RESUMO
Tenofovir disoproxil fumarate (TDF) is a prodrug of tenofovir that exhibits activity against HIV and hepatitis B. The goals of this study were to evaluate the molecular mechanism of TDF-induced toxicity in mice after 13 weeks of daily oral administration (50-1000 mg/kg) by correlating transcriptional changes with plasma drug levels and traditional toxicology end points. Plasma levels and systemic exposure of tenofovir increased less than dose proportionally and were similar on days 1 and 91. No overt toxicity was observed following the completion of TDF administration. The kidneys of TDF-treated mice were histopathologically normal. This result is consistent with the genomic microarray results, which showed no significant differences in kidney transcriptional levels between TDF-treated animals and controls. In liver, after 4 and 13 weeks, cytomegaly was observed in mice treated with 1000 mg/kg of TDF, but mice recovered from this effect following cessation of administration. Analysis of liver transcripts on day 91 reported elevated levels of Cdkn1a in TDF-treated animals compared with controls, which may have contributed to the inhibition of liver cell cycle progression.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/toxicidade , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Organofosfonatos/toxicidade , Inibidores da Transcriptase Reversa/toxicidade , Adenina/sangue , Adenina/farmacocinética , Adenina/toxicidade , Administração Oral , Animais , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/farmacocinética , Inibidor de Quinase Dependente de Ciclina p21/genética , Feminino , Perfilação da Expressão Gênica , Rim/anatomia & histologia , Rim/metabolismo , Fígado/metabolismo , Fígado/patologia , Camundongos Endogâmicos BALB C , Análise de Sequência com Séries de Oligonucleotídeos , Organofosfonatos/sangue , Organofosfonatos/farmacocinética , Inibidores da Transcriptase Reversa/sangue , Inibidores da Transcriptase Reversa/farmacocinética , Tenofovir , Testes de Toxicidade Subcrônica , Transcrição Gênica/efeitos dos fármacosRESUMO
A 2-week study in rats identified target organs of oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased white blood cell levels, a class effect of benzimidazole anthelmintics, returned to normal during the recovery period. The no observed adverse effect level was determined to be >5 but <25 mg/kg/d and the maximum tolerated dose 100 mg/kg/d. The highest dose, 200 mg/kg/d, resulted in significant toxicity and mortality, leading to euthanization of the main study animals in this group after 7 days. Oxfendazole did not exhibit genetic toxicology signals in standard Ames bacterial, mouse lymphoma, or rat micronucleus assays nor did it provoke safety concerns when evaluated for behavioral effects in rats or cardiovascular safety effects in dogs. These results support the transition of oxfendazole to First in Human safety studies preliminary to its evaluation in human helminth diseases.
Assuntos
Anti-Helmínticos/farmacocinética , Benzimidazóis/farmacocinética , Administração Oral , Animais , Anti-Helmínticos/efeitos adversos , Anti-Helmínticos/toxicidade , Benzimidazóis/efeitos adversos , Benzimidazóis/toxicidade , Sistema Cardiovascular/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Feminino , Leucemia L5178/genética , Masculino , Camundongos , Testes para Micronúcleos , Testes de Mutagenicidade , Ratos , Ratos Sprague-DawleyRESUMO
Sprague Dawley rats (10/sex/group) were given a single intravenous (iv) dose of CUMI-101 to determine acute toxicity of CUMI-101 and radiation dosimetry estimations were conducted in baboons with [(11)C]CUMI-101. Intravenous administration of CUMI-101 did not produce overt biologically or toxicologically significant adverse effects except transient hypoactivity immediately after dose in the mid- and high-dose groups, which is not considered to be a dose-limiting toxic effect. No adverse effects were observed in the low-dose group. The no observed adverse effect level (NOAEL) is considered to be 44.05 µg/kg for a single iv dose administration in rats. The maximum tolerated dose (MTD) was estimated to be 881 µg/kg for a single iv dose administration. The Medical Internal Radiation Dose (MIRDOSE) estimates indicate the maximum permissible single-study dosage of [(11)C]CUMI-101 in humans is 52 mCi with testes and urinary bladder as the critical organ for males and females, respectively.
Assuntos
Piperazinas/farmacocinética , Agonistas do Receptor 5-HT1 de Serotonina/farmacocinética , Triazinas/farmacocinética , Animais , Radioisótopos de Carbono , Feminino , Ligantes , Masculino , Papio , Piperazinas/toxicidade , Tomografia por Emissão de Pósitrons , Radiometria , Ratos , Ratos Sprague-Dawley , Agonistas do Receptor 5-HT1 de Serotonina/toxicidade , Distribuição Tecidual , Triazinas/toxicidadeRESUMO
By using Affymetrix Mouse Genome Arrays and 20 biological replicates per experimental condition, the predictive value of liver and blood gene expression profiles previously identified was validated as predictive of Listeria monocytogenes infection severity (lethal and nonlethal infection). The ability of these genes to predict the outcome of antibiotic treatment was also assessed. Lethally infected BALB/c mice were treated with amoxicillin at 10 or 20 mg/kg; only the higher dose prevented death. The liver genes predicted that 70% of the animals treated at 10 mg/kg, but only 25% of the mice treated at 20 mg/kg, belonged to the lethal infection group, and this prediction was similar to the ultimate mortality outcome. These results confirm the value of microarrays as tools to predict host response to infection and efficacy of antibacterial therapy. These results might lead to applications that would help clinicians to adjust antibiotic dosages for efficient treatment but yet without toxicity.
Assuntos
Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Listeriose/tratamento farmacológico , Listeriose/genética , Análise de Sequência com Séries de Oligonucleotídeos , Animais , Feminino , Perfilação da Expressão Gênica , Genes Bacterianos , Marcadores Genéticos , Listeria monocytogenes/genética , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Pentamethyl-6-chromanol (PMCol), a chromanol-type compound related to vitamin E, was proposed as an anticancer agent with activity against androgen-dependent cancers. In repeat dose-toxicity studies in rats and dogs, PMCol caused hepatotoxicity, nephrotoxicity, and hematological effects. The objectives of this study were to determine the mechanisms of the observed toxicity and identify sensitive early markers of target organ injury by integrating classical toxicology, toxicogenomics, and metabolomic approaches. PMCol was administered orally to male Sprague-Dawley rats at 200 and 2000 mg/kg daily for 7 or 28 days. Changes in clinical chemistry included elevated alanine aminotransferase, total bilirubin, cholesterol and triglycerides-indicative of liver toxicity that was confirmed by microscopic findings (periportal hepatocellular hydropic degeneration and cytomegaly) in treated rats. Metabolomic evaluations of liver revealed time- and dose-dependent changes, including depletion of total glutathione and glutathione conjugates, decreased methionine, and increased S-adenosylhomocysteine, cysteine, and cystine. PMCol treatment also decreased cofactor levels, namely, FAD and increased NAD(P)+. Microarray analysis of liver found that differentially expressed genes were enriched in the glutathione and cytochrome P450 pathways by PMCol treatment. Reverse transcription-polymerase chain reaction of six upregulated genes and one downregulated gene confirmed the microarray results. In conclusion, the use of metabolomics and toxicogenomics demonstrates that chronic exposure to high doses of PMCol induces liver damage and dysfunction, probably due to both direct inhibition of glutathione synthesis and modification of drug metabolism pathways. Depletion of glutathione due to PMCol exposure ultimately results in a maladaptive response, increasing the consumption of hepatic dietary antioxidants and resulting in elevated reactive oxygen species levels associated with hepatocellular damage and deficits in liver function.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Cromanos/toxicidade , Fígado/efeitos dos fármacos , Animais , Biomarcadores/sangue , Biomarcadores/urina , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cromanos/sangue , Cromanos/urina , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , Metabolômica , Estrutura Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , ToxicogenéticaRESUMO
Vancomycin, one of few effective treatments against methicillin-resistant Staphylococcus aureus, is nephrotoxic. The goals of this study were to (1) gain insights into molecular mechanisms of nephrotoxicity at the genomic level, (2) evaluate gene markers of vancomycin-induced kidney injury, and (3) compare gene expression responses after iv and ip administration. Groups of six female BALB/c mice were treated with seven daily iv or ip doses of vancomycin (50, 200, and 400 mg/kg) or saline, and sacrificed on day 8. Clinical chemistry and histopathology demonstrated kidney injury at 400 mg/kg only. Hierarchical clustering analysis revealed that kidney gene expression profiles of all mice treated at 400 mg/kg clustered with those of mice administered 200 mg/kg iv. Transcriptional profiling might thus be more sensitive than current clinical markers for detecting kidney damage, though the profiles can differ with the route of administration. Analysis of transcripts whose expression was changed by at least twofold compared with vehicle saline after high iv and ip doses of vancomycin suggested the possibility of oxidative stress and mitochondrial damage in vancomycin-induced toxicity. In addition, our data showed changes in expression of several transcripts from the complement and inflammatory pathways. Such expression changes were confirmed by relative real-time reverse transcription-polymerase chain reaction. Finally, our results further substantiate the use of gene markers of kidney toxicity such as KIM-1/Havcr1, as indicators of renal injury.
Assuntos
Antibacterianos/toxicidade , Biomarcadores/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Vancomicina/toxicidade , Fosfatase Alcalina/análise , Análise de Variância , Animais , Antibacterianos/administração & dosagem , Nitrogênio da Ureia Sanguínea , Análise por Conglomerados , Feminino , Expressão Gênica/efeitos dos fármacos , Inflamação/metabolismo , Injeções Intraperitoneais , Injeções Intravenosas , Rim/química , Rim/patologia , Camundongos , Camundongos Endogâmicos BALB C , Análise de Sequência com Séries de Oligonucleotídeos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Vancomicina/administração & dosagem , gama-Glutamiltransferase/análiseRESUMO
The purpose of this study was to evaluate gene expression profiles in the liver and blood for prediction of infection severity from Listeria monocytogenes (LM). Mice were injected with medium broth (control) or a nonlethal or lethal dose of LM and sacrificed 6 h later. Gene expression changes were determined using Affymetrix MGU74Av2 GeneChips and confirmed by real-time polymerase chain reaction analysis. We identified discernable genes whose gene expression profiles can be used in pattern recognition to predict and classify samples in differently treated groups, with >or=90% accuracy in liver samples and 80% accuracy in blood at prediction; however, different genes were predictive in each tissue. Our results suggest that gene expression profiling in response to LM in mice may be able to distinguish samples in groups with varying severity of infection and provide information in finding molecular mechanisms and early biomarkers for subsequent conventional clinical endpoints.