Feasibility of Pay for Performance and Transparency Interventions on the Selection and Quality of Observational Management for Patients With Low-Risk Prostate Cancer in the Community Practice.

Introduction: Practice-level strategies to improve the use of conservative management for low-risk prostate cancer have not been rigorously evaluated. We examined the feasibility of implementation and preliminary outcomes of a pay-for-performance (P4P) and a transparency intervention at the practice level.

Methods: We conducted a pilot study within a Southern California urology practice network.

Correlation of lactulose-to-mannitol ratios in plasma and urine for intestinal permeability assessment in pigs.

Objective: The lactulose-to-mannitol ratio test is a test to assess the disorders associated with gut permeability. The test requires an oral administration of the mixture of lactulose and mannitol and urine collection. The urinary ratio of lactulose to mannitol is an indicator of intestinal permeability.

Stability of Ketoprofen Methylester in Plasma of Different Species.

Background: Pharmacokinetic and pharmacodynamic assessment of ester-containing drugs can be impacted by hydrolysis of the drugs in plasma samples post blood collection. The impact is different in the plasma of different species.

Objective: This study evaluated the stability of a prodrug, ketoprofen methylester (KME), in commercially purchased and freshly collected plasma of mouse, rat, dog, cat, pig, sheep, cattle and horse.

Assessment of Inhibition of Bovine Hepatic Cytochrome P450 by 43 Commercial Bovine Medicines Using a Combination of Assays and Pharmacokinetic Data from the Literature.

Background: There has been a lack of information about the inhibition of bovine medicines on bovine hepatic CYP450 at their commercial doses and dosing routes.

Objective: The aim of this work was to assess the inhibition of 43 bovine medicines on bovine hepatic CYP450 using a combination of in vitro assay and Cmax values from pharmacokinetic studies with their commercial doses and dosing routes in the literature.

Methods: Those drugs were first evaluated through a single point inhibitory assay at 3 μM in bovine liver microsomes for six specific CYP450 metabolisms, phenacetin o-deethylation, coumarin 7- hydroxylation, tolbutamide 4-hydroxylation, bufuralol 1-hydroxylation, chlorzoxazone 6-hydroxylation and midazolam 1'-hydroxylation.

Pharmacokinetics and brain distribution of amitraz and its metabolites in rats.

Amitraz is an acaricide and insecticide widely used in agriculture and veterinary medicine. Although central nervous system (CNS) toxicity is one of major toxicities following oral ingestion of amitraz, the understanding of the cause of the toxicity is limited. This study evaluated the systemic and brain exposure of amitraz and its major metabolites, BTS27271, 2',4'-formoxylidide, and 2,4-dimethylaniline following administration of amitraz in male Sprague-Dawley rats.

Hepatic Flavin-containing Monooxygenase and Aldehyde Oxidase Activities in Male Domestic Pigs at Different Ages.

Background: Age has a significant impact on activities of hepatic metabolizing enzymes in humans and animals. Flavin-containing Monooxygenase (FMO) and Aldehyde Oxidase (AO) are two important hepatic enzymes. Understanding of the impact of age on these two enzymes is still limited in pigs.

Determination of genotoxic epoxide at trace level in drug substance by direct injection GC/MS.

A novel direct injection gas chromatography method coupled with selective ion monitoring mass spectrometry (GC/SIM-MS) was developed for quantitation of trace levels of high boiling point (HBP) epoxide genotoxic impurity (GTI) in drug substance. The injector temperature was optimized with the aims to minimize matrix effects and enhance SIM signal response. The final injector temperature 160°C was selected after balancing between these two factors.

Assessment of inhibition of porcine hepatic cytochrome P450 enzymes by 48 commercial drugs.

Drug interactions due to inhibition of hepatic cytochrome P450 (CYP450) enzymes are not well understood in veterinary medicine. Forty-eight commercial porcine medicines were selected to evaluate their potential inhibition on porcine hepatic CYP450 enzymes at their commercial doses and administration routes. Those drugs were first assessed through a single point inhibitory assay at 3 µM in porcine liver microsomes for six specific CYP450 metabolisms (phenacetin o-deethylation, coumarin 7-hydroxylation, tolbutamide 4-hydroxylation, bufuralol 1-hydroxylation, chlorozoxazone 6-hydroxylation and midazolam 1'-hydroxylation).

Development of chitosan nanoparticles as drug delivery system for a prototype capsid inhibitor.

Oral delivery of biopharmaceutics drug disposition classification system (BDDCS) Class II or IV drugs with poor aqueous solubility and poor enzymatic and/or metabolic stability is very challenging. Bay41-4109, a member of the heteroaryldihydropyrimidine (HAP) family, inhibits HBV replication by destabilizing capsid assembly. It pertains to class II of the BDDCS which has a practically insoluble solubility which is 38 μg/mL (LYSA) and the oral delivery resulted in low bioavailability.

Development of an in vitro screen for compound bioaccumulation in Haemonchus contortus.

The objective of the current study was to establish an in vitro screen and a highly sensitive analytical assay to delineate key physicochemical properties that favor compound bioaccumulation in the L3 life stage of a Haemonchus contortus isolate. Time-dependent studies revealed that absorption and elimination kinetics during the first 6 hr of exposure were sufficient to achieve maximum bioaccumulation for the majority of compounds tested. In subsequent studies, the larvae were incubated for 6 hr in a medium containing 146 compounds (5 μM initial concentration), including both human and veterinary medicines, characterized by a broad range of physicochemical properties.

Existence of hepatitis C virus NS5B variants naturally resistant to non-nucleoside, but not to nucleoside, polymerase inhibitors among untreated patients.

Objectives: To characterize the effect of hepatitis C virus (HCV) polymerase intrinsic genetic heterogeneity on the inhibitory activity of nucleoside and non-nucleoside HCV polymerase inhibitors.

Methods: The sensitivity of genotype (GT) 1 HCV NS5B clinical isolates from treatment-naive patients to nucleoside and non-nucleoside polymerase inhibitors was assessed. The genetic diversity at the population level, as well as that of their quasispecies, was correlated with the observed reduced sensitivity to inhibitors.

Development of prodrug 4-chloro-3-(5-methyl-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotriazin-7-yl)phenyl benzoate (TG100801): a topically administered therapeutic candidate in clinical trials for the treatment of age-related macular degeneration.

Age-related macular degeneration (AMD) is one of the leading causes of loss of vision in the industrialized world. Attenuating the VEGF signal in the eye to treat AMD has been validated clinically. A large body of evidence suggests that inhibitors targeting the VEGFr pathway may be effective for the treatment of AMD.

Detection of small inflammatory and metastatic lymph nodes in rabbits by sonography: evaluation with the resistive index ratio.

Objective: The aim of this prospective study was to determine whether the resistive index (RI) ratio based on high-resolution spectral Doppler sonography would be useful in the differential diagnosis of small inflammatory and metastatic lymph nodes in rabbit models.

Methods: The infected and metastatic lymph node models we used were created by subcutaneously inoculating methicillin-susceptible Staphylococcus aureus and VX2 tumor cells respectively into the left hind limbs of 10 New Zealand White rabbits. High-resolution sonography was performed to investigate the popliteal fossa lymph nodes 2 weeks after the inoculation.

In silico and in vitro pharmacogenetic analysis in mice.

Combining the experimental efficiency of a murine hepatic in vitro drug biotransformation system with in silico genetic analysis produces a model system that can rapidly analyze interindividual differences in drug metabolism. This model system was tested by using two clinically important drugs, testosterone and irinotecan, whose metabolism was previously well characterized. The metabolites produced after these drugs were incubated with hepatic in vitro biotransformation systems prepared from the 15 inbred mouse strains were measured.

Applications of NIR in early stage formulation development. Part I. Semi-quantitative blend uniformity and content uniformity analyses by reflectance NIR without calibration models.

This article describes a semi-quantitative reflectance near infrared (SQ-NIR) method for blend uniformity (BU) and content uniformity (CU) analyses in early stage formulation development. Applicability of the method depends upon three factors: separation of NIR signals of the active pharmaceutical ingredient (API) from placebo; strength of the signal; and a quantitative relationship between API concentration and NIR signal. Based on these three criteria, suitable NIR signals of the API, separated from those of placebo through suitable pretreatment of the spectra, can be used for BU and CU calculations without calibration models.

Metabolism and pharmacokinetics of a novel Src kinase inhibitor TG100435 ([7-(2,6-dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine) and its active N-oxide metabolite TG100855 ([7-(2,6-dichloro-phenyl)-5-methylbenzo[1,2,4]triazin-3-yl]-{4-[2-(1-oxy-pyrrolidin-1-yl)-ethoxy]-phenyl}-amine).

TG100435 ([7-(2,6-dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine) is a novel multitargeted, orally active protein tyrosine kinase inhibitor. The inhibition constants (K(i)) of TG100435 against Src, Lyn, Abl, Yes, Lck, and EphB4 range from 13 to 64 nM. TG100435 has systemic clearance values of 20.

Discovery of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine--a potent, orally active Src kinase inhibitor with anti-tumor activity in preclinical assays.

We describe the identification of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine (3), a potent, orally active Src inhibitor with desirable PK properties, demonstrated activity in human tumor cell lines and in animal models of tumor growth.