RESUMEN
BACKGROUND: High-density lipoprotein (HDL) exerts a variety of anti-atherothrombotic functions, including a potent anti-inflammatory impact. In line, the direct pro-inflammatory effects of C-reactive protein (CRP) can be attenuated by HDL in vitro. OBJECTIVE: To evaluate whether this also holds true in humans, we assessed the ability of reconstituted HDL to neutralize CRP-mediated activation of coagulation and inflammation. METHODS: Fifteen healthy male volunteers received an infusion of recombinant human (rh)CRP (1.25 mg kg(-1) body weight). In eight of these volunteers, an infusion of human apoAI reconstituted with phosphatidylcholine (apoAI-PC; 80 mg kg(-1) body weight) preceded rhCRP infusion. RESULTS: Infusion of rhCRP alone elicited an inflammatory response and thrombin generation. In individuals who received apoAI-PC prior to rhCRP, these effects were abolished. Parallel tests in primary human endothelial cells showed that apoAI-PC preincubation with rhCRP abolished the CRP-mediated activation of inflammation as assessed by IL-6 release. Although we were able to show that rhCRP co-eluted with HDL after size-exclusion chromatography, plasmon surface resonance indicated the absence of a direct interaction between HDL and CRP. CONCLUSION: Infusion of apoAI-PC prior to rhCRP in humans completely prevents the direct atherothrombotic effects of rhCRP. These findings imply that administration of apoAI-PC may offer benefit in patients with increased CRP.
Asunto(s)
Apolipoproteína A-I/farmacología , Proteína C-Reactiva/farmacología , Inflamación/prevención & control , Trombosis/etiología , Adulto , Apolipoproteína A-I/administración & dosificación , Aterosclerosis , Proteína C-Reactiva/administración & dosificación , Células Endoteliales , Humanos , Inflamación/inducido químicamente , Masculino , Persona de Mediana Edad , Fosfatidilcolinas/administración & dosificación , Proteínas RecombinantesAsunto(s)
Diabetes Mellitus Tipo 2/fisiopatología , Endotelio Vascular/fisiología , Endotelio Vascular/fisiopatología , Lipoproteínas HDL/farmacología , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Antebrazo/irrigación sanguínea , Humanos , Infusiones Intravenosas , Lipoproteínas HDL/administración & dosificación , Valores de ReferenciaRESUMEN
OBJECTIVE: To evaluate the safety and tolerability of prolonged-release nicotinic acid (Niaspan) added to statin therapy in patients at increased cardiovascular risk. METHODS: This was a 6-month, prospective, observational, multicentre, open-label evaluation of prolonged-release nicotinic acid (maximum dose 2000 mg/day) in statin-treated patients with cardiovascular disease and/or type 2 diabetes. The primary endpoint was the safety and tolerability of prolonged-release nicotinic acid, with special regard to treatment-related adverse drug reactions (ADRs). Secondary endpoints were changes in lipids and 10-year cardiovascular risk (Prospective Cardiovascular Münster (PROCAM) score). RESULTS: The study population included 1053 patients: 50% had hypertension, diabetes and/or metabolic syndrome (National Cholesterol Education Program/Adult Treatment Panel III criteria) and 80% had cardiovascular disease. Flushing (mostly mild or moderate) occurred in 430 patients (40.8%). Other ADRs occurred in 125 patients (12.5%), most commonly pruritus (2.7%), gastro-intestinal symptoms (3.8%) and nervous system-related complaints (3.8%). Serious ADRs were uncommon (0.6%). All patients recovered completely from these ADRs after treatment discontinuation. In total, 11.1% of the patients discontinued study medication for flushing and 8.4% for other ADRs. There was no evidence of hepatotoxicity or myopathy. New-onset hyperglycaemia was negligible. Overall tolerability of prolonged-release nicotinic acid treatment (n = 734 patients at closeout) was 'very good' in 130 (17.7%), 'good' in 262 (35.7%), and 'acceptable' in 144 (19.6%) patients. High-density lipoprotein (HDL) cholesterol increased by 23%, triglycerides decreased by 15% and LDL-C decreased by 4%. CONCLUSIONS: Prolonged-release nicotinic acid was safe and generally well tolerated and effective in combination with statin therapy in patients at high risk of cardiovascular events, with a side-effect profile consistent with previous clinical experience.
Asunto(s)
Enfermedades Cardiovasculares/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipolipemiantes/efectos adversos , Niacina/efectos adversos , Preparaciones de Acción Retardada , Quimioterapia Combinada , Femenino , Rubor/inducido químicamente , Humanos , Hipolipemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Niacina/uso terapéutico , Estudios ProspectivosRESUMEN
The concentration of high-density lipoprotein (HDL) cholesterol has a strong inverse relationship to the incidence of cardiovascular disease. The protective effect of HDL cholesterol is due not only to its promotion of reverse cholesterol transport from the vascular wall to the liver, but also to its anti-inflammatory, antioxidative and antithrombotic effects. Patients with low HDL cholesterol concentrations are at increased risk for cardiovascular disease and may be considered for treatment with lipid-lowering drugs, such as statins, niacin and fibrates. Currently, only a limited number of HDL-increasing agents have demonstrated beneficial effects of increasing HDL in studies with intermediary endpoints. Among these drugs are apolipoprotein A-1 variants, inhibitors of the cholesterol ester transfer protein JTT-705 and torcetrapib.
Asunto(s)
Arteriosclerosis/sangre , Enfermedades Cardiovasculares/sangre , HDL-Colesterol/sangre , HDL-Colesterol/fisiología , Colesterol/metabolismo , Arteriosclerosis/epidemiología , Enfermedades Cardiovasculares/epidemiología , LDL-Colesterol/sangre , Humanos , Hipolipemiantes/uso terapéutico , Factores de RiesgoRESUMEN
BACKGROUND: The inverse relation between high-density lipoprotein cholesterol (HDL-C) and cardiovascular (CV) disease underscores the need for clinical evaluation of the effect of HDL-C increasing drugs on the prevalence of CV disease. METHODS: We review the efficacy of Niaspan on serum lipids and the occurrence of side effects either alone or in combination with statins, in randomised controlled trials (RCT) and comparative cohort trials (CCT). RESULTS: In four RCTs, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and lipoprotein(a) (Lp(a)) were decreased by 13, 26, and 17%, respectively, whereas HDL-C increased by 18%. In four CCTs a combination of Niaspan and statins showed an additional 22% reduction in LDL-C, 8% in TG and 6% in Lp(a) levels, compared with Niaspan monotherapy. Statin therapy had a minor additional effect of 1% on a total of 25% HDL-C increase during Niaspan treatment. Flushes occurred in 69% of the patients without any additional toxicity during combination therapy. CONCLUSION: Niaspan effectively raises HDL-C with concomitant beneficial effects on TG and LDL-C. Niaspan can be combined safely with statins and is also effective in patients with combined dyslipidaemia and type 2 diabetes mellitus. Trials on CV endpoints evaluating the effect of statins with Niaspan are urgently needed to settle whether this combination can confirm the high expectations for cardiovascular outcome.
Asunto(s)
HDL-Colesterol/efectos de los fármacos , Enfermedad de la Arteria Coronaria/prevención & control , Hipolipemiantes/uso terapéutico , Niacina/uso terapéutico , Enfermedad de la Arteria Coronaria/epidemiología , Preparaciones de Acción Retardada , Quimioterapia Combinada , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipolipemiantes/administración & dosificación , Hipolipemiantes/efectos adversos , Niacina/administración & dosificación , Niacina/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: The benefit of preoperative biliary drainage in jaundiced patients undergoing pancreaticoduodenectomy for a suspected malignancy of the periampullary region is still under debate. This study evaluated preoperative biliary drainage in relation to postoperative outcomes. STUDY DESIGN: At the Academic Medical Center, Amsterdam, the Netherlands, a cohort of 311 patients undergoing pancreaticoduodenectomy from June 1992 up to and including December 1999 was studied. Of this cohort 21 patients with external or surgical biliary drainage were excluded and 232 patients who had received preoperative internal biliary drainage were divided into three groups corresponding with severity of jaundice according to preoperative plasma bilirubin levels: < 40 microM (n = 177), 40 to 100 microM (n = 32), and > 100 microM (n = 23) were designated as groups 1, 2, and 3, respectively. These groups were compared with patients who underwent immediate surgery (n = 58) without preoperative drainage. RESULTS: The median number of stent (re)placements was 2 (range 1 to 6) with a median drainage duration of 41 days (range 2 to 182 days) and a stent dysfunction rate of 33%. Although patients in group 1 were better drained than patients in groups 2 and 3 (median reduction of bilirubin levels 82%, 57%, and 37%, respectively, p < 0.01), there was no difference in overall morbidity among the drained groups (50%, 50%, and 52%, respectively). There was no significant difference in overall morbidity between patients with and without preoperative biliary drainage (50% and 55%, respectively). CONCLUSIONS: Preoperative biliary drainage did not influence the incidence of postoperative complications, and although it can be performed safely in jaundiced patients it should not be used routinely.