Efficacy and safety of teneligliptin, a dipeptidyl peptidase-4 inhibitor, combined with metformin in Korean patients with type 2 diabetes mellitus: a 16-week, randomized, double-blind, placebo-controlled phase III trial.

The aim of the present study was to assess the efficacy and safety of teneligliptin in combination with metformin in Korean patients with type 2 diabetes mellitus who were inadequately controlled with metformin monotherapy. Patients [glycated haemoglobin (HbA1c) 7.0-10.0%, on stable metformin ≥1000 mg/day] were randomized 2 : 1 to receive 20 mg teneligliptin plus metformin (n = 136) or placebo plus metformin (n = 68). The primary endpoint was the change in HbA1c levels from baseline to week 16. The mean baseline HbA1c was 7.9% in the teneligliptin group and 7.8% in the placebo group. The differences between the teneligliptin and placebo groups regarding changes in HbA1c and fasting plasma glucose levels were -0.78 % and -1.24 mmol/l (22.42 mg/dl), respectively, at week 16. The incidence of adverse events was similar between the groups. The addition of teneligliptin once daily to metformin was effective and generally well tolerated in Korean patients with type 2 diabetes.

Lactobacillus pentosus var. plantarum C29 ameliorates age-dependent memory impairment in Fischer 344 rats.

UNLABELLED: To understand the anti-inflammaging effect of lactic acid bacteria, we selected NF-κB activation-inhibitory Lactobacillus pentosus var. plantarum C29 and investigated its memory-enhancing and anti-inflammatory effects in aged Fischer 344 rats. C29 (2 × 10(9) CFU rat(-1) ), which was orally administered once a day (6 days per week) for 8 weeks, significantly restored age-reduced spontaneous alternation to 95.2% of that seen in young rats (P < 0.05). C29 treatment also shortened the escape latency on the 4th day to 53.8% of that seen in young rats (P < 0.05). Twenty hours after the last training session, C29 significantly increased the swimming time within the platform quadrant, which was shortened in the aged control rats. Oral administration of C29 restored age-reduced doublecortin (DCX) and brain-derived neurotrophic factor (BDNF) expression and cAMP response element binding protein (CREB) activation in aged rats. Treatment of aged rats with C29 suppressed the expression of p16, cyclooxygenase-2, and inducible nitric oxide synthase, as well as the activation of Akt, mTOR, and NF-κB in the hippocampus. These findings suggest that C29 ameliorates ageing-dependent memory impairment by inhibiting NF-κB signalling pathway, inducing DCX and BDNF expression and activating CREB. SIGNIFICANCE AND IMPACT OF THE STUDY: The anti-inflammatory Lactobacillus pentosus var. plantarum C29 had the memory-enhancing effect in aged Fischer 344 rats by restoring doublecortin and brain-derived neurotrophic factor expression and suppressing p16 expression and NF-κB activation in the brain. Therefore, C29 may be useful in ameliorating age-related degenerative dementia.

Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise.

AIMS: Canagliflozin is a sodium glucose co-transporter 2 inhibitor in development for type 2 diabetes mellitus (T2DM). The efficacy and safety of canagliflozin were evaluated in subjects with T2DM inadequately controlled with diet and exercise. METHODS: In this 26-week, randomized, double-blind, placebo-controlled, phase 3 trial, subjects (N = 584) received canagliflozin 100 or 300 mg or placebo once daily. Primary endpoint was the change from baseline in haemoglobin A1c (HbA1c) at week 26. Secondary endpoints included the proportion of subjects achieving HbA1c < 7.0%; change from baseline in fasting plasma glucose (FPG), 2-h postprandial glucose (PPG) and systolic blood pressure (BP); and percent change in body weight, high-density lipoprotein cholesterol (HDL-C) and triglycerides. Adverse events (AEs) were recorded throughout the study. RESULTS: At week 26, HbA1c was significantly reduced from baseline with canagliflozin 100 and 300 mg compared with placebo (-0.77, -1.03 and 0.14%, respectively; p < 0.001 for both). Both canagliflozin doses significantly decreased FPG, 2-h PPG, body weight and systolic BP (p < 0.001 for all), and increased HDL-C compared with placebo (p < 0.01 for both). Overall incidences of AEs were modestly higher with canagliflozin versus placebo; rates of serious AEs and AE-related discontinuations were low and similar across groups. Incidences of genital mycotic infections, urinary tract infections and osmotic diuresis-related AEs were higher with canagliflozin; these led to few discontinuations. The incidence of hypoglycaemia was low across groups. CONCLUSION: Canagliflozin treatment improved glycaemic control, reduced body weight and was generally well tolerated in subjects with T2DM inadequately controlled with diet and exercise.

Efficacy and safety of glimepiride/metformin sustained release once daily vs. glimepiride/metformin twice daily in patients with type 2 diabetes.

AIMS: The study investigated the clinical equivalence in reducing haemoglobin A1c (A1C) between glimepiride/metformin sustained release (GM-SR) 2/500 mg, a fixed-dose combination, once daily and glimepiride/metformin (GM) 1/250 mg, a fixed-dose combination, twice daily in patients with type 2 diabetes (T2D). METHODS: A multicentre, randomised, double-blind, double-dummy study was conducted in 14 hospitals in Korea. Inclusion criteria were age 30-75 years, T2D diagnosis no longer than 10 years previously, A1C between 7% and 10%, and body mass index <40 kg/m(2) . A total of 207 subjects were randomised into the GM-SR group (n=101) or the GM group (n=106). Participants were assessed at baseline, 8 weeks and 16 weeks after treatment. RESULTS: After 16 weeks treatment, no difference in baseline-adjusted changes of A1C (primary efficacy variable) was observed between the two groups (-0.59% for GM-SR group vs. -0.61% for GM group, 95% CI: -0.17 to 0.21; p=0.84). In addition, there were no significant differences in secondary efficacy parameters between the two groups, including changes in A1C up to week 8, changes in fasting plasma glucose (FPG) and 2-h-postprandial plasma glucose up to week 8 and week 16, response rate, drug compliance and hypoglycaemic events. However, there was a difference in baseline-adjusted changes of FPG between the two groups (-1.01 mmol/l for GM-SR group vs. -1.52 mmol/l for GM group, p=0.01 in the intention to treat set). CONCLUSIONS: GM-SR 2/500 mg once daily was as effective as GM 1/250 mg twice daily in lowering A1C. In addition, no difference was noted in hypoglycaemic events between the two groups.

Hepatocellular carcinoma in patients with chronic liver disease: a comparison of gadoxetic acid-enhanced MRI and multiphasic MDCT.

AIM: To compare the diagnostic performances of gadoxetic acid-enhanced magnetic resonance imaging (MRI) and multiphasic multidetector computed tomography (MDCT) in the detection of hepatocellular carcinoma (HCC) in patients with chronic liver disease. MATERIALS AND METHODS: Institutional review board approval was obtained for this study and informed consent was obtained from all patients. Fifty-one patients (43 men, eight women; age range 32-80 years) with 73 HCCs underwent gadoxetic acid-enhanced MRI and multiphasic MDCT. Two readers independently analysed each image in three separate reading sessions. The alternative free-response receiver operating characteristic (AFROC) method was used to analyse the diagnostic accuracy. Positive and negative predictive values and sensitivity were evaluated. RESULTS: A total of 73 HCCs were detected in 51 patients. Although not significant (p>0.05), the areas under the receiver operating characteristic curves were 0.877 and 0.850 for MDCT, 0.918 and 0.911 for dynamic MRI, and 0.905 and 0.918 for combined interpretation of dynamic and hepatobiliary phase MR images. Differences in sensitivity, specificity, and positive and negative predictive values between the readers were not statistically significant (p>0.05). Combined interpretation of dynamic and hepatobiliary phase MRI images was more useful than MDCT in the detection of HCC lesions ≤1cm in diameter for one reader (p=0.043). CONCLUSION: Gadoxetic acid-enhanced MRI and MDCT show similar diagnostic performances for the detection of HCC in patients with chronic liver disease. However, the combined interpretation of dynamic and hepatobiliary phase MRI images may improve diagnostic accuracy in the detection of HCC lesions ≤1cm in diameter.

Long-term efficacy of entecavir therapy in chronic hepatitis B patients with antiviral resistance to lamivudine and adefovir.

No studies have reported the long-term effects of entecavir switching in patients with multidrug resistance who developed resistance after lamivudine/adefovir sequential therapy. We evaluated the efficacy of 96 weeks of entecavir therapy in patients with resistance to lamivudine/adefovir sequential therapy. In total, 33 patients with chronic hepatitis B virus (HBV) infection with evidence of active viral replication (HBV DNA levels ≥ 10(5) copies/mL) or a history of treatment failure to lamivudine/adefovir sequential therapy between April 2007 and July 2009 were treated with entecavir (1.0 mg daily) for at least 48 weeks. The rates of alanine transaminase (ALT) normalization and HBV DNA negativity were 66.7% (14/21) and 24.2% (8/33) at 48 weeks, respectively. The initial HBV DNA level was the only factor that was inversely associated with serum HBV DNA negativity after 48 weeks of entecavir therapy (P < 0.023). At 96 weeks, the rates of ALT normalization and HBV DNA negativity were 77.8% (7/9) and 16.7% (3/18), respectively. Viral breakthrough occurred in 21.2% (7/33) and 78.9% (15/19) of patients at 48 and 96 weeks, respectively. Patients who achieved a HBV DNA level of <4 log(10) copies/mL at 48 weeks maintained a similar HBV DNA level and a normal ALT level until 96 weeks. Entecavir monotherapy for 96 weeks was not efficacious for patients with lamivudine/adefovir-resistant HBV. The initial HBV DNA level was the only predictive factor for antiviral efficacy. However, patients who achieved a HBV DNA level of <4 log(10) copies/mL with a normal ALT level at 48 weeks should maintain, rather than stop, entecavir therapy.

Calpain mediates degradation of cytoskeletal proteins during Jurkat T-cell death induced by Entamoeba histolytica.

Entamoeba histolytica is known to induce host cell death via activation of calpain and caspases. In this study, we investigated the specific proteases involved in the degradation of cytoskeletal proteins during Jurkat T-cell death induced by E. histolytica. Amoebic trophozoites induced marked degradation of paxillin, Cas, vimentin, vinculin and talin, as well as α- or ß-spectrin, in Jurkat T cells. The cleavage effects of E. histolytica were strongly retarded by pretreatment with a calpain inhibitor, but not with a pan-caspase inhibitor. In addition, calpain knockdown with siRNA in Jurkat T cells effectively inhibited E. histolytica-induced PARP, paxillin, α-spectrin, ß-spectrin and talin degradation, as compared to scrambled siRNA. These results suggest that calpain plays a crucial role in the cleavage of cytoskeletal proteins during cell death induced by E. histolytica.

Reactive oxygen species-dependent necroptosis in Jurkat T cells induced by pathogenic free-living Naegleria fowleri.

Naegleria fowleri, a free-living amoeba, is the causative pathogen of primary amoebic meningoencephalitis in humans and experimental mice. N. fowleri is capable of destroying tissues and host cells through lytic necrosis. However, the mechanism by which N. fowleri induces host cell death is unknown. Electron microscopy indicated that incubation of Jurkat T cells with N. fowleri trophozoites induced necrotic morphology of the Jurkat T cells. N. fowleri also induced cytoskeletal protein cleavage, extensive poly (ADP-ribose) polymerase hydrolysis and lactate dehydrogenase (LDH) release. Although no activation of caspase-3 was observed in Jurkat T cells co-incubated with amoebae, intracellular reactive oxygen species (ROS) were strongly generated by NADPH oxidase (NOX). Pretreating cells with necroptosis inhibitor necrostatin-1 or NOX inhibitor diphenyleneiodonium chloride (DPI) strongly inhibited amoeba-induced ROS generation and Jurkat cell death, whereas pan-caspase inhibitor z-VAD-fmk did not. N. fowleri-derived secretory products (NfSP) strongly induced intracellular ROS generation and cell death. Necroptotic effects of NfSP were effectively inhibited by pretreating NfSP with proteinase K. Moreover, NfSP-induced LDH release and intracellular ROS accumulation were inhibited by pretreating Jurkat T cells with DPI or necrostatin-1. These results suggest that N. fowleri induces ROS-dependent necroptosis in Jurkat T cells.

Relative accuracy of CT and MRI in the differentiation of benign from malignant pancreatic cystic lesions.

AIMS: To assess the diagnostic accuracies of multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) for differentiating benign from malignant lesions and suggesting the specific diagnoses for pancreatic cystic lesions, and to assess whether review of both MDCT and MRI is beneficial. MATERIALS AND METHODS: Patients with various neoplastic and non-neoplastic pancreatic cystic lesions that were identifiable by biopsy or surgery, who underwent both MRI and MDCT (n=63), were retrospectively reviewed by three reviewers. The likelihood of malignancy was recorded on a five-point scale, and a specific diagnosis was given. ROC analysis was performed and the sensitivity, specificity for the characterization of malignancy, and the accuracy of specific diagnoses were calculated. RESULTS: MDCT and MRI yielded comparable results for the characterization of malignancy (Az: 0.639, 0.735, 0.806 for MDCT and 0.732, 0.753, 0.792 for MRI, for each reviewer). The accuracies of specific diagnosis based on MDCT or MRI were 61.9 versus 55.6% for reviewer 1; 76.2 versus 76.2% for reviewer 2; and 65.1 versus 61.9% for reviewer 3. There was a trend toward better prediction of malignancy (Az: 0.787, 0.745, 0.849 for each reviewer), and better accuracy in suggesting a specific diagnosis (77.8, 73, and 73% for each reviewer) for MDCT+MRI over MDCT or MRI alone, although it was statistically significant for one reviewer in the comparison of MDCT versus MDCT+MRI for the prediction of malignancy, and MRI versus MDCT for suggesting a specific diagnosis. CONCLUSIONS: MDCT and MRI have equivalent accuracy for characterizing pancreatic cystic lesions as benign or malignant, and suggesting a specific diagnosis. Combined review of MDCT and MRI was not significantly better but may have the potential to improve diagnostic accuracy in equivocal cases.

SpermCheck Fertility, an immunodiagnostic home test that detects normozoospermia and severe oligozoospermia.

BACKGROUND: A simple and inexpensive home sperm test could be of considerable value to couples attempting to conceive and to men curious about their fertility potential. A two-strip lateral flow immunochromatographic diagnostic device that allows men to evaluate their sperm count at low cost in the privacy of their own homes is described. METHODS: The ability of SpermCheck Fertility to predict sperm counts obtained using a hemacytometer procedure based on standard World Health Organization methodology was assessed. Test results obtained by lay users were also compared with those obtained by trained laboratory professionals, and the ease of use of the device was evaluated in consumer studies. RESULTS: A total of 225 semen samples were analyzed in the method comparison, and the performance of SpermCheck Fertility was excellent with over 96% of all samples correctly classified as normozoospermic (> or =2 x 10(7) sperm/ml), oligozoospermic (5 x 10(6)-2 x 10(7) sperm/ml) or severely oligozoospermic (<5 x 10(6) sperm/ml). Consumer studies with 164 lay users demonstrated that SpermCheck Fertility was easy to use. Lay users and laboratory professionals agreed 95% of the time when reading the same test independently. Overall, the correct response rate on a 20-question survey about the test was over 97%. CONCLUSIONS: SpermCheck Fertility is a simple and reliable immunodiagnostic test that can quickly inform men as to whether their sperm count is normal, low or very low. This home test can assist couples in deciding whether to seek comprehensive clinical evaluation of the fertility status of the male partner.

Calpain-dependent cleavage of SHP-1 and SHP-2 is involved in the dephosphorylation of Jurkat T cells induced by Entamoeba histolytica.

Host cell death induced by Entamoeba histolytica is an important mechanism for both host defence and microbial immune evasion during human amoebiasis. However, the signalling pathways underlying cell death induced by E. histolytica are not fully understood. This study investigated the involvement of the protein tyrosine phosphatases (PTPs) SHP-1 and SHP-2 in the dephosphorylation associated with E. histolytica-induced host cell death. Incubation with E. histolytica resulted in a marked decrease in protein tyrosine phosphorylation levels and degradation of SHP-1 or SHP-2 in Jurkat cells. Pre-treatment of cells with a calpain inhibitor, calpeptin, impeded the amoeba-induced dephosporylation and cleavage of SHP-1 or SHP-2. Additionally, inhibition of PTPs with phenylarsine oxide (PAO) attenuated Entamoeba-induced dephosphorylation and DNA fragmentation in Jurkat T cells. These results suggest that calpain-dependent cleavage of SHP-1 and SHP-2 may contribute to protein tyrosine dephosphorylation in Jurkat T cell death induced by E. histolytica.

Transcatheter arterial chemo-lipiodol infusion for unresectable hepatocellular carcinoma in 96 high-risk patients.

AIM: To evaluate the safety and efficacy of transcatheter arterial chemo-lipiodol infusion (TACL) in high-risk patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: From January 2005 to April 2009, 96 patients underwent TACL. All patients had diffuse, infiltrative or multifocal tumours. Twenty-nine (30%) patients had an increased serum bilirubin level (>or=2mg/dl), and 75 patients (78%) had a low serum albumin level (<3.5mg/dl). The Child-Pugh (CP) score was 9 or more in 13 (14%) patients. Sixty-five patients (68%) had major portal vein occlusion. Sixteen patients (17%) had biliary dilatation. RESULTS: TACL was technically successful in all patients. After TACL, 18 (19%) of the 96 patients showed tumour response using computed tomography (CT) criteria. The 30 day mortality and morbidity rates were 1 and 2%, respectively. The median survival period was 8.6 months, and the overall 6 month, 1, 2, and 3 year survival rates were 59, 44, 26, and 15%, respectively. Portal vein occlusion (p<0.001) was the only significant risk factor associated with the length of the survival period after TACL, whereas the CP score (p=0.498), serum bilirubin level (p=0.153), serum albumin level (p=0.399), and biliary obstruction (p=0.636) had no significant effect. CONCLUSIONS: TACL can be performed safely in high risk HCC patients resulting in a median survival rate of 8.6 months in the present series.

Pharmacokinetics and the antiplatelet effect of a new clopidogrel formulation, clopidogrel besylate, in healthy subjects.

BACKGROUND: Clopidogrel, a thienopyridine derivative, is an inhibitor of platelet aggregation induced by adenosine diphosphate (ADP). We compared the pharmacokinetics and the antiplatelet effect of two clopidogrel formulations (clopidogrel besylate (test) and clopidogrel bisulfate (reference)). SUBJECTS AND METHODS: The study was conducted in 40 healthy subjects in a randomized, open-label, 2-period crossover manner. Each subject received a single loading dose of 150 mg clopidogrel on Day 1 followed by a daily dose of 75 mg clopidogrel from Day 2 to Day 7. After the first dose blood samples for pharmacokinetic analysis of clopidogrel and SR26334 were collected over 24 h. The pharmacodynamic variables, i.e., the inhibition of ADP-induced platelet aggregation, were measured over 264 h. RESULTS: No serious adverse events occurred during the study period. The mean plasma concentration-time profiles of clopidogrel and SR26334 for the two formulations were comparable. The 90% confidence intervals (CIs) for the log-transformed ratios for pharmacokinetic parameters (Cmax and AUC) of SR26334 fell within the predefined pharmacokinetic equivalence range of 80 - 125%. However, the upper limits of 90% CI of Cmax and AUC for clopidogrel exceeded the equivalence range. The two formulations showed similar antiplatelet profiles. The 90% CIs of DeltaEmax and DeltaAUEC of platelet aggregation inhibition fell within the equivalence range of 80 - 125%. CONCLUSION: Both clopidogrel formulations were well-tolerated. The study population showed no serious AEs. The test formulation proved pharmacokinetically non-inferior to the reference formulation. The test formulation showed an antiplatelet effect on ADP-induced platelet aggregation similar to the reference formulation. The two formulations were considered pharmacodynamically equivalent in terms of platelet aggregation inhibition.

Pharmacokinetic comparison and bioequivalence of two leflunomide formulations in humans: a single dose, randomized, open-label, two-way crossover study.

BACKGROUND AND AIMS: Leflunomide is a disease-modifying antirheumatic drug (DMARD) with comparable efficacy to methotrexate in the treatment of rheumatoid arthritis. We compared the pharmacokinetic characteristics of two leflunomide formulations in healthy subjects and assessed whether these formulations were bioequivalent. SUBJECTS AND METHODS: A randomized, two-way, crossover study was conducted in 24 healthy male volunteers to compare the pharmacokinetics of two leflunomide formulations after administration of a single 20 mg dose of each drug with a 7 week washout period. Blood samples for the analysis of A77 1726, the main active metabolite of leflunomide, were obtained 624 h after drug administration. RESULTS: After administering a single dose of 20 mg of each leflunomide formulation, the mean AUC(0-t) and Cmax values of A771726 were 487.3 +/- 167.6 microg*h/ml and 2.24 +/- 0.85 microg/ml for the reference formulation and 468.5 +/- 148.6 microg*h/ml and 1.98 +/- 0.45 microg/ml for the test formulation, respectively. The 90% confidence intervals of the test/reference mean ratios for AUC(0-t), AUC(0-inf), and Cmax fell within the predetermined equivalence range of 0.8 - 1.25. No serious adverse events occurred during the study period. CONCLUSIONS: The two leflunomide formulations showed similar pharmacokinetic profiles in terms of A77 1726, and the test formulation was found to be bioequivalent to the reference formulation with respect to the rate and extent of leflunomide absorption.

ABCG2 polymorphisms, 34G>A and 421C>A in a Korean population: analysis and a comprehensive comparison with other populations.

BACKGROUND AND OBJECTIVE: ABCG2, also known as Breast Cancer Resistance Peptide (BCRP) or mitoxantrone-resistant protein, is the second member of the G-family of ABC transporters. The frequencies of ABCG2 34G>A and 421C>A polymorphisms in a Korean population were assessed using a newly developed multiplex pyrosequencing method, and compared with the corresponding frequencies seen in other ethnic groups. METHOD: We designed a multiplex pyrosequencing method to simultaneously detect ABCG2 421C>A and 34G>A polymorphisms and analysed the allele frequencies of these polymorphisms in 250 Korean subjects. RESULTS: The results showed 100% concordance between single and multiplex pyrosequencing methods. We also validated the polymorphisms identified by pyrosequencing with a direct sequencing method using randomly selected samples. The allele frequencies of ABCG2 421C>A and 34G>A in the population tested were 0·298 and 0·190 respectively. The allele frequency of the 421C>A polymorphism is comparable to other Asian populations, including Japanese and Chinese. However, both frequencies are different from those of Caucasians and Africans. CONCLUSIONS: The multiplex pyrosequencing method used to detect two ABCG2 polymorphisms concurrently is a rapid and reliable genotyping method for the detection of important ABCG2 genetic polymorphisms. The ABCG2 34G>A and 421C>A polymorphisms are frequently found in the Korean population. The frequencies are similar to those seen in other Asian populations including Japanese and Chinese, but very different to those of Caucasian and African-American populations.

Assessment of CYP2C19 genetic polymorphisms in a Korean population using a simultaneous multiplex pyrosequencing method to simultaneously detect the CYP2C19*2, CYP2C19*3, and CYP2C19*17 alleles.

BACKGROUND AND OBJECTIVE: CYP2C19 is a drug-metabolizing enzyme showing various genetic polymorphisms that may cause marked interindividual and interethnic variability in the disposition of its substrates. We assessed CYP2C19 genetic polymorphisms in a Korean population using a newly developed multiplex pyrosequencing method. METHOD: A multiplex pyrosequencing method to simultaneously detect CYP2C19*2, *3, and *17 alleles was designed. We established the frequency of these CYP2C19 alleles in 271 Korean subjects using the multiplex pyrosequencing method. RESULTS: The results showed 100% concordance between single and multiplex pyrosequencing methods. We also validated the polymorphisms identified by pyrosequencing with direct sequencing method. The allele frequencies of CYP2C19*2, CYP2C19*3, and CYP2C19*17 were 0·284, 0·101 and 0·015 respectively. These frequencies are similar to that reported for other Asian populations including Japanese and Chinese but different from that of Caucasians and Africans. CONCLUSIONS: The multiplex pyrosequencing method to detect CYP2C19*2, CYP2C19*3, and CYP2C19*17 concurrently, seems to be a rapid and reliable genotyping method for the detection of important CYP2C19 genetic polymorphisms. Similar to studies conducted on other Asian populations, this study reported that in the Korean population tested, the CYP2C19*2 and CYP2C19*3 alleles were relatively frequently found, whereas the frequency of CYP2C19*17 was very low.

Primary serous papillary carcinoma of the peritoneum mimicking pelvic actinomycosis: a case report and brief literature review.

Primary serous papillary carcinoma of the peritoneum is a rare tumor, histologically similar to primary ovarian carcinoma. Pelvic CT and MRI are helpful to diagnose primary carcinoma of the peritoneum. We present a case of primary serous carcinoma of the peritoneum mimicking pelvic actinomycosis in a 59-year-old woman. Pelvic CT and MRI suggested pelvic actinomycosis. Exploratory laparotomy was performed to remove the mass and the diagnosis was confirmed by pathology. A subtotal hysterectomy, left salpingo-oophorectomy and omentectomy were performed. Histopathology examination revealed peritoneal carcinomatosis and primary serous carcinoma of the peritoneum. Pelvic CT and MRI were limited in their ability to differentiate inflammation, such as actinomycosis, from primary carcinoma of the peritoneum.

Effect of CYP3A5*3 genotype on serum carbamazepine concentrations at steady-state in Korean epileptic patients.

BACKGROUND AND OBJECTIVE: Carbamazepine (CBZ) is metabolized mainly by the CYP3A family of enzymes, which includes CYP3A4 and CYP3A5. Several studies have suggested that the CYP3A5*3 genotype influences the pharmacokinetics of CYP3A substrates. The present study aimed to assess the effect of the CYP3A5*3 genotype on serum concentration of CBZ at the steady-state in Korean epileptic patients. METHOD: The serum concentrations of CBZ in 35 Korean epileptic patients were measured and their CYP3A5 genotype was determined. Fourteen patients were CYP3A5 expressors (two for CYP3A5*1/*1 and 12 for CYP3A5*1/*3) and 21 patients were CYP3A5 non-expressors (CYP3A5*3/*3). Dose-normalized concentrations (mean +/- SD) of CBZ were 9.9 +/- 3.4 ng/mL/mg for CYP3A5 expressors and 13.1 +/- 4.5 ng/mL/mg for CYP3A5 non-expressors (P = 0.032). The oral clearance of CBZ was significantly higher in CYP3A5 non-expressors than that of CYP3A5 expressors (0.056 +/-0.017 L/h/kg vs. 0.040 +/- 0.014 L/h/kg, P = 0.004). The CYP3A5 genotype affected the CBZ concentrations in Korean epileptic patients and is a factor that may contribute to inter-individual variability in CBZ disposition in epileptic patients.

Identification of aldo-keto reductase (AKR7A1) and glutathione S-transferase pi (GSTP1) as novel renal damage biomarkers following exposure to mercury.

The kidney is one of the main targets for toxicity induced by xenobiotics. Sensitive detection of early impairment is critical to assess chemical-associated renal toxicity. The aim of this study was to identify potential nephrotoxic biomarkers in rat kidney tissues after exposure to mercury (Hg), a representative nephrotoxicant, and to evaluate these new biomarkers employing in vivo and in vitro systems. Mercuric chloride was administered orally to Sprague-Dawley rats for 2 weeks. Proteomic analysis revealed that aldo-keto reductase (AKR7A1) and glutathione S-transferase pi (GSTP1) were significantly elevated in kidney after Hg exposure. While the levels of conventional nephrotoxic clinical markers including blood urea nitrogen and serum creatinine were not elevated, the mRNA and protein levels of AKR7A1 and GSTP1 were increased upon Hg exposure in a dose-dependent manner. The increases in AKR7A1 and GSTP1 were also observed in rat kidneys after an extended exposure for 6 weeks to low-dose Hg. In in vitro rat kidney proximal tubular cells, changes in AKR7A1 and GSTP1 levels correlated well with the extent of cytotoxicity induced by Hg, cadmium, or cisplatin. AKR7A1 and GSTP1 were identified as new candidates for Hg-induced nephrotoxicity, suggesting that these biomarkers have potential for evaluating or predicting nephrotoxicity.

Comparative pharmacokinetic and pharmacodynamic characteristics of amlodipine besylate and amlodipine nicotinate in healthy subjects.

BACKGROUND AND AIM: Amlodipine, a dihydropyridine calcium antagonist, is prescribed for the management of angina and hypertension, and is sold as amlodipine besylate. However, a new salt formulation, amlodipine nicotinate, has recently been developed. Here, we evaluated the comparative pharmacokinetic and pharmacodynamic characteristics of the nicotinate and besylate forms of amlodipine. SUBJECTS AND METHODS: A randomized, 2-way crossover study was conducted in 18 healthy male volunteers to compare the pharmacokinetics and pharmacodynamics of these two forms, i.e. amlodipine nicotinate (test) and amlodipine besylate (reference), after administration of a single dose of 5 mg of each drug and a washout period between doses of 4 weeks. Blood samples for the pharmacokinetic analysis of amlodipine were obtained over the 144-hour period after administration. Systolic and diastolic blood pressures and pulse rates were recorded immediately prior to each blood sampling. RESULTS: All participants completed both treatment periods, and no serious adverse events occurred during the study period. After administering a single dose of each formulation, mean AUC0-infinity and Cmax values were 190.91+/-60.49 ng x h/ml and 3.87+/-1.04 ng/ml for the test formulation and 203.15+/-52.05 ng x h/ml and 4.01+/-0.60 ng/ml for the reference formulation, respectively. The 90% confidence intervals of test/reference mean ratios for AUC0- infinity and Cmax fell within the predetermined equivalence range of 80 - 125%. Pharmacodynamic profiles including systolic and diastolic blood pressures and pulse rates exhibited no significant differences between the two formulations. CONCLUSION: The two amlodipine formulations showed similar pharmacokinetic and pharmacodynamic characteristics and the new amlodipine formulation, amlodipine nicotinate, was found to be equivalent for pharmacokinetics to the currently available amlodipine besylate with respect to the rate and extent of amlodipine absorption.