MCPI: a sub-minute Monte Carlo dose calculation engine for prostate implants

An accelerated Monte Carlo code [Monte Carlo dose calculation for prostate implant (MCPI)] is developed for dose calculation in prostate brachytherapy. MCPI physically simulates a set of radioactive seeds with arbitrary positions and orientations, merged in a three-dimensional (3D) heterogeneous phantom representing the prostate and surrounding tissue. MCPI uses a phase space data source-model to account for seed self-absorption and seed anisotropy. A "hybrid geometry" model (full 3D seed geometry merged in 3D mesh of voxels) is used for rigorous treatment of the interseed attenuation and tissue heterogeneity effects. MCPI is benchmarked against the MCNP5 code for idealized and real implants, for 103Pd and 125I seeds. MCPI calculates the dose distribution (2-mm voxel mesh) of a 103Pd implant (83 seeds) with 2% average statistical uncertainty in 59 s using a single Pentium 4 PC (2.4 GHz). MCPI is more than 10(3) and 10(4) times faster than MCNP5 for prostate dose calculations using 2- and 1-mm voxels, respectively. To illustrate its usefulness, MCPI is used to quantify the dosimetric effects of interseed attenuation, tissue composition, and tissue calcifications. Ignoring the interseed attenuation effect or slightly varying the prostate tissue composition may lead to 6% decreases of D100, the dose delivered to 100% of the prostate. The presence of calcifications, covering 1%-5% of the prostate volume, decreases D80, D90, and D100 by up to 32%, 37%, and 58%, respectively. In conclusion, sub-minute dose calculations, taking into account all dosimetric effects, are now possible for more accurate dose planning and dose assessment in prostate brachytherapy.     

Genotype phenotype correlations in Israeli colorectal cancer patients

While genetic factors clearly play a key role in colorectal cancer (CRC) pathogenesis and in determining its phenotypic features, the precise genes that involved are largely unknown. To gain insight into these genes, consecutive Israeli CRC patients were genotyped using SNPs from within candidate genes: APC, beta-Catenin, K-RAS, DCC, P16, PTEN, RB1, P15, APOE, ERCC2, P53, MTHFR and hMSH2. Genotyping of consecutive, unselected colorectal cancer patients was done mostly by utilizing the MassARRAY technology (Sequenom) and to a lesser extent DGGE, ARMS and direct DNA sequencing. Correlation of genotypes with specific phenotypic features was carried out for all patients and separately for the Ashkenazim. Overall, 456 patients were analyzed, the majority (64.25%) being of Ashkenazi origin; mean age at diagnosis was 65.6 +/- 14 (range 25-90 years), and the mean follow-up was 4.7 +/- 0.28 (range 0-30 years). Statistically significant associations were noted between SNPs in beta-catenin and APOE and a positive family history of cancer (beta-catenin: p=0.034, APOE: p=0.033); tumor location and a DCC SNP (p=0.038) and the P53 R72P mutation and survival (p=0.0336). In Ashkenazi patients, ERCC2 and MTHFR genes' SNPs were associated with age at diagnosis (ERCC2: p=0.025, MTHFR: p=0.0005); a P53 polymorphism, APOE and Rb SNPs with a family history of cancer (P53 p=0.034;APOE p=0.04, Rb p= 0.022); DCC SNP with tumor location (p=0.014); and p15 SNP with tumor grade (p=0.032). This preliminary study shows that genetic factors play a role in determining CRC phenotypic features and that a larger cohort with longer follow-up is clearly needed.     

A technique to harvest Descemet's membrane with viable endothelial cells for selective transplantation

PURPOSE: To describe a surgical technique using an artificial anterior chamber to facilitate harvest of Descemet's membrane (DM) and endothelium for corneal endothelial cell transplantation. DESIGN: Laboratory investigation. METHODS: Corneoscleral buttons of seven human donor eyes were mounted endothelial side up on an artificial anterior chamber. Keeping the endothelial side with its usual concavity, a manual trephination was made on the posterior surface with a 9.0-mm trephine, inside the Schwalbe line and just past the DM in depth. The chamber was filled with air, causing the endothelial side of the donor cornea to assume a convex configuration. The DM along with its endothelium was separated from the posterior stroma using a blunt cyclodialysis spatula. Drops of trypan blue 0.3% and alizarin red S 0.2% (n = 6) were applied. The stained DMs were examined under a light microscope and photographed to calculate the percentage of endothelial cell damage. Histology was done on the unstained cornea. RESULTS: The DM carrying endothelium was successfully removed from the posterior stroma in all seven eyes. Although the DM appears to be very friable, all samples were removed in toto without rupture. Vital staining showed a mean endothelial cell loss of 8.46% (standard deviation (SD) 6.9). Direct light microscopy demonstrated the preservation of endothelial cell morphology. CONCLUSIONS: This technique appears to be a safe and straightforward method to harvest DM for endothelial cell transplantation. Further studies are underway to determine the optimal method of insertion of the obtained healthy DM with endothelial cells through small corneal incisions.     

Effect of pentoxifylline on hepatic injury caused in the rat by the administration of carbon tetrachloride or acetaminophen

The effect of pentoxifylline (PTX) on acute liver injury caused by CCl4 or acetaminophen was studied in the rat. PTX was given twice daily (18, 36 or 72 mg/kg), intraperitoneally (ip) for 5 days prior to CCl4 or acetaminophen. In addition, the effect of PTX administered simultaneously with CCl4 or acetaminophen was evaluated. Rats were killed 72 h or 48 h after CCl4 or acetaminophen administration, respectively. The administration of PTX at 72 mg/kg, conferred significant protection against the hepatotoxic actions of CCl4, reducing serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels to 31%, 59.2% and 63%, respectively. Histological examination showed a decrease in centrilobular necrotic areas in rats pretreated with PTX. Histochemical investigation revealed a decrease in glycogen and protein contents caused by CCl4 and these were prevented by PTX pretreatment. When administered with CCl4, PTX did not reduce CCl4-induced hepatic injury. In contrast, hepatic injury induced by acetaminophen was prevented by prior or co-treatment with PTX. Accordingly, with 72 mg/kg of PTX, the elevation of AST, ALT and ALP levels was lower by 45%, 80.6%, 54.3% for the former and by 32.4%, 77.2%, 52.4% for the latter, respectively. Stained sections were subjected to morphometric evaluation using computerized image analyzer. Quantitative analysis of the acetaminophen area of damage showed a reduction by 34.8, 65.5 and 89.2% by 18, 36 or 72 mg/kg for PTX, respectively. Rats treated with PTX revealed more or less normal hepatocyte architecture as well as marked improvement in protein and glycogen content. The study demonstrates that prior but not co-toxicant administration of PTX in a model of CCl4-induced liver injury results in less liver damage. In contrast, PTX is equally protective, when given either as a pretreatment or with acetaminophen exposure.     

Inhibition of hepatic neoglucogenesis and glucose-6-phosphatase by quercetin 3-O-alpha(2''-galloyl)rhamnoside isolated from Bauhinia megalandra leaves

In intact microsomes, quercetin 3-O-alpha-(2'-galloyl)rhamnoside (QGR) inhibits glucose-6-phosphatase (G-6-Pase) in a concentration-dependent manner. QGR increased the G-6-Pase K(m) for glucose-6-phosphate without change in the V(max). The flavonol did not change the kinetic parameters of disrupted microsomal G-6-Pase or intact or disrupted microsomal G-6-Pase pyrophosphatase (PPase) activity. This result allowed the conclusion that QGR competitively inhibits the glucose-6-phosphate (G-6-P) transporter (T1) without affecting the catalytic subunit or the phosphate/pyrophosphate transporter (T2) of the G-6-Pase system.QGR strongly inhibits the neoglucogenic capacity of rat liver slices incubated in a Krebs-Ringer bicarbonate buffer, supplemented with lactate and oleate saturated albumin.The QGR G-6-Pase inhibition might explain the decrease in the liver slice neoglucogenic capacity and, in turn, could reduce glucose levels in diabetic patients.     

5-(Phenylthio)acyclouridine: a powerful enhancer of oral uridine bioavailability: relevance to chemotherapy with 5-fluorouracil and other uridine rescue regimens

Purpose The purpose of this investigation was to evaluate the effectiveness of oral 5-(phenylthio)acyclouridine (PTAU) in improving the pharmacokinetics and bioavailability of oral uridine. PTAU is a potent and specific inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. This compound was designed as a lipophilic inhibitor in order to facilitate its access to the liver and intestine, the main organs involved in uridine catabolism. PTAU is fully absorbed after oral administration with 100% oral bioavailability.Methods Uridine (330, 660 or 1320 mg/kg) and/or PTAU (30, 45, 60, 120, 240 or 480 mg/kg) were orally administered to mice. The plasma levels of uridine, its catabolite uracil, and PTAU were measured using HPLC, and pharmacokinetic analysis was performed.Results Oral PTAU up to 480 mg/kg per day is not toxic to mice. Oral PTAU at 30, 45, 60, 120 and 240 mg/kg has a prolonged plasma half-life of 2–3 h, and peak plasma PTAU concentrations (C_max) of 41, 51, 74, 126 and 161 M with AUCs of 70, 99, 122, 173 and 225 mol h/l, respectively. Coadministration of uridine with PTAU did not have a significant effect on the pharmacokinetic parameters of plasma PTAU at any of the doses tested. Coadministration of PTAU (30, 45, 60 and 120 or 240 mg/kg) with uridine (330, 660 or 1320 mg/kg) elevated the concentration of plasma uridine over that following the same dose of uridine alone, a result of reduced metabolic clearance of uridine as evidenced by decreased plasma exposure (C_max and AUC) to uracil. Plasma uridine was elevated with the increase of uridine dose at each PTAU dose tested and no plateau was reached. Coadministration of PTAU at 30, 45, 60, 120 and 240 mg/kg improved the low oral bioavailability (7.7%) of uridine administered at 1320 mg/kg by 4.3-, 5.9-, 9.9-, 11.7- and 12.5-fold, respectively, and reduced the AUC of plasma uracil (1227.8 mol h/l) by 5.7-, 6.8-, 8.2-, 6.3-, and 6.9-fold, respectively. Similar results were observed when PTAU was coadministered with lower doses of uridine. Oral PTAU at 30, 45, 60, 120 and 240 mg/kg improved the oral bioavailability of 330 mg/kg uridine by 1.7-, 2.4-, 2.6-, 5.2- and 4.3- fold, and that of 660 mg/kg uridine by 2.3-, 2.7-, 3.3-, 4.6- and 6.7-fold, respectively.Conclusion The excellent pharmacokinetic properties of PTAU, and its extraordinary effectiveness in improving the oral bioavailability of uridine, could be useful to rescue or protect from host toxicities of 5-fluorouracil and various chemotherapeutic pyrimidine analogues used in the treatment of cancer and AIDS, as well as in the management of medical disorders that are remedied by the administration of uridine including CNS disorders (e.g. Huntingtons disease, bipolar disorder), liver diseases, diabetic neuropathy, cardiac damage, various autoimmune diseases, and transplant rejection.     

Assessment of drug permeability distributions in two different model skins

Past in vitro studies with human skin have indicated that drug permeability coefficient (Kp) distributions do not always follow a Gaussian-normal pattern. This has major statistical implications, exemplified by the fact that use of t-tests to evaluate significance is limited to normally distributed populations. Percutaneous absorption research often involves using animal or synthetic skins to simulate less readily available human skin. However, negligible work has been performed on assessing the permeability variabilities of these model membranes. This paper aims to fill this gap. To this end, four studies were undertaken representing two different drugs (caffeine and testosterone) with each drug penetrating through two different model skins (silicone membrane and pig skin). It was determined that in the silicone membrane studies, both compounds' Kp distributions could be fitted to a normal pattern. In contrast, in the pig skin studies, there were notable differences between each drug. While the testosterone Kp values could be fitted to a normal distribution, this was not possible with the caffeine Kp data, which could be fitted to a log-normal distribution. There is some evidence from the literature as well as physicochemical considerations that these outcomes may reflect general trends that are dependent upon both membrane and penetrant properties.