Multi-microdialysis analytical system to monitor acetaminophen and its pharmacokinetic interaction with A. bidentata in rat blood, forelimb extensor muscle, brain striatum, and the knee joint cavity.

Acetaminophen (APAP), or paracetamol, is one of the most widespread and commonly used non-prescription pain medication in the world, and is effective at managing wide range of pain, including headache, muscle ache, and minor arthritic pain. While the pharmacokinetics of APAP is generally understood, there is a lack of data for its transfer ratio especially into the knee. A novel multi-microdialysis model was developed to simultaneously sample from blood, forelimb extensor muscle, brain striatum, and the knee joint cavity in the same experimental subject to investigate the potential interaction between APAP and Achyranthes bidentata Blume (A. bidentata), another widely used traditional Chinese medicininal herb especially for pain in the lower extremity. Rats were pre-treated with A. bidentata extract (ABex), APAP was then administered (60 mg/kg, i.v.), dialysates then subsequently analyzed using HPLC-PDA. Our analysis demonstrated that APAP concentrations, achieved after its administration either alone or in combination with ABex (1 and 3 g/kg, q.d. gavage), could be modelled effectively with a one-compartment model. The distribution ratio (AUCorgan/AUCblood) of blood-to-muscle, blood-to-brain and blood-to-knee was 0.372 ± 0.053, 0.277 ± 0.095 and 0.191 ± 0.042, respectively after administration of APAP (60 mg/kg, i.v.). No significant difference was observed between the pharmacokinetics of APAP administered alone and in combination with ABex; and APAP concentration exceed the half maximal effective concentration (EC50) in all sampled organs for close to 3 hours with one single dose of drug administration, providing evidence for its broad-range analgesic effect.

Spilled gallstone mimicking intra-abdominal seeding of gallbladder adenocarcinoma: A case report.

BACKGROUND: Gallbladder rupture is common in laparoscopic cholecystectomy because the gallbladder is usually in acute or chronic inflammation status. The gallstones may sometime be spilled into the peritoneal cavity, resulting in intra-abdominal abscess if the gallstones were not retrieved. The diagnosis of intra-abdominal abscess caused by unretrieved gallstone can usually be correctly identified in the routine imaging studies, such as abdominal ultrasonography or computed tomography (CT). Here we present a case of abscess formation from unretrieved gallstone following laparoscopic cholecystectomy, which mimics the imaging findings of metastatic gallbladder adenocarcinoma. CASE SUMMARY: This case described a 78-year-old man who received laparoscopic cholecystectomy and gallbladder adenocarcinoma was diagnosed after surgery. After adjuvant chemotherapy, the following up abdominal CT showed several small nodules at right upper abdomen and peritoneal carcinomatosis is considered. Repeated laparoscopic surgery for the excision of seeding tumor was conducted and the pathological diagnosis of the nodules and mass was inflammatory tissues and gallbladder stone. CONCLUSION: Spilled gallstones are a common complication during laparoscopic cholecystectomy and some gallstones fail to be retrieved due to the size or the restricted view of laparoscopic surgery. For spilled gall bladder stones, surgeons may consider regular computerized tomography follow-up, and if necessary, laparoscopic examination can be used as a means of confirming the diagnostic and treatment.

Transplacental transfer of acetaminophen in pregnant rats.

Acetaminophen is among the most widely used analgesics; however, the proportion and mechanism of transplacental transfer of unbound acetaminophen with actual pharmacological activity remain unknown. Our hypothesis is that acetaminophen gradually penetrates the blood-placenta barrier to reach the fetus. A multiple microdialysis coupled to liquid chromatography with photodiode array detection method was developed to monitor acetaminophen levels in the maternal blood, placenta, fetus, and amniotic fluid of a pregnant rat and investigate this hypothesis. The pharmacokinetic data indicates that acetaminophen exhibits a nonlinear behavior in the maternal blood within the dosage regimen of 100 and 300 mg/kg. In addition, acetaminophen penetrates the placenta, fetus, and amniotic fluid during treatment. The transplacental transfer ratio represented by the area under the concentration curve (AUC) ratio for the conceptus (the collective term for the fetus, placenta, and amniotic fluid) and maternal blood (AUCtissue/AUCblood) was approximately 11-23 % after acetaminophen (100 and 300 mg/kg) administration. However, the transporter of multidrug resistance-associated protein (MRP) inhibitor MK-571 did not significantly change the transplacental transfer ratio. This basic study provides constructive information for the clinical application of acetaminophen in pregnant women.

Modulation of the transport of valproic acid through the blood-brain barrier in rats by the Gastrodia elata extracts.

HEADINGS ETHNOPHARMACOLOGICAL RELEVANCE: Valproic acid (VPA) is primarily used as a medicine for the treatment of seizures. Gastrodia elata (G. elata) extract has been used as an alternative medicine for epilepsy patients. Cotreatment with VPA and G. elata extract is commonly prescribed in Taiwan and mainland China. Nevertheless, the mechanism of the blood-brain barrier (BBB) transportation effect of G. elata extract on VPA has not been characterized. AIM OF STUDY: Our hypothesis is that G. elata extract modulates the BBB penetration of VPA through specific transporter transfer. MATERIALS AND METHODS: A validated liquid chromatography-tandem mass spectrometry and multiple microdialysis method was developed to simultaneously monitor VPA in the blood and brain of rats. To investigate the mechanism of BBB modulation by the G. elata extract on VPA in the brain, cyclosporin A, a P-glycoprotein (P-gp) inhibitor and organic anion transporting polypeptide (OATP) inhibitor, was coadministered with the G. elata extract and VPA. RESULTS: The pharmacokinetic results demonstrated that the VPA penetration ratio of the BBB, determined by the area under the concentration curve (AUC) ratio of VPA (AUCbrain/AUCblood), was approximately 0.36. After treatment with the G. elata extract (1 and 3 g/kg, p.o. for 5 consecutive days), the VPA penetration ratios were significantly enhanced to 1.47 and 1.02, respectively. However, in the experimental group coadministered cyclosporin A, the G. elata extract was unable to enhance the BBB transportation of VPA. Instead, the VPA penetration ratio in the brain was suppressed back to 0.38. CONCLUSIONS: The present study reveals that the enhancement effect of the transporter mechanism of G. elata extract on VPA transport into the brain occurs through the OATP transporter but not the P-gp transporter.

Preclinical Pharmacokinetics and Pharmacodynamics of Coptidis Preparation in Combination with Lovastatin in High-Fat Diet-Induced Hyperlipidemic Rats.

Lovastatin is a standard therapy for dyslipidemia. Alternatively, some ethnomedicines, such as Coptidis preparation, have been used for the treatment of dyslipidemia. Statins and complementary and alternative medicines may possess individual mechanisms of action against dyslipidemia. We hypothesize that the combination of Coptidis preparation and lovastatin may have synergistic effects for the treatment of dyslipidemia. To investigate this hypothesis, we developed a validated ultra-high-performance liquid chromatography-tandem mass spectrometry method to monitor lovastatin and its metabolites for pharmacokinetic studies in rats. This study was divided into four groups: lovastatin (10 mg/kg, p.o.) alone and lovastatin (10 mg/kg, p.o.) + Coptidis preparation (0.3, 1, or 3 g/kg, p.o.) for five consecutive days. In pharmacodynamic studies, a high-fat diet (HFD) was used to induce dyslipidemia in experimental rat models. The HFD rats were divided into four groups: treatment with HFD, HFD + lovastatin (100 mg/kg, p.o.), HFD + Coptidis preparation (1 g/kg, p.o.), and HFD + lovastatin (50 mg/kg, p.o.) + Coptidis preparation (1 g/kg, p.o.) for 28 consecutive days. The pharmacokinetic results demonstrated that Coptidis preparation significantly augmented the conversion of lovastatin into its main metabolite lovastatin acid in vivo. The pharmacodynamic results revealed that the Coptidis preparation and half-dose lovastatin group reduced the body weight, liver weight, and visceral fat in HFD rats. These findings provide constructive preclinical pharmacokinetic and pharmacodynamic applications of Coptidis preparation on the benefit of hyperlipidemia.

Preclinical Pharmacokinetic Interaction and Histopathological Analyses of Hedyotis diffusa on Sorafenib in Rats.

Sorafenib is one of the most effective target therapeutic agents for patients with late-stage hepatocellular carcinoma. To seek possible alternative adjuvant agents to enhance the efficacy and improve the side effect of sorafenib, Hedyotis diffusa, one of the most prescribed phytomedicines for treating liver cancer patients in Taiwan, was evaluated in this work. We hypothesized that H. diffusa extract is a safety herb combination on the pharmacokinetic and pharmacodynamic effects of sorafenib. We designed treatments of sorafenib in combination with or without H. diffusa extract to examine its pharmacokinetic properties and effects on liver inflammation. The HPLC-photodiode-array method was designed for monitoring the plasma level and pharmacokinetic parameter of sorafenib in rat plasma. The pharmacokinetic results demonstrated that the area under the curve of sorafenib (10 mg/kg, p.o.) in combination with various doses of H. diffusa formulation (1, 3, and 10 g/kg, p.o.) for 5 consecutive days were 5560 ± 1392, 7965 ± 2055, 7271 ± 1371, and 8821 ± 1705 min µg/mL, respectively, no significant difference when compared with sorafenib treatment alone. Furthermore, the hepatic activity in rats administered with sorafenib with/without H. diffusa extract was quantitatively scored by modified hepatic activity index grading. H. diffusa extract in the range of 1 to 10 g/kg per day did not elicit significant herb-induced hepatotoxicity in rats, based on the histopathological study. Consequently, our findings provided positive safety outcomes for the administration of sorafenib in combination with the phytomedicine H. diffusa.

Herb-Drug Interaction between the Traditional Hepatoprotective Formulation and Sorafenib on Hepatotoxicity, Histopathology and Pharmacokinetics in Rats.

Sorafenib has been used as a standard therapy for advanced hepatocellular carcinoma (HCC). In Asia, patients with HCC are potentially treated with the combination of sorafenib and Chinese herbal medicines to improve the efficiency and reduce the side effects of sorafenib. However, limited information about the herb-drug interactions is available. We hypothesize that the Chinese herbal medicine may exert hepatoprotective effects on the sorafenib-treated group. The aim of this study is to investigate the pharmacokinetic mechanism of drug-drug interactions of sorafenib including interacting with hepatoprotective formulation, Long-Dan-Xie-Gan-Tang formulation (LDXGT) and with two cytochrome P450 3A4 (CYP3A4) inhibitors, grapefruit juice and ketoconazole. Liver enzyme levels and histopathology of liver slices were used to evaluate sorafenib-induced hepatotoxicity and the potential hepatoprotective effects of the LDXGT formulation on subjects treated with the combination of sorafenib and the herbal medicine. In this study, a validated HPLC-photodiode array analytical system was developed for the pharmacokinetic study of sorafenib in rats. As the result of the pharmacokinetic data, pretreatment with the LDXGT formulation did not significantly interact with sorafenib compared with sorafenib oral administration alone. Furthermore, grapefruit juice and ketoconazole did not significantly affect sorafenib metabolism. Furthermore, pretreatment with variable, single or repeat doses of the LDXGT formulation did not suppress or exacerbate the sorafenib-induced hepatotoxicity and histopathological alterations. According to these results, the LDXGT formulation is safe, but has no beneficial effects on sorafenib-induced hepatotoxicity. A detailed clinical trial should be performed to further evaluate the efficacy or adverse effects of the LDXGT formulation in combination with sorafenib in humans.

Prescription frequency and patterns of Chinese herbal medicine for liver cancer patients in Taiwan: a cross-sectional analysis of the National Health Insurance Research Database.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Chinese herbal medicine (CHM) is frequently provided to HCC patients. The aim of this study was to understand the prescription frequency and patterns of CHM for HCC patients by analyzing the claims data from the National Health Insurance (NHI) in Taiwan. METHODS: We identified 73918 newly diagnosed HCC subjects from the database of Registry for Catastrophic Illness during 2002 to 2009 and to analyze the frequency and pattern of corresponding CHM prescriptions for HCC patients. RESULTS: There were a total of 685,079 single Chinese herbal prescriptions and 553,952 Chinese herbal formula prescriptions used for 17,373 HCC subjects before 2 years of HCC diagnosis. Among the 13,093 HCC subjects who used CHMs after HCC diagnosis, there were 462,786 single Chinese herbal prescriptions and 300,153 Chinese herbal formula prescriptions were counted. By adjusting with person-year and ratio of standardized incidence rate, the top ten prescribed single herbal drugs and Chinese herbal formulas for HCC patients were described in our study. Among them, we concluded that, Oldenlandia diffusa (Chinese herbal name: Bai-Hua-She-She-Cao), Radix et Rhizoma Rhei (Da Huang) and the herbal preparation of Xiao-Chai-Hu-Tang and Gan-Lu-Yin, were the most obviously increased and important CHMs been used for HCC patients. CONCLUSION: We established an accurate and validated method for the actual frequency and patterns of CHM use in treating HCC in Taiwan. We propose that these breakthrough findings may have important implications for HCC therapy, clinical trials and modernization of CHM.

Efficient programming of human mesenchymal stem cell-derived hepatocytes by epigenetic regulations.

BACKGROUND AND AIM: In view of its unique properties of detoxification and involvement of metabolic and biochemical functions, in vitro hepatocyte culture serves as a valuable material for drug screening and mechanistic analysis for pathology of liver diseases. The restriction of rapid de-differentiation and inaccessibility of human hepatocytes from routine clinical procedure, however, limits its use. METHODS: To address this issue, the effort to direct human mesenchymal stem cells (hMSCs) into hepatocytes using a modified protocol was proposed. With the additional treatment of histone deacetylase inhibitor (HDACi) and DNA methyltransferase inhibitor (DNMTi), in vitro hMSC-derived hepatocytes were cultivated and their hepatic characteristics were examined. RESULTS: By using a modified protocol, it was shown that Trichostatin A and 5-aza-2-deoxycitidine protected differentiating cells from death and could sufficiently trigger a wide range of liver-specific markers as well as liver functions including albumin production, glycogen storage, and urea cycle in hMSC-derived hepatocytes. The increased mRNA expression for hepatitis C virus (HCV) entry including CD81, Occludin, LDL receptor, and scavenger receptor class B type I in hMSC-derived hepatocytes was also detected, implying its potential to be utilized as an in vitro model to analyze dynamic HCV infection. CONCLUSIONS: The present study successfully established a protocol to direct hMSCs into hepatocyte-like cells suggesting the beneficial impact to apply HDACi and DNMTi as potent modulators for hMSCs to liver differentiation.

Body mass index and cholesterol level predict surgical outcome in patients with hepatocellular carcinoma in Taiwan - a cohort study.

Curative surgical resection (CSR) remains the most effective therapeutic intervention for patients with hepatocellular carcinoma (HCC); however, frequent post-surgical recurrence leads to high cancer related mortality. This study aimed to clarify the role of body mass index (BMI) and serum cholesterol level in predicting post-surgical outcomes in HCC patients after CSR. A total of 484 HCC patients including 213 BMIhigh and 271 BMIlow patients were included. Overall survival (OS) and recurrence-free survival (RFS) rates were examined in patients with differential BMI and serum cholesterol level. The analysis showed that significant different 1-, 3- and 5-year cumulative OS rates (P-value=0.015) and RFS rate (P-value=0.010) between BMIlow and BMIhigh patients. Further analysis in groups with differential serum cholesterol levels among BMIlow and BMIhigh patients indicated that the BMIlow/Chollow patients exhibited the significant lower cumulative OS and RFS rates in comparison with the remaining subjects (P-value=0.007 and 0.039 for OS and RFS rates, respectively). In conclusion, the coexistence of low BMI and low serum cholesterol level could serve as prognostic factors to predict post-operative outcomes in HCC patients undergoing surgical hepatectomy.

Appendectomy timing: Will delayed surgery increase the complications?

BACKGROUND: This study investigated whether the time from emergency room registration to appendectomy (ETA) would affect the incidence of perforation and postoperative complications in patients with acute appendicitis. METHODS: Patients who underwent an appendectomy at the Ren-Ai branch of Taipei City Hospital between January 2010 and October 2012 were retrospectively reviewed. Their demographics, white blood cell count, C-reactive protein, body temperature, computed tomography scan usage, operation method, pathology report, postoperative complication, length of hospital stay, and ETA were abstracted. Multivariate analysis was performed to search the predictors, including ETA, of outcomes for the perforation and postoperative complication rates. RESULTS: A total of 236 patients were included in the study. Perforation occurred in 12.7% (30/236) and postoperative complications developed in 24.1% (57/236) of these patients. There were 121 patients with ETA <8 hours, 88 patients with ETA of 8-24 hours, and 27 patients with ETA >24 hours; patients with ETA >24 hours had significantly longer hospital stay. Univariate analysis showed that perforated patients were significantly older, and had higher C-reactive protein level, longer hospital stay, and higher complication rate. Patients who developed postoperative complications were significantly older, and had higher neutrophil count, less use of computed tomography, and higher open appendectomy rate. After multivariate analysis, age ≥55 years was the only predictor for perforation [odds ratio (OR) = 3.65; 95% confidence interval (CI), 1.54-8.68]; for postoperative complications, age ≥55 years (OR = 1.65; 95% CI, 1.84-3.25), perforated appendicitis (OR = 3.17; 95% CI, 1.28-7.85), and open appendectomy (OR = 3.21; 95% CI, 1.36-7.58) were associated. ETA was not a significant predictor in both analyses. CONCLUSION: In our study, it was observed that although longer ETA was associated with longer hospitalization, ETA was not correlated with postoperative complications. Our results inclined toward the position that appendectomy can be performed as a semielective surgery.

Preventive and therapeutic role of traditional Chinese herbal medicine in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. The clinical management of HCC remains a substantial challenge. Although surgical resection of tumor tissues seems promising, a high recurrence and/or metastasis rate accounting for disease-related death has led to an urgent need for improved postsurgical preventive/therapeutic clinical intervention. Developing advanced target-therapy agents such as sorafenib appears to be the only effective clinical intervention for patients with HCC to date, but only limited trials have been conducted in this regard. Because of their enhanced preventive/therapeutic effects, traditional Chinese herbal medicine (CHM)-derived compounds are considered suitable agents for HCC treatment. The CHM-derived compounds also possess multilevel, multitarget, and coordinated intervention effects, making them ideal candidates for inhibition of tumor progression and HCC metastasis. This article reviews the anticancer activity of various CHMs with the hope of providing a better understanding of how to best use CHM for HCC treatment.

Diabetes worsens the surgical outcomes in cirrhotic patients with hepatocellular carcinoma.

Diabetes is a known risk factor for developing hepatocellular carcinoma (HCC). Reported rates of diabetes are higher in chronic hepatitis, cirrhosis and HCC patients. However, its effects on postoperative recurrence and survival with HCC are controversial. This study offers a retrospective analysis of the impacts of diabetes on postoperative recurrence and survival in patients with cirrhosis and HCC. A total of 389 cirrhotic patients who underwent curative resection for primary HCC at our institution between January 2000 and December 2008 were enrolled. Of them, 272 (70%) patients were classified into a non-diabetes group and 117 (30%) patients into the diabetes group. The diabetes group was divided into an oral hypoglycemic agent (OHA) control group (n = 100) and an insulin control group (n = 17). The result indicates that the diabetes group had a higher postoperative recurrence rate and poorer long-term survival rate (p = 0.001 vs. 0.01). There was no significant difference in recurrence-free survival rate between the OHA control group and the insulin control group (p = 0.17). The insulin control group had a poorer long-term surgical outcome than the OHA control group (p = 0.035). In conclusion, our results suggest that diabetes is an independent risk factor for postoperative recurrence and surgical survival of cirrhotic HCC patients. Cirrhotic HCC patients with diabetes who received hepatic resection should be closely followed-up for postoperative recurrence and long-term outcome. Moreover, an effective peri-operative sugar control planning in HCC patients with diabetes should be established.