RESUMO
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 the 28-day toxicity studies, all treatment-related findings were monitorable and reversible. Methemoglobinemia, which was observed in dogs and to a lesser extent in rats, is also observed with acetaminophen. This finding is considered not relevant to humans due to species differences in metabolism. Thyroid hypertrophy and hyperplasia were also observed in dogs and were shown to be a consequence of a species-specific UGT induction also demonstrated with increased thyroid hormone metabolism. Indirect bilirubin elevation was observed in rats as a result of UGT1A1 Inhibition. JNJ-10450232 (NTM-006) had no toxicologically relevant findings in safety pharmacology or genotoxicity studies. Together, these data supported progressing into safety and efficacy studies in humans.
RESUMO
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. Basic predictive approaches were applied to determine potential interactions in vivo. A physiologically-based pharmacokinetic (PBPK) model was developed and clinical DDI simulations were performed to determine the likelihood of cytochrome P450 (CYP) inhibition by canagliflozin. RESULTS: Canagliflozin was primarily metabolized by uridine 5'-diphospho-glucuronosyltransferase 1A9 and 2B4 enzymes. Canagliflozin was a substrate of efflux transporters (P-glycoprotein, breast cancer resistance protein and multidrug resistance-associated protein-2) but was not a substrate of uptake transporters (organic anion transporter polypeptide isoforms OATP1B1, OATP1B3, organic anion transporters OAT1 and OAT3, and organic cationic transporters OCT1, and OCT2). In inhibition assays, canagliflozin was shown to be a weak in vitro inhibitor (IC50 ) of CYP3A4 (27 µmol l -1 , standard error [SE] 4.9), CYP2C9 (80 µmol l -1 , SE 8.1), CYP2B6 (16 µmol l-1 , SE 2.1), CYP2C8 (75 µmol l -1 , SE 6.4), P-glycoprotein (19.3 µmol l -1 , SE 7.2), and multidrug resistance-associated protein-2 (21.5 µmol l -1 , SE 3.1). Basic models recommended in DDI guidelines (US Food & Drug Administration and European Medicines Agency) predicted moderate to low likelihood of interaction for these CYPs and efflux transporters. PBPK DDI simulations of canagliflozin with CYP probe substrates (simvastatin, S-warfarin, bupropion, repaglinide) did not show relevant interaction in humans since mean areas under the concentration-time curve and maximum plasma concentration ratios for probe substrates with and without canagliflozin and its 95% CIs were within 0.80-1.25. CONCLUSIONS: In vitro DDI followed by a predictive or PBPK approach was applied to determine DDI potential of canagliflozin. Overall, canagliflozin is neither a perpetrator nor a victim of clinically important interactions.
Assuntos
Canagliflozina/administração & dosagem , Hipoglicemiantes/administração & dosagem , Modelos Biológicos , Animais , Área Sob a Curva , Canagliflozina/farmacocinética , Canagliflozina/farmacologia , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Técnicas In Vitro , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Proteínas de Membrana Transportadoras/metabolismo , Xenopus laevisRESUMO
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. In a 6-month mechanistic study utilization of a glucose-free diet prevented carbohydrate malabsorption and its sequelae, including increased calcium absorption and urinary calcium excretion, and hyperostosis. Cell proliferation in the kidney and adrenal medulla was increased in rats maintained on standard diet and administered canagliflozin (100mg/kg), and in addition an increase in the renal injury biomarker KIM-1 was observed. Increased cell proliferation is considered as a proximal event in carcinogenesis. Effects on cell proliferation, KIM-1 and calcium excretion were inhibited in rats maintained on the glucose-free diet, indicating they are secondary to carbohydrate malabsorption and are not direct effects of canagliflozin.
Assuntos
Erros Inatos do Metabolismo dos Carboidratos , Carcinogênese , Glucosídeos/farmacologia , Síndromes de Malabsorção , Inibidores do Transportador 2 de Sódio-Glicose , Tiofenos/farmacologia , Animais , Canagliflozina , Moléculas de Adesão Celular/metabolismo , Proliferação de Células , Imuno-Histoquímica , Rim/patologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
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. In the present study, liver RNA samples from drug-treated rats from more recent experiments were examined for statistical fit to the OS/RM signature. Of all 97 drugs examined, in addition to the nine drugs noted above, 19 more were identified as OS/RM-producing compounds-chlorpromazine, clozapine, cyproterone acetate, dantrolene, dipyridamole, glibenclamide, isoniazid, ketoconazole, methapyrilene, naltrexone, nifedipine, sulfamethoxazole, tamoxifen, coumarin, ritonavir, amitriptyline, valproic acid, enalapril, and chloramphenicol. Importantly, all of the OS/RM drugs listed above have been linked to idiosyncratic hepatotoxicity, excepting chloramphenicol, which does not have a package label for hepatotoxicity, but does have a black box warning for idiosyncratic bone marrow suppression. Most of these drugs are not acutely toxic in the rat. The OS/RM signature should be useful to avoid idiosyncratic hepatotoxicity of drug candidates.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/genética , Perfilação da Expressão Gênica , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Toxicogenética/métodos , Animais , Bases de Dados Genéticas , Regulação da Expressão Gênica/efeitos dos fármacos , Marcadores Genéticos , Fígado/metabolismo , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Ratos , Ratos Sprague-DawleyRESUMO
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.
Assuntos
Glucosídeos/metabolismo , Hipoglicemiantes/metabolismo , Tiofenos/metabolismo , Administração Oral , Adulto , Animais , Bile/metabolismo , Canagliflozina , Radioisótopos de Carbono , Cães , Fezes/química , Feminino , Glucosídeos/sangue , Glucosídeos/farmacocinética , Glucosídeos/urina , Glucuronídeos/metabolismo , Humanos , Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/urina , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Tiofenos/sangue , Tiofenos/farmacocinética , Tiofenos/urina , Distribuição Tecidual , Adulto JovemRESUMO
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 (2.5% [0.2% to 4.9%]). Among prisoners aged 55 to 84 years, crude average annual death rates due to cancer and CVD were high and substantially exceeded death rates due to other causes. Among prisoners aged 25 to 44 years, crude average annual death rates due to infection exceeded death rates due to other causes. Continued improvements in the prevention, screening, and treatment of these conditions are warranted in correctional health care settings.
Assuntos
Mortalidade , Prisões/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Humanos , Masculino , Pessoa de Meia-Idade , Texas/epidemiologiaRESUMO
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.v. administration at 6 mg/kg. Selected variants along with Doxil/Caelyx (formulation 1, Doxil-control) were tested for antitumor activity in the MDA-MB-231 xenograft mouse model following 3 repeated administrations at 2 mg/kg or 3 mg/kg (once weekly for 3 weeks) and/or toxicity in Cynomolgus monkeys following 6 repeated administrations at 2.5 or 4.0 mg/kg. Formulations 1-4 were tested for antitumor activity and formulations 1, 2, 6 and 7 were evaluated in a monkey toxicity study. The toxicokinetics of total doxorubicin was determined after the first and last dose in the monkey toxicity study. RESULTS: In the albino mouse, formulations 2 and 3 had plasma pharmacokinetic profiles similar to Doxil-control (formulation 1). Although these three formulations had similar pharmacokinetic profiles, formulation 2 showed significantly (P < 0.05) longer survival time and better efficacy (reduced tumor volume) over other formulations tested for antitumor activity at the 3 mg/kg dose. In monkeys, formulation 2 gave systemic exposure of doxorubicin approximately the same as formulation 1; however, multi-focal degeneration of renal cortical tubules and hypocellularity of the bone marrow were observed with formulation 2 but not with formulation 1 (Doxil-control). Formulations 6 and 7 gave lower exposure to doxorubicin compared to Doxil-control, but were associated with higher severity and frequency of toxic effects (hematological effects, elevated liver enzymes). It was concluded that plasma pharmacokinetics and systemic exposure of doxorubicin did not correlate well with the antitumor activity and toxicity profiles for PLD products. Hence, a conventional bioequivalence approach is not appropriate for establishing therapeutic equivalence of generic PLD products. A carefully designed clinical study evaluating clinical safety, efficacy and pharmacokinetics should be considered for establishing the therapeutic equivalency of generic versions of Doxil.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/análogos & derivados , Polietilenoglicóis/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Área Sob a Curva , Química Farmacêutica , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Doxorrubicina/sangue , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Doxorrubicina/toxicidade , Esquema de Medicação , Feminino , Coração/efeitos dos fármacos , Humanos , Macaca fascicularis , Camundongos , Camundongos Nus , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/toxicidade , Análise de Sobrevida , Equivalência Terapêutica , Transplante Heterólogo , Resultado do TratamentoRESUMO
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.
Assuntos
Doença Crônica/epidemiologia , Prisioneiros , Adolescente , Adulto , Feminino , Humanos , Masculino , Auditoria Médica , Sistemas Computadorizados de Registros Médicos , Pessoa de Meia-Idade , Vigilância da População/métodos , Estudos Retrospectivos , Texas/epidemiologia , Adulto JovemRESUMO
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. Crude annual HCV death rates, age- and race-adjusted summary rates, and average annual percent changes were estimated. The proportion of deaths due to chronic liver disease/cirrhosis, liver cancer, hepatitis B, and HIV for which HCV was identified as an intervening or contributing cause of death was calculated. RESULTS: Among Texas male prisoners, HCV death rates were high and increased over the 10-year study period by an average 21% annually, with the largest increase occurring among Hispanic prisoners. HCV was identified as an intervening or contributing cause of death in 15% of chronic liver disease/cirrhosis deaths, 33% of liver cancer deaths, 81% of hepatitis B deaths, and 7% of HIV deaths. CONCLUSIONS: Because HCV-related deaths among Texas male prisoners are high and increasing, particularly among Hispanics, targeted prevention, screening, and treatment of HCV infections should be among the priorities of U.S. correctional healthcare systems.
Assuntos
Hepatite C/mortalidade , Prisões/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Infecções por HIV/complicações , Infecções por HIV/mortalidade , Hepatite B/complicações , Hepatite B/mortalidade , Hepatite C/complicações , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/mortalidade , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Texas/epidemiologiaRESUMO
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. In the present study, felbamate was compared to several other antiepileptic drugs (valproic acid, carbamazepine, phenobarbital, and phenytoin), using covalent binding of radiolabeled drugs and hepatic gene expression responses to evaluate oxidative stress/reactive metabolite potential. Despite causing only very mild effects on covalent binding parameters, felbamate produced robust effects on a previously established oxidative stress/reactive metabolite gene expression signature. The other antiepileptic drugs and acetaminophen are known hepatotoxicants at high doses in the rat, and all increased covalent binding to liver proteins in vivo and/or to liver microsomes from human and rat. With the exception of acetaminophen, valproic acid exhibited the highest covalent binding in vivo, whereas carbamazepine exhibited the highest levels in vitro. Pronounced effects on oxidative stress/reactive metabolite-responsive gene expression were observed after carbamazepine, phenobarbital, and phenytoin administration. Valproic acid had only minor effects on the oxidative stress/reactive metabolite indicator genes. The relative ease of detection of felbamate based on gene expression results in rat liver as having potential oxidative stressor/reactive metabolites indicates that this approach may be useful in screening for potential idiosyncratic toxicity. Together, measurements of gene expression along with covalent binding should improve the safety assessment of candidate drugs.
Assuntos
Anticonvulsivantes/toxicidade , Epilepsia/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fenilcarbamatos/toxicidade , Propilenoglicóis/toxicidade , Animais , Células Cultivadas , Epilepsia/patologia , Felbamato , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ligação Proteica , RatosRESUMO
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. Excretion of radioactivity was rapid and nearly complete at 96 h after dosing in all species. Unchanged drug excreted in urine was minimal (<2.3% of the administered dose) in all species. The primary metabolic pathways were O-glucuronidation (rabbit > mouse > dog > rat) of RWJ-333369 and hydrolysis of the carbamate ester followed by oxidation to 2-chloromandelic acid. The latter metabolite was subsequently metabolized in parallel to 2-chlorophenylglycine and 2-chlorobenzoic acid (combined hydrolytic and oxidative pathways: rat > dog > mouse > rabbit). Other metabolic pathways present in all species included chiral inversion in combination with O-glucuronidation and sulfate conjugation (directly and/or following hydroxylation of RWJ-333369). Species-specific pathways, including N-acetylation of 2-chlorophenylglycine (mice, rats, and dogs) and arene oxidation followed by glutathione conjugation of RWJ-333369 (mice and rats), were more predominant in rodents than in other species. Consistent with human metabolism, multiple metabolic pathways and renal excretion were mainly involved in the elimination of RWJ-333369 and its metabolites in animal species. Unchanged drug was the major plasma circulating drug-related substance in the preclinical species and humans.
Assuntos
Anticonvulsivantes/farmacocinética , Carbamatos/farmacocinética , Administração Oral , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/sangue , Anticonvulsivantes/urina , Biotransformação , Carbamatos/administração & dosagem , Carbamatos/sangue , Carbamatos/urina , Radioisótopos de Carbono , Cromatografia Líquida de Alta Pressão , Cães , Fezes/química , Feminino , Glucuronídeos/metabolismo , Hidrólise , Rim/metabolismo , Masculino , Camundongos , Estrutura Molecular , Oxirredução , Coelhos , Ratos , Ratos Sprague-Dawley , Contagem de Cintilação , Ésteres do Ácido Sulfúrico/metabolismo , Espectrometria de Massas em TandemRESUMO
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. Approximately 24 h following inhalational exposure to approximately 49 times the 50% lethal doses of Bacillus anthracis (Ames strain), monkeys were treated daily with vehicle, levofloxacin, or ciprofloxacin for 30 days. Ciprofloxacin was administered at 16 mg/kg twice a day. Following the 30-day treatment, monkeys were observed for 70 days. Nine of 10 control monkeys died within 9 days of exposure. No clinical signs were observed in fluoroquinolone-treated monkeys during the 30 treatment days. One monkey died 8 days after levofloxacin treatment, and two monkeys from the ciprofloxacin group died 27 and 36 days posttreatment, respectively. These deaths were probably related to the germination of residual spores. B. anthracis was positively cultured from several tissues from the three fluoroquinolone-treated monkeys that died. MICs of levofloxacin and ciprofloxacin from these cultures were comparable to those from the inoculating strain. These data demonstrate that a humanized dosing regimen of levofloxacin was effective in preventing morbidity and mortality from inhalational anthrax in rhesus monkeys and did not select for resistance.
Assuntos
Antraz/tratamento farmacológico , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Levofloxacino , Ofloxacino/farmacocinética , Ofloxacino/uso terapêutico , Aerossóis , Animais , Antraz/mortalidade , Antraz/patologia , Antibacterianos/administração & dosagem , Área Sob a Curva , Bacillus anthracis/efeitos dos fármacos , Simulação por Computador , Relação Dose-Resposta a Droga , Composição de Medicamentos , Feminino , Humanos , Exposição por Inalação , Macaca mulatta , Masculino , Testes de Sensibilidade Microbiana , Ofloxacino/administração & dosagem , Esporos Bacterianos/efeitos dos fármacosRESUMO
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.
Assuntos
Surtos de Doenças , Resistência a Meticilina , Prisioneiros , Infecções Estafilocócicas/epidemiologia , Staphylococcus aureus/efeitos dos fármacos , Adulto , Antibacterianos/farmacologia , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Prisões , Fatores de Risco , Texas/epidemiologiaRESUMO
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. An increased incidence in colon tumors compared to controls was observed for all of the thiazolidinedione-treated groups as well as the NID525-treated group. These results indicate that the tumor-promoting effect of PPARgamma agonists in the colon of C57BL/6J-APC(min)/+ mice is likely related to the pharmacological activity of this group of drugs and not the thiazolidinedione structure.