PURPOSE: Our previous study demonstrated the hypoglycemic effects of mulberry (Morus alba L.) leaf and the underlying mechanisms. Here we explored the potency of mulberry twigs (TW) and root barks (RB) in postprandial hypoglycemic effects in vitro and in vivo. METHODS: The major components of TW and RB were determined by high performance liquid chromatography (HPLC). Alpha-glucosidase inhibition and glucose/fructose uptake inhibition in Caco-2 cells were determined for TW, RB, and their major components, followed by an oral sugar tolerance test (OSTT) in streptozotocin-induced diabetic rats. Male Wistar rats were fed a high-fat diet for 2 weeks and then a single dose of streptozotocin (35 mg/kg B.W) was administered by intraperitoneal injection. Rats with fasting blood glucose levels above 126 mg/dL were randomly divided into 5 groups (n = 8/group) for the following treatments by gavage for 4 weeks: vehicle (normal control and diabetic control), 200 mg/kg B.W of TW or RB or 100 mg/kg B.W of oxyresveratrol (OXY). RESULTS: OXY and mulberroside A were identified as the major components of TW and OXY, mongolicin, and kuwanon H for RB. A significant inhibitory activity on alpha-glucosidase was found for TW, RB, and OXY (p = 0.0099). There was a dose-dependent inhibition of TW and RB on the intestinal sugar uptakes in Caco-2 cells, showing a greater impact on fructose compared to glucose. The OSTT showed that TW and RB significantly delayed time to maximal concentration (p = 0.0088) and decreased maximal concentration (p = 0.0043) compared to the control group. CONCLUSION: These results suggest that TW and RB may have a postprandial hypoglycemic effect, particularly in the case of high fructose or sucrose intake. OXY was suggested as a contributor to the hypoglycemic effect of TW and RB. Further studies are needed for the systemic effect of TW and RB in circulation.
alpha-Glucosidases ; Animals ; Blood Glucose ; Caco-2 Cells ; Chromatography, Liquid ; Diet, High-Fat ; Fasting ; Fructose ; Glucose ; Humans ; Hypoglycemic Agents* ; Injections, Intraperitoneal ; Male ; Morus* ; Rats ; Rats, Wistar ; Streptozocin ; Sucrose

BACKGROUND/AIMS: Silibinin, the main component of silymarin, is used as a hepatoprotectant and exhibits anticancer effects against various cancer cells. This study evaluated the effects of a combination of silibinin with either gefitinib or sorafenib on hepatocellular carcinoma (HCC) cells. METHODS: Several different human HCC cell lines were used to test the growth-inhibiting effects and cell toxicity of silibinin both alone and in combination with either gefitinib or sorafenib. The cell viability and growth inhibition were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, trypan blue staining, and a colony-forming assay. Furthermore, changes in epidermal growth factor receptor (EGFR)-related signals were evaluated by Western blot analysis. RESULTS: Gefitinib, sorafenib, and silibinin individually exhibited dose-dependent antiproliferative effects on HCC cells. Combined treatment with silibinin enhanced the gefitinib-induced growth-inhibiting effects in some HCC cell lines. The combination effect of gefitinib and silibinin was synergistic in the SNU761 cell line, but was only additive in the Huh-BAT cell line. The combination effect may be attributable to inhibition of EGFR-dependent Akt signaling. Enhanced growth-inhibiting effects were also observed in HCC cells treated with a combination of sorafenib and silibinin. CONCLUSIONS: Combined treatment with silibinin enhanced the growth-inhibiting effects of both gefitinib and sorafenib. Therefore, the combination of silibinin with either sorafenib or gefitinib could be a useful treatment approach for HCC in the future.
Antineoplastic Agents/*pharmacology ; Carcinoma, Hepatocellular/metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; Down-Regulation/drug effects ; Drug Screening Assays, Antitumor ; Drug Synergism ; Humans ; Liver Neoplasms/metabolism/pathology ; Niacinamide/*analogs & derivatives/pharmacology ; Phenylurea Compounds/*pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Quinazolines/*pharmacology ; Receptor, Epidermal Growth Factor/metabolism ; Signal Transduction/drug effects ; Silymarin/*pharmacology

BACKGROUND/AIMS: The dose of mycophenolate mofetil (MMF) has been reduced in Asia due to side effects associated with the conventional fixed dose of 2-3 g/day. We aimed to determine the pharmacokinetics of a reduced dose of MMF and to validate its feasibility in combination with tacrolimus in living-donor liver transplantation (LDLT). METHODS: Two sequential studies were performed in adult LDLT between October 2009 and 2011. First, we performed a prospective pharmacokinetic study in 15 recipients. We measured the area under the curve from 0 to 12 hours (AUC0-12) for mycophenolic acid at postoperative days 7 and 14, and we performed a protocol biopsy before discharge. Second, among 215 recipients, we reviewed 74 patients who were initially administered a reduced dose of MMF (1.0 g/day) with tacrolimus (trough, 8-12 ng/mL during the first month, and 5-8 ng/mL thereafter), with a 1-year follow-up. We performed protocol biopsies at 2 weeks and 1 year post-LDLT. RESULTS: In the first part of study, AUC0-12 was less than 30 mgh/L in 93.3% of cases. In the second, validating study, 41.9% of the recipients needed dose reduction or cessation due to side effects within the first year after LDLT. At 12 months post-LDLT, 17.6% of the recipients were administered a lower dose of MMF (0.5 g/day), and 16.2% needed permanent cessation due to side effects. The 1- and 12-month rejection-free survival rates were 98.6% and 97.3%, respectively. CONCLUSIONS: A reduced dose of MMF was associated with low blood levels compared to the existing recommended therapeutic range. However, reducing the dose of MMF combined with a low level of tacrolimus was feasible clinically, with an excellent short-term outcome in LDLT.
Adult ; Aged ; Area Under Curve ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Gastrointestinal Diseases/etiology ; Graft Rejection/prevention & control ; Humans ; Immunosuppressive Agents/blood/*pharmacokinetics ; Leukopenia/etiology ; Liver/pathology ; Liver Failure/*therapy ; *Liver Transplantation ; Male ; Middle Aged ; Mycophenolic Acid/adverse effects/*analogs & derivatives/blood/pharmacokinetics ; ROC Curve ; Retrospective Studies ; Tacrolimus/therapeutic use ; Tissue Donors

Plasma pH can be altered during pregnancy and at labor. Membrane excitability of smooth muscle including uterine muscle is suppressed by the activation of K+ channels. Because contractility of uterine muscle is regulated by extracellular pH and humoral factors, K+ conductance could be connected to factors regulating uterine contractility during pregnancy. Here, we showed that TASK-2 inhibitors such as quinidine, lidocaine, and extracellular acidosis produced contraction in uterine circular muscle of mouse. Furthermore, contractility was significantly increased in pregnant uterine circular muscle than that of non-pregnant muscle. These patterns were not changed even in the presence of tetraetylammonium (TEA) and 4-aminopyridine (4-AP). Finally, TASK-2 inhibitors induced strong myometrial contraction even in the presence of L-methionine, a known inhibitor of stretchactivated channels in myometrium. When compared to non-pregnant myometrium, pregnant myometrium showed increased immunohistochemical expression of TASK-2. Therefore, TASK-2, seems to play a key role during regulation of myometrial contractility in the pregnancy and provides new insight into preventing preterm delivery.
4-Aminopyridine ; Acidosis ; Animals ; Contracts ; Female ; Hydrogen-Ion Concentration ; Lidocaine ; Membranes ; Methionine ; Mice ; Muscle, Smooth ; Muscles ; Myometrium ; Plasma ; Pregnancy ; Quinidine ; Relaxation ; Uterine Contraction ; Uterus

OBJECTIVES: We investigated the tolerability, safety, and treatment response to flexible-dose paliperidone ER in patients with non-acute schizophrenia in whom previous antipsychotic drugs were ineffective. METHODS: This 24-week interim analysis of the 48-week multicenter, prospective, open-label study assessed effectiveness using the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Schizophrenia-Severity (CGI-SCH-S) Scale, Personal and Social Performance (PSP) and Drug Attitude Inventory (DAI). Safety and tolerability were assessed using the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) and Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS). RESULTS: Effectiveness was assessed in 169 patients. Significant improvement in the PANSS total score was observed by week-1 and continued until week-24. The response rate was 33%. The CGI-SCH-S and PSP total scores significantly improved during 24 weeks ; however, no change occurred in the total DAI. Fifty-nine percent of patients reported adverse events, of which extrapyramidal symptoms were the most frequent (19.0%). The DIEPSS and LUNSERS scores were improved after 24 week. CONCLUSIONS: Switching to the flexible-dose paliperidone ER from an ineffective antipsychotic drug was safe, tolerable, and showed a good treatment response in Korean patients with schizophrenia.
Antipsychotic Agents ; Humans ; Isoxazoles ; Prospective Studies ; Pyrimidines ; Schizophrenia

Dermatomyositis is a distinctive entity that is identified by a characteristic rash that accompanies or more often precedes proximal muscle weakness. There is a well recognized association between dermatomyositis and several cancers, such as ovarian cancer, lung cancer, pancreas cancer, stomach cancer and colorectal cancers and non-Hodgkin Lymphoma. But dermatomyositis associated with intrahepatic cholangiocarcinoma has not yet been reported in Korea. We experienced a case of dermatomyositis associated with infiltrative intrahepatic cholangiocarcinoma and we report on this unusual case along with reviewing the related literature.
Cholangiocarcinoma ; Colorectal Neoplasms ; Dermatomyositis ; Exanthema ; Korea ; Liver Neoplasms ; Lung Neoplasms ; Lymphoma, Non-Hodgkin ; Muscle Weakness ; Ovarian Neoplasms ; Pancreatic Neoplasms ; Stomach Neoplasms

We elucidated the distribution of interstitial cells of Cajal (ICC) in human stomach, using cryosection and c-Kit immunohistochemistry to identify c-Kit positive ICC. Before c-Kit staining, we routinely used hematoxylin and eosin (HE) staining to identify every structure of human stomach, from mucosa to longitudinal muscle. HE staining revealed that the fundus greater curvature (GC) had prominent oblique muscle layer, and c-Kit immunostaining c-Kit positive ICC cells were found to have typical morphology of dense fusiform cell body with multiple processes protruding from the central cell body. In particular, we could observe dense processes and ramifications of ICC in myenteric area and longitudinal muscle layer of corpus GC. Interestingly, c-Kit positive ICC-like cells which had morphology very similar to ICC were found in gastric mucosa. We could not find any significant difference in the distribution of ICC between fundus and corpus, except for submucosa where the density of ICC was much higher in gastric fundus than corpus. Furthermore, there was no significant difference in the density of ICC between each area of fundus and corpus, except for muscularis mucosa. Finally, we also found similar distribution of ICC in normal and cancerous tissue obtained from a patient who underwent pancreotomy and gastrectomy. In conclusion, ICC was found ubiquitously in human stomach and the density of ICC was significantly lower in the muscularis mucosa of both fundus/corpus and higher in the submucosa of gastric fundus than corpus.
Eosine Yellowish-(YS) ; Gastrectomy ; Gastric Fundus ; Gastric Mucosa ; Hematoxylin ; Humans ; Immunohistochemistry ; Interstitial Cells of Cajal ; Mucous Membrane ; Muscles ; Stomach

To elucidate the mechanism of cyclic nucleotides, such as adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5' -cyclic monophosphate (cGMP), in the regulation of human gastric motility, we examined the effects of forskolin (FSK), isoproterenol (ISO) and sodium nitroprusside (SNP) on the spontaneous, high K+ and acetylcholine (ACh)-induced contractions of corporal circular smooth muscle in human stomach. Gastric circular smooth muscle showed regular spontaneous contraction, and FSK, ISO and SNP inhibited its phasic contraction and basal tone in a concentration-dependent manner. High K+ (50 mM) produced sustained tonic contraction, and ACh (10 micrometer) produced initial transient contraction followed by later sustained tonic contraction with superimposed phasic contractions. FSK, ISO and SNP inhibited high K+-induced tonic contraction and also ACh-induced phasic and tonic contraction in a reversible manner. Nifedipine (1 micrometer), inhibitor of voltage-dependent L-type calcium current (VDCC(L)), almost abolished ACh-induced phasic contractions. These findings suggest that FSK, ISO and SNP, which are known cyclic nucleotide stimulators, inhibit smooth muscle contraction in human stomach partly via inhibition of VDCCL.
Acetylcholine ; Adenosine ; Calcium ; Contracts ; Forskolin ; Guanosine ; Humans ; Isoproterenol ; Muscle, Smooth ; Nifedipine ; Nitroprusside ; Nucleotides, Cyclic ; Relaxation ; Stomach

In our previous study, we found that spermine and putrescine inhibited spontaneous and acetylcholine (ACh)-induced contractions of guinea-pig stomach via inhibition of L-type voltage- dependent calcium current (VDCCL). In this study, we also studied the effect of spermidine on mechanical contractions and calcium channel current (IBa), and then compared its effects to those by spermine and putrescine. Spermidine inhibited spontaneous contraction of the gastric smooth muscle in a concentration-dependent manner (IC50=1.1+/-0.11 mM). Relationship between inhibition of contraction and calcium current by spermidine was studied using 50 mM high K+-induced contraction: Spermidine (5 mM) significantly reduced high K+(50 mM)-induced contraction to 37+/-4.7% of the control (p<0.05), and inhibitory effect of spermidine on IBa was also observed at a wide range of test potential in current/voltage (I/V) relationship. Pre- and post-application of spermidine (5 mM) also significantly inhibited carbachol (CCh) and ACh-induced initial and phasic contractions. Finally, caffeine (10 mM)-induced contraction which is activated by Ca2+-induced Ca2+release (CICR),` was also inhibited by pretreatment of spermidine (5 mM). These findings suggest that spermidine inhibits spontaneous and CCh-induced contraction via inhibition of VDCCL and Ca2+releasing mechanism in guinea-pig stomach.
Acetylcholine ; Caffeine ; Calcium ; Calcium Channels ; Carbachol ; Contracts ; Muscle, Smooth ; Putrescine ; Relaxation ; Spermidine ; Spermine ; Stomach

PURPOSE: Post-authorization survey(PAS) is a useful tool for obtainting wider range of data on the safety and efficacy of new drugs following their approval, as they can detect uncommon, unreported adverse events(AEs), which enables more attention to be directed to the practioners. Especially, the limited number of patients in oncology trial cannot usually give the actual incidence of AEs. METHODS: Since Nov. 1998, when docetaxel gained Korean approval in the treatment of breast cancer, a PAS to investigate its safety profiles has been conducted targeting more than 600 patients over 4 calendar years. RESULTS: Case report forms from 626 out of 646 patients were assessable for safety and 444 for efficacy. The patient characteristics are: mean age, 48.1 years; male/female 4/622; Wt/Ht/BSA 57.9 kg/156.1 cm/1.56 m2 ; stage I-II/III/IV 109 (18.2%)/125 (20.8%)/366(61.0%). In 344 patients, 960 AEs were reported in severity of mild/moderate/severe in 6.7, 40.9 and 51.1 % of cases. From AE results, 36.0% needed dose reduction; 34.3% transient interruption of the cycle; and 1.3% permanent discontinuation of docetaxel. Thirty five serious AEs such as febrile neutropenia, alopecia, diarrhea, abdominal pain and headache were reported in 21 patients. Unexpected AEs such as skin ulcer, discoloration of skin, H. Zoster infection, ulticaria, facial flush, chest pain, hemoptysis, pneumonia, stridor, nasal bleeding, photophobia, haematuria, Cushing's syndrome, hyperglycemia and insomnia were reported regardless of any causal relationship. Factors affecting the development of AEs were age, stage, concomitant medication other than chemotherapeutic agents and the number of cycles treated. The efficacy was evaluable in 444 patients with overall response rate of 36.5% (CR/PR 6.3/30.2%). Factors affecting the efficacy were stage, concommitant medication other than chemotherapeutic agents and the number of treatment cycles. CONCLUSION: This post-authorization survey on the safety and efficacy of docetaxel in breast cancer offers oncology practice in the real world without subject selection as is the case in clinical trials, although it was performed to fulfill the registrative requirement of the Korean health authority with limited data. The efficacy and safety profile of docetaxel in breast cancer was no much different from those reported in clinical trials.
Abdominal Pain ; Alopecia ; Breast Neoplasms* ; Breast* ; Chest Pain ; Cushing Syndrome ; Diarrhea ; Epistaxis ; Febrile Neutropenia ; Headache ; Hemoptysis ; Herpes Zoster ; Humans ; Hyperglycemia ; Incidence ; Photophobia ; Pneumonia ; Respiratory Sounds ; Skin ; Skin Ulcer ; Sleep Initiation and Maintenance Disorders