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1.
J Stroke Cerebrovasc Dis ; 17(2): 86-94, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18346651

RESUMEN

Patients with diabetes mellitus (DM) are at risk for Helicobacter pylori infection. This infection has been linked to atherosclerosis and its vascular complications. The aim of this study was to evaluate the: (1) prevalence of H pylori infection in patients with DM; (2) association between diabetic vascular complications and H pylori infection; and (3) influence of H pylori infection on atherosclerosis and inflammatory biomarkers. In this study, we evaluated 80 patients with DM for atherosclerosis; cardiac, cerebral, and peripheral vascular diseases; retinopathy; neuropathy; and nephropathy. We estimated the blood levels of glucose, glycosylated hemoglobin, complete blood cell count, erythrocytic sedimentation rate, lipid profile, tumor necrosis factor-alpha, interleukin (IL)-6, and anti-H pylori IgG antibodies. H pylori infection was detected in 85% of patients versus 76.7% for control subjects. Carotid artery intima-media thickness was significant in H pylori-infected patients. IL-6 and tumor necrosis factor-alpha were significantly associated with H pylori infection. In multivariate analysis, blood glucose, triglycerides, erythrocytic sedimentation rate, IL-6, and tumor necrosis factor-alpha increased the odds for atherothrombotic cause of cerebral ischemia in H pylori infection. We concluded that H pylori infection is common in DM and seems to be linked to the presence of atherosclerosis and ischemic cerebrovascular stroke. This effect could be mediated by increasing cytokine levels.


Asunto(s)
Aterosclerosis/microbiología , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Angiopatías Diabéticas/microbiología , Infecciones por Helicobacter/complicaciones , Helicobacter pylori , Accidente Cerebrovascular/microbiología , Aterosclerosis/sangre , Aterosclerosis/epidemiología , Estudios de Casos y Controles , Citocinas/sangre , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Angiopatías Diabéticas/sangre , Angiopatías Diabéticas/epidemiología , Femenino , Infecciones por Helicobacter/sangre , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/microbiología , Humanos , Inflamación/microbiología , Mediadores de Inflamación/sangre , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Prevalencia , Medición de Riesgo , Factores de Riesgo , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/epidemiología
2.
Toxicol Lett ; 155(1): 35-40, 2005 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-15585357

RESUMEN

Hepatocellular damage is thought to occur as a result of cytochrome P450-mediated oxidation of cocaine to norcocaine (NC), a precursor of the hepatotoxic nitrosonium ion. However, this damage occurs only in male mice, with females exhibiting minimal biochemical and histological signs of hepatocellular stress. The objective of this study was to determine the plasma time course and tissue disposition of cocaine and its metabolites to further investigate the role that metabolism may play in the gender difference observed. Male and female CF-1 mice were orally administered 20mg/kg cocaine hydrochloride once daily for 7 days. Blood samples were withdrawn at various time points post-injection and analyzed for cocaine and its metabolites benzoylecgonine (BE), norcocaine, ecgonine methyl ester (EME), and ecgonine (E). In addition, tissue concentrations of cocaine and its metabolites were determined in liver, heart, brain, and kidney tissue. The results demonstrated that the plasma elimination half-life of cocaine is nearly three times longer in males versus females. Non-hepatotoxic hydrolysis metabolites BE, EME, and E were higher in female tissues while norcocaine was detected in tissues of male animals only. This study revealed that differences in cocaine pharmacokinetics and the resultant differences in the biodisposition of cocaine and its metabolites in tissues contribute to the mechanism of gender difference seen in cocaine hepatotoxicity.


Asunto(s)
Cocaína/análogos & derivados , Cocaína/farmacocinética , Animales , Biotransformación , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Cromatografía Líquida de Alta Presión , Cocaína/sangre , Cocaína/metabolismo , Cocaína/toxicidad , Femenino , Indicadores y Reactivos , Masculino , Ratones , Caracteres Sexuales , Distribución Tisular
3.
Toxicol Mech Methods ; 15(6): 383-9, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-20021060

RESUMEN

Oral cocaine administration results in hepatic necrosis, increased plasma transaminase concentration, and decreased antioxidative capability, which is potentiated by lipopolysaccharide (LPS) in male CF-1 mice. Females administered the same treatment regimen display none of the hepatotoxic effects seen in their male counterparts. This study was conducted to further dissect the mechanism responsible for this gender difference in cocaine hepatotoxicity (CH) and lipopolysaccharide potentiation of CH. Male and female CF-1 mice were orally administered 20 mg/kg cocaine hydrochloride once daily for 7 days. Four hours after the last cocaine administration the mice were administered 12 x 10(6) EU LPS intraperitoneally. The activity of plasma esterase (butyrylcholinesterase), the enzyme responsible for the major pathway of cocaine metabolism to nonhepatotoxic metabolites, was measured. Aminotransferase release and histological analysis were used to determine hepatotoxicity. The concentration of the hepatotoxic precursor norcocaine was measured in the plasma and liver. Regardless of treatment, males were shown to have only 30% of the plasma esterase activity displayed by females. In addition, administration of testosterone to ovariectomized females resulted in a 70% reduction in plasma esterase activity when compared with surgically unaltered females. Moreover, hepatic norcocaine was not detected in the plasma or liver of surgically unaltered female animals, while it was present in males and testosterone-supplemented ovariectomized females. These results indicate that plasma esterase activity is heavily influenced by sex hormones, predominantly testosterone, in CF-1 mice. Suppression of plasma esterase by testosterone correlates with decreased norcocaine production and is therefore responsible, in part, for the increased CH seen following oral administration with and without LPS exposure in male CF-1 mice.

4.
Toxicology ; 179(1-2): 9-19, 2002 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-12204538

RESUMEN

The oxidative metabolism of cocaine by the microsomal monooxygenase enzymes has been postulated to be essential for cocaine mediated hepatotoxicity (CMH). Endotoxin (lipopolysaccharide, LPS), a well-known cause of hepatic damage, previously has been demonstrated to dramatically increase CMH. The mechanism of this interaction has not been clearly elucidated, but cocaine oxidative metabolism appears to sensitize hepatocytes so that subsequent exposure to small amounts of LPS can further augment CMH. This study was conducted to investigate if dimethylaminoethyl-2,2-diphenylvalerate (SKF-525A) pretreatment inhibits LPS potentiation of CMH. For 5 consecutive days, male CF-1 mice were administered daily SKF-525A (50 mg/kg) or sterile saline followed an hour later by cocaine (20 mg/kg) or sterile saline. Four hours following the last cocaine or saline treatment, the mice were administered sterile saline 12x10(6) EU LPS/kg, i.p. The mice were sacrificed 18 h later by decapitation. Pretreatment with SKF-525A reversed the hepatic injury caused by cocaine alone or cocaine and LPS treatments, as indicated by both histologic evaluation and serum alanine transaminase (ALT) and aspartate transaminase (AST) activities. In particular, SKF-525A completely reversed the effects of cocaine alone on liver and blood reduced gluthathione (GSH), glutathione peroxidase (GPx) and catalase (CAT) and hepatic glutathione reductase (GRx) activities. However, SKF-525A was ineffective against the effect of LPS alone on liver and blood GPx and CAT or on hepatic GSH and GRx, suggesting that these effects were not mediated by cytochrome P450 oxidative metabolism. The pattern of biochemical changes persisting with SKF-525A pretreatment in the LPS and cocaine group resembled those of the LPS alone group. The results suggest that cytochrome P450 oxidative metabolism of cocaine is largely responsible for CMH with potentiation by LPS achieved through a different mechanism involving oxidative stress.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Cocaína/metabolismo , Cocaína/toxicidad , Endotoxinas/toxicidad , Lipopolisacáridos/toxicidad , Animales , Biotransformación , Catalasa/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Cocaína/farmacocinética , Inhibidores Enzimáticos/farmacología , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Hígado/metabolismo , Hígado/patología , Pruebas de Función Hepática , Masculino , Ratones , Oxidación-Reducción , Proadifeno/farmacología
5.
Toxicology ; 188(1): 101-14, 2003 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-12748044

RESUMEN

The abuse of cocaine (COC) in combination with ketamine (KET) among pregnant women was shown to be high. Transplacental exposure is not the only route by which a newborn may be exposed to these agents, but they can also distribute into breast milk. Chronic COC exposure is associated with immunological modulation in human and animal models. The effect of sub-chronic exposure to COC and KET alone and in combination on the developing immune system was assessed in neonatal male Sprague-Dawley (SD) rats. To simulate the route of exposure during lactation, newborn male rats were treated orally with saline, COC alone (20 mg/kg), KET alone (50 mg/kg), or KET (50 mg/kg) followed 15 min later by COC (20 mg/kg) from days 1 to 21 of life. Pups were sacrificed 30 min following the last treatment. Total circulating leukocyte and lymphocyte counts were decreased with relative neutrophilia, while spleen/body weight ratio and IgM antibody response to sheep red blood cells (SRBCs) were increased in animals treated with COC. Moreover, treatment with COC alone increased serum interleukin 10 (IL-10) concentration; however, it did not affect serum interferon gamma (IFN-gamma) concentration. On the other hand, KET treatment did not produce any significant change of any of these parameters. However, when co-administered with COC, the immunomodulatory effects of COC were prevented. COC caused a significant increase in serum corticosterone concentration that KET effectively prevented. Lack of significant change of plasma and tissue concentrations of norcocaine (NC) suggested no role for COC metabolism in COC-induced immunomodulation. However, the results of this study indicate that COC-induced immunomodulatory reactions and their prevention by KET most likely occurred through neuroendocrinal mechanisms.


Asunto(s)
Adyuvantes Inmunológicos/toxicidad , Anestésicos Disociativos/toxicidad , Cocaína/toxicidad , Ketamina/toxicidad , Narcóticos/toxicidad , Alanina Transaminasa/sangre , Anestésicos Disociativos/inmunología , Animales , Animales Recién Nacidos , Recuento de Células Sanguíneas , Cocaína/inmunología , Corticosterona/sangre , Femenino , Inmunoglobulina M/sangre , Interferón gamma/sangre , Interleucina-10/sangre , Ketamina/inmunología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Masculino , Narcóticos/inmunología , Embarazo , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Bazo/efectos de los fármacos , Bazo/inmunología , Trastornos Relacionados con Sustancias/inmunología , Timo/efectos de los fármacos , Timo/inmunología
6.
Toxicol Lett ; 129(1-2): 167-76, 2002 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-11879988

RESUMEN

Ketamine has gained attention recently because of re-emergence of its abuse especially in combination with cocaine. When more than one drug is present simultaneously, the potential for drug--drug interaction exists, which can be pharmacokinetic, pharmacodynamic or both in nature. The objective of this study was to investigate the effect of ketamine on plasma cocaine pharmacokinetics to assess the role that the kinetic component may play in the interaction of these agents. Moreover, the effect of repetitive administration of ketamine pretreatment on the pharmacokinetics of cocaine was addressed. Male Sprague-Dawley rats were treated with cocaine alone (5 mg/kg i.v.), ketamine alone (100 mg/kg by gavage), or ketamine followed by cocaine (the same routes and doses). Blood samples were withdrawn at different time points post-injection and analyzed for determination of cocaine, its metabolites (benzoylecgonine and norcocaine) and ketamine. The results demonstrated that ketamine caused a significant decrease in cocaine's area under the curve (AUC) and elimination half-life while its total clearance was increased. The AUC of benzoylecgonine was increased by 1.5-fold after the combination compared with cocaine alone. However, cocaine did not affect ketamine's pharmacokinetic parameters. In the pretreatment study, ketamine was given orally for 3 days, followed 18 h later by a single i.v. of cocaine. Further enhancement of cocaine metabolism occurred with the appearance of norcocaine. This investigation revealed that ketamine enhances cocaine metabolism and may affect its toxicological profile.


Asunto(s)
Anestésicos Disociativos/farmacología , Cocaína/farmacocinética , Ketamina/farmacología , Animales , Área Bajo la Curva , Interacciones Farmacológicas , Masculino , Ratas , Ratas Sprague-Dawley
7.
J Toxicol Environ Health A ; 65(14): 977-93, 2002 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-12133232

RESUMEN

Cocaine produces hepatotoxicity by a mechanism that remains undefined but that has been linked to its oxidative metabolism. Endotoxin (lipopolysaccharide, LPS) is also a well-known cause of hepatic damage, where exposure to non-injurious doses of LPS increases the toxicity of certain hepatotoxins. This study was conducted to investigate the possible potentiation of cocaine-mediated hepatotoxicity (CMH) by LPS. Male CF-1 mice were administered oral cocaine hydrochloride for 5 consecutive days at a dose of 20 mg/kg with and without 12 x 10(6) EU LPS/kg given intraperitoneally 4 h after the last cocaine injection. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured as markers of liver injury. Blood and liver glutathione (GSH) levels were determined, as well as the activities of glutathione peroxidase (GPx) and catalase (CAT). In addition, the activity of liver glutathione reductase (GRx) was measured. The results demonstrate that endotoxin potentiated the hepatotoxicity of cocaine. Serum ALT and AST were significantly elevated with the combined cocaine and LPS treatment versus all other treatments. While cocaine alone resulted in centrilobular necrosis, the cocaine and LPS combination produced submassive necrosis. The increased hepatic GSH content and GRx activity observed with cocaine alone were not observed with the combination treatment, rendering the liver more susceptible to oxidative stress. Moreover, there was a significant decrease in the activities of hepatic GPx and CAT, particularly with the combination treatment. In conclusion, this study demonstrates that LPS potentiates the hepatotoxicity of cocaine as revealed by an array of biochemical and morphological markers.


Asunto(s)
Cocaína/toxicidad , Lipopolisacáridos/toxicidad , Hígado/efectos de los fármacos , Salmonella enteritidis , Alanina Transaminasa/sangre , Alanina Transaminasa/efectos de los fármacos , Animales , Aspartato Aminotransferasas/sangre , Aspartato Aminotransferasas/efectos de los fármacos , Catalasa/efectos de los fármacos , Catalasa/metabolismo , Cocaína/administración & dosificación , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Glutatión/sangre , Glutatión/efectos de los fármacos , Glutatión/metabolismo , Glutatión Peroxidasa/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/efectos de los fármacos , Glutatión Reductasa/metabolismo , Lipopolisacáridos/administración & dosificación , Hígado/citología , Hígado/patología , Masculino , Ratones , Ratones Endogámicos
8.
J Toxicol Environ Health A ; 66(3): 223-39, 2003 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-12521669

RESUMEN

Cocaine produces hepatotoxicity by a mechanism that remains undefined but has been linked to its oxidative metabolism. Endotoxin (lipopolysaccharide, LPS) is also a well-known cause of hepatic damage, and exposure to noninjurious doses of LPS increases the toxicity of certain hepatotoxins. Previously it was demonstrated that exposure to noninjurious doses of LPS dramatically increases cocaine-mediated hepatotoxicity (CMH). This study was conducted to investigate whether pretreatment with N-acetylcysteine (NAC), a glutathione (GSH) precursor and an antioxidant agent, inhibits LPS potentiation of CMH. For 5 consecutive days, male CF-1 mice were administered daily oral NAC (200 mg/kg) or sterile saline followed an hour later by cocaine (20 mg/kg) or sterile saline. Four hours following the last cocaine or saline treatment, the mice were administered 12 x 10(6) EU LPS/kg or sterile saline. For the cocaine alone and cocaine and LPS groups, NAC pretreatment significantly decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities with absence of necrotic hepatic lesions, indicating a reduction of liver injury. In addition, in all groups pretreated with NAC, hepatic GSH concentration was significantly increased, as were hepatic and blood glutathione peroxidase (GPx) and catalase (CAT) activities. In conclusion, the results demonstrate that NAC pretreatment exerted a protective effect against LPS potentia-tion of CMH.


Asunto(s)
Acetilcisteína/farmacología , Cocaína/metabolismo , Cocaína/toxicidad , Endotoxinas/toxicidad , Lipopolisacáridos/toxicidad , Hígado/patología , Animales , Cocaína/farmacocinética , Hígado/metabolismo , Pruebas de Función Hepática , Masculino , Ratones , Oxidación-Reducción
9.
J Toxicol Environ Health A ; 66(3): 241-51, 2003 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-12521670

RESUMEN

The coabuse of cocaine and ketamine occurs with high frequency. The presence of another active substance with cocaine allows for the potential of various drug-drug interactions to occur. This study investigated the tissue distribution after the administration of cocaine or ketamine alone and their combination in rat. Cocaine (5 mg/kg iv), ketamine (100 mg/kg by gavage), or ketamine followed by cocaine (same doses and routes of administration) was utilized. Tissue contents of cocaine and norcocaine were significantly lowered at 5, 15, and 30 min following ketamine administration versus cocaine alone. However, tissue contents of benzoylecgonine were significantly higher in the combination group compared to cocaine alone. On the other hand, cocaine administration did not affect the tissue disposition of ketamine. The results suggest that ketamine decreased cocaine tissue content, which may affect its pharmacological and toxicological profiles.


Asunto(s)
Anestésicos Disociativos/farmacología , Cocaína/farmacocinética , Ketamina/farmacología , Análisis de Varianza , Animales , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Interacciones Farmacológicas , Masculino , Ratas , Ratas Sprague-Dawley , Distribución Tisular
10.
J Toxicol Environ Health A ; 66(7): 647-55, 2003 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-12746137

RESUMEN

The effect of a chemical mixture on the dermal penetration of arsenic or nickel was assessed by applying arsenic-73 or nickel-63 alone or with the chemical mixture to dermatomed male pig skin samples in flow-through diffusion cells. The chemical mixture consisted of chloroform, phenanthrene, and toluene for arsenic penetration studies and phenol, toluene, and trichloroethylene (TCE) for nickel studies. These are predominant chemicals found at hazardous waste sites. Arsenic and nickel bind to skin after dermal exposure. Total penetration of arsenic and nickel in the chemical mixture were significantly increased by 33% and 20% compared to arsenic and nickel alone, respectively. While more radioactivity penetrated skin with chemical treatment than metal alone, significantly less radioactivity was loosely adsorbed to skin and could be easily washed off from the skin surface with soap and water. The results of this study indicate that the potential health risk from dermal exposure to arsenic or nickel is enhanced if other chemicals are present.


Asunto(s)
Arsenicales/efectos adversos , Residuos Peligrosos/efectos adversos , Níquel/toxicidad , Absorción Cutánea/efectos de los fármacos , Animales , Intoxicación por Arsénico/etiología , Arsenicales/química , Cloroformo/química , Cloroformo/toxicidad , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Residuos Peligrosos/análisis , Masculino , Níquel/química , Fenantrenos/química , Fenantrenos/toxicidad , Porcinos , Factores de Tiempo , Tolueno/química , Tolueno/toxicidad
11.
Arab J Gastroenterol ; 14(1): 14-9, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23622804

RESUMEN

BACKGROUND AND STUDY AIMS: There is controversy regarding whether a specific hepatitis C virus (HCV) genotype is associated with diabetes mellitus. This study aimed to investigate HCV genotype distribution in diabetics and its relation to some clinical and laboratory variables in HCV-positive diabetic versus non-diabetic Egyptians in East Delta. PATIENTS AND METHODS: The study included 100 HCV-positive patients of which 66 were diabetic in addition to 35 healthy adults as a control group. Clinical assessment, laboratory measurements of plasma glucose, insulin, C-peptide, C-reactive protein (CRP), tumour necrosis factor-α (TNF-α) and liver functions (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT)) as well as HCV genotype determination were done, and AST/platelet ratio index (APRI) and Homoeostasis Model of Assessment-Insulin Resistance (HOMA-IR) were calculated. RESULTS: The main results were the presence of HCV genotype 3, in 31.8% of the diabetic group and in 26.5% of the non-diabetic group, while the remainder of cases had genotype 4, the predominant genotype in Egypt. This is the first report of the presence of HCV genotype 3 in about 30% of an Egyptian cohort. However, there was no significant difference in genotype distribution between both groups. Further, there were significantly higher values of HOMA-IR, insulin and C-peptide in HCV-positive groups in comparison to the control group, while TNF-α was significantly higher in the HCV-positive diabetic group. However, there were no significant differences between both genotypes regarding these parameters. CONCLUSION: Although this study reveals for the first time the presence of HCV genotype 3 in a significant percentage of a group of Egyptian patients, where the majority were diabetic, the association between diabetes and certain HCV genotypes could not be confirmed on the basis of our findings. Hence, taking into consideration the impact of such a finding on the treatment decisions of those patients, further studies are warranted to explore these findings to a greater extent.


Asunto(s)
Diabetes Mellitus/virología , Genotipo , Hepacivirus/genética , Hepatitis C/sangre , Hepatitis C/virología , Adulto , Alanina Transaminasa/sangre , Análisis de Varianza , Aspartato Aminotransferasas/sangre , Glucemia , Péptido C/sangre , Proteína C-Reactiva/metabolismo , Diabetes Mellitus/sangre , Egipto , Femenino , Homeostasis , Humanos , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Estadísticas no Paramétricas , Factor de Necrosis Tumoral alfa/sangre , gamma-Glutamiltransferasa/sangre
12.
Int J Toxicol ; 24(1): 43-50, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-15981739

RESUMEN

Gender is known to play a role in the bioavailability, metabolism, and lethality of many toxic substances. This study was conducted to investigate the influence of gender on cocaine hepatotoxicity (CH) and lipopolysaccharide (LPS) potentiation of CH. Male and female CF-1 mice were orally administered 20 mg/kg body weight cocaine hydrochloride once daily for 7 days. Four hours after the last cocaine administration, the mice were administered 12 x 10(6) EU LPS (or equal volume of sterile saline) intraperitoneally. Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were evaluated as indices of liver injury. Blood and liver glutathione (GSH), glutathione reductase (GRx), and catalase (CAT) activities were also determined to investigate the extent of oxidative stress induced by the treatments. Serum ALT and AST concentrations were elevated in all males receiving cocaine alone or cocaine + LPS. Furthermore, blood GSH and CAT were decreased and GRx activity was elevated in these same animals. Histological analysis revealed a high degree of hepatic focal necrosis in the male cocaine group, and severe hemorrhagic necrosis in the male cocaine + LPS group. Unlike males, females showed no damage resulting from cocaine or cocaine + LPS exposure, whereas testosterone-supplemented ovariectomized females displayed histological and biochemical profiles statistically similar to males. The results demonstrate that the extent of CH or LPS-potentiated CH is influenced by gender and sex hormones, particularly testosterone.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Cocaína/toxicidad , Lipopolisacáridos/toxicidad , Hígado/efectos de los fármacos , Factores Sexuales , Administración Oral , Alanina Transaminasa/sangre , Alanina Transaminasa/efectos de los fármacos , Animales , Aspartato Aminotransferasas/sangre , Aspartato Aminotransferasas/efectos de los fármacos , Catalasa/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/enzimología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Sinergismo Farmacológico , Femenino , Glutatión/sangre , Glutatión Reductasa/sangre , Humanos , Inyecciones Intraperitoneales , Hígado/enzimología , Hígado/patología , Masculino , Ratones , Ratones Endogámicos , Necrosis , Ovariectomía , Testosterona/farmacología
13.
J Appl Toxicol ; 22(2): 123-8, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-11920937

RESUMEN

Cocaine abuse is an extensive problem in the USA. During the past decade, ketamine abuse also has emerged as a public health concern and is now considered a controlled substance. The prevalence of the simultaneous use of cocaine and ketamine has been shown to be high. Previous research indicates that ketamine affects the enzymes that metabolize cocaine. In order to investigate this pharmacokinetic interaction, it was necessary to identify and quantitate each compound. The aim of this study is to develop a method of detecting and resolving cocaine, its metabolites and ketamine. A new precise, accurate and sensitive reversed-phase high-performance liquid chromatography method has been developed and validated. This assay employed a phosphate-buffered aqueous mobile phase (pH 6.9) with an organic component consisting of acetonitrile and methanol and a C-18 column as stationary phase at 225 nm wavelength. Minimum detection limits were 5 ng ml(-1) for cocaine and 10 ng ml(-1) for benzoylecgonine, norcocaine and ketamine. Linearity was demonstrated over a broad range of concentration in plasma, with good sensitivity for ketamine, cocaine and cocaine metabolites.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Cocaína/análogos & derivados , Cocaína/sangre , Ketamina/sangre , Detección de Abuso de Sustancias/métodos , Animales , Cocaína/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
14.
Int J Toxicol ; 23(3): 163-70, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15204719

RESUMEN

This study was conducted to investigate the effect of a 7-day treatment as well as the influence of gender on cocaine hepatotoxicity (CH). Lipopolysaccharide (LPS) potentiation of CH was also investigated. Male and female CF-1 mice were orally administered 20 mg/kg body weight cocaine hydrochloride once daily for 7 days. Four hours after the last cocaine administration, the mice were administered 12 x 10(6) EU LPS (or equal volume of sterile saline) intraperitoneally. Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were evaluated as indices of liver injury. Blood and liver glutathione (GSH), glutathione reductase (GRx), and catalase (CAT) activities were also determined to investigate the oxidation stress induced by the treatment. Plasma ALT and AST concentrations were elevated in all males receiving cocaine alone or cocaine + LPS. Furthermore, blood GSH and CAT were decreased and GRx activity was elevated in the same males. Histological analysis revealed a high degree of focal necrosis in the male cocaine group, and severe necrosis in the male cocaine + LPS group. Unlike males, females showed no effect of either cocaine alone or cocaine + LPS treatments. These results indicate that gender plays a significant role in CH and its potentiation by LPS and lengthening the administration by two treatments increased the severity of cocaine + LPS hepatotoxicity dramatically in male mice.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Cocaína/toxicidad , Lipopolisacáridos/toxicidad , Hígado/efectos de los fármacos , Administración Oral , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/enzimología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Sinergismo Farmacológico , Femenino , Inyecciones Intraperitoneales , Hígado/enzimología , Hígado/patología , Pruebas de Función Hepática , Masculino , Ratones , Ratones Endogámicos , Necrosis , Salmonella enteritidis , Factores Sexuales
15.
Int J Toxicol ; 22(4): 305-16, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-12933325

RESUMEN

Exposure to small, noninjurious doses of the inflammagen, bacterial endotoxin (lipopolysaccharide, LPS) augments the toxicity of certain hepatotoxicants, including cocaine. The mechanism of this interaction has not been clearly elucidated, but it seems that aspects of the inflammatory response initiated by exposure to LPS may be responsible. In particular, this study examined the role of Kupffer cells and the modulating effects of nitric oxide (NO) and reactive oxygen species (ROS) on the LPS potentiation of cocaine-mediated hepatotoxicity (CMH). Mice were administered oral cocaine hydrochloride for 5 consecutive days at a dose of 20 mg/kg with and without 12 x 10(6) EU LPS/kg given intraperitoneally (IP) 4 hours after the last cocaine injection. Pretreatment regimens consisted of administration of 300 mg/kg, IP, of aminoguanidine (AM) or 1,3-dimethylthiourea (DMU) at 1 hour or 15 minutes, respectively, before each cocaine administration. In another group, mice were pretreated with saline using the same cocaine and LPS treatment protocol, but received a single pretreatment of 7 mg gadolinium chloride (GdCl(3))/kg intravenously (IV), or sterile saline 24 hours prior to the LPS administration. The GdCl(3) (Kupffer cell inhibitor) pretreatment inhibited the LPS potentiation of CMH, but did not reverse the effects of cocaine alone. On the other hand, AM (NO synthase inhibitor), decreased the synthesis of NO as observed by the decrease in the plasma nitrate/nitrite level and completely reversed the hepatotoxic effects of cocaine and LPS alone and in combination. Moreover, DMU (hydroxyl free radical scavenger) ameliorated the effects of cocaine and significantly reduced the hepatotoxicity observed with the cocaine and LPS administration. These data suggest that cocaine sensitizes the liver and subsequent activation of Kupffer cells by LPS leads to the formation of increased levels of NO, which can promote oxidant stress and thus provide an environment favoring the generation of more reactive species such as the hydroxyl free radical.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Cocaína/toxicidad , Lipopolisacáridos/toxicidad , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Sinergismo Farmacológico , Glutatión/metabolismo , Hígado/metabolismo , Hígado/patología , Hepatopatías/metabolismo , Hepatopatías/patología , Masculino , Ratones , Nitratos/sangre , Nitratos/metabolismo , Óxido Nítrico/sangre , Nitritos/sangre , Nitritos/metabolismo , Salmonella enteritidis , Transaminasas/sangre , Factor de Necrosis Tumoral alfa/metabolismo
16.
J Appl Toxicol ; 22(1): 31-5, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-11807927

RESUMEN

During water treatment, potentially hazardous chemical by-products may be formed. Alachlor (2-chloro-N-(2, 6-diethylphenyl)-N-(methoxymethyl) acetamide) is a widely used pre-emergence herbicide. The present study investigated the toxicity of alachlor and its disinfection by-products on freshly isolated rat hepatocytes. Hepatocytes were harvested by a collagenase perfusion technique and were exposed to different concentrations of alachlor and its by-products for up to 2 h. Cell viability, the leakage of aspartate transaminase (AST) and alanine transaminase (ALT) and glutathione (GSH) depletion were determined throughout the incubation period. The cell viability of the hepatocytes exposed to 100 microg ml(-1) alachlor was decreased by 20% compared with the control after 60 min of incubation. At the same concentration of alachlor the leakage of ALT and AST was increased by 56% and 45%, respectively. Cell viability of the hepatocytes was decreased upon exposure to 2-chloro-N-(3-chloro-2,6-diethylphenyl)-N-(methoxymethyl) acetamide (CCDMA) and 2-chloro-N-(3-chloro-2,6-diethylphenyl) acetamide (CCDA)--the by-products of alachlor and chlorine--after 60 min of exposure. At 100 microg ml(-1) CCDMA the AST leakage was increased significantly (73%) after 30 min of incubation. The reaction mixture of alachlor (100 microg ml(-1)) and chlorine dioxide (1 ppm) caused significant increases in cell loss and ALT and AST levels by 22%, 40% and 34%, respectively, as early as 15 min incubation. Alachlor (100 and 200 microg ml(-1)) caused significant decreases in GSH contents (62%) in isolated hepatocytes. The reaction mixture of alachlor and chlorine dioxide led to significant glutathione depletion (44%) after 60 min of incubation. The by-products of alachlor and chlorine--CCDMA and CCDA--depleted GSH almost completely (93%). This investigation suggested that the by-products formed from the reaction of alachlor and chlorine decreased GSH and increased the leakage of liver enzymes, especially AST.


Asunto(s)
Acetamidas/toxicidad , Hepatocitos/efectos de los fármacos , Herbicidas/toxicidad , Hígado/efectos de los fármacos , Acetamidas/metabolismo , Alanina Transaminasa/metabolismo , Animales , Aspartato Aminotransferasas/metabolismo , Supervivencia Celular/efectos de los fármacos , Cloro/metabolismo , Cloro/toxicidad , Desinfectantes/toxicidad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Glutatión/metabolismo , Hepatocitos/enzimología , Hepatocitos/metabolismo , Herbicidas/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Ratas , Ratas Sprague-Dawley , Pruebas de Toxicidad , Contaminantes Químicos del Agua/efectos adversos , Abastecimiento de Agua
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