RESUMEN
Amblyomma americanum (Linnaeus) (Acari: Ixodidae) (lone star tick) is an aggressive, generalist parasite that vectors numerous important human and animal pathogens. In recent decades its geographic range has expanded northwards from endemic regions in the southeastern and southcentral United States. In 2019 five questing A. americanum ticks, comprising two life stages were detected at one site in southwestern Michigan, satisfying one CDC criterium for an established population for the first time in recent history in the state. To better characterize the extent of emerging A. americanum, we conducted active surveillance (i.e., drag sampling) in summer 2020 throughout Michigan's southern counties and detected one adult A. americanum from each of six widespread sites, including where they had been detected in 2019. A larger established population was identified at another site in Berrien County, which yielded 691 A. americanum comprising three life stages, and questing phenologies here were similar to that reported for other endemic regions. Statewide surveillance in 2021 revealed no A. americanum outside of Berrien County, but establishment criteria were met again at the two sites where established populations were first detected respectively in 2019 and 2020. These observations may represent the successful invasion of A. americanum into Michigan. Data from passive (1999-2020) and active surveillance (2004-2021) efforts, including a domestic animal sentinel program (2015-2018), are reported to provide context for this nascent invasion. Continued active surveillance is needed to help inform the public, medical professionals, and public health officials of the health risks associated with this vector.
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Ixodidae , Garrapatas , Amblyomma , Animales , Humanos , Michigan , Salud PúblicaRESUMEN
Ferroptosis is a form of programmed cell death associated with inflammation, neurodegeneration, and ischemia. Vitamin E (alpha-tocopherol) has been reported to prevent ferroptosis, but the mechanism by which this occurs is controversial. To elucidate the biochemical mechanism of vitamin E activity, we systematically investigated the effects of its major vitamers and metabolites on lipid oxidation and ferroptosis in a striatal cell model. We found that a specific endogenous metabolite of vitamin E, alpha-tocopherol hydroquinone, was a dramatically more potent inhibitor of ferroptosis than its parent compound, and inhibits 15-lipoxygenase via reduction of the enzyme's non-heme iron from its active Fe3+ state to an inactive Fe2+ state. Furthermore, a non-metabolizable isosteric analog of vitamin E which retains antioxidant activity neither inhibited 15-lipoxygenase nor prevented ferroptosis. These results call into question the prevailing model that vitamin E acts predominantly as a non-specific lipophilic antioxidant. We propose that, similar to the other lipophilic vitamins A, D and K, vitamin E is instead a pro-vitamin, with its quinone/hydroquinone metabolites responsible for its anti-ferroptotic cytoprotective activity.
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Apoptosis/efectos de los fármacos , Araquidonato 15-Lipooxigenasa/metabolismo , Hierro/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Vitaminas/farmacología , alfa-Tocoferol/análogos & derivados , Animales , Línea Celular , Citoprotección/efectos de los fármacos , Ratones , alfa-Tocoferol/farmacologíaRESUMEN
BACKGROUND: Leigh syndrome is a mitochondrial disease caused by respiratory chain deficiency, and there are no proven effective therapies. EPI-743 is a potent cellular oxidative stress protectant and results of clinical trials for mitochondrial diseases are accumulating. CASE: At 5months, a girl presented with the scarce eye movement and diminished muscle tone. She was diagnosed with Leigh encephalopathy from blood and cerebrospinal fluid lactate elevation and MRI findings. Sequence analysis for mitochondrial DNA revealed a T10158C mutation in the mitochondrial encoded ND3 gene in complex I. RESULTS: At 8months, succinate was prescribed expected to restore the electron transport chain system. After that her condition got worse and succinate was discontinued. Subsequent administration of EPI-743 improved her eye movement, fine motor movements of the extremities, and bowel movement. She is now 5years old. Although brain atrophy has progressed, she has still respiratory free time. CONCLUSION: Our patient showed visible improvement with EPI-743 treatment and the only patient surviving after 4years. There is a possibility that EPI-743 is modifying the natural course of the syndrome.
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Antioxidantes/uso terapéutico , Enfermedad de Leigh/tratamiento farmacológico , Ubiquinona/análogos & derivados , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Preescolar , Progresión de la Enfermedad , Complejo I de Transporte de Electrón/genética , Femenino , Humanos , Ácido Láctico/sangre , Enfermedad de Leigh/diagnóstico por imagen , Enfermedad de Leigh/genética , Enfermedad de Leigh/fisiopatología , Respiración Artificial , Ubiquinona/uso terapéuticoRESUMEN
The objective of the current experiment was to determine the adequate dose and impact of graded concentrations of garlic diallyl disulfide (DADS) and diallyl trisulfide (DATS) on growth performance, total-tract nutrient and energy digestibility, serum immune parameters, and ileal morphology in broiler chickens. At 28-d post-hatch, male broiler chickens were allotted on the basis of initial body weight (1.34 ± 0.106 kg) in a randomized complete block desing ( RCBD: ) to one of six treatments that consisted of an oral gavage of 0, 0.45, 0.90, 1.80, 3.6, or 7.2 mg of DADS + DATS per kg bodyweight (BW) with 8 replicate cages per treatment and 4 birds per cage. The DADS + DATS was administered to birds by daily oral gavage for a period of 6 d. Growth performance was recorded and excreta were collected for analysis of DM, nitrogen ( N: ), and energy ( E: ) digestibility and on the last day of the experiment, the median bird in each cage was euthanized and the mid ileum was excised for morphological and gene expression measurements and blood was collected for serum natural antibody and complement assays. Body weight gain and villus height were linearly increased (P < 0.01) with oral gavage of DADS + DATS. There was a quadratic effect (P < 0.01) of the oral gavage on digestibility of DM, N, and E that corresponded to an average broken-line regression-derived adequate dose of 1.16 mg DADS + DATS per kg BW. Supplementation of DADS + DATS by oral gavage had no impact on gene expression markers although there was a tendency for an increase (P = 0.10) in serum natural antibody activity due to treatment. Results from the current study indicate that supplementation of a gavage containing DADS + DATS improves BW gain, ileal morphology, and digestibility of DM, N, and E and may affect serum immune parameters in broiler chickens. The average broken-line regression-derived adequate dose to optimize BW gain and villus height response was 2.51 mg DADS + DATS per kg BW.
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Compuestos Alílicos/metabolismo , Fenómenos Fisiológicos Nutricionales de los Animales , Pollos/fisiología , Dieta/veterinaria , Suplementos Dietéticos , Disulfuros/metabolismo , Sulfuros/metabolismo , Administración Oral , Compuestos Alílicos/administración & dosificación , Alimentación Animal/análisis , Animales , Proteínas Aviares/metabolismo , Análisis Químico de la Sangre/veterinaria , Pollos/crecimiento & desarrollo , Citocinas/metabolismo , Digestión/inmunología , Disulfuros/administración & dosificación , Íleon/inmunología , Íleon/fisiología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Masculino , Distribución Aleatoria , Sulfuros/administración & dosificación , Proteínas de Uniones Estrechas/metabolismoAsunto(s)
ADN Mitocondrial/genética , Micronutrientes/uso terapéutico , Enfermedades Mitocondriales/tratamiento farmacológico , Mutación , Atrofia Óptica Hereditaria de Leber/tratamiento farmacológico , Ubiquinona/análogos & derivados , Niño , Humanos , Masculino , Enfermedades Mitocondriales/genética , Atrofia Óptica Hereditaria de Leber/genética , Linaje , Reacción en Cadena de la Polimerasa , Hermanos , Resultado del Tratamiento , Ubiquinona/uso terapéutico , Agudeza Visual/efectos de los fármacos , Campos Visuales/efectos de los fármacosRESUMEN
BACKGROUND: Genetically defined Leigh syndrome (LS) is a rare, fatal inherited neurodegenerative disorder that predominantly affects children. Although mitochondrial dysfunction has clearly been associated with oxidative stress, few studies have specifically examined Leigh syndrome patients' blood glutathione levels. In this study, we analyzed the balance between oxidized and reduced glutathione in lymphocytes of 10 patients with genetically confirmed LS and monitored the effects of glutathione status following 6 months of treatment with EPI-743, a novel redox therapeutic. METHODS: Lymphocytes were obtained from blood samples of 10 children with a genetically confirmed diagnosis of LS and in 20 healthy subjects. Total, reduced, oxidized and protein-bound glutathione levels were determined by HPLC analysis. Erythrocyte superoxide dismutase and glutathione peroxidase enzyme activities were measured by spectrophotometric assays. Plasma total thiols, carbonyl contents and malondialdehyde were assessed by spectrophotometric and fluorometric assays. RESULTS: A significant impairment of all glutathione forms was detected in patients, including a profound decrease of total and reduced glutathione (GSH) associated with high levels of all oxidized glutathione forms (GSSG+GS-Pro; OX). These findings negatively correlated with the glutathione peroxidase activity, which underwent a significant decrease in patients. After treatment with EPI-743, all patients showed a significant increase in reduced glutathione levels and 96% decrease of OX/GSH ratio. CONCLUSIONS: The data presented here strongly support glutathione as a "redox blood signature" in mitochondrial disorders and its use as a clinical trial endpoint in the development of mitochondrial disease therapies.
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Glutatión/sangre , Encefalomiopatías Mitocondriales/sangre , Ubiquinona/análogos & derivados , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Eritrocitos/enzimología , Glutatión Peroxidasa/metabolismo , Humanos , Lactante , Malondialdehído/sangre , Encefalomiopatías Mitocondriales/tratamiento farmacológico , Oxidación-Reducción , Superóxido Dismutasa/metabolismo , Resultado del Tratamiento , Ubiquinona/uso terapéuticoRESUMEN
While decreased ATP production and redox imbalance are central to mitochondrial disease pathogenesis, efforts to develop effective treatments have been hampered by the lack of imaging markers of oxidative stress. In this study we wished to determine if Tc99m-HMPAO, a SPECT imaging marker of cerebral blood flow and glutathione/protein thiol content, could be used to monitor the effect(s) of EPI-743, an oral redox modulating, para-benzoquinone based therapeutic for mitochondrial disease. We hypothesized that treatment changes in HMPAO uptake would be inversely proportional to changes in oxidative stress within the brain and directly correlate to clinical response to EPI-743 therapy. Twenty-two patients with mitochondrial disease were treated with EPI-743. Each underwent baseline and 3-month Tc99m-HMPAO SPECT scanning along with clinical/neurologic evaluations. Diseases treated were: Leigh syndrome (n=7), polymerase γ deficiency (n=5), MELAS (n=5), Friedreich ataxia (n=2), Kearns-Sayre syndrome, Pearson syndrome, and mtDNA depletion syndrome. Neuro-anatomic uptake analyses of HMPAO were performed with NeuroGam™ (Segami Corp.) statistical software and clinical response was assessed by the Newcastle Paediatric Mitochondrial Disease Scale or Newcastle Mitochondrial Disease Adult Scale depending on patient age. For all 22 patients there was a significant linear correlation between the change in cerebellar uptake of HMPAO and the improvement in Newcastle score (r=0.623, **p=0.00161). The MELAS subgroup showed a significant relationship of whole brain uptake (n=5, r=0.917, *p=0.028) to improvement in Newcastle score. We conclude that Tc99m-HMPAO SPECT scanning has promise as a general marker of the oxidative state of the brain and its response to redox modulating therapies. Further studies will be needed to confirm these findings in a more homogenous study population.
Asunto(s)
Encéfalo/diagnóstico por imagen , Enfermedades Mitocondriales/diagnóstico por imagen , Enfermedades Mitocondriales/tratamiento farmacológico , Exametazima de Tecnecio Tc 99m , Tomografía Computarizada de Emisión de Fotón Único , Ubiquinona/análogos & derivados , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxidación-Reducción/efectos de los fármacos , Resultado del Tratamiento , Ubiquinona/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND: Genetically defined Leigh syndrome is a rare, fatal inherited neurodegenerative disorder that predominantly affects children. No treatment is available. EPI-743 is a novel small molecule developed for the treatment of Leigh syndrome and other inherited mitochondrial diseases. In compassionate use cases and in an FDA Expanded Access protocol, children with Leigh syndrome treated with EPI-743 demonstrated objective signs of neurologic and neuromuscular improvement. To confirm these initial findings, a phase 2A open label trial of EPI-743 for children with genetically-confirmed Leigh syndrome was conducted and herein we report the results. METHODS: A single arm clinical trial was performed in children with genetically defined Leigh syndrome. Subjects were treated for 6 months with EPI-743 three times daily and all were eligible for a treatment extension phase. The primary objective of the trial was to arrest disease progression as assessed by neuromuscular and quality of life metrics. Results were compared to the reported natural history of the disease. RESULTS: Ten consecutive children, ages 1-13 years, were enrolled; they possessed seven different genetic defects. All children exhibited reversal of disease progression regardless of genetic determinant or disease severity. The primary endpoints--Newcastle Pediatric Mitochondrial Disease Scale, the Gross Motor Function Measure, and PedsQL Neuromuscular Module--demonstrated statistically significant improvement (p<0.05). In addition, all children had an improvement of one class on the Movement Disorder-Childhood Rating Scale. No significant drug-related adverse events were recorded. CONCLUSIONS: In comparison to the natural history of Leigh syndrome, EPI-743 improves clinical outcomes in children with genetically confirmed Leigh syndrome.
Asunto(s)
Enfermedad de Leigh/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Ubiquinona/análogos & derivados , Adolescente , Niño , Preescolar , Ensayos de Uso Compasivo , Progresión de la Enfermedad , Esquema de Medicación , Femenino , Humanos , Lactante , Enfermedad de Leigh/genética , Enfermedad de Leigh/metabolismo , Enfermedad de Leigh/patología , Masculino , Mitocondrias/genética , Mitocondrias/metabolismo , Desempeño Psicomotor/efectos de los fármacos , Calidad de Vida , Índice de Severidad de la Enfermedad , Ubiquinona/farmacocinética , Ubiquinona/farmacología , Ubiquinona/uso terapéuticoRESUMEN
This study tested the ability of A0001 (α-tocopheryl quinone; EPI-A0001), a potent antioxidant, to improve in vitro measures, glucose metabolism, and neurological function in Friedreich ataxia. We used an in vitro study of protection from cell toxicity followed by a double-blind, randomized, placebo-controlled trial of 2 doses of A0001 in 31 adults with Friedreich ataxia. The primary clinical trial outcome was the Disposition Index, a measure of diabetic tendency, from a frequently sampled intravenous glucose tolerance test, evaluated 4 weeks into therapy. Secondary neurologic measures included the Friedreich Ataxia Rating Scale. A0001 potently inhibited cell death in Friedreich ataxia models in vitro. For the clinical trial, mean guanine-adenine-adenine repeat length was 699, and mean age was 31 years. Four weeks after treatment initiation, differences in changes in the Disposition Index between subjects treated with A0001 and placebo were not statistically significant. In contrast, a dose-dependent improvement in the Friedreich Ataxia Rating Scale score was observed. Patients on placebo improved 2.0 rating scale points, whereas patients on low-dose A0001 improved by 4.9 points (P = .04) and patients on a high dose improved by 6.1 points (P < .01). Although A0001 did not alter the Disposition Index, it caused a dose-dependent improvement in neurologic function, as measured by the Friedreich Ataxia Rating Scale. Longer studies will assess the reproducibility and persistence of neurologic benefit.
Asunto(s)
Antioxidantes/uso terapéutico , Ataxia de Friedreich/tratamiento farmacológico , Vitamina E/análogos & derivados , Adolescente , Adulto , Animales , Antioxidantes/administración & dosificación , Antioxidantes/efectos adversos , Biomarcadores/metabolismo , Método Doble Ciego , Femenino , Fibroblastos/metabolismo , Ataxia de Friedreich/genética , Ataxia de Friedreich/metabolismo , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Humanos , Proteínas de Unión a Hierro/metabolismo , Linfocitos/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Mitocondrias/metabolismo , Mutación Puntual , Tamaño de la Muestra , Resultado del Tratamiento , Vitamina E/administración & dosificación , Vitamina E/efectos adversos , Vitamina E/uso terapéutico , Adulto Joven , FrataxinaRESUMEN
OBJECTIVE: To evaluate the safety and efficacy of a new therapeutic agent, EPI-743, in Leber hereditary optic neuropathy (LHON) using standard clinical, anatomic, and functional visual outcome measures. DESIGN: Open-label clinical trial. SETTING: University medical center. Patients Five patients with genetically confirmed LHON with acute loss of vision were consecutively enrolled and treated with the experimental therapeutic agent EPI-743 within 90 days of conversion. Intervention During the course of the study, 5 consecutive patients received EPI-743, by mouth, 3 times daily (100-400 mg per dose). MAIN OUTCOME MEASURES: Treatment effect was assessed by serial measurements of anatomic and functional visual indices over 6 to 18 months, including Snellen visual acuity, retinal nerve fiber layer thickness measured by optical coherence tomography, Humphrey visual fields (mean decibels and area with 1-log unit depression), and color vision. Treatment effect in this clinical proof of principle study was assessed by comparison of the prospective open-label treatment group with historical controls. RESULTS: Of 5 subjects treated with EPI-743, 4 demonstrated arrest of disease progression and reversal of visual loss. Two patients exhibited a total recovery of visual acuity. No drug-related adverse events were recorded. CONCLUSIONS: In a small open-label trial, EPI-743 arrested disease progression and reversed vision loss in all but 1 of the 5 consecutively treated patients with LHON. Given the known natural history of acute and rapid progression of LHON resulting in chronic and persistent bilateral blindness, these data suggest that the previously described irreversible priming to retinal ganglion cell loss may be reversed.
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Atrofia Óptica Hereditaria de Leber/tratamiento farmacológico , Ubiquinona/análogos & derivados , Adolescente , Ceguera/etiología , Ceguera/prevención & control , Niño , Cromatografía Líquida de Alta Presión , Visión de Colores , Aprobación de Drogas , Servicios Médicos de Urgencia , Ojo/patología , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Enfermedades Mitocondriales/complicaciones , Atrofia Óptica Hereditaria de Leber/genética , Retina/patología , Espectrometría de Masas en Tándem , Tomografía de Coherencia Óptica , Ubiquinona/efectos adversos , Ubiquinona/farmacocinética , Ubiquinona/uso terapéutico , Estados Unidos , United States Food and Drug Administration , Agudeza Visual , Pruebas del Campo Visual , Adulto JovenRESUMEN
We report on the synthesis, biological and pharmacological activity of the tocoquinone natural product, α-tocopherol quinone (ATQ); an oxidative metabolite of α-tocopherol. ATQ is a potent cellular protectant against oxidative stress, whose biological activity is dependent upon its ability to undergo reversible two-electron redox cycling. ATQ is orally bioavailable, with a favorable pharmacokinetic profile and has demonstrated a beneficial clinical response in patients with Friedreich's ataxia. ATQ is a member of a broader class of vitamin E derived quinone metabolites which may be ascribable in whole or in part to the activity of vitamin E.
Asunto(s)
Ciencias de la Nutrición , Quinonas/química , Vitamina E/química , Animales , Células CHO , Cricetinae , Perros , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Fibroblastos/metabolismo , Ataxia de Friedreich/metabolismo , Humanos , Hidrolasas/química , Ratones , Pruebas de Micronúcleos , Modelos Químicos , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Oxidación-Reducción , Estrés Oxidativo , Ratas , Vitamina E/análogos & derivados , Vitamina E/metabolismo , Vitamina E/farmacología , alfa-Tocoferol/metabolismoRESUMEN
Inherited mitochondrial respiratory chain disorders are progressive, life-threatening conditions for which there are limited supportive treatment options and no approved drugs. Because of this unmet medical need, as well as the implication of mitochondrial dysfunction as a contributor to more common age-related and neurodegenerative disorders, mitochondrial diseases represent an important therapeutic target. Thirteen children and one adult with genetically-confirmed mitochondrial disease (polymerase γ deficiency, n=4; Leigh syndrome, n=4; MELAS, n=3; mtDNA deletion syndrome, n=2; Friedreich ataxia, n=1) at risk for progressing to end-of-life care within 90 days were treated with EPI-743, a novel para-benzoquinone therapeutic, in a subject controlled, open-label study. Serial measures of safety and efficacy were obtained that included biochemical, neurological, quality-of-life, and brain redox assessments using technetium-99m-hexamethylpropyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) radionuclide imaging. Twelve patients treated with EPI-743 have survived; one polymerase γ deficiency patient died after developing pneumonia and one patient with Surf-1 deficiency died after completion of the protocol. Of the 12 survivors, 11 demonstrated clinical improvement, with 3 showing partial relapse, and 10 of the survivors also had an improvement in quality-of-life scores at the end of the 13-week emergency treatment protocol. HMPAO SPECT scans correlated with clinical response; increased regional and whole brain HMPAO uptake was noted in the clinical responders and the one subject who did not respond clinically had decreased regional and whole brain HMPAO uptake. EPI-743 has modified disease progression in >90% of patients in this open-label study as assessed by clinical, quality-of-life, and non-invasive brain imaging parameters. Data obtained herein suggest that EPI-743 may represent a new drug for the treatment of inherited mitochondrial respiratory chain disorders. Prospective controlled trials will be undertaken to substantiate these initial promising observations. Furthermore, HMPAO SPECT imaging may be a valuable tool for the detection of central nervous system redox defects and for monitoring response to treatments directed at modulating abnormal redox.
Asunto(s)
Benzoquinonas/uso terapéutico , Enfermedades Genéticas Congénitas/tratamiento farmacológico , Enfermedades Mitocondriales/tratamiento farmacológico , Ubiquinona/análogos & derivados , Adolescente , Adulto , Benzoquinonas/efectos adversos , Benzoquinonas/farmacología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Células Cultivadas , Niño , Preescolar , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Regulación de la Expresión Génica/efectos de los fármacos , Enfermedades Genéticas Congénitas/diagnóstico por imagen , Humanos , Masculino , Enfermedades Mitocondriales/diagnóstico por imagen , Estrés Oxidativo , Oximas , Tomografía Computarizada de Emisión de Fotón Único , Ubiquinona/efectos adversos , Ubiquinona/farmacología , Ubiquinona/uso terapéuticoRESUMEN
We report that α-tocotrienol quinone (ATQ3) is a metabolite of α-tocotrienol, and that ATQ3 is a potent cellular protectant against oxidative stress and aging. ATQ3 is orally bioavailable, crosses the blood-brain barrier, and has demonstrated clinical response in inherited mitochondrial disease in open label studies. ATQ3 activity is dependent upon reversible 2e-redox-cycling. ATQ3 may represent a broader class of unappreciated dietary-derived phytomolecular redox motifs that digitally encode biochemical data using redox state as a means to sense and transfer information essential for cellular function.
Asunto(s)
Envejecimiento/efectos de los fármacos , Antioxidantes/metabolismo , Antioxidantes/farmacología , Benzoquinonas/química , Benzoquinonas/farmacología , Estrés Oxidativo/efectos de los fármacos , Envejecimiento/fisiología , Animales , Antioxidantes/química , Células Cultivadas , Perros , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Estructura Molecular , Ratas , Tocotrienoles , Vitamina E/análogos & derivados , Vitamina E/química , Vitamina E/farmacologíaRESUMEN
OBJECTIVE: Increased cardiovascular risk in hemodialysis patients may be related to augmented oxidative stress and inflammation, for which no proven beneficial therapies are available. STUDY DESIGN: We examined the effects of gamma tocopherol and docosahexaenoic acid (DHA) administration on inflammation and oxidative stress markers in hemodialysis patients in a randomized, double-blinded, placebo-controlled, clinical trial. Active treatment consisted of capsules containing gamma tocopherol (308 mg) and DHA (800 mg). SETTING: Outpatient dialysis center. PATIENTS: Seventy maintenance hemodialysis patients. MAIN OUTCOME MEASURES: Plasma concentrations of interleukin-6 (IL-6) and protein carbonyl content were determined by enzyme-linked immunosorbant assay. C-reactive protein was measured by nephelometry. The F(2) isoprostanes were measured by gas chromatography-mass spectrometry. Erythrocyte DHA content was measured by gas chromatography. RESULTS: Sixty-three patients were enrolled, and 57 completed the study. No serious adverse events were attributed to either active treatment or placebo. In the treatment group, but not in the placebo group, there were significant decreases in IL-6 (21.4 +/- 3.5 to 16.8 +/- 3.7 pg/mL), white blood cell (WBC) count (7.4 +/- 0.3 to 6.9 +/- 0.4 10(3)/microL), and neutrophil fraction of WBCs (4.8 +/- 0.3 to 4.4 +/- 0.3 10(3)/microL), at P < .05 for all. There were no significant changes in plasma concentrations of CRP, F(2) isoprostanes, or carbonyls in either group. CONCLUSION: Thus, gamma tocopherol and DHA are well-tolerated and reduce selected biomarkers of inflammation in hemodialysis patients. Larger randomized, clinical trials will be required to determine if gamma tocopherol and DHA can reduce cardiovascular complications in hemodialysis patients.
Asunto(s)
Ácidos Docosahexaenoicos/uso terapéutico , Inflamación/prevención & control , Fallo Renal Crónico/terapia , Estrés Oxidativo , Diálisis Renal , gamma-Tocoferol/uso terapéutico , Adulto , Anciano , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Cromatografía de Gases , Suplementos Dietéticos , Ácidos Docosahexaenoicos/efectos adversos , Método Doble Ciego , Ensayo de Inmunoadsorción Enzimática , Eritrocitos/química , F2-Isoprostanos , Femenino , Cromatografía de Gases y Espectrometría de Masas , Humanos , Inflamación/epidemiología , Interleucina-6/sangre , Fallo Renal Crónico/complicaciones , Masculino , Persona de Mediana Edad , Nefelometría y Turbidimetría , Estrés Oxidativo/efectos de los fármacos , Carbonilación Proteica/efectos de los fármacos , Resultado del Tratamiento , gamma-Tocoferol/efectos adversosRESUMEN
BACKGROUND: The metabolism of alpha and gamma tocopherol, the major components of vitamin E, have not been studied in uremic patients. The major pathway of tocopherol metabolism is via phytyl side chain oxidation, leaving carboxyethyl-hydroxychromans (CEHC) as metabolites. Alpha and gamma CEHC are water soluble, renally excreted, with known potent anti-inflammatory and antioxidative properties. METHODS: We examined serum alpha and gamma tocopherol and respective CEHC concentrations in 15 healthy subjects and 15 chronic hemodialysis patients. RESULTS: Serum alpha tocopherol levels were similar in hemodialysis patients (12.03 +/- 1.34 microg/mL) and healthy subjects (11.21 +/- 0.20 microg/mL), while serum gamma tocopherol levels were significantly greater in hemodialysis patients (3.17 +/- 0.37 microg/mL) compared to healthy subjects (1.08 +/- 0.06 microg/mL, P < 0.0001). Serum alpha and gamma CEHC levels were tenfold and sixfold higher in hemodialysis patients compared to healthy subjects, respectively (both P < 0.0001). Serum alpha and gamma tocopherol levels and CEHC metabolites were also measured after supplementation of alpha- or gamma-enriched mixed tocopherols in both hemodialysis patients and healthy subjects. Tocopherol administration resulted in modest or nonsignificant changes in serum tocopherol concentrations, while markedly increasing serum CEHC concentrations in both healthy subjects and hemodialysis patients. Hemodialysis resulted in no change in the serum alpha or gamma tocopherol concentrations while decreasing serum alpha CEHC and gamma CEHC levels by 63% and 53%, respectively (both P = 0.001 versus predialysis). Fourteen-day administration of gamma-enriched but not alpha tocopherols lowered median C-reactive protein (CRP) significantly in hemodialysis patients (4.4 to 2.1 mg/L, P < 0.02). CONCLUSION: First, serum alpha and gamma CEHC accumulate in uremic patients compared to healthy subjects; second, supplementation with tocopherols dramatically increases serum CEHC levels in both healthy subjects and hemodialysis patients; and, finally, CEHC accumulation may mediate anti-inflammatory and antioxidative effects of tocopherols in hemodialysis patients.
Asunto(s)
Fallo Renal Crónico/metabolismo , alfa-Tocoferol/metabolismo , gamma-Tocoferol/metabolismo , Reacción de Fase Aguda/sangre , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , Cromanos/sangre , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Interleucina-6/sangre , Fallo Renal Crónico/sangre , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Diálisis Renal , alfa-Tocoferol/administración & dosificación , alfa-Tocoferol/sangre , gamma-Tocoferol/administración & dosificación , gamma-Tocoferol/sangreRESUMEN
Metabolic inactivation of the antitumor antibiotic bleomycin is believed to be mediated exclusively via the action of bleomycin hydrolase, a cysteine proteinase that is widely distributed in nature. While the spectrum of antitumor activity exhibited by the bleomycins is believed to reflect the anatomical distribution of bleomycin hydrolase within the host, little has been done to characterize the product of the putative inactivation at a chemical or biochemical level. The present report describes the synthesis of deamidobleomycin demethyl A(2) (3) and deamido bleomycin A(2) (4), as well as the respective aglycones. These compounds were all accessible via the key intermediate N(alpha)-Boc-N(beta)-[1-amino-3(S)-(4-amino-6-carboxy-5-methylpyrimidin-2-yl)propion-3-yl]-(S)-beta-aminoalanine tert-butyl ester (16). Synthetic deamido bleomycin A(2) was shown to be identical to the product formed by treatment of bleomycin A(2) with human bleomycin hydrolase, as judged by reversed-phase HPLC analysis and (1)H NMR spectroscopy. Deamido bleomycin A(2) was found to retain significant DNA cleavage activity in DNA plasmid relaxation assays and had the same sequence selectivity of DNA cleavage as bleomycin A(2). The most significant alteration of function noted in this study was a reduction in the ability of deamido bleomycin A(2) to mediate double-strand DNA cleavage, relative to that produced by BLM A(2).