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. Fecal excretion was the primary route of elimination of drug-derived radioactivity in both animals and humans. In BDC mice and rats, most radioactivity was excreted in bile. The extent of radioactivity excreted in urine as a percentage of the administered [ 14 C]canagliflozin dose was 1.2%-7.6% in animals and approximately 33% in humans. The primary pathways contributing to the metabolic clearance of canagliflozin were oxidation in animals and direct glucuronidation of canagliflozin in humans. Unchanged canagliflozin was the major component in systemic circulation in all species. In human plasma, two pharmacologically inactive O-glucuronide conjugates of canagliflozin, M5 and M7, represented 19% and 14% of total drug-related exposure and were considered major human metabolites. Plasma concentrations of M5 and M7 in mice and rats from repeated dose safety studies were lower than those in humans given canagliflozin at the maximum recommended dose of 300 mg. However, biliary metabolite profiling in rodents indicated that mouse and rat livers had significant exposure to M5 and M7. Pharmacologic inactivity and high water solubility of M5 and M7 support glucuronidation of canagliflozin as a safe detoxification pathway.

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. The study population consisted of the total census of inmates who were incarcerated in the Texas Department of Criminal Justice for any duration from September 1, 2006 through August 31, 2007 (N=234,031). Information on medical diagnoses was obtained from a system-wide electronic medical record system. Overall crude prevalence estimates for the selected conditions were as follows: hypertension, 18.8%; asthma, 5.4%; diabetes, 4.2%; ischemic heart disease, 1.7%; chronic obstructive pulmonary disease, 0.96%; and cerebrovascular disease, 0.23%. Nearly one quarter (24.5%) of the study population had at least one of the selected conditions. Except for asthma, crude prevalence estimates of the selected conditions increased monotonically with age. Nearly two thirds (64.6%) of inmates who were >or=55 years of age had at least one of the selected conditions. Except for diabetes, crude prevalence estimates for the selected conditions were lower among Hispanic inmates than among non-Hispanic White inmates and African American inmates. Although age-standardized prevalence estimates for the selected conditions did not appear to exceed age-standardized estimates from the US general population, a large number of inmates were affected by one or more of these conditions. As the prison population continues to grow and to age, the burden of these conditions on correctional and community health care systems can be expected to increase.

We explored the possible role of transforming growth factor .I1 (TGF-fi), a cytokine that appears to be an TGF-,8 had no effect on haptoglobin or a,-acid glycoprotein secretion, either directly or in the presence of interleukin 6, which is capable of inducing these proteins. These studies demonstrate that TGF-fi can affect hepatic synthesis and secretion of a subset of acute-phase proteins, both directly and by modulating the effect of interleukin 6. The affected group of plasma proteins is distinct from those affected by other recognized acute-phase protein-inducing cytokines. These findings support the view that combinations of cytokines mediate the response of the hepatocyte to inflammatory stimuli.Tissue injury and infection lead to a broad array of systemic and metabolic alterations, collectively termed the acutephase response (1, 2). Among these alterations are changes in hepatic synthesis of a number of plasma proteins, referred to as acute-phase proteins; synthesis of some proteins, the positive acute-phase proteins, increases, while synthesis of others, the negative acute-phase proteins, decreases. Studies in primary hepatocyte cultures and hepatoma cell lines have shown that hepatic synthesis of human acute-phase proteins can be influenced by several cytokines including interleukin 6 (IL-6), a major inducer ofacute-phase changes, interleukins la and -p8 (IL-1), cachectin/tumor necrosis factor a (TNF), interferon y, and leukemia inhibitory factor (3-18). One cytokine can modulate the effect of other cytokines in human model systems-e.g., IL-1 diminishes the inducing effect of IL-6 on fibrinogen synthesis (7,12,18) and interferon yThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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.

RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-; CAS Registry Number 194085-75-1) is a novel neuromodulatorin clinical development for the treatment of epilepsy. To study the disposition of RWJ-333369, eight healthy male subjects received a single oral dose of 500 mg of 14 C-RWJ-333369. Urine, feces, and plasma were collected for analysis for up to 1 week after dosing. Radioactivity was mainly excreted in urine (93.8 ؎ 6.6%) and much less in feces (2.5 ؎ 1.6%). RWJ-333369 was extensively metabolized in humans, since only low amounts of parent drug were excreted in urine (1.7% on average) and feces (trace amounts). The major biotransformation pathways were direct O-glucuronidation (44% of the dose), and hydrolysis of the carbamate ester followed by oxidation to 2-chloromandelic acid, which was subsequently metabolized in parallel to 2-chlorophenyl glycine and 2-chlorobenzoic acid (mean percentage of the dose for the three acids together was 36%). Other routes were chiral inversion followed by O-glucuronidation (11%), and aromatic hydroxylation in combination with sulfate conjugation (5%). In plasma, unchanged drug accounted for 76.5% of the total radioactivity, with the R-enantiomer and the O-glucuronide of the parent drug as the only measurable plasma metabolites. With the use of very sensitive liquid chromatography-tandem mass spectrometry techniques, only traces of aromatic (pre)mercapturic acid conjugates were detected in urine (each <0.3% of the dose), suggesting a low potential for reactive metabolite formation. In conclusion, the disposition of RWJ-333369 in humans is characterized by virtually complete absorption, extensive metabolism, and unchanged drug as the only significant circulating species. (Rogawski, 2006). In preclinical studies (data on file), this drug has demonstrated broad anticonvulsant activity in acute rodent seizure models and in the kindled rat model of partial epilepsy. It has shown efficacy in attenuating the frequency of spontaneous recurrent seizures in the kainite post-status epilepticus rat model of temporal lobe epilepsy (Grabenstatter and Dudek, 2004) and suppressing spike and wave discharges in the GAERS (Genetic Absence Epilepsy Rat from Strasbourg) model of generalized absence epilepsy (Nehlig et al., 2005). Overall, the preclinical profile suggests that the drug will be useful in the treatment of epilepsy and other neurologic conditions where neurostabilization is desirable. RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-; CAS Registry Number 194085-75-1) is a new neuromodulator currently under clinical investigation for adjunctive treatment of epilepsyThe objective of the present study was to investigate the absorption, metabolism, and excretion of RWJ-333369 in humans and to identify and quantify its major and minor metabolites after a single oral dose of 500 mg of 14 C-RWJ-333369 to healthy male subjects. absorption, distribution, metabolism, and excretion characterization of RWJ-333369 in preclinical species and comparison ...