RESUMEN
Alzheimer's disease (AD) is a complex, multifactorial disease in which different neuropathological mechanisms are likely involved, including those associated with pathological tau and Aß species as well as neuroinflammation. In this context, the development of single multitargeted therapeutics directed against two or more disease mechanisms could be advantageous. Starting from a series of 1,5-diarylimidazoles with microtubule (MT)-stabilizing activity and structural similarities with known NSAIDs, we conducted structure-activity relationship studies that led to the identification of multitargeted prototypes with activities as MT-stabilizing agents and/or inhibitors of the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways. Several examples are brain-penetrant and exhibit balanced multitargeted in vitro activity in the low µM range. As brain-penetrant MT-stabilizing agents have proven effective against tau-mediated neurodegeneration in animal models, and because COX- and 5-LOX-derived eicosanoids are thought to contribute to Aß plaque deposition, these 1,5-diarylimidazoles provide tools to explore novel multitargeted strategies for AD and other neurodegenerative diseases.
Asunto(s)
Inhibidores de la Ciclooxigenasa/farmacología , Imidazoles/farmacología , Inhibidores de la Lipooxigenasa/farmacología , Enfermedades Neurodegenerativas/tratamiento farmacológico , Relación Estructura-Actividad , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Araquidonato 5-Lipooxigenasa/metabolismo , Técnicas de Química Sintética , Inhibidores de la Ciclooxigenasa/química , Evaluación Preclínica de Medicamentos/métodos , Femenino , Humanos , Imidazoles/química , Leucotrienos/biosíntesis , Inhibidores de la Lipooxigenasa/química , Masculino , Ratones Endogámicos , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Terapia Molecular Dirigida , Prostaglandinas/metabolismo , RatasRESUMEN
A randomised controlled trial (RCT) of high-dose v. low-dose fish oil in recent-onset rheumatoid arthritis (RA) demonstrated that the group allocated to high-dose fish oil had increased remission and decreased failure of disease-modifying anti-rheumatic drug (DMARD) therapy. This study examines the relationships between plasma phospholipid levels of the n-3 fatty acids in fish oil, EPA and DHA, and remission and DMARD use in recent-onset RA. EPA and DHA were measured in blood samples from both groups of the RCT. The data were analysed as a single cohort, and Cox proportional hazards models were used to examine relationships between plasma phospholipid (PL) EPA and DHA and various outcome measures. When analysed as a single cohort, plasma PL EPA was related to time to remission, with a one unit increase in EPA (1% total fatty acids) associated with a 12% increase in the probability of remission at any time during the study period (hazard ratio (HR)=1.12; 95% CI 1.02, 1.23; P=0.02). Adjustment for smoking, anti-cyclic citrullinated peptide antibodies and 'shared epitope' HLA-DR allele status did not change the HR. Plasma PL EPA, adjusted for the same variables, was negatively related to time to DMARD failure (HR=0.85; 95% CI 0.72, 0.99; P=0.047). The HR for DHA and time to remission or DMARD failure were similar in magnitude to those for EPA, but not statistically significant. Biomarkers of n-3 status, such as plasma PL EPA, have the potential to predict clinical outcomes relevant to standard drug treatment of RA patients.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/dietoterapia , Suplementos Dietéticos , Ácidos Docosahexaenoicos/sangre , Ácido Eicosapentaenoico/sangre , Aceites de Pescado/uso terapéutico , Fosfolípidos/sangre , Adulto , Anciano , Antirreumáticos/administración & dosificación , Artritis Reumatoide/sangre , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Autoanticuerpos/análisis , Biomarcadores/sangre , Estudios de Cohortes , Terapia Combinada , Ácidos Docosahexaenoicos/administración & dosificación , Ácidos Docosahexaenoicos/análisis , Ácidos Docosahexaenoicos/uso terapéutico , Método Doble Ciego , Resistencia a Medicamentos , Ácido Eicosapentaenoico/administración & dosificación , Ácido Eicosapentaenoico/análisis , Ácido Eicosapentaenoico/uso terapéutico , Femenino , Aceites de Pescado/administración & dosificación , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Péptidos Cíclicos/antagonistas & inhibidores , Fosfolípidos/química , Modelos de Riesgos Proporcionales , Inducción de RemisiónRESUMEN
BACKGROUND: The effects of fish oil (FO) in rheumatoid arthritis (RA) have not been examined in the context of contemporary treatment of early RA. This study examined the effects of high versus low dose FO in early RA employing a 'treat-to-target' protocol of combination disease-modifying anti-rheumatic drugs (DMARDs). METHODS: Patients with RA <12â months' duration and who were DMARD-naïve were enrolled and randomised 2:1 to FO at a high dose or low dose (for masking). These groups, designated FO and control, were given 5.5 or 0.4â g/day, respectively, of the omega-3 fats, eicosapentaenoic acid + docosahexaenoic acid. All patients received methotrexate (MTX), sulphasalazine and hydroxychloroquine, and DMARD doses were adjusted according to an algorithm taking disease activity and toxicity into account. DAS28-erythrocyte sedimentation rate, modified Health Assessment Questionnaire (mHAQ) and remission were assessed three monthly. The primary outcome measure was failure of triple DMARD therapy. RESULTS: In the FO group, failure of triple DMARD therapy was lower (HR=0.28 (95% CI 0.12 to 0.63; p=0.002) unadjusted and 0.24 (95% CI 0.10 to 0.54; p=0.0006) following adjustment for smoking history, shared epitope and baseline anti-cyclic citrullinated peptide. The rate of first American College of Rheumatology (ACR) remission was significantly greater in the FO compared with the control group (HRs=2.17 (95% CI 1.07 to 4.42; p=0.03) unadjusted and 2.09 (95% CI 1.02 to 4.30; p=0.04) adjusted). There were no differences between groups in MTX dose, DAS28 or mHAQ scores, or adverse events. CONCLUSIONS: FO was associated with benefits additional to those achieved by combination 'treat-to-target' DMARDs with similar MTX use. These included reduced triple DMARD failure and a higher rate of ACR remission.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Ácidos Docosahexaenoicos/administración & dosificación , Ácido Eicosapentaenoico/administración & dosificación , Adulto , Anciano , Artritis Reumatoide/sangre , Sedimentación Sanguínea , Método Doble Ciego , Quimioterapia Combinada , Intervención Médica Temprana , Femenino , Aceites de Pescado/administración & dosificación , Humanos , Hidroxicloroquina/uso terapéutico , Isoxazoles/uso terapéutico , Leflunamida , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Inducción de Remisión , Sulfasalazina/uso terapéutico , Resultado del TratamientoRESUMEN
Randomised controlled trials (RCT) examining the effects of fish oil supplementation on cardiac outcomes have yielded varying results over time. Although RCT are placed at the top of the evidence hierarchy, this methodology arose in the framework of pharmaceutical development. RCT with pharmaceuticals differ in important ways from RCT involving fish oil interventions. In particular, in pharmaceutical RCT, the test agent is present only in the intervention group and not in the control group, whereas in fish oil RCT, n-3 fats are present in the diet and in the tissues of both groups. Also, early phase studies with pharmaceuticals determine pharmacokinetics and pharmacodynamics to design the dose of the RCT intervention so that it is in a predicted linear dose-response range. None of this happens in fish oil RCT, and there is evidence that both baseline n-3 intake and tissue levels may be sufficiently high in the dose-response range that it is not possible to demonstrate a clinical effect with a RCT. When these issues are considered, it is possible that the changing pattern of fish consumption and fish oil use over time, especially in cardiac patients, can explain the disparity where benefit was observed in the early fish oil trials but not in the more recent trials.
Asunto(s)
Aceites de Pescado/administración & dosificación , Cardiopatías/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Dieta , Ácidos Docosahexaenoicos/sangre , Relación Dosis-Respuesta a Droga , Ácido Eicosapentaenoico/sangre , Eritrocitos/química , Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-3/análisis , Aceites de Pescado/análisis , Humanos , Preparaciones FarmacéuticasRESUMEN
BACKGROUND: Omega-3 (n-3) fatty acid supplementation is becoming increasingly popular. However given its antithrombotic properties the potential for severe adverse events (SAE) such as bleeding has safety implications, particularly in an older adult population. A systematic review of randomized control trials (RCT) was conducted to explore the potential for SAE and non-severe adverse events (non-SAE) associated with n-3 supplementation in older adults. METHODS: A comprehensive search strategy using Medline and a variety of other electronic sources was conducted. Studies investigating the oral administration of n-3 fish oil containing eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or both against a placebo were sourced. The primary outcome of interest included reported SAE associated with n-3 supplementation. Chi-square analyses were conducted on the pooled aggregate of AEs. RESULTS: Of the 398 citations initially retrieved, a total of 10 studies involving 994 older adults aged ≥60 years were included in the review. Daily fish oil doses ranged from 0.03 g to 1.86 g EPA and/or DHA with study durations ranging from 6 to 52 weeks. No SAE were reported and there were no significant differences in the total AE rate between groups (n-3 intervention group: 53/540; 9.8%; placebo group: 28/454; 6.2%; p = 0.07). Non-SAE relating to gastrointestinal (GI) disturbances were the most commonly reported however there was no significant increase in the proportion of GI disturbances reported in participants randomized to the n-3 intervention (n-3 intervention group: 42/540 (7.8%); placebo group: 24/454 (5.3%); p = 0.18). CONCLUSIONS: The potential for AEs appear mild-moderate at worst and are unlikely to be of clinical significance. The use of n-3 fatty acids and the potential for SAE should however be further researched to investigate whether this evidence is consistent at higher doses and in other populations. These results also highlight that well-documented data outlining the potential for SAE following n-3 supplementation are limited nor adequately reported to draw definitive conclusions concerning the safety associated with n-3 supplementation. A more rigorous and systematic approach for monitoring and recording AE data in clinical settings that involve n-3 supplementation is required.
Asunto(s)
Suplementos Dietéticos/efectos adversos , Aceites de Pescado/efectos adversos , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-3/efectos adversos , Aceites de Pescado/administración & dosificación , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Gastrointestinales/epidemiología , Humanos , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
The health benefits of the (n-3) PUFA, EPA, and DHA have created a demand for fish and fish oil, the main sources of these PUFA. Production animals, such as poultry, are potential alternate and sustainable sources of EPA and DHA, provided these fatty acids can be synthesized from plant-derived α-linolenic acid [ALA, 18:3(n-3)]. Because elongases are potential control points in the conversion of ALA to DHA in rats, we examined the chicken elongases, ELOVL2 and ELOVL5, which had not been characterized. ELOVL2 activity was limited to C20-22 PUFA substrates and the major product of ELOVL2 metabolism of EPA was 24:5(n-3). This indicates that ELOVL2 can sequentially elongate EPA to docosapentaenoic acid [DPA, 22:5(n-3)] and then onto 24:5(n-3). ELOVL5 selectivity was broader with elongation of C18-22 PUFA substrates. The ability of chicken ELOVL5 to efficiently synthesize 24:5(n-3) is unique compared with ELOVL5 enzymes from other species. The expression of ELOVL5 was higher than ELOVL2 in livers of broiler chickens and their expression did not change when dietary ALA was increased from 0.6 to 1.3% of dietary energy for 42 d. The expression of both genes was higher than previously seen in rats. The chicken elongase enzymes are unlike those of any species studied to date, because both ELOVL2 and ELOVL5 have the ability to efficiently elongate DPA. In addition, the relative abundance of ELOVL2 and ELOVL5 in the liver suggests that chickens may be able to metabolize more DPA through to 24:5(n-3), the precursor of DHA, compared with other species such as rats.
Asunto(s)
Acetiltransferasas/metabolismo , Proteínas Aviares/metabolismo , Ácidos Grasos Omega-3/metabolismo , Hígado/enzimología , Acetiltransferasas/genética , Animales , Animales Endogámicos , Proteínas Aviares/genética , Pollos , Grasas Insaturadas en la Dieta/administración & dosificación , Elongasas de Ácidos Grasos , Ácidos Grasos Monoinsaturados/administración & dosificación , Ácidos Grasos Monoinsaturados/metabolismo , Regulación Enzimológica de la Expresión Génica , Isoenzimas/genética , Isoenzimas/metabolismo , Hígado/metabolismo , Masculino , Concentración Osmolar , Fosfolípidos/metabolismo , ARN Mensajero/metabolismo , Distribución Aleatoria , Aceite de Brassica napus , Proteínas Recombinantes/metabolismo , Australia del Sur , Especificidad por Sustrato , Ácido alfa-Linolénico/administración & dosificación , Ácido alfa-Linolénico/metabolismoAsunto(s)
Ácidos Grasos Omega-3/metabolismo , Ácidos Grasos Omega-6/metabolismo , Osteoartritis de la Rodilla/metabolismo , Sinovitis/metabolismo , Animales , Artritis Experimental , Biomarcadores/metabolismo , Suplementos Dietéticos , Modelos Animales de Enfermedad , Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-6/administración & dosificación , Aceites de Pescado/administración & dosificación , Humanos , Osteoartritis de la Rodilla/complicaciones , Osteoartritis de la Rodilla/dietoterapia , Sinovitis/dietoterapia , Sinovitis/etiologíaRESUMEN
An open-label study reported that ingestion of a fish oil concentrate decreased the incidence of atrial fibrillation (AF) after coronary artery bypass grafting (CABG) surgery. However, a general cardiac surgery population involves valve and CABG surgeries. We undertook a double-blinded randomized controlled trial to examine the effectiveness of fish oil supplementation on the incidence of postsurgical AF after CABG and valve procedures. The primary end point was incidence of AF in the first 6 days after surgery. Two hundred patients were randomized to receive fish oil (providing 4.6 g/day of long-chain ω-3 fatty acids) or a control oil starting 3 weeks before surgery; 194 subjects completed the study, with 47 of 97 subjects in the control group and 36 of 97 subjects in the fish oil group developing AF (odds ratio 0.63, 95% confidence interval [CI] 0.35 to 1.11). There was a nonstatistically significant delay in time to onset of AF in the fish oil group (hazard ratio 0.66, 95% CI 0.43 to 1.01). There was a significant decrease in mean length of stay in the intensive care unit in the fish oil group (ratio of means 0.71, 95% CI 0.56 to 0.90). In conclusion, in a mixed cardiac surgery population, supplementation with dietary fish oil did not result in a significant decrease in the incidence of postsurgical AF. However, there was a significant decrease in time spent in the intensive care unit.
Asunto(s)
Fibrilación Atrial/prevención & control , Procedimientos Quirúrgicos Cardíacos , Aceites de Pescado/uso terapéutico , Complicaciones Posoperatorias/prevención & control , Anciano , Suplementos Dietéticos , Método Doble Ciego , Femenino , Humanos , Incidencia , Unidades de Cuidados Intensivos/estadística & datos numéricos , Tiempo de Internación/estadística & datos numéricos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Placebos , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: It has been suggested that omega-3 polyunsaturated fatty acids (n-3 PUFAs) may prevent the development of atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to evaluate the impact of these agents on development of the AF substrate in heart failure (HF). METHODS: In this study, HF was induced by intracoronary doxorubicin infusions. Twenty-one sheep [7 with n-3 PUFAs treated HF (HF-PUFA), 7 with olive oil-treated HF controls (HF-CTL), 7 controls (CTL)] were studied. Open chest electrophysiologic study was performed with assessment of biatrial effective refractory period (ERP) and conduction. Cardiac function was monitored by magnetic resonance imaging. Atrial n-3 PUFAs levels were quantified using chromatography. Structural analysis was also performed. RESULTS: Atrial n-3 PUFAs levels were twofold to threefold higher in the HF-PUFA group. n-3 PUFAs prevented the development of HF-related left atrial enlargement (P = .001) but not left ventricular/atrial dysfunction. Atrial ERP was significantly lower in the HF-PUFA group (P <.001), but ERP heterogeneity was unchanged. In addition, n-3 PUFAs suppressed atrial conduction abnormalities seen in HF of prolonged P-wave duration (P = .01) and slowed (P <.001) and heterogeneous (P <.05) conduction. The duration of induced AF episodes in HF-PUFA was shorter (P = .02), although AF inducibility was unaltered (P = NS). A 20% reduction of atrial interstitial fibrosis was seen in the HF-PUFA group (P <.05). CONCLUSION: In this ovine HF study, chronic n-3 PUFAs use protected against adverse atrial remodeling by preventing atrial enlargement, fibrosis, and conduction abnormalities leading to shorter AF episodes despite lower ERP.
Asunto(s)
Función Atrial/efectos de los fármacos , Ácidos Grasos Omega-3/administración & dosificación , Atrios Cardíacos/efectos de los fármacos , Insuficiencia Cardíaca/prevención & control , Animales , Función Atrial/fisiología , Modelos Animales de Enfermedad , Electrocardiografía , Ácidos Grasos Omega-3/farmacocinética , Estudios de Seguimiento , Sistema de Conducción Cardíaco/efectos de los fármacos , Sistema de Conducción Cardíaco/fisiopatología , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/fisiopatología , Ovinos , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: To examine interactions between fish oil and paracetamol for inhibition of prostaglandin synthesis in patients with rheumatoid arthritis (RA). METHODS: Patients from an early RA clinic who were treated with a standardized combination DMARD regimen were enrolled. They were advised to consume an anti-inflammatory dose of fish oil containing the n-3 fatty acid, eicosapentaenoic acid (EPA), or a comparator oil. High EPA and Low EPA groups were defined by blood EPA levels >3.5% or <2%, respectively, of plasma phospholipid fatty acids. Participants provided a blood sample before, and 1h after ingestion of 1g paracetamol. The blood was incubated in different ways to allow measurement of COX-2 generated prostaglandin E(2) (PGE(2)) and COX-1 generated thromboxane A(2) (TXA(2)). RESULTS: Paracetamol suppressed the eicosanoid measures of COX-1 and COX-2 activities and the suppression was greater in the High EPA group. The results indicate that the combination of fish oil and paracetamol suppresses PGE(2) synthesis by an amount equivalent to that from maximum therapeutic doses of NSAIDs. CONCLUSION: Paracetamol is recommended for first-line use ahead of NSAIDs for symptom relief in RA or OA. Combining paracetamol with fish oil will enhance suppression of nociceptive PGE(2) synthesis and thereby may provide additive symptomatic benefits.
Asunto(s)
Acetaminofén/farmacología , Artritis Reumatoide/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Dinoprostona/biosíntesis , Ácido Eicosapentaenoico/farmacología , Prostaglandina-Endoperóxido Sintasas/sangre , Acetaminofén/uso terapéutico , Artritis Reumatoide/sangre , Artritis Reumatoide/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Sinergismo Farmacológico , Ácido Eicosapentaenoico/sangre , Ácido Eicosapentaenoico/uso terapéutico , Humanos , Fosfolípidos/sangre , Fosfolípidos/química , Tromboxano A2/biosíntesisRESUMEN
There is high level evidence (meta-analysis of randomized, controlled trials) for symptomatic benefits from fish oil use in rheumatoid arthritis, and there is biologic plausibility for its clinical effects. Fish oil also has safety advantages in reducing cardiovascular risk via direct cardiovascular effects and via nonsteroidal anti-inflammatory drug-sparing. This is an important aspect of fish oil use, given the increased cardiovascular risk in rheumatoid arthritis. Perceived barriers to clinical use are readily addressed.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Ácidos Grasos Omega-3/uso terapéutico , Inflamación/tratamiento farmacológico , Artritis Reumatoide/dietoterapia , Artritis Reumatoide/metabolismo , Grasas de la Dieta/farmacocinética , Humanos , Inflamación/dietoterapia , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Increased consumption of fish and/or fish oil was associated with decreased risk of sudden cardiac death (SCD). The study aim was to evaluate the antiarrhythmic effect of dietary fish oil on the inducibility of ventricular tachycardia (VT) at high risk of SCD. Patients with coronary artery disease undergoing defibrillator implantation were recruited if sustained monomorphic VT could be induced by programmed extra stimuli at 2 cycle lengths. After the initial study, 12 patients consumed 3 g/d of encapsulated fish oil for approximately 6 weeks before a repeated electrophysiologic study. To control for fluctuations in the inducibility of VT, an additional 14 patients with no dietary manipulation were also studied. Aggressiveness of stimulation required to induce VT was ranked from least aggressive to most aggressive based on cycle length and number of extra stimuli, with noninducibility ranked highest. At the repeated electrophysiologic study, in the fish-oil group, 42% had no inducible VT, 42% required more aggressive stimulation to induce VT, 8% required identical stimulation, and 8% required less stimulation compared with 7%, 36%, 36%, and 21% in the control group, respectively. Overall, there was a change to noninducible or less inducible VT in the fish-oil group, but no change in the control group (p = 0.003 and p = 0.65, respectively; Wilcoxon's sign-rank test). In conclusion, dietary n-3 fatty acid supplementation decreased the inducibility of VT in patients at risk of SCD. These findings suggest that dietary fish oil can have an antiarrhythmic effect.
Asunto(s)
Ácidos Grasos Omega-3/uso terapéutico , Isquemia Miocárdica/dietoterapia , Taquicardia Ventricular/prevención & control , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/prevención & control , Femenino , Aceites de Pescado/uso terapéutico , Estudios de Seguimiento , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/mortalidad , Estudios Prospectivos , Taquicardia Ventricular/etiología , Taquicardia Ventricular/mortalidad , Resultado del TratamientoRESUMEN
BACKGROUND: Increased fish or fish-oil consumption is associated with reduced risk of cardiac mortality, especially sudden death. This benefit putatively arises from the incorporation of the long-chain n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into cardiomyocyte phospholipids. OBJECTIVE: The study examined the kinetics of incorporation of n-3 fatty acids into human myocardial membrane phospholipids during supplementation with fish oil and alpha-linolenic acid-rich flaxseed oil. DESIGN: Patients with low self-reported fish intake (<1 fish meal/wk and no oil supplements) accepted for elective cardiac surgery involving cardiopulmonary bypass were randomly allocated to 1 of 6 groups: no supplement; fish oil (6 g EPA+DHA/d) for either 7, 14, or 21 d before surgery; flaxseed oil; or olive oil (both 10 mL/d for 21 d before surgery). Right atrial appendage tissue removed during surgery and blood collected at enrollment and before surgery were analyzed for phospholipid fatty acids. RESULTS: Surgery rescheduling resulted in a range of treatment times from 7 to 118 d. In the fish-oil-treated subjects, accumulation of EPA and DHA in the right atrium was curvilinear with time and reached a maximum at approximately 30 d of treatment and displaced mainly arachidonic acid. Flaxseed oil supplementation yielded a small increase in atrial EPA but not DHA, whereas olive oil did not significantly change atrial n-3 fatty acids. CONCLUSION: The results of the present study show that dietary n-3 fatty acids are rapidly incorporated into human myocardial phospholipids at the expense of arachidonic acid during high-dose fish-oil supplementation.
Asunto(s)
Enfermedades Cardiovasculares/metabolismo , Ácidos Grasos Omega-3/farmacocinética , Aceites de Pescado/química , Miocardio/metabolismo , Fosfolípidos/metabolismo , Anciano , Puente Cardiopulmonar , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/cirugía , Suplementos Dietéticos , Ácidos Docosahexaenoicos/administración & dosificación , Ácidos Docosahexaenoicos/farmacocinética , Ácido Eicosapentaenoico/administración & dosificación , Ácido Eicosapentaenoico/farmacocinética , Ácidos Grasos Omega-3/metabolismo , Femenino , Aceites de Pescado/administración & dosificación , Humanos , Aceite de Linaza/administración & dosificación , Aceite de Linaza/química , Masculino , Lípidos de la Membrana/química , Lípidos de la Membrana/metabolismo , Persona de Mediana Edad , Miocardio/citología , Aceite de Oliva , Fosfolípidos/química , Aceites de Plantas/administración & dosificación , Aceites de Plantas/química , Factores de RiesgoRESUMEN
OBJECTIVES: To assess the safety and efficacy of combination therapy in recent-onset rheumatoid arthritis (RA), with dose adjustments determined by response, in a clinic setting over 3 years. METHODS: Disease-modifying antirheumatic drug (DMARD)-naive patients with RA of median duration of 12 weeks (n = 61) attending an early arthritis clinic were treated with methotrexate, sulfasalazine, hydroxychloroquine, and fish oil. Dosage adjustments and additions of further DMARDs were contingent on response to therapy and tolerance. Outcome measures for efficacy were Disease Activity Score (DAS28), clinical remission, and modified Sharp radiographic score and for safety, adverse events, and DMARD withdrawal. RESULTS: At baseline, subjects had at least moderately active disease (mean +/- SD DAS28 was 5.3 +/- 1.1), impaired function as measured by the modified Health Assessment Questionnaire (mHAQ) (0.9 +/- 0.5), and 37% had bone erosions. By 3 months, 29% were in remission; this increased to 54% at 3 years. The greatest fall in DAS28 and improvement in mHAQ scores occurred in the first 12 months. Erosions were detected in 62% at 3 years. The mean dose of parenteral glucocorticoid was equivalent to 0.1 mg/d of prednisolone. After 3 years, 48% remained on triple therapy; fish oil was consumed by 75% of patients, and 21% used nonsteroidal anti-inflammatory drugs. Gastrointestinal intolerance was the most frequent unwanted event (leading to DMARD withdrawal in 17 patients). Sulfasalazine was most frequently withdrawn (30%). CONCLUSION: This implementation study demonstrates the feasibility, safety, and efficacy of combination therapy with inexpensive DMARDs, fish oil, and minimal glucocorticoid use, in routine clinical practice using predefined rules for dosage adjustment.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Adulto , Anciano , Antiinflamatorios no Esteroideos/efectos adversos , Antirreumáticos/efectos adversos , Artritis Reumatoide/fisiopatología , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Aceites de Pescado/efectos adversos , Aceites de Pescado/uso terapéutico , Glucocorticoides/efectos adversos , Humanos , Hidroxicloroquina/efectos adversos , Hidroxicloroquina/uso terapéutico , Estudios Longitudinales , Masculino , Metotrexato/efectos adversos , Metotrexato/uso terapéutico , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud/métodos , Índice de Severidad de la Enfermedad , Sulfasalazina/efectos adversos , Sulfasalazina/uso terapéutico , Resultado del TratamientoRESUMEN
OBJECTIVE: Rheumatoid arthritis (RA) is associated with increased risk for cardiovascular (CV) events through multiple factors. Fish oil has been shown to reduce symptoms in RA and to reduce CV risk. We assessed the effect of an antiinflammatory dose of fish oil on CV risk factors within a program of combination chemotherapy for patients with early RA. METHODS: Patients who chose not to take fish oil (n = 13) were compared with patients who achieved a sustained elevation of eicosapentaenoic acid (EPA) in plasma phospholipid fatty acids (> 5% total fatty acids) while taking fish oil over a 3-year period (n = 18). We examined cellular content of arachidonic acid (AA), synthesis of thromboxane A2 and prostaglandin E2, use of nonsteroidal antiinflammatory drugs (NSAID), traditional CV lipid risk factors, and disease activity at 3 years. RESULTS: At 3 years, AA (as a proportion of AA plus long-chain n-3 fatty acids that can compete with AA for cyclooxygenase metabolism) was 30% lower in platelets and 40% lower in peripheral blood mononuclear cells in subjects taking fish oil. Serum thromboxane B2 was 35% lower and lipopolysaccharide-stimulated whole-blood prostaglandin E2 was 41% lower with fish oil ingestion compared to no fish oil. NSAID use was reduced by 75% from baseline with fish oil (p < 0.05) and by 37% without fish oil (NS). Favorable changes in fasting blood lipids were seen with, but not without fish oil. Remission at 3 years was more frequent with fish oil use (72%) compared to no fish oil (31%). CONCLUSION: Fish oil reduces cardiovascular risk in patients with RA through multiple mechanisms.
Asunto(s)
Artritis Reumatoide/complicaciones , Artritis Reumatoide/tratamiento farmacológico , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Suplementos Dietéticos , Aceites de Pescado/uso terapéutico , Adulto , Anciano , Antirreumáticos/uso terapéutico , Ácido Araquidónico/metabolismo , Dinoprostona/metabolismo , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Eicosanoides/metabolismo , Femenino , Aceites de Pescado/administración & dosificación , Aceites de Pescado/efectos adversos , Humanos , Hidroxicloroquina/uso terapéutico , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Factores de Riesgo , Sulfasalazina/uso terapéutico , Tromboxano A2/metabolismoRESUMEN
There is a general belief among doctors, in part grounded in experience, that patients with arthritis need nonsteroidal anti-inflammatory drugs (NSAIDs). Implicit in this view is that these patients require the symptomatic relief provided by inhibiting synthesis of nociceptive prostaglandin E2, a downstream product of the enzyme cyclo-oxygenase (COX), which is inhibited by NSAIDs. However, the concept of 'safe' NSAIDs has collapsed following a multiplicity of observations establishing increased risk for cardiovascular events associated with NSAID use, especially but not uniquely with the new COX-2-selective NSAIDs. This mandates greater parsimony in the use of these agents. Fish oils contain a natural inhibitor of COX, reduce reliance on NSAIDs, and reduce cardiovascular risk through multiple mechanisms. Fish oil thus warrants consideration as a component of therapy for arthritis, especially rheumatoid arthritis, in which its symptomatic benefits are well established. A major barrier to the therapeutic use of fish oil in inflammatory diseases is ignorance of its mechanism, range of beneficial effects, safety profile, availability of suitable products, effective dose, latency of effects and instructions for administration. This review provides an evidence-based resource for doctors and patients who may choose to prescribe or take fish oil.
Asunto(s)
Artritis/terapia , Aceites de Pescado/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis/tratamiento farmacológico , Artritis Reumatoide/terapia , Toma de Decisiones , Humanos , Médicos , Reproducibilidad de los ResultadosAsunto(s)
Antiinflamatorios/administración & dosificación , Artritis Psoriásica/terapia , Aceites de Pescado/administración & dosificación , Antiinflamatorios/efectos adversos , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Psoriásica/fisiopatología , Enfermedades Cardiovasculares/terapia , Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-3/análisis , Aceites de Pescado/efectos adversos , Aceites de Pescado/química , Humanos , PhocidaeRESUMEN
Flaxseed, echium, and canola oils contain alpha-linolenic acid (18:3n-3, ALA) in a range of concentrations. To examine their effect on elevating cardiac levels of long-chain n-3 FA, diets based on these n-3-containing vegetable oils were fed to rats for 4 wk. Sunflower oil, which contains little ALA, was a comparator. Despite canola oil having the lowest ALA content of the three n-3-containing vegetable oils, it was the most potent for elevating DHA (22:6n-3) levels in rat hearts and plasma. However, the relative potencies of the dietary oils for elevation of EPA (20:5n-3) in heart and plasma followed the same rank order as their ALA content, i.e., flaxseed > echium > canola > sunflower oil. This paradox may be explained by lower ALA intake leading to decreased competition for Delta6 desaturase activity between ALA and the 24:5n-3 FA precursor to DHA formation.
Asunto(s)
Grasas Insaturadas en la Dieta/farmacología , Ácidos Grasos Omega-3/metabolismo , Miocardio/metabolismo , Aceites de Plantas/farmacología , Animales , Ácido Araquidónico/sangre , Ácido Araquidónico/metabolismo , Grasas Insaturadas en la Dieta/administración & dosificación , Grasas Insaturadas en la Dieta/metabolismo , Ácidos Docosahexaenoicos/sangre , Ácidos Docosahexaenoicos/metabolismo , Ácido Eicosapentaenoico/sangre , Ácido Eicosapentaenoico/metabolismo , Ácidos Grasos/análisis , Ácidos Grasos/metabolismo , Ácidos Grasos Omega-3/sangre , Ácidos Grasos Omega-3/farmacología , Ácidos Grasos Omega-6/sangre , Ácidos Grasos Omega-6/metabolismo , Ácidos Grasos Insaturados/sangre , Ácidos Grasos Insaturados/metabolismo , Femenino , Corazón/efectos de los fármacos , Miocardio/química , Fosfolípidos/química , Fosfolípidos/metabolismo , Aceites de Plantas/química , Aceites de Plantas/metabolismo , Ratas , Ácido alfa-Linolénico/análisis , Ácido alfa-Linolénico/metabolismo , Ácido alfa-Linolénico/farmacologíaRESUMEN
INTRODUCTION: Rheumatoid arthritis is a common inflammatory condition. A large number of patients seek alternative or complementary therapies of which diet is an important component. This article reviews the evidence for diet in rheumatoid arthritis along with the associated concept of oral tolerization. METHODS: References were taken from Medline from 1966 to September 2004. The keywords, rheumatoid arthritis, diet, n-3 fatty acids, vitamins, and oral tolerization, were used. RESULTS: Randomized controlled trials (RCTs) indicate that dietary supplementation with n-3 fatty acids provides modest symptomatic benefit in groups of patients with rheumatoid arthritis. Epidemiological studies and RCTs show cardiovascular benefits in the broader population and patients with ischemic heart disease. A number of mechanisms through which n-3 fats may reduce inflammation have been identified. In a small number of patients with rheumatoid arthritis, other dietary manipulation such as fasting, vegan, and elimination diets may have some benefit. However, many of these diets are impractical or difficult to sustain long term. CONCLUSIONS: Dietary manipulation provides a means by which patients can a regain a sense of control over their disease. Dietary n-3 supplementation is practical and can be easily achieved with encapsulated or, less expensively, bottled fish oil.