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1.
Ther Deliv ; 9(11): 811-821, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30444461

RESUMEN

AIM: Deoxycholic acid (DCA) has improved gliclazide oral absorption, while Eudragit® (ED) polymers have improved formulation stability of antidiabetic drugs. The aim of the study is to test if DCA and ED encapsulation will optimize the release and stability of the potential antidiabetic drug probucol (PB). MATERIALS & METHODS: The PB formulations were prepared using ED polymers and DCA, and formulations were analyzed for their rheological and biological properties. RESULTS: Rheological properties and size distribution were similar among all groups. ß-cell survival and biological activities were best with NM30D microcapsules. The inflammatory profile and oxidative stress effects of microcapsules remained similar among all groups. CONCLUSION: ED NM30D and DCA incorporation can exert positive and stabilizing effects on PB oral microcapsules.


Asunto(s)
Antioxidantes/administración & dosificación , Portadores de Fármacos/química , Hipoglucemiantes/administración & dosificación , Células Secretoras de Insulina/efectos de los fármacos , Probucol/administración & dosificación , Administración Oral , Animales , Antioxidantes/farmacocinética , Disponibilidad Biológica , Cápsulas , Línea Celular , Supervivencia Celular/efectos de los fármacos , Ácido Desoxicólico/química , Composición de Medicamentos/métodos , Evaluación Preclínica de Medicamentos , Liberación de Fármacos , Interacciones Hidrofóbicas e Hidrofílicas , Hipoglucemiantes/farmacocinética , Células Secretoras de Insulina/metabolismo , Ratones , Estrés Oxidativo/efectos de los fármacos , Ácidos Polimetacrílicos/química , Probucol/farmacología
2.
Ther Deliv ; 9(10): 703-709, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30277134

RESUMEN

AIM: To enhance the bioavailability and brain uptake of probucol and examine whether it attenuates neuroinflammation and neurodegeneration by utilizing a sodium alginate nanoencapsulation technique. MATERIALS & METHODS: Wild-type mice were given either low-fat standard chow, high-fat (HF) diet to induce neuroinflammation and neurodegeneration, HF diet supplemented with nanocapsuled probucol at a concentration of 0.1% (w/w), HF diet supplemented with noncapsulated probucol at the same concentration of 0.1%, or HF diet supplemented with noncapsulated probucol at higher concentration (1%) for 24 weeks. RESULTS & CONCLUSION: The nanoencapsulation increased the plasma and brain concentration of probucol significantly compared with the mice that was given the same dosage of probucol without capsulation, and significantly suppressed the neuroinflammation and neurodegeneration.


Asunto(s)
Portadores de Fármacos/química , Composición de Medicamentos/métodos , Inflamación/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Fármacos Neuroprotectores/administración & dosificación , Probucol/administración & dosificación , Alginatos/química , Animales , Disponibilidad Biológica , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Cápsulas , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Inflamación/etiología , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Nanopartículas/química , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/patología , Fármacos Neuroprotectores/farmacocinética , Probucol/farmacocinética
3.
Malar J ; 15: 472, 2016 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-27634686

RESUMEN

BACKGROUND: Artemisinin-based combination therapy (ACT) has been adopted as national policy for the first-line treatment in large number of malaria-endemic regions. However, artemisinin-resistant parasites have emerged and are spreading, with slow-cleaning parasites being reported in patients treated with ACT. It means that more parasites are exposed to the partner drug alone and the risk of developing resistant parasites against the partner drug is increasing. Therefore, the development of a new method to enhance the effect of artemisinin is required. In this study, the potential effect of probucol as a combination drug of dihydroartemisinin (DHA), an artemisinin derivative, was examined. METHODS: C57BL/6 J mice infected with Plasmodium yoelii XL-17 were treated with probucol and/or DHA. The mice were fed with a probucol mixed diet from 2 weeks before infection and through infection period. DHA was injected to mice three to 5 days post infection once a day. In addition, 0.5 % (w/w) probucol was mixed with vitamin E supplemented diet (800 mg/kg) and fed to mice infected with P. yoelii XL-17 to examine the mechanisms of probucol on murine malaria. Furthermore, 8-OHdG, a biomarker of oxidized DNA, was detected in infected red blood cells (iRBC) taken from infected mice by immunofluorescent staining. RESULTS: With dose-dependent manner, both probucol and DHA decreased parasitaemia and increased survival rate of mice infected with P. yoelii XL-17. A significantly larger amount of 8-OHdG was detected in iRBC taking from probucol-treated mice than control mice. In addition, a large amount of vitamin E supplementation eliminated the effect of probucol against P. yoelii XL-17 infection and lowered the effect of probucol on host plasma vitamin E concentration. The effective doses for probucol and DHA were 0.5 % and 30 mg/kg, respectively, in each single treatment. While the combination treatment of 0.25 % probucol and 7.5 mg/kg DHA was effective in all mice from P. yoelii XL-17 infection. CONCLUSION: This study demonstrated that probucol has some impact on malaria by oxidative stress through the induction of host plasma vitamin E deficiency. Moreover, the effective dose of DHA on malaria was decreased by prophylactic treatment of probucol. This finding indicates that probucol might be a candidate for a prophylactic treatment drug to enhance the effect of DHA.


Asunto(s)
Antimaláricos/administración & dosificación , Antimaláricos/farmacología , Artemisininas/administración & dosificación , Artemisininas/farmacología , Malaria/tratamiento farmacológico , Probucol/administración & dosificación , Probucol/farmacología , Animales , Quimioprevención/métodos , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , Plasmodium yoelii/efectos de los fármacos , Resultado del Tratamiento
4.
Eur J Pharm Biopharm ; 76(2): 238-44, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20637868

RESUMEN

The capability of transglycosylated materials, α-glycosyltransferase-treated stevia (Stevia-G) and α-glycosyl hesperidin (Hsp-G), to enhance the bioavailability of poorly water-soluble drugs was investigated. Spray-dried particles (SDPs) of drug/transglycosylated material, such as, flurbiprofen (FP)/Stevia-G, probucol (PRO)/Stevia-G, FP/Hsp-G, and PRO/Hsp-G were prepared. All SDPs showed pronounced improvement in both dissolution rate and apparent drug solubility. The amount of dissolved PRO was significantly improved to that of untreated PRO crystals when prepared as SDPs of PRO/Stevia-G or PRO/Hsp-G. There was no cytotoxicity to Caco-2 cells at levels of 10% Stevia-G or Hsp-G solution. Values for the area under the plasma concentration-time curve (AUC) of untreated PRO, SDPs of PRO/Hsp-G and PRO/Stevia-G after oral administration to rats were 4.94±2.06, 26.08±4.52 and 48.79±9.97µgh/mL, respectively. Interestingly, AUC values in cases of the FP system were in the order of untreated FP

Asunto(s)
Excipientes/química , Hesperidina/química , Extractos Vegetales/química , Stevia/química , Administración Oral , Animales , Área Bajo la Curva , Disponibilidad Biológica , Células CACO-2 , Excipientes/toxicidad , Flurbiprofeno/administración & dosificación , Flurbiprofeno/química , Flurbiprofeno/farmacocinética , Glicosilación , Hesperidina/toxicidad , Humanos , Masculino , Extractos Vegetales/toxicidad , Probucol/administración & dosificación , Probucol/química , Probucol/farmacocinética , Ratas , Ratas Sprague-Dawley , Solubilidad , Pruebas de Toxicidad
5.
Vopr Virusol ; 54(3): 26-32, 2009.
Artículo en Ruso | MEDLINE | ID: mdl-19537094

RESUMEN

The antiviral activity of Panavir was studied on a model of mice infected with the strain Sofjin of tick-borne encephalitis (TBE) virus. The efficacy of Panavir was studied in the treatment of the chronic (monotherapy; 30 patients) and acute febrile and meningeal (combined therapy; n = 113) forms of TBE. Panavir was found to have a positive effect on the clinical course of TBE and the immune mechanisms of the body's protection.


Asunto(s)
Antioxidantes/uso terapéutico , Encefalitis Transmitida por Garrapatas/tratamiento farmacológico , Probucol/uso terapéutico , Adulto , Anciano , Animales , Animales Recién Nacidos , Anticuerpos Antivirales/sangre , Antígenos/sangre , Antioxidantes/administración & dosificación , Evaluación Preclínica de Medicamentos , Encefalitis Transmitida por Garrapatas/sangre , Encefalitis Transmitida por Garrapatas/inmunología , Femenino , Humanos , Inyecciones Intravenosas , Recuento de Linfocitos , Subgrupos Linfocitarios/inmunología , Masculino , Ratones , Persona de Mediana Edad , Probucol/administración & dosificación , Resultado del Tratamiento
6.
Horm Metab Res ; 40(7): 473-8, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18404599

RESUMEN

Cilostazol, an antiplatelet drug, and probucol, a cholesterol-lowering drug, are reported to ameliorate atherosclerosis in animal models. However, their combined effect on atherosclerosis is unclear. We therefore evaluated their combined effect on atherosclerotic lesions in LDL receptor-deficient mice. Male LDL receptor-deficient mice were fed a high fat diet with or without cilostazol alone, probucol alone, or with cilostazol and probucol in combination, for 8 weeks. Body weight and plasma lipid levels were measured before and during treatment. At the end of treatment, the size distribution of plasma lipoproteins was analyzed by HPLC and then plasma HDL cholesterol levels and en face aortic atherosclerotic lesion areas were measured. Probucol alone significantly decreased both total cholesterol and HDL cholesterol, while cilostazol alone did not decrease total cholesterol, but significantly increased HDL cholesterol. Both cilostazol alone and probucol alone significantly decreased atherosclerotic lesion areas, and their combined administration showed more significant decreases than when each drug was administered singly. The combination of cilostazol and probucol was more effective in preventing atherosclerotic lesion formation than the administration of each drug alone; this may provide us with a new strategy for treating atherosclerosis.


Asunto(s)
Aterosclerosis/prevención & control , Dieta Aterogénica , Probucol/administración & dosificación , Receptores de LDL/genética , Tetrazoles/administración & dosificación , Animales , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/farmacología , Aorta/efectos de los fármacos , Aorta/patología , Apolipoproteína A-I/sangre , Colesterol/sangre , Cilostazol , Combinación de Medicamentos , Evaluación Preclínica de Medicamentos , Masculino , Ratones , Ratones Noqueados , Probucol/farmacología , Tetrazoles/farmacología
7.
Artículo en Alemán | MEDLINE | ID: mdl-17013773

RESUMEN

In vitro studies have shown that antioxidants (e. g. beta-carotene, vitamin C and vitamin E) can interfere with some pathomechanisms of atherosclerosis and therefore might have a protective effect. From the investigated antioxidants vitamin E showed the best effect. Some animal and epidemiological studies confirmed such a protective effect in vivo especially after administration of high doses of vitamin E. However, most of the placebo-controlled studies for primary or secondary prevention failed to show a protective effect even after administration of high doses. In addition, other studies demonstrated a risk for adverse effects due to antioxidant supplementation (beta-carotene and vitamin E). Our review summarises the principle of antioxidant supplementation and a number of relevant epidemiological and clinical studies for prevention of atherosclerosis. The obtained results suggest that supplementation of antioxidants cannot be recommended for the normal population.


Asunto(s)
Antioxidantes/uso terapéutico , Aterosclerosis/prevención & control , Suplementos Dietéticos , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Animales , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/uso terapéutico , Antioxidantes/administración & dosificación , Ácido Ascórbico/administración & dosificación , Ácido Ascórbico/uso terapéutico , Aterosclerosis/epidemiología , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Oxidantes/fisiología , Prevención Primaria , Probucol/administración & dosificación , Probucol/uso terapéutico , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Especies Reactivas de Oxígeno , Riesgo , Factores de Riesgo , Factores Sexuales , Factores de Tiempo , Tocoferoles/administración & dosificación , Tocoferoles/uso terapéutico , Vitamina E/administración & dosificación , Vitamina E/efectos adversos , Vitamina E/uso terapéutico , Vitaminas/administración & dosificación , Vitaminas/uso terapéutico , beta Caroteno/administración & dosificación , beta Caroteno/efectos adversos , beta Caroteno/uso terapéutico
8.
Chang Gung Med J ; 29(6): 561-7, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-17302219

RESUMEN

BACKGROUND: Shear stress caused by arteriovenous fistula (AVF) enhances endothelium-dependent relaxation (EDR) but oxidized low-density lipoprotein (ox- LDL) counteracts its effect. Probucol, a lipid soluble antioxidant, may preserve EDR of AVF by limiting oxidation of LDL. METHODS: Twenty New Zealand rabbits, fed with 2% cholesterol chow for 4 weeks, underwent AVF. They were then divided into two groups: continuing with 2% cholesterol chow alone (group I) and 2% cholesterol chow with 1% probucol supplement (group II). Another 10, fed regular chow, were assigned to the control (group III). The levels of cholesterol and LDL were measured. Segments of the AVF afferent arteries were harvested to check intimal thickness, and endothelium-dependent and independent relaxations, after 4 weeks dietary treatment had been completed. RESULTS: Both cholesterol and LDL levels were significantly elevated after 4 weeks of cholesterol feeding. These profiles reached higher levels at 8 weeks in group I and were less increased in group II. The intimal hyperplasia ratio was 48% in group I, 34% in group II and 24% in group III. Maximal EDR response to either acetylcholine or receptor-independent calcium ionophore A23187 in group II was greater than that in group I (66 +/- 1.9% versus 38 +/- 1.2%, p = 0.02; 76 +/- 2.4% versus 30 +/- 0.8%, p = 0.01) and not different from that in group III (74 +/- 2.4%, 84 +/- 3.7%). There was no similar difference of denuded arterial rings among the three groups (76 +/- 3.2%, 78 +/- 3.7%, 82 +/- 4.1%). CONCLUSION: Cholesterol can limit EDR of AVF and produce vulnerability to early occlusion and thrombosis. Probucol supplement under hyperlipidemia status preserves EDR and not endothelium-independent relaxation.


Asunto(s)
Antioxidantes/administración & dosificación , Fístula Arteriovenosa/fisiopatología , Endotelio Vascular/fisiología , Hipercolesterolemia/fisiopatología , Probucol/administración & dosificación , Vasodilatación , Animales , Colesterol/sangre , Factores Relajantes Endotelio-Dependientes/fisiología , Hiperplasia , Lipoproteínas LDL/sangre , Estrés Oxidativo , Conejos , Túnica Íntima/patología
9.
J Biochem Mol Toxicol ; 19(5): 336-46, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-16292755

RESUMEN

Vitamin E and probucol are well-known antioxidants that prevent cells from the oxidative stress, which is a risk factor of atherosclerosis. Male rabbits were fed either 0.03% vitamin E or 0.05% probucol in a 0.5% high-cholesterol (HC) diet for 8 weeks. Vitamin E and probucol significantly suppressed an increase in plasma total-cholesterol (total-C) and low-density lipoprotein cholesterol compared to HC-control group. However, plasma high-density lipoprotein-cholesterol (HDL-C) and HDL-C/total-C ratio levels and plasma paraoxonase activity were only significantly higher in vitamin E group after 8 weeks. Hepatic ACAT activity was significantly lower in both vitamin E and probucol groups than in HC-control group, while HMG-CoA reductase activity was the highest only in the probucol group. Total fecal sterol content was significantly higher in probucol and vitamin E groups than in the two control groups. Some atherogenic signs were discovered in the aortic fatty streak of HC-control group, yet not in other groups. Hepatic mRNA expressions of apo B-100 and apo C-III were significantly lower in probucol group than in other groups. Vitamin E supplementation was found to alter the plasma HDL-C-related factors; meanwhile, probucol supplementation was very effective in enhancing cholesterol metabolism, except for a negative effect that reduced plasma HDL-C concentration.


Asunto(s)
Anticolesterolemiantes/administración & dosificación , Arildialquilfosfatasa/sangre , HDL-Colesterol/sangre , Probucol/administración & dosificación , Vitamina E/administración & dosificación , Alanina Transaminasa/sangre , Animales , Aorta/efectos de los fármacos , Aspartato Aminotransferasas/sangre , Secuencia de Bases , Peso Corporal/efectos de los fármacos , Cartilla de ADN , Expresión Génica , Hígado/efectos de los fármacos , Masculino , Conejos
10.
J Atheroscler Thromb ; 12(3): 132-7, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-16020912

RESUMEN

Oxysterols induce apoptosis in vascular endothelial cells in vitro, but it is not clear whether they do so in vivo. We intravenously injected an oxysterol, cholestan-3beta, 5alpha, 6beta-triol, into rats and quantitatively analyzed endothelial cell apoptosis in the aorta. Oxysterol significantly promoted apoptosis in a time- and dose-dependent fashion. The apoptosis had increased 4.5-fold 6 hrs after injection, and returned to the background level at 48 hrs. An extract of the Chinese herb Danshen as well as probucol abolished triol-induced endothelial cell apoptosis in vitro and in vivo. Since apoptotic cells are quickly cleared, oxysterol-induced apoptosis could significantly affect endothelial integrity over a long period of time. Radical scavengers may be useful for the prevention of endothelial damage.


Asunto(s)
Antioxidantes/administración & dosificación , Apoptosis/efectos de los fármacos , Colestanoles/administración & dosificación , Medicamentos Herbarios Chinos/administración & dosificación , Células Endoteliales/efectos de los fármacos , Hipolipemiantes/administración & dosificación , Fenantrolinas/administración & dosificación , Animales , Aorta/citología , Aorta/efectos de los fármacos , Técnicas de Cultivo de Célula , Relación Dosis-Respuesta a Droga , Humanos , Inyecciones Intravenosas , Masculino , Probucol/administración & dosificación , Ratas , Ratas Sprague-Dawley , Salvia miltiorrhiza , Venas Umbilicales/citología , Venas Umbilicales/efectos de los fármacos
11.
Acta Oncol ; 42(4): 304-8, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-12899501

RESUMEN

Cardiotoxicity is a serious side effect of cancer treatment with the commonly used drug 5-fluorouracil (5-FU). The pathophysiology of this is unclear. Experimental studies show a thrombogenic effect of 5-FU, secondary to a direct toxic effect on the endothelium, possibly mediated by radical generation. Probucol is a lipid-lowering drug with strong antioxidant properties. The aim of this study was to evaluate the possibility of using probucol treatment to protect against the toxicity of 5-FU on vascular endothelium of the central artery in the ears of rabbits. Five groups of rabbits were treated with 1) 5-FU, 2) saline, 3) probucol high-dose and saline, 4) probucol high-dose and 5-FU, 5) probucol low-dose and 5-FU. Damage to the arterial endothelium was evaluated by scanning electron microscopy. Damage to the endothelium in 5-FU + probucol-treated animals was minimal and comparable to that of the control group. Intima disruption or thrombus formation was seen with 5-FU only. The results of the study indicate that treatment with probucol prevents 5-FU-induced endothelial injury.


Asunto(s)
Anticolesterolemiantes/farmacología , Antimetabolitos Antineoplásicos/toxicidad , Endotelio Vascular/efectos de los fármacos , Fluorouracilo/toxicidad , Probucol/farmacología , Trombosis/prevención & control , Animales , Anticolesterolemiantes/administración & dosificación , Arterias/efectos de los fármacos , Arterias/ultraestructura , Endotelio Vascular/ultraestructura , Inyecciones Intraperitoneales , Masculino , Microscopía Electrónica de Rastreo , Probucol/administración & dosificación , Conejos , Trombosis/inducido químicamente
12.
Proc Natl Acad Sci U S A ; 100(12): 7283-8, 2003 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-12771386

RESUMEN

Mice with homozygous null mutations in the high-density lipoprotein receptor SR-BI (scavenger receptor class B, type I) and apolipoprotein E genes fed a low-fat diet exhibit a constellation of pathologies shared with human atherosclerotic coronary heart disease (CHD): hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarctions, cardiac dysfunction (heart enlargement, reduced systolic function and ejection fraction, and ECG abnormalities), and premature death (mean age 6 weeks). They also exhibit a block in RBC maturation and abnormally high plasma unesterified-to-total cholesterol ratio (0.8) with associated abnormal lipoprotein morphology (lamellar/vesicular and stacked discoidal particles reminiscent of those in lecithin/cholesterol acyltransferase deficiency and cholestasis). Treatment with the lipid-lowering, antiatherosclerosis, and antioxidation drug probucol extended life to as long as 60 weeks (mean 36 weeks), and at 5-6 weeks of age, virtually completely reversed the cardiac and most RBC pathologies and corrected the unesterified to total cholesterol ratio (0.3) and associated distinctive abnormal lipoprotein morphologies. Manipulation of the timing of administration and withdrawal of probucol could control the onset of death and suggested that critical pathological changes usually occurred in untreated double knockout mice between approximately 3 (weaning) and 5 weeks of age and that probucol delayed heart failure even after development of substantial CHD. The ability of probucol treatment to modulate pathophysiology in the double knockout mice enhances the potential of this murine system for analysis of the pathophysiology of CHD and preclinical testing of new approaches for the prevention and treatment of cardiovascular disease.


Asunto(s)
Anticolesterolemiantes/farmacología , Apolipoproteínas E/deficiencia , Antígenos CD36/metabolismo , Enfermedad Coronaria/prevención & control , Proteínas de la Membrana , Probucol/farmacología , Receptores Inmunológicos , Receptores de Lipoproteína , Factores de Edad , Animales , Anticolesterolemiantes/administración & dosificación , Apolipoproteínas E/genética , Antígenos CD36/genética , Diferenciación Celular/efectos de los fármacos , Enfermedad Coronaria/tratamiento farmacológico , Enfermedad Coronaria/genética , Enfermedad Coronaria/patología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Eritrocitos/efectos de los fármacos , Eritrocitos/patología , Humanos , Lipoproteínas/sangre , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocardio/patología , Probucol/administración & dosificación , Receptores Depuradores , Receptores Depuradores de Clase B
13.
Atherosclerosis ; 163(2): 249-59, 2002 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12052471

RESUMEN

Oxidative modification of lipoproteins may trigger and maintain atherogenesis. We compared the effects of different antioxidants (alpha-tocopherol, probucol, ubiquinone-10) at doses similar to those used in humans in Watanabe Heritable Hyperlipidemic (WHHL) rabbits for 12 months. Aortic lesions were analyzed for their extent and cellular composition of lesions, mean thickness of fibrous caps and density of smooth muscle cells therein, content of antioxidants, non-oxidized and oxidized lipids. Compared to controls, probucol significantly lowered the extent and macrophage content of lesions and increased the existence and smooth muscle cell density of fibrous caps. alpha-Tocopherol supplementation increased the aortic content of vitamin E, but had no decreasing effect on either the accumulation of macrophage-specific antigen in the aorta or lesion size. Nevertheless, both probucol and alpha-tocopherol significantly decreased in vitro LDL oxidizability, measured under typically strong oxidative conditions. Ubiquinone-10 supplement increased lesion size and the fraction of lesions containing fibrous caps; however, LDL oxidizability remained unaffected by ubiquinone-10 treatment. None of the antioxidants tested lowered oxidized lipids within aortic tissue; however, long-term treatment with probucol provided the most effective anti-atherosclerotic effect, while alpha-tocopherol may be pro-atherogenic and ubiquinone-10 exerts ambivalent effects. Our data suggest that (i) widely used oxidation measures, such as ex-vivo LDL oxidizability, do not reflect the degree of atherosclerosis; and (ii) long-term beneficial effects of relatively low doses of antioxidants may be outweighed by high levels of plasma cholesterol in WHHL rabbits.


Asunto(s)
Antioxidantes/administración & dosificación , Arteriosclerosis/tratamiento farmacológico , Probucol/administración & dosificación , Ubiquinona/análogos & derivados , Ubiquinona/administración & dosificación , alfa-Tocoferol/administración & dosificación , Animales , Antioxidantes/farmacocinética , Aorta/metabolismo , Aorta/patología , Arteriosclerosis/metabolismo , Arteriosclerosis/patología , Coenzimas , Modelos Animales de Enfermedad , Femenino , Humanos , Lípidos/sangre , Lipoproteínas LDL/metabolismo , Masculino , Probucol/farmacocinética , Conejos , Ubiquinona/metabolismo , Ubiquinona/farmacocinética , Vitamina E/metabolismo , alfa-Tocoferol/farmacocinética
14.
Atherosclerosis ; 154(2): 387-98, 2001 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-11166771

RESUMEN

The oxidation hypothesis of atherosclerosis implies that antioxidants are able to inhibit lipoprotein oxidation in the arterial wall and thereby retard atherogenesis. Since most of the animal studies performed have used very high doses of antioxidants, it is to date unknown whether antioxidants are effective antiatherosclerotic agents when given in pharmacological doses. Here we addressed this question using homozygous Watanabe heritable hyperlipidaemic (WHHL) rabbits as an animal model of atherosclerosis. The rabbits were divided into four groups, each consisting of ten animals. They received either a standard diet or a diet containing 4.3 mg ubiquinone-10, or 4.3 mg vitamin E or 15 mg probucol/kg body weight daily. After 12 months, the extent of aortic atherosclerosis was assessed as the intima thickness, media thickness and intima-to-media ratio in 14 cross sections equally distributed over the whole aorta. To evaluate the antioxidant effects of the diet, lipophilic and hydrophilic antioxidants, lipids, fatty acids and plasma oxidizability were measured after 0, 3 and 6 months of feeding. We found that supplementation with probucol significantly decreased aortic intima-to-media ratio compared to controls. The antiatherosclerotic action of probucol was accompanied by its beneficial action on plasma oxidizability and some plasma antioxidants. No decrease in aortic atherosclerosis was measured in ubiquinone-10- and vitamin E-supplemented rabbits, despite the fact that both antioxidants decreased plasma oxidizability and ubiquinone-10 increased the plasma levels of antioxidants. Taken together, these data suggest that pharmacological doses of probucol retard atherogenesis in WHHL rabbits by an antioxidant mechanism, while ubiquinone-10 and vitamin E at these dosages are ineffective in this highly hyperlipidaemic model. The measurement of some oxidation-related parameters in plasma, such as lipophilic antioxidants, polyunsaturated fatty acids and lipoprotein oxidizability, may be useful in assessing the risk of atherogenesis in humans.


Asunto(s)
Antioxidantes/administración & dosificación , Arteriosclerosis/prevención & control , Hiperlipidemias/terapia , Oxidación-Reducción/efectos de los fármacos , Administración Oral , Animales , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/farmacocinética , Antídotos/administración & dosificación , Antídotos/farmacocinética , Antioxidantes/farmacocinética , Aorta/efectos de los fármacos , Aorta/patología , Arteriosclerosis/sangre , Arteriosclerosis/etiología , Arteriosclerosis/patología , Dieta , Relación Dosis-Respuesta a Droga , Ácidos Grasos Insaturados/sangre , Hiperlipidemias/sangre , Hiperlipidemias/complicaciones , Lipoproteínas/sangre , Probucol/administración & dosificación , Probucol/farmacocinética , Conejos , Túnica Íntima/efectos de los fármacos , Túnica Íntima/patología , Ubiquinona/administración & dosificación , Ubiquinona/farmacocinética , Vitamina E/administración & dosificación , Vitamina E/farmacocinética
15.
Diabetologia ; 41(2): 157-64, 1998 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-9498648

RESUMEN

Oxidative stress and dyslipidaemia are key features of diabetes mellitus and may be involved in mediating the vascular endothelial dysfunction associated with this disease. The aim of this study was to examine the effect of dietary lipid-lowering and antioxidant agents on vascular endothelial function and oxidative stress. Diabetic male Sprague-Dawley rats (i.v. streptozotocin, 45 mg/kg) were fed for 4 weeks on a standard diet or on a diet supplemented with either the lipid-lowering antioxidant probucol (1% w/w in diet) or the 3-hydroxy 3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitor simvastatin (0.01% w/w in diet). Responses to noradrenaline, acetylcholine, and sodium nitroprusside were assessed in small mesenteric arteries (mean internal diameter 300+/-5 microm, n = 80) mounted on a small vessel myograph. Plasma concentrations of total cholesterol and triglycerides were significantly raised in standard-fed diabetic rats and significantly reduced in probucol and simvastatin-fed diabetic rats 8-epi-prostaglandin (PG)F2alpha, an indicator of oxidative stress, was raised in liver and aorta from diabetic rats compared to controls. Probucol supplementation reduced 8-epi-PGF2alpha in aorta and liver of diabetic rats but increased 8-epi-PGF2alpha content in plasma and aorta from control animals. The abnormal relaxation to acetylcholine in arteries from the diabetic rats (pEC550 diabetic 6.763+/-0.172 vs control 7.541+/-0.175; p < 0.05) was not improved by probucol or simvastatin. These data, therefore, do not support a role for oxidative stress or dyslipidaemia in mediating the impaired ACh-induced endothelium-dependent relaxation of small mesenteric arteries from the streptozotocin-diabetic rat.


Asunto(s)
Antioxidantes/farmacología , Diabetes Mellitus Experimental/fisiopatología , Endotelio Vascular/efectos de los fármacos , Hipolipemiantes/farmacología , Probucol/farmacología , Simvastatina/farmacología , Animales , Antioxidantes/administración & dosificación , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/metabolismo , Dieta , Dinoprost/análogos & derivados , Dinoprost/sangre , Dinoprost/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Endotelio Vascular/fisiopatología , F2-Isoprostanos , Hipolipemiantes/administración & dosificación , Peroxidación de Lípido/efectos de los fármacos , Lípidos/sangre , Masculino , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/fisiopatología , Relajación Muscular/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Probucol/administración & dosificación , Probucol/sangre , Probucol/metabolismo , Ratas , Ratas Sprague-Dawley , Simvastatina/administración & dosificación , Distribución Tisular
16.
Arterioscler Thromb Vasc Biol ; 16(12): 1465-72, 1996 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-8977450

RESUMEN

Previous studies have demonstrated that compared with more buoyant LDL, dense LDL (D-LDL) is more susceptible to oxidation and less readily protected from oxidation by antioxidant enrichment. However, diets enriched in monounsaturated fatty acids (MUFAs) appear particularly effective in protecting D-LDL from oxidation. We therefore evaluated in 12 non-insulin-dependent diabetes mellitus subjects the effects of supplementation with alpha-tocopherol (1600 IU/d) and probucol (1 g/d) alone and in combination with an MUFA-enriched diet on LDL and LDL subfraction susceptibility to oxidation and monocyte release of superoxide anion. Subjects received either alpha-tocopherol or probucol for 4 months, and during the fourth month both groups also received an MUFA-enriched diet. alpha-Tocopherol levels were significantly increased in LDL and LDL subfractions (P < .05) after 3 months of supplementation. MUFA-enriched diets led to further increases in alpha-tocopherol in LDL fractions in the alpha-tocopherol group as well as in those receiving probucol. In the alpha-tocopherol-supplemented group, lag times were increased significantly (1.6- to 2.0-fold) for all LDL fractions, although the absolute increase was least for D-LDL. Although probucol supplementation increased lag times of LDL and LDL subfractions three- to fourfold, D-LDL was still more readily oxidized. In both the alpha-tocopherol- and probucol-supplemented groups the benefit of adding MUFA-enriched diets was greatest for D-LDL, with further increases in lag time of 26% and 18%, respectively. Neither antioxidant supplementation nor the addition of an MUFA-enriched diet reduced unstimulated or phorbol ester-stimulated monocyte superoxide anion production. These data demonstrate the markedly different effects that antioxidants and diet may have on different LDL subfractions, which may be particularly important in individuals with non-insulin-dependent diabetes mellitus, who frequently have increased amounts of D-LDL.


Asunto(s)
Antioxidantes/administración & dosificación , Diabetes Mellitus Tipo 2/metabolismo , Ácidos Grasos Monoinsaturados/administración & dosificación , Peroxidación de Lípido/efectos de los fármacos , Lipoproteínas LDL/metabolismo , Adulto , Anciano , Dieta , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Probucol/administración & dosificación , Vitamina E/administración & dosificación
17.
J Clin Invest ; 95(6): 2520-9, 1995 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-7769097

RESUMEN

Excess vascular oxidative stress and the local formation of oxidized LDL (ox-LDL) have been implicated in the development of impaired endothelium-dependent arterial relaxation in hypercholesterolemia and atherosclerosis. Dietary antioxidants limit LDL oxidation in vitro and treatment of cholesterol-fed rabbits with dietary antioxidants preserves endothelium-derived relaxing factor (EDRF) action. To investigate the mechanism(s) responsible for these observations, we examined EDRF action, vascular oxidative stress, and antioxidant protection in male New Zealand White rabbits using four dietary treatments. Animals consumed standard chow (chow group) or chow supplemented with: (a) 0.5% cholesterol (0.5% cholesterol group); (b) 1% cholesterol (1% cholesterol group); or (c) 1% cholesterol and 1% probucol (probucol group). After 28 d of dietary treatment, segments of thoracic aorta from the 0.5 and 1% cholesterol groups demonstrated impairment of acetylcholine-mediated endothelium-dependent arterial relaxation compared to chow-fed animals (57 +/- 11% and 45 +/- 9% vs 78 +/- 3%, respectively; P < 0.05). In contrast, vessels from the probucol group demonstrated normal relaxation to acetylcholine (83 +/- 5%). Plasma cholesterol levels and the extent of atherosclerosis were similar among all cholesterol-fed groups. Probucol treatment was associated a threefold increase in LDL resistance to copper-induced oxidative modification (P < 0.05) and a reduction in tissue lipid peroxidation (as assessed by thiobarbituric acid-reactive substances; P < 0.05) compared to animals fed cholesterol alone. Most importantly, both of these changes were strongly correlated with preserved EDRF action. Moreover, cholesterol feeding was associated with a dose-dependent increase in vascular superoxide generation and lysophosphatidylcholine content, both of which were prevented by probucol treatment. From these findings, we conclude that probucol, a lipid-soluble antioxidant, preserves EDRF action in cholesterol-fed rabbits in association with limiting vascular oxidative stress and superoxide generation.


Asunto(s)
Antioxidantes/farmacología , Arteriosclerosis/prevención & control , Colesterol/metabolismo , Dieta Aterogénica , Endotelio Vascular/fisiología , Probucol/administración & dosificación , Superóxidos/metabolismo , Vasodilatación , Animales , Arterias/fisiología , Peso Corporal , Lípidos/sangre , Lipoproteínas LDL/metabolismo , Masculino , Óxido Nítrico/fisiología , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Conejos , Túnica Íntima/citología
18.
J Parasitol ; 81(1): 99-103, 1995 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-7876987

RESUMEN

Feeding 20% (w/w) menhaden-fish oil in a standard laboratory chow diet for 4 wk partially protected CBA/CaJ mice from the central nervous system consequences of infection with Plasmodium berghei (ANKA). Full protection (complete survival for 14 days postinfection) could be obtained by feeding a purified pro-oxidant vitamin E-deficient diet containing 4% (w/w) menhaden oil (MO - VE diet). The purified pro-oxidant MO - VE diet also exerted a pronounced suppressive effect against the parasite (depressed 6-day parasitemias). The anitmalarial effect of the MO - VE diet could be prevented by supplementing the diet with vitamin E or with either of 2 synthetic antioxidants, N,N'-diphenyl-p-phenylenediamine or probucol. These results suggest that the fish oil exerts its antimalarial effect by imposing a dietary-induced oxidative stress on the infected host erythrocyte, the parasite, or both. Nutritional manipulation of host oxidative stress status may be a useful adjunct therapy in patients undergoing treatment with pro-oxidant antimalarials such as drugs of the qinghaosu family.


Asunto(s)
Aceites de Pescado/uso terapéutico , Malaria Cerebral/prevención & control , Estrés Oxidativo , Plasmodium berghei , Alimentación Animal , Animales , Antioxidantes/administración & dosificación , Antioxidantes/farmacología , Modelos Animales de Enfermedad , Aceites de Pescado/administración & dosificación , Malaria Cerebral/dietoterapia , Malaria Cerebral/metabolismo , Masculino , Ratones , Ratones Endogámicos CBA , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Fenilendiaminas/administración & dosificación , Fenilendiaminas/farmacología , Probucol/administración & dosificación , Probucol/farmacología , Vitamina E/farmacología , Deficiencia de Vitamina E/complicaciones
19.
Ann Nutr Metab ; 39(2): 99-106, 1995.
Artículo en Inglés | MEDLINE | ID: mdl-7625776

RESUMEN

The inhibitory effect of probucol on ferrous-iron-induced microsomal lipid peroxidation was compared to that of alpha-tocopherol and butylated hydroxytoluene (BHT). Male Wistar rats were fed with diets containing 1% probucol, 0.2% BHT or 0.1% alpha-tocopherol for 30 days. There were no effects of dietary antioxidants on growth parameters, although liver weight was significantly higher in the BHT-fed rats. Probucol reduced serum levels of total and free cholesterol, while BHT feeding increased the concentrations of serum thiobarbituric-acid-reactive substances, HDL cholesterol and hepatic phospholipid. alpha-Tocopherol had no effect on these parameters. Incorporation of both, probucol and alpha-tocopherol, decreased the susceptibility of microsomes to lipid peroxidation in vitro, while BHT incorporation increased hepatic microsomal lipid peroxidation. These results suggest the possible usefulness of probucol for treatment of both hypercholesterolemia and elevated hepatic microsomal lipid peroxidation, while alpha-tocopherol decreases only an elevated lipid peroxidation. BHT works as a prooxidant.


Asunto(s)
Antioxidantes/farmacología , Peroxidación de Lípido/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Animales , Antioxidantes/administración & dosificación , Hidroxitolueno Butilado/farmacología , Colesterol/sangre , Dieta , Ácidos Grasos/análisis , Ácidos Grasos/metabolismo , Alimentos Fortificados , Hipercolesterolemia/sangre , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/metabolismo , Metabolismo de los Lípidos , Peroxidación de Lípido/fisiología , Hígado/metabolismo , Hígado/fisiología , Hígado/ultraestructura , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/fisiología , Fosfolípidos/análisis , Fosfolípidos/metabolismo , Probucol/administración & dosificación , Probucol/farmacología , Probucol/uso terapéutico , Ratas , Ratas Wistar , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Vitamina E/administración & dosificación , Vitamina E/farmacología
20.
Eur J Clin Invest ; 24(11): 759-65, 1994 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-7890014

RESUMEN

This study investigates the hypothesis that lipid soluble antioxidants may increase the resistance of low-density lipoprotein (LDL) to oxidation and also enhance vascular endothelial responses in humans. In a double-blind parallel group study, 24 hypercholesterolaemic patients already on treatment with simvastatin (20 mg day-1), were randomized to supplementary treatment with probucol (500 mg bd), vitamin E (400 IU daily) or placebo for 8 weeks. Mean serum cholesterol before antioxidant treatment was 7.00 mmol l-1. Resistance of LDL to oxidation by copper was increased by 830% in the probucol group and by 30% in the vitamin E group. However, thiobarbituric acid reacting substances in whole serum were not altered by either antioxidant. Probucol lowered HDL- and LDL-cholesterol levels and increased the QT interval. Forearm vascular responses, as measured by venous occlusion plethysmography, to acetylcholine, glyceryl trinitrate and NG-monomethyl-L-arginine, were not significantly changed by antioxidant treatment. Probucol has a major, and vitamin E a minor, effect on LDL resistance to oxidation but neither compound appears to alter forearm vascular responses in vivo.


Asunto(s)
LDL-Colesterol/sangre , Antebrazo/irrigación sanguínea , Hiperlipidemias/tratamiento farmacológico , Probucol/administración & dosificación , Vitamina E/administración & dosificación , Adulto , LDL-Colesterol/efectos de los fármacos , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , Hiperlipidemias/sangre , Hipolipemiantes/administración & dosificación , Lovastatina/administración & dosificación , Lovastatina/análogos & derivados , Masculino , Persona de Mediana Edad , Oxidación-Reducción/efectos de los fármacos , Probucol/efectos adversos , Flujo Sanguíneo Regional , Simvastatina , Vitamina E/efectos adversos , Vitamina E/sangre
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