Evaluation of the transporter-mediated herb-drug interaction potential of DA-9801, a standardized dioscorea extract for diabetic neuropathy, in human in vitro and rat in vivo

BACKGROUND: Drug transporters play important roles in the absorption, distribution, and elimination of drugs and thereby, modulate drug efficacy and toxicity. With a growing use of poly pharmacy, concurrent administration of herbal extracts that modulate transporter activities with drugs can cause serious adverse reactions. Therefore, prediction and evaluation of drug-drug interaction potential is important in the clinic and in the drug development process. DA-9801, comprising a mixed extract of Dioscoreae rhizoma and Dioscorea nipponica Makino, is a new standardized extract currently being evaluated for diabetic peripheral neuropathy in a phase II clinical study. METHOD: The inhibitory effects of DA-9801 on the transport functions of organic cation transporter (OCT)1, OCT2, organic anion transporter (OAT)1, OAT3, organic anion transporting polypeptide (OATP)1B1, OATP1B3, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) were investigated in HEK293 or LLC-PK1 cells. The effects of DA-9801 on the pharmacokinetics of relevant substrate drugs of these transporters were also examined in vivo in rats. RESULTS: DA-9801 inhibited the in vitro transport activities of OCT1, OCT2, OAT3, and OATP1B1, with IC(50) values of 106, 174, 48.1, and 273 μg/mL, respectively, while the other transporters were not inhibited by 300 μg/mL DA-9801. To investigate whether this inhibitory effect of DA-9801 on OCT1, OCT2, and OAT3 could change the pharmacokinetics of their substrates in vivo, we measured the pharmacokinetics of cimetidine, a substrate for OCT1, OCT2, and OAT3, and of furosemide, a substrate for OAT1 and OAT3, by co-administration of DA-9801 at a single oral dose of 1,000 mg/kg. Pre-dose of DA-9801 5 min or 2 h prior to cimetidine administration decreased the C(max) of cimetidine in rats. However, DA-9801 did not affect the elimination parameters such as half-life, clearance, or amount excreted in the urine, suggesting that it did not inhibit elimination process of cimetidine, which is governed by OCT1, OCT2, and OAT3. Moreover, DA-9801 did not affect the pharmacokinetic characteristics of furosemide, as evidenced by its unchanged pharmacokinetic parameters. CONCLUSION: Inhibitory effects of DA-9801 on OCT1, OCT2, and OAT3 observed in vitro may not necessarily translate into in vivo herb-drug interactions in rats even at its maximum effective dose

Cholestatic Hepatitis and Thrombocytosis in a Secondary Syphilis Patient

The incidence of acute hepatitis in syphilis patient is rare. First of all, our patient presented with hepatitis comorbid with thrombocytosis. To our knowledge, this is only the second report of syphilitic hepatitis with thrombocytosis. The 42-yr-old male complained of flulike symptoms and skin eruptions on his palms and soles. Laboratory findings suggested an acute hepatitis and thrombocytosis. Serologic test results were positive for VDRL. He recovered from his symptoms and elevated liver related enzymes with treatment. Because syphilitic hepatitis can present without any typical signs of accompanying syphilis, syphilis should be considered as a possible cause in acute hepatitis patients

Ultrasound-guided supraclavicular brachial plexus block in pediatric patients -A report of four cases-

Supraclavicular brachial plexus blocks are not common in pediatric patients due to the risk of pneumothorax. Ultrasonography is an important tool for identifying nerves during regional anesthesia. Directly visualizing the target nerves and monitoring the distribution of the local anesthetic are potentially significant. In addition, ultrasound monitoring helps avoid complications, such as inadvertent intravascular injection or pneumothorax. This paper reports four cases of pediatric patients who received ultrasound-guided supraclavicular brachial plexus block for upper limb surgery

Epidemiologic features of pediatric genital injury in emergency departments in Korea

Purpose Genital injury is a common pediatric injury. Given the lack of nationwide data, the authors aimed to show age group-related epidemiologic features of genital injury in Korea. Methods We reviewed the data from 2011-2016 Emergency Department-based Injury In-depth Surveillance registry, which involves 23 emergency departments in Korea. From the dataset, we included children (< 18 years) with the International Classification of Diseases, 10th Revision codes related to genital injury as the final diagnosis with excluding those with other codes or combined injuries. Age groups were defined as follows; infants (< 1 year), toddlers (1-3), preschoolers (4-6), schoolers (7-12), and adolescents (13-17). The clinical features and outcomes were analyzed. Results A total of 3,030 children were included with the median age of 6 years (interquartile range, 4-10) and the proportion of girls of 53.0%. Only 144 children (4.8%) were transported by the emergency medical service providers. The most common mechanism and place were blunt injury (1,826 [60.3%]) and home (1,535 [50.7%]), respectively. Of the codes, “Contusion of external genital organs (S30.2)” was most common (1,574 [51.9%]). As for outcomes, 2,770 children (91.4%) were discharged, 252 (8.3%) were hospitalized (intensive care units, 1 child [0.03%]), and 108 (3.6%) underwent surgery. Severe injury occurred in 111 children (3.7%) without a mortality. With increasing age in the age groups, non-accidental injury, school and sports-related injuries, hospitalization, and surgery (All Ps < 0.001). Conclusion Genital injury may occur at evening, in spring and summer, at home, and in the form of accidental or blunt injury. Most children are discharged. Contrary to these general features, older children tend to undergo more frequently non-accidental injury, school and sports-related injuries, hospitalization, and surgery. Thus, we need age-specific strategies for injury prevention

Electrically Robust Single-Crystalline WTe2 Nanobelts for Nanoscale Electrical Interconnects

As the elements of integrated circuits are downsized to the nanoscale, the current Cu-based interconnects are facing limitations due to increased resistivity and decreased current-carrying capacity because of scaling. Here, the bottom-up synthesis of single-crystalline WTe2 nanobelts and low- and high-field electrical characterization of nanoscale interconnect test structures in various ambient conditions are reported. Unlike exfoliated flakes obtained by the top-down approach, the bottom-up growth mode of WTe2 nanobelts allows systemic characterization of the electrical properties of WTe2 single crystals as a function of channel dimensions. Using a 1D heat transport model and a power law, it is determined that the breakdown of WTe2 devices under vacuum and with AlOx capping layer follows an ideal pattern for Joule heating, far from edge scattering. High-field electrical measurements and self-heating modeling demonstrate that the WTe2 nanobelts have a breakdown current density approaching approximate to 100 MA cm(-2), remarkably higher than those of conventional metals and other transition-metal chalcogenides, and sustain the highest electrical power per channel length (approximate to 16.4 W cm(-1)) among the interconnect candidates. The results suggest superior robustness of WTe2 against high-bias sweep and its possible applicability in future nanoelectronics

Overexpression of p53, Mutation of hMLH1 and Microsatellite Instability in Gastric Carcinomas: Clinicopathologic Implications and Prognosis

Purpose: Mutated p53 is a tumor suppressor gene, hMLH1 is a mismatch repair gene, and hypermethylation of hMLH1 follows microsatellite instability (MSI). This research`s aim is to investigate mutated p53, inactivated hMLH1 and MSI in gastric cancer and their clinicopathologic implications. Methods: Between 2003 and 2007, 618 patients underwent curative radical gastrectomy for gastric cancer at Seoul National University Bundang Hospital in Korea. We reviewed their medical charts and the pathologic reports with immunohistochemistry for p53, hMLH1 and polymerase chain reaction for MSI in 509, 499, and 561 cases, respectively. These genetic markers were statistically compared with clinicopathologic features and postoperative survival. Results: The expression ratios of mutated p53, inactivated hMLH1, and MSI were 32.8%, 8.4%, and 8.7%, respectively. Mutation of p53 occurred more frequently in aged group (over 40), differentiated group (against the non-differentiated group), intestinal type, infiltrative type and positive lymph node metastasis group. Inactivated hMLH1 occurred more frequently in aged group, differentiated group, intestinal type and expanding growth type group. MSI was found more frequently in aged group, intestinal type and expanding growth type group. All three genetic markers had no significant associations with the 5-year survival. Conclusion: We identified significant relationships between mutated p53, inactivated hMLH1, and MSI with some clinicopathologic features of gastric cancer. However, there were no apparent relationships between p53, hMLH1, and MSI and prognosis.KU KB, 2007, J KOREAN SURG SOC, V72, P283WOERNER SM, 2006, CANCER BIOMARK, V2, P69LIU P, 2005, WORLD J GASTROENTERO, V11, P4904Lee HS, 2002, MODERN PATHOL, V15, P632Nakajima T, 2001, INT J CANCER, V94, P208Samowitz WS, 2001, AM J PATHOL, V158, P1517Rugge M, 2000, J CLIN PATHOL-MOL PA, V53, P207Wu MS, 2000, GENE CHROMOSOME CANC, V27, P403OH SH, 2000, J KOREAN SURG SOC, V59, P206Fleisher AS, 1999, CANCER RES, V59, P1090Leung SY, 1999, CANCER RES, V59, P159Monig SP, 1997, DIGEST DIS SCI, V42, P2463Thibodeau SN, 1996, CANCER RES, V56, P4836Starzynska T, 1996, CANCER, V77, P2005DosSantos NR, 1996, GASTROENTEROLOGY, V110, P38Peddanna N, 1995, ANTICANCER RES, V15, P2055TAMURA G, 1995, CANCER RES, V55, P1933SERUCA R, 1995, INT J CANCER, V64, P32CORREA P, 1994, CANCER RES, V54, pS1941BODMER W, 1994, NAT GENET, V6, P217RHYU MG, 1994, ONCOGENE, V9, P29UCHINO S, 1993, INT J CANCER, V54, P759TAHARA E, 1993, J CANCER RES CLIN, V119, P265CORREA P, 1992, CANCER RES, V52, P6735MARTIN HM, 1992, INT J CANCER, V50, P859HOLLSTEIN MC, 1991, CANCER RES, V51, P4102YONISHROUACH E, 1991, NATURE, V352, P345HARRIS AL, 1990, J PATHOL, V162, P5