Decreased absorption of midazolam in the stomach due to low pH induced by co-administration of Banha-sasim-tang

OBJECTIVES: Banha-sasim-tang (BST), which consists of seven different herbs, is one of the most popular herbal formulae for treating gastrointestinal disorders in Eastern Asia. The commonly used herbal medicine is often co-administered with other therapeutic drugs, which raises the possibility of herb–drug interactions and may modify the clinical safety profile of therapeutic drugs. METHODS: We investigated the potential herb–drug interactions between BST extract and midazolam (MDZ) in mice. The area under the plasma concentration-time curve (AUC) of MDZ and 1ʹ-hydroxymidazolam (1ʹ-OH-MDZ) was evaluated for both oral and intraperitoneal administration of MDZ, following oral administration of BST (0.5 and 1 g/kg). RESULTS: It was found that the AUC of MDZ and 1ʹ-OH-MDZ was lower in case of oral administration of MDZ. Administration of BST extract was not associated with hepatic cytochrome P450 activity. BST extract induced a strong reduction in pH and it has been reported that oral mucosal absorption of MDZ is lower at low pH. The decreased absorption rate of MDZ might be caused by the ingredients of BST and may not be related to other factors such as increased excretion of MDZ by P-glycoprotein. CONCLUSIONS: The altered pharmacokinetics of midazolam caused by co-administration with BST in vivo could be attributed to a decrease in pH and subsequent reduction of MDZ absorption rate.

Protective effect of butylated hydroxylanisole against hydrogen peroxide-induced apoptosis in primary cultured mouse hepatocytes

Butylated hydroxyanisole (BHA) is a synthetic phenolic compound consisting of a mixture of two isomeric organic compounds: 2-tert-butyl-4-hydroxyanisole and 3-tert-butyl-4-hydroxyanisole. We examined the effect of BHA against hydrogen peroxide (H2O2)-induced apoptosis in primary cultured mouse hepatocytes. Cell viability was significantly decreased by H2O2 in a dose-dependent manner. Additionally, H2O2 treatment increased Bax, decreased Bcl-2, and promoted PARP-1 cleavage in a dose-dependent manner. Pretreatment with BHA before exposure to H2O2 significantly attenuated the H2O2-induced decrease of cell viability. H2O2 exposure resulted in an increase of intracellular reactive oxygen species (ROS) generation that was significantly inhibited by pretreatment with BHA or N-acetyl-cysteine (NAC, an ROS scavenger). H2O2-induced decrease of cell viability was also attenuated by pretreatment with BHA and NAC. Furthermore, H2O2-induced increase of Bax, decrease of Bcl-2, and PARP-1 cleavage was also inhibited by BHA. Taken together, results of this investigation demonstrated that BHA protects primary cultured mouse hepatocytes against H2O2-induced apoptosis by inhibiting ROS generation.

Protective Effects of Diallyl Sulfide against Thioacetamide-Induced Toxicity: A Possible Role of Cytochrome P450 2E1

Effects of diallyl sulfide (DAS) on thioacetamide-induced hepatotoxicity and immunotoxicity were investigated. When male Sprague-Dawley rats were treated orally with 100, 200 and 400 mg/kg of DAS in corn oil for three consecutive days, the activity of cytochrome P450 (CYP) 2E1-selective p-nitrophenol hydroxylase was dose-dependently suppressed. In addition, the activities of CYP 2B-selective benzyloxyresorufin O-debenzylase and pentoxyresorufin O-depentylase were significantly induced by the treatment with DAS. Western immunoblotting analyses also indicated the suppression of CYP 2E1 protein and/or the induction of CYP 2B protein by DAS. To investigate a possible role of metabolic activation by CYP enzymes in thioacetamide-induced hepatotoxicity, rats were pre-treated with 400 mg/kg of DAS for 3 days, followed by a single intraperitoneal treatment with 100 and 200 mg/kg of thioacetamide in saline for 24 hr. The activities of serum alanine aminotransferase and aspartate aminotransferase significantly elevated by thioacetamide were protected in DAS-pretreated animals. Likewise, the suppressed antibody response to sheep erythrocytes by thioacetamide was protected by DAS pretreatment in female BALB/c mice. Taken together, our present results indicated that thioacetamide might be activated to its toxic metabolite(s) by CYP 2E1, not by CYP 2B, in rats and mice.

A Comparison of the In Vitro Inhibitory Effects of Thelephoric Acid and SKF-525A on Human Cytochrome P450 Activity

Thelephoric acid is an antioxidant produced by the hydrolysis of polyozellin, which is isolated from Polyozellus multiplex. In the present study, the inhibitory effects of polyozellin and thelephoric acid on 9 cytochrome P450 (CYP) family members (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) were examined in pooled human liver microsomes (HLMs) using a cocktail probe assay. Polyozellin exhibited weak inhibitory effects on the activities of all 9 CYPs examined, whereas thelephoric acid exhibited dose- and time-dependent inhibition of all 9 CYP isoforms (IC50 values, 3.2-33.7 muM). Dixon plots of CYP inhibition indicated that thelephoric acid was a competitive inhibitor of CYP1A2 and CYP3A4. In contrast, thelephoric acid was a noncompetitive inhibitor of CYP2D6. Our findings indicate that thelephoric acid may be a novel, non-specific CYP inhibitor, suggesting that it could replace SKF-525A in inhibitory studies designed to investigate the effects of CYP enzymes on the metabolism of given compounds.

Post-Translational Modification of Proteins in Toxicological Research: Focus on Lysine Acylation

Toxicoproteomics integrates the proteomic knowledge into toxicology by enabling protein quantification in biofluids and tissues, thus taking toxicological research to the next level. Post-translational modification (PTM) alters the three-dimensional (3D) structure of proteins by covalently binding small molecules to them and therefore represents a major protein function diversification mechanism. Because of the crucial roles PTM plays in biological systems, the identification of novel PTMs and study of the role of PTMs are gaining much attention in proteomics research. Of the 300 known PTMs, protein acylation, including lysine formylation, acetylation, propionylation, butyrylation, malonylation, succinylation, and crotonylation, regulates the crucial functions of many eukaryotic proteins involved in cellular metabolism, cell cycle, aging, growth, angiogenesis, and cancer. Here, I reviewed recent studies regarding novel types of lysine acylation, their biological functions, and their applicationsin toxicoproteomics research.

Correlations between Magnitude of Refractive Error and Other Optical Components in Korean Myopes

PURPOSE: We evaluated ocular optical components and their interrelationships in myopic Korean patients. METHODS: In this prospective observational study, 1,011 consecutive patients were recruited from a refractive surgery clinic. The best-corrected visual acuity was >20 / 20 in all patients. The refractive error, axial length (AL), anterior chamber depth (ACD), lens thickness (LT), and vitreous chamber depth (VCD) were measured by an autorefractor and partial coherence laser interferometry (IOL Master). Central corneal thickness (CCT) was measured by ORBscan II topography. RESULTS: The refractive errors had a positive correlation with LT but negative correlations with AL, ACD, VCD, and CCT. As the axial length increased, the ACD, VCD, and CCT increased but the LT decreased. The CCT had a positive correlation with gender, refractive errors, ACD, VCD, and AL but no correlation with age. The mean CCT was increased in proportion to the increase in AL. CONCLUSIONS: In myopic Korean patients, as axial elongation progressed, the VCD and ACD deepened and the CCT thickened but the LT decreased. The CCT had a positive correlation with the degree of myopia and the AL.

An Open Label Multi-Center Prospective Observational Study of Paliperidone Extended Release to Assess the Medication Satisfaction and Treatment Response in Patients with Schizophrenia / 대한정신약물학회지

OBJECTIVE: The aim of this study was to demonstrate changes of subjective medication satisfaction and clinical benefit after once-daily paliperidone extended release (ER) in treatment of schizophrenia. METHODS: In an open-label, observational, and multicenter study, 374 patients with schizophrenia who switched to paliperidone ER due to any reason were recruited. Medication Satisfaction Questionnaire (MSQ), Clinical Global Impression-Severity (CGI-S), Clinical Global Impression-Improvement and visual analogue scale for sleep (VAS) were assessed at baseline, 4 weeks and 8 weeks after treatment. We also examined the type, frequency, and severity of adverse events newly formed. RESULTS: Among 374 patients, 320 patients (76.5%) were included in the intent-to-treat analysis set. The mean dose of paliperidone ER was 5.33+/-2.31 mg/day at the initiation. At the endpoint, the mean dose of paliperidone ER was 6.68+/-3.13 mg/day. The percentages of patients satisfied with medication were changed from 40.9% at baseline to 67.8% at endpoint (p<0.001). Both CGI-S scores and VAS for daytime drowsiness were significantly decreased after 8 weeks (both p<0.0001) and mean scores of MSQ and VAS for sleep quality were improved after 8 weeks (both p<0.0001). CONCLUSION: After switching to paliperidone ER, 67.8% of patients with schizophrenia who had any reason to switch medication showed subjective satisfaction for medication and clinical improvement without significant adverse events. Regarding that medication satisfaction was associated with changes of clinical states, medication satisfaction can be used for measures for clinical scales in the treatment of schizophrenia.

Positional Reproducibility and Effects of a Rectal Balloon in Prostate Cancer Radiotherapy

Despite the increasing use of the rectal balloon in prostate cancer radiotherapy, many issues still remain to be verified objectively including its positional reproducibility and relevance to treatment morbidity. We have developed a custom rectal balloon that has a scale indicating the depth of insertion and dilates symmetrically ensuring positional reproducibility. Fifty patients with prostate cancer treated by definitive 3D-conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) with rectal balloon were analyzed. Each of first five patients undergone computed tomography (CT) three times with a rectal balloon. The positional reproducibility was tested by Intraclass Correlation Coefficient (ICC) from the CT-to-CT fusion images. Planning variables and clinical acute toxicities were compared between when or not applying balloon. An ICC of greater than 0.9 in all directions revealed an excellent reproducibility of the balloon. Rectal balloon improved considerably the mean dose and V(45Gy)-V(65Gy) in plan comparison, and especially in 3D-CRT the rectal volume exposed to more than 60 Gy dropped from 41.3% to 19.5%. Clinically, the balloon lowered acute toxicity, which was lowest when both the balloon and IMRT were applied simultaneously. The rectal balloon carries excellent reproducibility and reduces acute toxicity in 3D-CRT and IMRT for prostate cancer.

Mesenteric and Omental Cysts in Infancy and Childhood

Mesenteric and omental cysts are rare lesions of childhood. These cysts are similar to cystic hygromas in other parts of the body morphologically and pathologically. From 1980 to 1997, 8 children were diagnosed and treated for mesenteric or omental cysts. Their ages ranged from 18 days to 6 years. There were 5 boys and 3 girls. The main presenting symptom was abdominal pain. Operative procedures were complete cysts excision, complete excision with intestinal resection, or complete excision with intestinal resection and colostomy. Accurate preoperative diagnosis was possible with the current ultrasonographic imaging techniques. Complete excision of the lesion was possible in all patients and resulted in an excellent outcome.

Congenital Diaphragmatic Eventration in infant

Although diaphragmatic eventration in newborn infants is generally regarded as a rare condition, the need for accurate diagnosis and appropriate intervention according to the etiological factors is well known. Recently authors experienced five consecutive cases of diaphragmatic eventration. All requiring surgery. All were seen within the second month of life ranging one to 55 days after birth. And all were male infants. All eventration were left sided. Respiratory symptoms were present in 4 cases, and the remainder had no symptoms other than inability to gain weight. The radiologic changes were pronounced in all cases, the dome of the diaphragm reaching from the third to fifth intercostal spaces. Regarding surgical technique, the authors favored Diaphragmatic plication through the abdomen, which gave excellent clinical and radiological results. No postoperative mortality was noted.