RESUMEN
OBJECTIVE: To study the possibility of increasing the very long-chain n-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in humans by means of consumption of a common food product, Scandinavian caviar paste, suitable for strategic enrichment with a high concentration of these fatty acids, and to measure the potential inducement of lipid peroxidation. DESIGN: A randomized double blind repeated measures experiment. SUBJECTS AND INTERVENTIONS: In total, 16 healthy, nonsmoking subjects (eight men and eight women, age 42+/-12 y) were included in the study. Eight consumed 25 g ordinary caviar paste daily for 3 weeks, and eight the same amount of caviar paste enriched with a very stable fish oil (7%, wt/wt). Blood lipids, plasma phospholipid fatty acids and lipid peroxidation were measured. RESULTS: alpha-Linoleic acid was significantly decreased after intake of both ordinary (-8%, P<0.05) and fish oil caviar (-10%, P<0.05), as was the sum of all n-6 fatty acids (-6%, P<0.05 and -8%, P<0.001, respectively). The fatty acids EPA and DHA, as well as the sum of all n-3 fatty acids, increased significantly in both caviar groups but more in the group given fish oil caviar paste (EPA: +51%, P<0.05 and +100%, P<0.001, respectively; DHA: +24%, P<0.01 and +29%, P<0.001, respectively; sum of n-3:+27%, P<0.05 and +40%, P<0.001, respectively). Lipid peroxidation, measured as the thiobarbituric acid-malondialdehyde adduct, was increased by 26% (P<0.05) after intake of ordinary caviar paste, but was unchanged after intake of fish oil-enriched caviar paste. CONCLUSION: Scandinavian caviar paste is a spread naturally enriched with n-3 polyunsaturated fatty acids that can be included in the diet to achieve an increase in these fatty acids. However, changing to caviar paste enriched with stable fish oil will lead to a considerably greater increase in EPA and DHA. SPONSORSHIP: Swedish Medical Research Council; Cardinova AB, Uppsala, Sweden.
Asunto(s)
Huevos , Ácidos Grasos/sangre , Aceites de Pescado/farmacología , Alimentos Fortificados , Peroxidación de Lípido/efectos de los fármacos , Fosfolípidos/sangre , Adulto , Anciano , Animales , Método Doble Ciego , Femenino , Aceites de Pescado/administración & dosificación , Productos Pesqueros , Humanos , Peroxidación de Lípido/fisiología , Masculino , Persona de Mediana Edad , Valores de Referencia , Países Escandinavos y Nórdicos , Estadísticas no ParamétricasRESUMEN
Oxidatively modified LDL (ox-LDL) activates a lectin-like receptor, LOX-1, which results in the expression of adhesion molecules on endothelial surface. We investigated the regulation of the expression of transforming growth factor-beta(1) (TGF-beta(1)) and its receptors by ox-LDL and the functional significance of this interaction with regard to adhesion molecule expression in human coronary artery endothelial cells (HCAECs). Ox-LDL, in a time- and concentration-dependent manner, upregulated the expression of all 3 subtypes (1, 2, and 3 [including endoglin]) of TGF-beta(1) receptors and decreased active TGF-beta(1) synthesis (all P<0.05 versus control and native-LDL-treated cells). Treatment of HCAECs with a monoclonal antibody to LOX-1 attenuated ox-LDL-mediated upregulation of TGF-beta(1) receptors and decrease in TGF-beta(1) synthesis (P<0.05 versus ox-LDL alone). Ox-LDL also enhanced the expression of P-selectin and ICAM-1 as well as monocyte adhesion to HCAECs (P<0.05 versus control untreated cells). Pretreatment with recombinant TGF-beta(1) attenuated the enhanced expression of adhesion molecules and monocyte adhesion to HCAECs (P<0.05 versus ox-LDL alone). Effects of recombinant TGF-beta(1) were blocked by antibody to TGF-beta(1) receptor type 2, but not by antibody to endoglin. Thus ox-LDL, via activation of LOX-1, increases the expression of TGF-beta(1) receptors and decreases TGF-beta(1) synthesis in HCAECs. Recombinant TGF-beta(1), by binding to TGF-beta(1) type 2 receptors, modulates ox-LDL-mediated expression of adhesion molecules and monocyte adhesion to HCAECs.
Asunto(s)
Moléculas de Adhesión Celular/biosíntesis , Endotelio Vascular/metabolismo , Lipoproteínas LDL/farmacología , Receptores de LDL/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Anticuerpos/farmacología , Adhesión Celular/efectos de los fármacos , Línea Celular , Vasos Coronarios/citología , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/metabolismo , Reactivos de Enlaces Cruzados/farmacología , Relación Dosis-Respuesta a Droga , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Lipoproteínas LDL/biosíntesis , Monocitos/efectos de los fármacos , Selectina-P/genética , Selectina-P/metabolismo , ARN Mensajero/metabolismo , Receptores de LDL/antagonistas & inhibidores , Receptores de LDL Oxidadas , Receptores de Factores de Crecimiento Transformadores beta/biosíntesis , Receptores Depuradores de Clase E , Factor de Crecimiento Transformador beta/farmacología , Factor de Crecimiento Transformador beta1RESUMEN
BACKGROUND: alpha-Tocopherol has received much attention in the primary and secondary prevention of coronary artery disease. Absence of other isoforms, such as gamma- and delta-tocopherol, in commercial preparations of vitamin E may account for the inconsistent results of clinical trials. Since platelet aggregation is intimately involved in thrombogenesis, the relative effects of alpha-, gamma-, and delta-tocopherol and their combination were examined on human platelet aggregation, lipid peroxidation, and constitutive nitric oxide synthase (cNOS) activity. METHODS AND RESULTS: Human platelets were incubated with the three different isoforms of tocopherol and their combination for 30 minutes, and then ADP-induced platelet aggregation measured. All three isoforms of tocopherol markedly and similarly decreased platelet aggregation in a concentration (120--480 microM)-dependent manner. All three tocopherols also decreased the level of the lipid peroxidation product, malondialdehyde (MDA), and increased NO release (P < 0.05 vs control). These isoforms of tocopherol did not affect cNOS protein expression, but enhanced cNOS phosphorylation in platelets. The combination of three tocopherols in a concentration found in nature was more potent than alpha-, gamma-, or delta-tocopherol alone in this regard. CONCLUSION: These observations suggest that all three major isoforms of tocopherol have a similar effect on human platelet aggregation. The three isoforms appear to attenuate platelet aggregation at least in part via a decrease in free radical generation and an increase in platelet cNOS activity. The combination of tocopherols has a synergistic platelet inhibitory effect. Future clinical trials should concentrate on the combination of these three isoforms of tocopherols.
Asunto(s)
Peroxidación de Lípido/efectos de los fármacos , Óxido Nítrico Sintasa/metabolismo , Agregación Plaquetaria/efectos de los fármacos , Vitamina E/farmacología , Análisis de Varianza , Plaquetas/metabolismo , Ácidos Grasos/farmacología , Humanos , Técnicas In Vitro , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III , Fosforilación/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Isoformas de Proteínas/farmacología , Vitamina E/análogos & derivados , Vitamina E/metabolismo , Vitamina E/uso terapéuticoRESUMEN
Myocardial hypoxia-reoxygenation (H-R) is associated with upregulation of inducible nitric oxide synthase (iNOS), decrease in endothelial NOS (eNOS), and increase in protein kinase B (PKB). Previous work also shows that transforming growth factor-beta(1) (TGF-beta(1)) can attenuate myocardial injury induced by H-R. We examined the modulation of NOS and PKB expression in response to H-R by TGF- beta(1). Myocytes from Sprague-Dawley rat hearts were cultured and exposed to hypoxia (95% N(2)-5% CO(2), PO(2) ~30 mmHg) for 24 h and reoxygenation (95% air-5% CO(2)) for 3 h. Myocytes were then examined for lactate dehydrogenase (LDH) release, iNOS activity (conversion of L-[(3)H]arginine to L-[(3)H]citrulline), iNOS and eNOS expression, and PKB phosphorylation. H-R alone resulted in myocyte injury, upregulation of iNOS activity and expression, decrease in eNOS expression, and increase in PKB phosphorylation (all P < 0.05 vs. cells cultured in normoxic conditions). Treatment of myocytes with TGF-beta(1) (1 ng/ml) resulted in a reduction in LDH release, attenuation of the alterations in NOS expression (both iNOS and eNOS), and PKB phosphorylation in response to H-R (all P < 0.05 vs. H-R alone). These observations suggest that TGF-beta(1) decreases H-R injury and attenuates alterations in NOS and PKB phosphorylation in myocytes exposed to H-R.
Asunto(s)
Hipoxia de la Célula/fisiología , Miocardio/metabolismo , Óxido Nítrico Sintasa/metabolismo , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Hipoxia de la Célula/efectos de los fármacos , Células Cultivadas , Masculino , Daño por Reperfusión Miocárdica/metabolismo , Miocardio/citología , Óxido Nítrico Sintasa de Tipo II , Óxido Nítrico Sintasa de Tipo III , Oxígeno/metabolismo , Oxígeno/farmacología , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt , Ratas , Ratas Sprague-Dawley , Factor de Crecimiento Transformador beta/farmacología , Factor de Crecimiento Transformador beta1RESUMEN
Angiotensin-II (Ang-II) participates in the development and progression of atherosclerosis by activating type 1 (AT(1)) receptors. In vitro studies show that inflammatory factors, such as P-selectin and MCP-1, which can be upregulated by Ang-II, play an important role in atherogenesis. We examined the effect of AT(1) receptor blockade with losartan on the expression of P-selectin and MCP-1 in hypercholesterolemic rabbits. Since AT(1) receptor blockade is associated with feedback upregulation of renin-angiotensin system (RAS), we also examined alterations in plasma Ang-II levels by losartan therapy. Male NZW rabbits were fed regular chow (high cholesterol diet or high cholesterol diet + losartan 25 mg/kg/day). As expected, there was a marked intimal proliferation in association with increase in serum cholesterol (P < 0.001). In addition, there was a modest increase in plasma Ang-II levels (P < 0.05), and a significant increase in the expression of AT(1) receptors, P-selectin and MCP-1 in aortas of high cholesterol diet rabbits. Concurrent administration of losartan with high cholesterol diet attenuated aortic intimal proliferation induced a fivefold increase in plasma Ang-II levels and caused a marked decrease in expression of P-selectin and MCP-1 without change in serum lipid levels and aortic AT(1) receptor expression. These observations in hypercholesterolemic animal models show that AT(1) receptor blockade is associated with modulation of P-selectin and MCP-1 expression concurrent with reduction in intimal proliferation. The rise in plasma Ang-II does not appear to limit the potential beneficial effect of losartan.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Quimiocina CCL2/metabolismo , Hiperlipidemias/metabolismo , Hiperlipidemias/patología , Selectina-P/metabolismo , Angiotensina II/sangre , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Aorta/patología , Arteriosclerosis/etiología , Arteriosclerosis/prevención & control , Dieta Aterogénica , Hiperlipidemias/complicaciones , Hiperlipidemias/tratamiento farmacológico , Losartán/farmacología , Masculino , Conejos , Receptor de Angiotensina Tipo 1 , Receptor de Angiotensina Tipo 2RESUMEN
The effect of a combination of aspirin and fish oil on eicosanoids was studied. Four subjects were given 37.5 mg aspirin orally, and 6 weeks later they received a natural, stable fish oil daily for 1 week before taking the same single dose of aspirin. Blood samples for determination of whole blood production of eicosanoids were taken before and after each experimental period. Serum thromboxane A(2)was decreased by 40% (P<0.05) after aspirin alone, but by 62% (P<0.01) after fish oil + aspirin. Serum prostacyclin (measured as 6-keto PGF(1a)) was decreased by aspirin in both cases. The sum of 6-keto PGF(1a)and its equipotent fish oil-derived analogue Delta(17)-6-keto PGF(1a)was reduced after aspirin intake (55%, NS), but after fish oil + aspirin the reduction was smaller (33%, NS). Leukotriene B(4)was increased by 19% (P<0.05) after aspirin, and decreased by 69% (P<0.05) after fish oil + aspirin. A combination of stable fish oil and aspirin thus improves the eicosanoid pattern more than aspirin alone.
Asunto(s)
Aspirina/farmacología , Eicosanoides/sangre , Ácido Eicosapentaenoico/análogos & derivados , Aceites de Pescado/farmacología , Leucotrieno B4/análogos & derivados , 6-Cetoprostaglandina F1 alfa/sangre , Adulto , Aspirina/administración & dosificación , Interacciones Farmacológicas , Eicosanoides/biosíntesis , Ácido Eicosapentaenoico/sangre , Aceites de Pescado/administración & dosificación , Humanos , Leucotrieno B4/sangre , Persona de Mediana Edad , Tromboxano B2/sangreRESUMEN
BACKGROUND: Previous studies indicate that the enteral bacterial urease is inhibited in victims of sudden infant death syndrome (SIDS). One possible inhibitor of this bacterial activity is nitrate. If ambient pollution by nitrate is involved in the etiology of SIDS only a fraction of the nitrate concentration not infrequently found in drinking water would be enough for this inhibition. METHODS: Occurrence of SIDS (n = 636) in Sweden during the period 1990 through 1996 were analysed regarding geographical and seasonal distribution in relation to the nitrate concentration in drinking water and changes in the groundwater level. RESULTS: Both the birth rate and the incidence of SIDS decreased during the study period. One quarter of the municipalities constituting 11% of the population had no cases, the maximum incidence being 6.5 per 1000 live births. Seasonality: The northernmost parts of the country had its highest incidence when the rest of the country had its lowest incidence, and the occurrence of individual deaths was associated with the recharge of groundwater which increases its nitrate content. The local incidence of SIDS was correlated (rs = 0.34-0.87) to maximally recorded concentrations of nitrate in drinking water. CONCLUSIONS: The seasonal distribution of SIDS was widely different from the south to the north of the country and seems to be associated with differences in the groundwater level changes subsequent to precipitation, frost penetration, and melting of snow. Use of drinking water with high peak concentrations or great variations in nitrate concentration was correlated to the incidence of SIDS.
Asunto(s)
Nitratos/análisis , Muerte Súbita del Lactante/epidemiología , Abastecimiento de Agua , Humanos , Incidencia , Lactante , Análisis de Regresión , Suecia/epidemiología , Agua/química , Contaminantes Químicos del Agua/análisisRESUMEN
BACKGROUND: We demonstrated earlier that angiotensin II (Ang II), by AT(1) receptor activation, upregulates oxidized LDL (ox-LDL) endothelial receptor LOX-1 gene expression and uptake of ox-LDL in human coronary artery endothelial cells (HCAECs). In this study, we investigated the regulation of Ang II receptors (AT1R and AT2R) by ox-LDL and the role of the redox-sensitive transcription factor NF-kappaB in this process. METHODS AND RESULTS: HCAECs were incubated with ox-LDL for 24 hours. Ox-LDL (10 to 40 microg protein/mL) upregulated AT1R but not AT2R, mRNA, or protein. Ox-LDL degraded IkappaBalpha in cytoplasm and activated transcription factor NF-kappaB (P65) in HCAEC nuclear extract. Treatment of cells with the antioxidant alpha-tocopherol (10 to 50 micromol/L) attenuated ox-LDL-mediated degradation of IkappaBalpha and activation of NF-kappaB (P65) and inhibited the upregulation of AT1R mRNA and protein. The role of NF-kappaB signal transduction was further examined by use of an NF-kappaB inhibitor, caffeic acid phenethyl ester (CAPE). Pretreatment of cells with CAPE inhibited ox-LDL-mediated degradation of IkappaBalpha and NF-kappaB activation and inhibited ox-LDL-induced upregulation of AT1R expression. Incubation of cells with both ox-LDL and Ang II increased cell injury, measured as cell viability and LDH release, compared with either ox-LDL or Ang II alone. alpha-Tocopherol as well as the specific AT1R blocker CV11974 (candesartan) attenuated the cell-injurious effects of ox-LDL. CONCLUSIONS: These observations suggest an important role of ox-LDL-mediated AT1R upregulation in cell injury. In this process, NF-kappaB activation seems to play a critical role in signal transduction. These findings provide a basis for the use of antioxidants and AT1R blockers in designing therapy of atherosclerosis.
Asunto(s)
Vasos Coronarios/metabolismo , Endotelio Vascular/metabolismo , Proteínas I-kappa B , Lipoproteínas LDL/metabolismo , FN-kappa B/metabolismo , Alcohol Feniletílico/análogos & derivados , Receptores de Angiotensina/metabolismo , Angiotensina II/metabolismo , Angiotensina II/farmacología , Antagonistas de Receptores de Angiotensina , Arterias/citología , Arterias/metabolismo , Ácidos Cafeicos/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Vasos Coronarios/citología , Proteínas de Unión al ADN/metabolismo , Endotelio Vascular/citología , Humanos , L-Lactato Deshidrogenasa/metabolismo , Lipoproteínas LDL/farmacología , Inhibidor NF-kappaB alfa , FN-kappa B/antagonistas & inhibidores , Alcohol Feniletílico/farmacología , ARN Mensajero/metabolismo , Receptor de Angiotensina Tipo 1 , Receptor de Angiotensina Tipo 2 , Receptores de Angiotensina/genética , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiología , Vitamina E/metabolismo , Vitamina E/farmacologíaRESUMEN
Experimental studies have demonstrated that vitamin E (alpha-tocopherol) may provide significant cytoprotection during cell injury. In this study, we examined the effects of alpha-tocopherol on oxidized low-density lipoprotein (ox-LDL)-induced apoptosis in human coronary artery endothelial cells (HCAECs). In addition, we examined the activation of NF-kappaB pathway in this process. Cultured HCAECs were treated with ox-LDL for 24 h. Incubation of HCAECs with ox-LDL resulted in apoptosis of HCAECs in a concentration-dependent manner, as determined by TUNEL and DNA laddering. Ox-LDL degraded IkappaB and activated NF-kappaB in HCAECs, as determined by Western blot analysis. Treatment with alpha-tocopherol (10 and 50 microM) decreased ox-LDL-mediated apoptosis as well as degradation of IkappaB and activation of NF-kappaB in HCAECs. High concentration of alpha-tocopherol (50 microM) was more effective than the low concentration of alpha-tocopherol (10 microM). Thus, ox-LDL induces apoptosis of HCAECs, in concurrence with degradation of IkappaB and activation of NF-kappaB. Alpha-tocopherol markedly decreases ox-LDL-induced effects.
Asunto(s)
Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Vasos Coronarios/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Lipoproteínas LDL/toxicidad , Vitamina E/farmacología , Células Cultivadas , Vasos Coronarios/metabolismo , Vasos Coronarios/patología , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Humanos , Proteínas I-kappa B/metabolismo , FN-kappa B/metabolismoRESUMEN
To investigate the prevalence of analgesics containing dextropropoxyphene (DXP) or codeine in individuals suspected of driving under the influence of drugs, we analysed all blood samples in which drugs were screened for in cases of suspected drunken driving in Sweden during the years 1992-1997. DXP was found in 130 (2.7%) and codeine in 388 (7.9%) of the 4896 drug-screened cases. The ratio between the number of DXP and of codeine cases and prescription of defined daily dose/1000 inhabitants during a 12-month period (DDD) was determined. The quotient for DXP was trebled from 1992 (0.99) to 1997 (2.89), while the codeine quotient decreased by 9% (from 6 to 5.5). The blood samples showed polydrug use in all but 28 cases of the 486 cases where DXP and/or codeine was found. In 71% of the 486 cases benzodiazepines were also present and in 38% of the cases amphetamine and/or cannabis were present. It was concluded that analgesics containing DXP or codeine are not drugs of primary interest in this specific population. Nevertheless, because of the high toxicity of DXP, especially when combined with alcohol or other drugs, the increase in the DXP prevalence gives reason for concern, since the studied population represents a group of individuals who use large doses of therapeutic or illegal drugs.
Asunto(s)
Analgésicos Opioides/sangre , Conducción de Automóvil , Codeína/sangre , Dextropropoxifeno/sangre , Adolescente , Adulto , Anciano , Consumo de Bebidas Alcohólicas , Anfetamina/sangre , Ansiolíticos/sangre , Benzodiazepinas , Cannabinoides/sangre , Cannabis , Estimulantes del Sistema Nervioso Central/sangre , Interacciones Farmacológicas , Femenino , Alucinógenos/sangre , Humanos , Drogas Ilícitas/sangre , Masculino , Persona de Mediana Edad , Polifarmacia , Prevalencia , Trastornos Relacionados con Sustancias/sangre , SueciaRESUMEN
BACKGROUND: Dextropropoxyphene (DXP) toxicity is highly potentiated by alcohol and the aim of this study was to determine the characteristics of non-suicidal deceased with simultaneous occurrence of alcohol and DXP in the blood. METHODS: The investigated population was based on the total medico-legal autopsy material in Sweden during the years 1992-1996. Toxicological analyses and death certificates were examined. RESULTS: Simultaneous occurrence of DXP and alcohol was detected in 425 cases. The mean blood alcohol concentration was 0.14%. One-third had a blood alcohol concentration >;0.20% and 42%, <0.1%. The majority of the cases were found between the ages 30 and 59 years;, 71% were male and 29% were female. Notes on alcoholism were found in 16% of the cases. CONCLUSION: Middle-aged, habitual or social-drinking men, on medication for pain, are most prone to combine DXP and alcohol and are most vulnerable to be victims of accidental poisoning due to the combination of DXP and alcohol. We propose strict regulations in prescription, or even a ban on prescription of DXP, and that physicians in the meantime pay extra attention to this risk category of patients and make sure that the patient is well informed of the life-threatening risks of simultaneous use of DXP and alcohol.
Asunto(s)
Intoxicación Alcohólica/complicaciones , Intoxicación Alcohólica/epidemiología , Analgésicos Opioides/envenenamiento , Dextropropoxifeno/envenenamiento , Accidentes/estadística & datos numéricos , Adulto , Distribución por Edad , Intoxicación Alcohólica/sangre , Intoxicación Alcohólica/prevención & control , Autopsia , Certificado de Defunción , Sobredosis de Droga , Prescripciones de Medicamentos , Control de Medicamentos y Narcóticos , Etanol/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Distribución por Sexo , Suecia/epidemiologíaRESUMEN
BACKGROUND: Infection with Chlamydia pneumoniae has been postulated to play a pathogenic role in atherosclerosis. We examined the role of infection with C pneumoniae in relation to the extent of coronary atherosclerosis. METHODS AND RESULTS: Coronary atherosclerosis was graded microscopically on a postmortem basis in a blinded fashion in 60 subjects as mild (n=18) or severe (n=42) atherosclerosis. Serum antibodies to C pneumoniae were measured by microimmunofluorescence test. Paraffin-embedded coronary artery specimens were examined for the presence of chlamydia by use of a genus-specific direct immunofluorescence monoclonal antibody. Frozen coronary artery specimens were examined by immunoperoxidase for the presence of C pneumoniae by use of a specific monoclonal antibody RR-402. Direct immunofluorescence was reactive in 86% of cases with severe atherosclerosis but in only 6% of cases with mild atherosclerosis (P<0.01), whereas immunoperoxidase staining was reactive in 80% and 38% of cases with severe and mild atherosclerosis, respectively (P<0. 01). Elevated IgG and IgA levels against C pneumoniae were not different in cases with severe and mild atherosclerosis (61% and 30% for severe atherosclerosis and 67% and 42% for mild atherosclerosis, respectively). CONCLUSIONS: This study supports the hypothesis that intracellular infection with C pneumoniae may relate to the severity of atherosclerosis in some subjects. Serum antibody titers against C pneumoniae do not differentiate between severe and mild atherosclerosis.
Asunto(s)
Arteriosclerosis/microbiología , Infecciones por Chlamydia/complicaciones , Chlamydophila pneumoniae/aislamiento & purificación , Enfermedad Coronaria/microbiología , Adulto , Anciano , Antígenos Bacterianos/análisis , Antígenos Bacterianos/inmunología , Arteriosclerosis/patología , Chlamydophila pneumoniae/química , Chlamydophila pneumoniae/inmunología , Enfermedad Coronaria/patología , Vasos Coronarios/patología , Reacciones Cruzadas , Femenino , Técnica del Anticuerpo Fluorescente Directa , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Results of therapy in patients with unstable coronary syndromes with antibiotics directed against Chlamydia pneumoniae have been variable, perhaps due to the heterogeneity of patients in these trials. HYPOTHESIS: The aim of the present study was to correlate the severity of coronary artery disease (CAD) with seropositivity against C. pneumoniae prospectively. METHODS: We measured the frequency of seropositivity (IgG levels > or = 1/64 and IgA levels > or = 1/16 against Chlamydia pneumoniae) in 110 patients with CAD and in 49 controls. RESULTS: As expected, traditional CAD risk factors were seen more often in patients with CAD than in controls. Mean values of total cholesterol (184 +/- 52 and 166 +/- 44 mg/dl, respectively) and triglyceride (143 +/- 60 and 112 +/- 63 mg/dl, respectively) in serum were significantly higher in patients with CAD than in controls (both p < 0.04). There were no significant differences between the two groups in serum high-density lipoprotein cholesterol (34 +/- 13 and 32 +/- 14 mg/dl, respectively) and lipoprotein (a) (Lp(a):241 +/- 247 and 223 +/- 263 mg/l, respectively) levels. The rate of IgG seropositivity was 52% (28/54) in patients with stable CAD, 41% (23/56) in patients with unstable CAD, and 35% in controls (p = NS). The rate of IgA seropositivity was 25% (14/54) in patients with stable CAD, 12% (6/49) in patients with unstable angina, and 12% (6/49) in controls (all p = NS). CONCLUSIONS: Only a small percentage of patients with CAD demonstrate seropositivity against Chlamydia pneumoniae. Antibiotic therapy in these selected patients, but not in the remaining patients, may be considered rational. These considerations may underlie the failure to see consistent benefits of antibiotic therapy in patients with CAD.
Asunto(s)
Infecciones por Chlamydia/diagnóstico , Chlamydophila pneumoniae/inmunología , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/microbiología , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Análisis de Varianza , Angina de Pecho/diagnóstico , Angina de Pecho/microbiología , Angina Inestable/diagnóstico , Angina Inestable/microbiología , Infecciones por Chlamydia/inmunología , Femenino , Humanos , Masculino , Probabilidad , Estudios Prospectivos , Sensibilidad y Especificidad , Pruebas Serológicas , Índice de Severidad de la EnfermedadRESUMEN
We examined the influence of dietary stable fish oil on aortic thrombosis, platelet aggregation, and superoxide dismutase (SOD) activity in a rat model. Twenty-nine Sprague-Dawley rats were fed regular chow supplemented with stable fish oil preparation (for 1 or 3 weeks), and 37 rats fed regular chow served as controls. The abdominal cavity was opened, and the abdominal aorta isolated. Whatman paper impregnated with 35% FeCl3 was wrapped around the surface of the aorta, and aortic flow was continuously recorded. In control rats, an occlusive platelet-fibrin-rich thrombus was formed in 21 +/- 3 min. Dietary fish oil in a time-dependent fashion delayed time to thrombus formation (24 +/- 2 min in rats fed fish oil for 1 week and 31 +/- 2 min in rats fed fish oil for 3 weeks), inhibited platelet aggregation (21 +/- 5% vs. 45 +/- 6%; p < 0.01) and increased SOD activity (p < 0.01). We conclude that dietary supplementation with stable fish oil delays formation of arterial thrombus, probably by reducing platelet aggregation and oxidative stress-associated arterial injury.
Asunto(s)
Aceites de Pescado/farmacología , Agregación Plaquetaria/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Trombosis/prevención & control , Animales , Dieta , Aceites de Pescado/administración & dosificación , Aceites de Pescado/uso terapéutico , Masculino , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/sangreRESUMEN
BACKGROUND: Thrombin plays a pivotal role in the development of septic shock. Porcine endotoxaemia can replicate this condition. We wanted to evaluate whether melagatran, a novel inhibitor of thrombin, would counteract some of the endotoxin-induced changes in this model. METHODS: Fifteen pigs were anaesthetised, monitored (circulatory and respiratory variables) and subjected to an infusion of E. coli endotoxin at 10 microg x kg(-1) x h(-1). Six pigs were given melagatran during the first 3 h of the 6-h endotoxaemic period. Nine controls were given the corresponding volume of saline instead of melagatran. Specimens from the liver and the left lung were taken for light microscopy post mortem. RESULTS: The endotoxin-induced increase in pulmonary capillary wedge pressure and drop in platelet count were significantly less pronounced in the melagatran-treated pigs. Deposits of pulmonary fibrin were significantly reduced in the melagatran group, without improving oxygenation. Light microscopy revealed no hepatic fibrin in the pigs treated with melagatran in contrast to the endotoxaemic controls. Hepatic neutrophil accumulation was reduced in the melagatran group as compared to controls. Hepatocellular degeneration and plasma levels of tumour necrosis factor alpha (TNF alpha) and bilirubin were of the same magnitude in both groups. CONCLUSION: Melagatran reduced pulmonary capillary wedge pressure, a retrograde reflection of the left ventricular end-diastolic filling pressure, and also pulmonary stasis in pigs subjected to endotoxaemic challenge. Pulmonary and hepatic fibrin depositions were reduced, but PaO2 levels or liver function markers were not affected by melagatran during the early phase of endotoxaemia. Obstruction of the intrahepatic bile ducts, by fibrin depositions, is not responsible for reduced excretion of conjugated bilirubin during endotoxaemia. The beneficial effects of melagatran during endotoxaemia were not due to any reduction of plasma TNF alpha.
Asunto(s)
Anticoagulantes/farmacología , Endotoxemia/sangre , Endotoxemia/fisiopatología , Fibrina/efectos de los fármacos , Fibrina/metabolismo , Glicina/análogos & derivados , Hemodinámica/efectos de los fármacos , Recuento de Plaquetas/efectos de los fármacos , Animales , Azetidinas , Bencilaminas , Femenino , Glicina/farmacología , Hígado/efectos de los fármacos , Hígado/fisiopatología , Masculino , Porcinos , Factor de Necrosis Tumoral alfa/análisisRESUMEN
To compare the characteristics of dextropropoxyphene (DXP) poisoning victims with those of victims of poisonings by antidepressants and sedatives, we examined all fatal poisonings due to DXP, antidepressants or sedatives among autopsies performed at one department of forensic medicine in Sweden during the six-year period from 1992 to 1997. In 202 cases, death was classified as fatal poisonings by DXP, antidepressants or sedatives. DXP caused death in 78 cases (39%), antidepressants in 49 (24%), and sedatives in 75 (37%). DXP as a single preparation was predominant in causing death. The second compound, flunitrazepam, caused death in 30 cases (15%). The victims of poisonings by DXP, antidepressants, or sedatives shared a similar history of alcohol/drug abuse, depression and somatic illness. They were mostly living alone at the time of death (>60%), the majority died at home (81%), and suicide was the most frequent manner of death (73%). Age seemed to be an important characteristic regarding the choice of drug. Younger people predominantly died of DXP (mean age 43 years, 95% confidence interval, CI 39-47), and elderly people of sedatives (mean age 59 years, CI 55-63). Antidepressants were found mainly in middle-aged victims (mean age 51 years, CI 48-54). The predominance of sedatives among the elderly might be explained by a very high prescription rate of such drugs in older age groups, but prescription rate could not explain the DXP predominance among younger people. We hypothesize that younger people are more prone to abuse therapeutic drugs for euphoric reasons than elderly people, and that because of its high toxicity, DXP leads to accidental deaths more often than sedatives.
Asunto(s)
Antidepresivos/envenenamiento , Dextropropoxifeno/envenenamiento , Hipnóticos y Sedantes/envenenamiento , Narcóticos/envenenamiento , Intoxicación/mortalidad , Adulto , Factores de Edad , Anciano , Amitriptilina/envenenamiento , Autopsia , Compuestos de Azabiciclo , Clomipramina/envenenamiento , Femenino , Flunitrazepam/envenenamiento , Humanos , Masculino , Persona de Mediana Edad , Fenotiazinas/envenenamiento , Piperazinas/envenenamiento , Trimeprazina/envenenamientoRESUMEN
OBJECTIVES: This study was designed to examine the differential effects of alpha- and gamma-tocopherol on parameters of oxidation-antioxidation and thrombogenesis. BACKGROUND: Experimental studies have shown that antioxidants, such as vitamin E (alpha-tocopherol), improve atherosclerotic plaque stability and vasomotor function, and decrease platelet aggregation and tendency to thrombus formation. METHODS: Sprague Dawley rats were fed chow mixed with alpha- or gamma-tocopherol (100 mg/kg/day) for 10 days. A filter soaked in 29% FeCl3 was applied around the abdominal aorta to study the patterns of arterial thrombosis. The aortic blood flow was observed and continuously recorded using an ultrasonic Doppler flow probe. ADP-induced platelet aggregation, low-density lipoprotein oxidation induced by phorbol 12-myristate 13-acetate (PMA)-stimulated leukocytes, superoxide anion generation and superoxide dismutase (SOD) activity were also measured. RESULTS: Both alpha- and gamma-tocopherol decreased platelet aggregation and delayed time to occlusive thrombus (all p < 0.05 vs. control). Both alpha- and gamma-tocopherol decreased arterial superoxide anion generation, lipid peroxidation and LDL oxidation (all p < 0.05 vs. control), and increased endogenous SOD activity (p < 0.05). The effects of gamma-tocopherol were more potent than those of alpha-tocopherol (p < 0.05). CONCLUSIONS: This study indicates that both alpha- and gamma-tocopherol decrease platelet aggregation and delay intraarterial thrombus formation, perhaps by an increase in endogenous antioxidant activity. Gamma-tocopherol is significantly more potent than alpha-tocopherol in these effects.
Asunto(s)
Peroxidación de Lípido/fisiología , Lipoproteínas LDL/sangre , Agregación Plaquetaria/fisiología , Superóxidos/sangre , Trombosis/sangre , Vitamina E/fisiología , Animales , Trombosis Coronaria/sangre , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
In Sweden, the frequency of fatal poisoning by dextropropoxyphene (DXP) ingestion is constantly high. There are seven preparations containing DXP on the Swedish market; in three of them DXP is the sole analgesic ingredient, while four of them are combinations of analgesics. In an attempt to assess the death rate attributable to each DXP preparation on the basis of toxicological analyses, altogether 834 cases of dextropropoxyphene-related death over a 5-year period (1992-1996) in Sweden have been reviewed. The ratio between number of fatal poisonings and prescription of defined daily dose/1000 inhabitants during a 12-month period (DDD) was determined. The highest ratio, 27, was attributed to unmixed preparations. The ratio for DXP + paracetamol-related deaths was 6.3, and for DXP + phenazone, 6.4, while the lowest ratio, 2, was found among the DXP + chlorzoxazone cases. The unmixed preparations, representing 26% of all DXP prescriptions during the study years, were implicated in 62% of the DXP fatalities, a considerable over-representation. Unmixed preparations, with their higher content of DXP, may be more attractive for many consumers because of their narcotic (euphoric) effects rather than for any analgetic superiority. Another possibility is that unmixed preparations may erroneously have been regarded as safer than when combined with paracetamol, as reports of poisoning with compounds containing DXP + paracetamol have been most frequently reported, probably due to their predominance on the market.
Asunto(s)
Analgésicos Opioides/envenenamiento , Dextropropoxifeno/envenenamiento , Prescripciones de Medicamentos/estadística & datos numéricos , Medicina Legal , Acetaminofén/sangre , Acetaminofén/envenenamiento , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Analgésicos no Narcóticos/sangre , Analgésicos no Narcóticos/envenenamiento , Analgésicos Opioides/sangre , Analgésicos Opioides/clasificación , Antiinflamatorios no Esteroideos/envenenamiento , Antipirina/envenenamiento , Dextropropoxifeno/sangre , Dextropropoxifeno/clasificación , Combinación de Medicamentos , Composición de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Suecia/epidemiologíaRESUMEN
The hypothesis that antitussives containing ethylmorphine are abused by alcoholics and drug addicts and that this may lead to fatal poisonings where ethylmorphine causes or contributes to death was investigated. For this purpose 14 cases were analysed where a blood ethylmorphine concentration above the therapeutic level of >/= 0.3 microg/g was found in autopsy blood samples. Alcohol was found in 8 of the 14 cases and alcoholism or drug addiction was noted on 8 of the 14 death certificates. Other drugs, mostly benzodiazepines, were found in all 14 cases. The cause of death was fatal poisoning in 8 of the 14 cases and although there were no mono-intoxications, the cause of death was specified as fatal ethylmorphine poisoning in 2 cases. Among the unspecified medicinal drug poisonings there were five cases with very high blood levels of ethylmorphine, indicating that this drug played an important contribution to the cause of death. The results indicate that deaths due to ethylmorphine in antitussive medicines may occur among drug addicts and alcoholics taking it in overdose. Physicians should therefore be restrictive in prescribing cough mixtures containing ethylmorphine to these categories of patients. Prescription of large amounts of the drug should be avoided.
Asunto(s)
Antitusígenos/envenenamiento , Causas de Muerte , Etilmorfina/envenenamiento , Intoxicación/etiología , Adulto , Intoxicación Alcohólica/diagnóstico , Intoxicación Alcohólica/patología , Ansiolíticos/análisis , Ansiolíticos/envenenamiento , Antitusígenos/análisis , Autopsia/legislación & jurisprudencia , Benzodiazepinas , Relación Dosis-Respuesta a Droga , Etilmorfina/análisis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Intoxicación/patología , Trastornos Relacionados con Sustancias/diagnóstico , Trastornos Relacionados con Sustancias/patología , SueciaRESUMEN
gamma-Tocopherol, produced by many plants, is the major form of tocopherol in the United States diet. It is an effecient protector of lipids against peroxidative damage. Epidemiologic studies show that supplementation of diet with gamma-tocopherol is inversely related to the risk of death from cardiovascular disease. This study was conducted to examine the role of gamma-tocopherol in oxidized LDL (ox-LDL)-induced nuclear factor (NF)-kappaB activation and apoptosis in human coronary artery endothelial cells (HCAECs). Cultured HCAECs were treated with ox-LDL (10-40 microgram/ml). Incubation of HCAECs with ox-LDL resulted in apoptosis of HCAECs, as determined by TUNEL and DNA laddering. Ox-LDL degraded IkappaB protein and activated NF-kappaB in HCAECs (both P < 0.01 vs control), as determined by Western blot. Treatment of cells with gamma-tocopherol attenuated ox-LDL-mediated degradation of IkappaB and activation of NF-kappaB (both P < 0.01 vs ox-LDL alone). The presence of gamma-tocopherol also reduced ox-LDL-induced apoptosis (P < 0.01 vs ox-LDL alone). A high concentration of gamma-tocopherol (50 micromol/L) was more effective than the low concentration of gamma-tocopherol (10 micromol/L) in this process. These observations show that ox-LDL induces apoptosis of HCAECs at least partially by activation of NF-kappaB signal transduction pathway. gamma-Tocopherol significantly decreases ox-LDL-induced apoptosis of HCAECs by inhibiting the activation of NF-kappaB.