Preclinical safety assessment of JNJ-10450232 (NTM-006), a structural analog of acetaminophen, that does not cause hepatotoxicity at supratherapeutic doses.

JNJ-10450232 (NTM-006) is a new molecular entity that is structurally related to acetaminophen. A comprehensive non-clinical safety program was conducted to support first-in-human and clinical efficacy studies based on preclinical data suggesting that the compound has comparable or enhanced antinociceptive and antipyretic efficacy without causing hepatotoxicity at supratherapeutic doses. No hepatic toxicity was noted in a mouse model sensitive to acetaminophen hepatotoxicity or in rats, dogs, and non-human primates in 28-day repeat dose toxicity studies at and above doses/exposures at which acetaminophen is known to cause hepatotoxicity.

In vitro and physiologically-based pharmacokinetic based assessment of drug-drug interaction potential of canagliflozin.

Aims: Canagliflozin is a recently approved drug for use in the treatment of type 2 diabetes. The potential for canagliflozin to cause clinical drug-drug interactions (DDIs) was assessed.

Methods: DDI potential of canagliflozin was investigated using in vitro test systems containing drug metabolizing enzymes or transporters.

Carbohydrate malabsorption mechanism for tumor formation in rats treated with the SGLT2 inhibitor canagliflozin.

Canagliflozin is an SGLT2 inhibitor used for the treatment of type 2 diabetes mellitus. Studies were conducted to investigate the mechanism responsible for renal tubular tumors and pheochromocytomas observed at the high dose in a 2-year carcinogenicity study in rats. At the high dose (100mg/kg) in rats, canagliflozin caused carbohydrate malabsorption evidenced by inhibition of intestinal glucose uptake, decreased intestinal pH and increased urinary calcium excretion.

Metabolism and excretion of canagliflozin in mice, rats, dogs, and humans.

Canagliflozin is an oral antihyperglycemic agent used for the treatment of type 2 diabetes mellitus. It blocks the reabsorption of glucose in the proximal renal tubule by inhibiting the sodium-glucose cotransporter 2. This article describes the in vivo biotransformation and disposition of canagliflozin after a single oral dose of [(14)C]canagliflozin to intact and bile duct-cannulated (BDC) mice and rats and to intact dogs and humans.

Oxidative stress/reactive metabolite gene expression signature in rat liver detects idiosyncratic hepatotoxicants.

Previously we reported a gene expression signature in rat liver for detecting a specific type of oxidative stress (OS) related to reactive metabolites (RM). High doses of the drugs disulfiram, ethinyl estradiol and nimesulide were used with another dozen paradigm OS/RM compounds, and three other drugs flutamide, phenacetin and sulindac were identified by this signature. In a second study, antiepileptic drugs were compared for covalent binding and their effects on OS/RM; felbamate, carbamazepine, and phenobarbital produced robust OS/RM gene expression.

Leading medical causes of mortality among male prisoners in Texas, 1992--2003.

Data from the Texas prison system and the Texas Vital Statistics Bureau were used to identify and assess the leading medical causes of death from 1992 to 2003 among male prisoners in Texas (N = 4,026). The leading medical causes of death were infection, cancer, cardiovascular disease (CVD), liver disease, and respiratory disease. Of these, only cancer showed a significant average annual increase in crude death rates (2.

Pharmacokinetics, efficacy and toxicity of different pegylated liposomal doxorubicin formulations in preclinical models: is a conventional bioequivalence approach sufficient to ensure therapeutic equivalence of pegylated liposomal doxorubicin products?

Purpose: To examine whether a conventional bioequivalence approach is sufficient to ensure the therapeutic equivalence of liposomal products, the pharmacokinetics, efficacy and toxicity of different formulation variants of the marketed Doxil(/Caelyx product, pegylated liposomal doxorubicin (PLD), were evaluated in several preclinical models.

Methods: Six different variants of the marketed PLD formulation were prepared by incorporating minor changes in the composition and liposome size of the original formulation. The pharmacokinetics of 5 formulations were evaluated in albino mice following i.

Prevalence of chronic medical conditions among inmates in the Texas prison system.

Given the rapid growth and aging of the US prison population in recent years, the disease profile and health care needs of inmates portend to have far-reaching public health implications. Although numerous studies have examined infectious disease prevalence and treatment in incarcerated populations, little is known about the prevalence of non-infectious chronic medical conditions in US prison populations. The purpose of this study was to estimate the prevalence of selected non-infectious chronic medical conditions among inmates in the Texas prison system.

HCV-related mortality among male prison inmates in Texas, 1994-2003.

Purpose: The prevalence of hepatitis C virus (HCV) infection is high among adult incarcerated populations, but HCV-related mortality data are lacking. The study purpose was to assess HCV-related mortality over time and across racial/ethnic categories from 1994 through 2003 among male prisoners in the Texas Department of Criminal Justice (TDCJ).

Methods: TDCJ decedent data were linked with Texas Vital Statistics multiple-cause-of-death data.

Evaluation of felbamate and other antiepileptic drug toxicity potential based on hepatic protein covalent binding and gene expression.

Felbamate is an antiepileptic drug that is associated with minimal toxicity in preclinical species such as rat and dog but has an unacceptable incidence of serious idiosyncratic reactions in man. Idiosyncratic reactions account for over half of toxicity-related drug failures in the marketplace, and improving the preclinical detection of idiosyncratic toxicities is thus of paramount importance to the pharmaceutical industry. The formation of reactive metabolites is common among most drugs associated with idiosyncratic drug reactions and may cause deleterious effects through covalent binding and/or oxidative stress.

Metabolism and excretion of RWJ-333369 [1,2-ethanediol, 1-(2-chlorophenyl)-, 2-carbamate, (S)-] in mice, rats, rabbits, and dogs.

The in vivo metabolism and excretion of RWJ-333369 [1,2-ethanediol, 1-(2-chlorophenyl)-, 2-carbamate, (S)-], a novel neuromodulator, were investigated in mice, rats, rabbits, and dogs after oral administration of (14)C-RWJ-333369. Plasma, urine, and feces samples were collected, assayed for radioactivity, and profiled for metabolites. In almost all species, the administered radioactive dose was predominantly excreted in urine (>85%) with less than 10% in feces.

Pharmacokinetic considerations and efficacy of levofloxacin in an inhalational anthrax (postexposure) rhesus monkey model.

Because the treatment of inhalational anthrax cannot be studied in human clinical trials, it is necessary to conduct efficacy studies using a rhesus monkey model. However, the half-life of levofloxacin was approximately three times shorter in rhesus monkeys than in humans. Computer simulations to match plasma concentration profile, area under the concentration-time curve (AUC), and time above MIC for a human oral dose of 500 mg levofloxacin once a day identified a dosing regimen in rhesus monkeys that would most closely match human exposure: 15 mg/kg followed by 4 mg/kg administered 12 h later.

Methicillin-resistant Staphylococcus aureus infection in the Texas prison system.

Recent reports indicate that correctional facility inmates may be at elevated risk for contracting methicillin-resistant Staphylococcus aureus (MRSA) infection because of overcrowding, poor hygiene, and high rates of diseases causing immunosuppression. The present study of 299,179 Texas inmates who were incarcerated between 1999-2001 indicated an incidence of 12 MRSA infections/1000 person-years. Inmates with circulatory disease, cardiovascular disease, diabetes, end-stage liver disease, end-stage renal disease, human immunodeficiency virus infection or acquired immunodeficiency syndrome, and skin diseases all exhibited elevated rates of MRSA infection.

Promotion of colon tumors in C57BL/6J-APC(min)/+ mice by thiazolidinedione PPARgamma agonists and a structurally unrelated PPARgamma agonist.

Thiazolidinedione PPARgamma agonists (troglitazone and rosiglitazone) were previously shown to promote colon tumor formation in C57BL/6J-APC(min)/+ mice, a model for human familial adenomatous polyposis. This study was conducted to determine if another thiazolidinedione PPARgamma agonist, pioglitazone, and a PPARgamma agonist structurally unrelated to the thiazolidinedione family, NID525, (a tetrazole-substituted phenoxymethylquinolone), would also promote colon tumors in this mouse model. Mice were treated in-feed with the thiazolidinediones troglitazone (150 mg/kg/day), rosiglitazone (20 mg/kg/day), or pioglitazone (150 mg/kg/day), or with NID525 (150 mg/kg/day) for 8 weeks.