.1 g/kg 55.61 ± 13.24 mg/dL) CONCLUSION: The results indicate that Zingiber mioga extracts exhibited significant in vitro α-glucosidase inhibition and antioxidant activity. Additionally, the tested extracts demonstrated in vivo anti-hyperglycemic effects using SD rat and db/db mice models. Our findings provide a strong rationale for the further evaluation of Zingiber mioga for the potential to contribute as a useful dietary strategy to manage postprandial hyperglycemia.

Selected tea and tea pomace extracts inhibit intestinal α-glucosidase activity in vitro and postprandial hyperglycemia in vivo.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by postprandial hyperglycemia, which is an early defect of T2DM and thus a primary target for anti-diabetic drugs. A therapeutic approach is to inhibit intestinal α-glucosidase, the key enzyme for dietary carbohydrate digestion, resulting in delayed rate of glucose absorption. Although tea extracts have been reported to have anti-diabetic effects, the potential bioactivity of tea pomace, the main bio waste of tea beverage processing, is largely unknown. We evaluated the anti-diabetic effects of three selected tea water extracts (TWE) and tea pomace extracts (TPE) by determining the relative potency of extracts on rat intestinal α-glucosidase activity in vitro as well as hypoglycemic effects in vivo. Green, oolong, and black tea bags were extracted in hot water and the remaining tea pomace were dried and further extracted in 70% ethanol. The extracts were determined for intestinal rat α-glucosidases activity, radical scavenging activity, and total phenolic content. The postprandial glucose-lowering effects of TWE and TPE of green and black tea were assessed in male Sprague-Dawley (SD) rats and compared to acarbose, a known pharmacological α-glucosidase inhibitor. The IC50 values of all three tea extracts against mammalian α-glucosidase were lower or similar in TPE groups than those of TWE groups. TWE and TPE of green tea exhibited the highest inhibitory effects against α-glucosidase activity with the IC50 of 2.04 ± 0.31 and 1.95 ± 0.37 mg/mL respectively. Among the specific enzymes tested, the IC50 values for TWE (0.16 ± 0.01 mg/mL) and TPE (0.13 ± 0.01 mg/mL) of green tea against sucrase activity were the lowest compared to those on maltase and glucoamylase activities. In the animal study, the blood glucose level at 30 min after oral intake (0.5 g/kg body wt) of TPE and TWE of both green and black tea was significantly reduced compared to the control in sucrose-loaded SD rats. The TPE of all three teas had significantly higher phenolic content than those of the TWE groups, which correlated strongly with the DPPH radical scavenging activity. This is the first report of tea pomace extract significantly inhibits intestinal α-glucosidase, resulting in delayed glucose absorption and thereby suppressed postprandial hyperglycemia. Our data suggest that tea pomace-derived bioactives may have great potential for further development as nutraceutical products and the reuse of otherwise biowaste as valuable bioresources for the industry.

Effect of long-term supplementation of low molecular weight chitosan oligosaccharide (GO2KA1) on fasting blood glucose and HbA1c in db/db mice model and elucidation of mechanism of action.

BACKGROUND: Type 2 diabetes is a serious problem for developed countries. Prevention of prediabetes progression to type 2 diabetes with the use of natural products appears to a cost-effective solution. Previously we showed that enzymatically digested low molecular weight chitosan-oligosaccharide with molecular weight (MW) below 1,000 Da (GO2KA1) has potential for hyperglycemia management. METHODS: In this study we evaluated the effect of long-term supplementation of GO2KA1 on hyperglycemia using a db/db mice model. Additionally, we evaluated the effect of GO2KA1 on sucrase and glucoamylase activities and expression, using the same db/db mice model. RESULTS: After 42 days we observed that GO2KA1 supplementation reduced both the blood glucose level and HbA1c in a similar manner with a known anti-diabetic drug, acarbose. When the sucrase and glucoamylase activities of GO2KA1 and control mice were evaluated using enzymatic assay, we observed that GO2KA1 significantly inhibited sucrase in all 3 parts of the intestine, while glucoamylase activity was significantly reduced only in the middle and lower part. When the sucrase-isomaltase (SI) complex expression on mRNA level was evaluated, we observed that GO2KA1 had minimal inhibitory effect on the upper part, more pronounced inhibitory effect on the middle part, while the highest inhibition was observed on the lower part. Our findings suggest that long-term GO2KA1 supplementation in db/db mice results to significant blood glucose and HbA1c reduction, to levels similar with those of acarbose. Furthermore, our findings confirm previous in vitro observations that GO2KA1 has inhibitory effect on carbohydrate hydrolysis enzymes, namely sucrase, maltase and SI complex. CONCLUSIONS: Results from this study provide a strong rationale for the use of GO2KA1 for type 2 diabetes prevention, via inhibition of carbohydrate hydrolysis enzymes. Based on the findings of this animal trial, clinical trials will be designed and pursued.

Effect of long-term dietary arginyl-fructose (AF) on hyperglycemia and HbA1c in diabetic db/db mice.

We have previously reported that Amadori compounds exert anti-diabetic effects by lowering sucrose-induced hyperglycemia in normal Sprague-Dawley rats. In the present study we extended our recent findings to evaluate whether α-glucosidase inhibitor arginyl-fructose (AF) lowers blood glucose level in diabetic db/db mice, a genetic model for type 2 diabetes. The db/db mice were randomly assigned to high-carbohydrate diets (66.1% corn starch) with and without AF (4% in the diet) for 6 weeks. Changes in body weight, blood glucose level, and food intake were measured daily for 42 days. Dietary supplementation of AF resulted in a significant decrease of blood glucose level (p < 0.001) and body weight (p < 0.001). The level of HbA1c, a better indicator of plasma glucose concentration over prolonged periods of time, was also significantly decreased for 6-week period (p < 0.001). Dietary treatment of acarbose® (0.04% in diet), a positive control, also significantly alleviated the level of blood glucose, HbA1c, and body weight. These results indicate that AF Maillard reaction product improves postprandial hyperglycemia by suppressing glucose absorption as well as decreasing HbA1c level.

Molecular weight dependent glucose lowering effect of low molecular weight Chitosan Oligosaccharide (GO2KA1) on postprandial blood glucose level in SD rats model.

This research investigated the effect of enzymatically digested low molecular weight (MW) chitosan oligosaccharide on type 2 diabetes prevention. Three different chitosan oligosaccharide samples with varying MW were evaluated in vitro for inhibition of rat small intestinal α-glucosidase and porcine pancreatic α-amylase (GO2KA1; <1000 Da, GO2KA2; 1000-10,000 Da, GO2KA3; MW > 10,000 Da). The in vitro results showed that all tested samples had similar rat α-glucosidase inhibitory and porcine α-amylase inhibitory activity. Based on these observations, we decided to further investigate the effect of all three samples at a dose of 0.1 g/kg, on reducing postprandial blood glucose levels in Sprague-Dawley (SD) rat model after sucrose loading test. In the animal trial, all tested samples had postprandial blood glucose reduction effect, when compared to control, however GO2KA1 supplementation had the strongest effect. The glucose peak (Cmax) for GO2KA1 and control was 152 mg/dL and 193 mg/dL, respectively. The area under the blood glucose-time curve (AUC) for GO2KA1 and control was 262 h mg/dL and 305 h mg/dL, respectively. Furthermore, the time of peak plasma concentration of blood glucose (Tmax) for GO2KA1 was significantly delayed (0.9 h) compared to control (0.5 h). These results suggest that GO2KA1 could have a beneficial effect for blood glucose management relevant to diabetes prevention in normal and pre-diabetic individuals. The suggested mechanism of action is via inhibition of the carbohydrate hydrolysis enzyme α-glucosidase and since GO2KA1 (MW < 1000 Da) had higher in vivo effect, we hypothesize that it is more readily absorbed and might exert further biological effect once it is absorbed in the blood stream, relevant to blood glucose management.

Venadaparib Is a Novel and Selective PARP Inhibitor with Improved Physicochemical Properties, Efficacy, and Safety.

PARP inhibitors have been approved by the FDA for use in the treatment of patients with ovarian, breast, pancreatic, and prostate cancers. PARP inhibitors show diverse suppressive effects on PARP family members and PARP-DNA trapping potency. These properties are associated with distinct safety/efficacy profiles. Here, we report the nonclinical characteristics of venadaparib (also known as IDX-1197 or NOV140101), a novel potent PARP inhibitor. The physiochemical properties of venadaparib were analyzed. Furthermore, the efficacy of venadaparib against PARP enzymes, PAR formation, and PARP trapping activities, and growth inhibition of cell lines with BRCA mutations were evaluated. Ex vivo and in vivo models were also established to study pharmacokinetics/pharmacodynamics, efficacy, and toxicity. Venadaparib specifically inhibits PARP-1 and -2 enzymes. Oral administration of venadaparib HCl at doses above 12.5 mg/kg significantly reduced tumor growth in the OV_065 patient-derived xenograft model. Intratumoral PARP inhibition remained at over 90% until 24 hours after dosing. Venadaparib had wider safety margins than olaparib. Notably, venadaparib showed favorable physicochemical properties and superior anticancer effects in homologous recombination-deficient in vitro and in vivo models with improved safety profiles. Our results suggest the possibility of venadaparib as a next-generation PARP inhibitor. On the basis of these findings, phase Ib/IIa studies on the efficacy and safety of venadaparib have been initiated.

In vitro and in vivo anti-hyperglycemic effects of Omija (Schizandra chinensis) fruit.

The entrocytes of the small intestine can only absorb monosaccharides such as glucose and fructose from our diet. The intestinal absorption of dietary carbohydrates such as maltose and sucrose is carried out by a group of α-glucosidases. Inhibition of these enzymes can significantly decrease the postprandial increase of blood glucose level after a mixed carbohydrate diet. Therefore, the inhibitory activity of Omija (Schizandra chinensis) extract against rat intestinal α-glucosidase and porcine pancreatic α-amylase were investigated in vitro and in vivo. The in vitro inhibitory activities of water extract of Omija pulp/skin (OPE) on α-glucosidase and α-amylase were potent when compared to Omija seeds extract (OSE). The postprandial blood glucose lowering effect of Omija extracts was compared to a known type 2 diabetes drug (Acarbose), a strong α-glucosidase inhibitor in the Sprague-Dawley (SD) rat model. In rats fed on sucrose, OPE significantly reduced the blood glucose increase after sucrose loading. Furthermore, the oxygen radical absorbance capacity (ORAC) of OSE and OPE was evaluated. OPE had higher peroxyl radical absorbing activity than OSE. These results suggest that Omija, which has high ORAC value with α-glucosidase inhibitory activity and blood glucose lowering effect, could be physiologically useful for treatment of diabetes, although clinical trials are needed.

In Vitro and in Vivo Anti-Hyperglycemic Activities of Taxifolin and Its Derivatives Isolated from Pigmented Rice (Oryzae sativa L. cv. Superhongmi).

Superhongmi is a new rice variety, which was developed for the enrichment of bioactive compounds through cross-breeding three varieties of rice breeds in Korea. The high-performance liquid chromatography coupled with a photodiode array detector quadrupole and tandem time-of-flight mass spectrometry (HPLC/PDA/QTOF-MS) analysis has revealed that superhongmi bran extract contained four taxifolin derivatives as well as cyanidin 3-glucoside. The high-performance countercurrent chromatography (CCC) and reversed-phase HPLC led to the isolation of aforementioned five compounds, and spectroscopic analysis identified cyanidin 3-glucoside (1), along with (2R,3R)-taxifolin 3-O-ß-d-glucopyranoside (2), (2R,3R)-4'-O-methyltaxifolin 3-O-ß-d-glucopyranoside (a novel compound) (3), (2R,3R)-taxifolin (4), and (2R,3R)-4'-O-methyltaxifolin (5). Compound 2 had the highest rat small intestinal sucrase inhibitory activity (0.54 mM) relevant for potentially managing postprandial hyperglycemia, followed by compound 1 (0.97 mM) and compound 4 (1.74 mM, IC50). The anti-hyperglycemic effect of compound 4 (taxifolin), a main peak in HPLC analysis was investigated using a Sprague-Dawley (SD) rat model. Compared to a control, taxifolin treatment (p < 0.001) reduced significantly after sucrose loading the observed postprandial blood glucose and the maximum blood glucose (Cmax) by 15% (203.60 ± 15.86 to 172.30 ± 12.74). These results indicate that taxifolin derivatives that inhibit the activity of carbohydrate-hydrolyzing enzymes resulting in reduced dietary carbohydrate absorption can potentially be used as a strategy to manage diabetes.

Effect of supplementation of low-molecular-weight chitosan oligosaccharide, GO2KA1, on postprandial blood glucose levels in healthy individuals following bread consumption.

The effect of chitosan oligosaccharide (GO2KA1) administration on postprandial blood glucose levels of subjects with normal blood glucose levels was evaluated following bread consumption. Postprandial blood glucose levels were determined for 2 h after bread ingestion with or without 500 mg of GO2KA1. GO2KA1 significantly lowered the mean, maximum, and minimum levels of postprandial blood glucose at 30 min after the meal. Postprandial blood glucose levels were decreased by about 25% (from 155.11±13.06 to 138.50±13.59, p<0.01) at 30 min when compared to control. Furthermore, we observed that the area under the concentration-time curve (AUCt) was decreased by about 6% (from 255.46±15.43 to 240.15±14.22, p<0.05) and the peak concentration of blood glucose (C max) was decreased by about 11% (from 157.94±10.90 to 140.61±12.52, p<0.01) when compared to control. However, postprandial the time to reach C max (Tmax) levels were the same as those found in control. Our findings suggest that GO2KA1 limits the increase in postprandial blood glucose levels following bread consumption.

The effect of glargine versus glimepiride on pancreatic ß-cell function in patients with type 2 diabetes uncontrolled on metformin monotherapy: open-label, randomized, controlled study.

The aim of present study is to assess whether if basal insulin, glargine, could improve insulin secretory function of ß-cells compared with glimepiride when metformin alone was failed. This was an open-label and multi-center study for 52 weeks in Korean patients with uncontrolled type 2 diabetes by metformin monotherapy. Subjects were randomized to glargine or glimepiride groups (n = 38 vs. 36, respectively). The primary endpoint was to compare changes in c-peptide via glucagon test after 48 weeks. Glycemic efficacy and safety endpoints (glycated hemoglobin (HbA1c), HOMA-B, fasting plasma glucose (FPG), lipid profiles, and hypoglycemic events) were also checked. The mean disease duration of all subjects was 88.2 months. Changes in C-peptide was no significant different between groups (P = 0.73), even though insulin secretion was not worsened in both groups at the endpoint. Glargine was not superior to glimepiride in other ß-cell function indexes such as HOMA-B (P = 0.28). HbA1c and FPG reduced significantly in each groups but not different between two groups. Although, severe hypoglycemia did not occur, symptomatic hypoglycemia was more frequent in glimepiride group (P = 0.01). Insulin glargine was as effective as glimepiride in controlling hyperglycemia and maintaining ß-cell function in Korean patients with type 2 diabetes during 48 weeks study period, after failure of metformin monotherapy. Hypoglycemic profile was favorable in the insulin glargine group and less weight gain was observed in the glimepiride group. Our results suggest that glargine and glimepiride can be considered after failure of metformin monotherapy.

Duration of diabetes and effectiveness of insulin in the management of insulin-naïve Korean patients uncontrolled on oral antidiabetic drugs: a sub-analysis of the MOdaliTy of Insulin treatment eValuation (MOTIV) registry results.

To investigate whether duration of diabetes has an impact on the effectiveness of insulinization in diabetes management. This open-label, noninterventional, observational registry was conducted at >500 centers in Korea. Patients with diabetes, on oral antidiabetic drugs, with HbA1c ≥7 % (53 mmol/mol) in the preceding 3 months, being considered for initiation of basal insulin by their physicians, were included. Data were collected at baseline and at 3 and 6 months. Of 6,616 patients evaluated, 62.5 % had diabetes for <10 years, while only 6.5 % patients had diabetes for ≥20 years. At the end of study, average HbA1c in patients with diabetes for <10 years, for 10 to <20 years, and for ≥20 years was 7.3 ± 1.0 % (56 ± 10.9 mmol/mol), 7.4 ± 1.0 % (57 ± 10.9 mmol/mol), and 7.6 ± 1.1 % (60 ± 12.0 mmol/mol), respectively. Over half the patients (50.7 %) with diabetes <10 years achieved HbA1c <7 % (53 mmol/mol) by the end of study, while only 42.1 and 35.1 % patients with diabetes for 10 to <20 and ≥20 years, respectively, achieved their target. The average insulin dosage required for per unit HbA1c reduction was significantly different among the groups according to duration of type 2 diabetes mellitus (p < 0.05). Among patients who achieved HbA1c <7 %, proportion of patients with hypoglycemia in the ≥20 years group was higher than that in the <10 years, 10 to <20 years groups. Early insulin administration provided a better glycemic control with less insulin dosage and lower frequency of hypoglycemic events. Thus, early insulinization might hold the key to better management of type 2 diabetes mellitus.

In vitro and in vivo antihyperglycemic effect of 2 amadori rearrangement compounds, arginyl-fructose and arginyl-fructosyl-glucose.

During the heat processing of raw ginseng to produce red ginseng, amino acid derivatives such as arginyl-fructose (AF) and arginyl-fructosyl-glucose (AFG) are formed at high levels, through amadori rearrangement, the early step of Maillard reaction, from arginine and glucose or maltose, respectively. However, very limited information is available about the effect of the structural difference between AF and AFG on various biological activities. This is the first report of the mode of action and effect of AF and AFG on the type 2 diabetes management related inhibition of postprandial hyperglycemia in vitro and in animal model. In our previous study, standards AF and AFG were chemically synthesized and in this study their inhibitory activities against rat intestinal α-glucosidases and porcine pancreatic α-amylase were investigated in vitro. The IC(50) value of the in vitro inhibitory activity of AF and AFG on rat intestinal sucrase was high and in similar levels (6.40 and 6.20 mM, respectively). Additionally, a mild pancreatic α-amylase inhibitory activity was observed, with IC(50) values 36.30 and 37.60 mM for AF and AFG, respectively. The effect of AF and AFG on the postprandial blood glucose increase after meal was investigated in Sprague Dawley rats fed on starch or sucrose meals. Both amadori compounds significantly reduced the postprandial blood glucose levels after starch or sucrose loading. These results indicate that AF and AFG, Maillard reaction products, may have antidiabetic effect by suppressing carbohydrate absorption in the gastrointestinal level, and thereby reducing the postprandial increase of blood glucose.

[Relationship between corrected QT interval and cardiovascular risk factors in young healthy adults: the Kangwha study].

OBJECTIVES: Prolongation of the heart rate-corrected QT (QTc) interval has been reported to be associated with cardiovascular morbidity and mortality. However, few studies have examined the relationship between the QTc interval and cardiovascular risk factors in young healthy people. The aim of this study was to examine the associations between the QTc interval and cardiovascular risk factors in young healthy adults. METHODS: This study was performed as part of the Kangwha study, which started in 1986, and is an on-going follow-up study on blood pressure and related cardiovascular risk factors. In follow-up examinations during 2005, cardiovascular risk factors, including anthropometrics, blood pressure, blood chemistry and carotid ultrasonography, were measured, and questionnaires on health behaviors completed by 127 men and 149 women aged 25 years. The QTc interval was measured on the resting 12-lead electrocardiogram using an automatic analysis program. RESULTS: The mean QTc interval was significantly longer in women (419+/-17ms) than in men (405+/-17ms) (p<0.001). A significant positive correlation was found between the QTc interval and waist-hip ratio (p=0.030) in men. Women showed a positive correlation between the QTc interval and systolic blood pressure (p=0.017). On a multiple regression analysis, the QTc interval was positively associated with the waist-hip ratio in men (p=0.012) and with the systolic blood pressure (p=0.020) in women. CONCLUSIONS: In young healthy Korean adults, the QTc interval was independently associated with the waist-hip ratio in men and with the systolic blood pressure in women.