- ICH GCP
- Registr klinických studií v USA
- Klinická studie NCT01322711
Atorvastatin, Aspirin, Oxidative Stress, Coagulation and Platelet Activation Indexes
Effects on Oxidative Stress, Coagulation, Platelet Activation and Inflammatory Indexes of Atorvastatin and/or Aspirin Treatment in Patients at High Risk of Vascular Events
Primary and secondary prevention trials with statins, as well as with antiplatelet, clearly demonstrated that these drugs are able to reduce cardiovascular events. Even if the principal mechanism of action of statins is to lower cholesterol, other effects, the so-called pleiotropic effects, have been considered as adjunctive properties potentially accounting for the anti-atherosclerotic effect of statins.
Inhibition of oxidative stress may be considered an intriguing pleiotropic effect in view of the fact that oxidative stress is thought to be a key event in the initiation and progression of atherosclerotic disease. Reduction of several markers of oxidative stress including isoprostanes, 8-hydroxydeoxyguanosine (8-OHdG), and nitrotyrosine have been observed after statin treatment. NADPH oxidase is among the most important sources of reactive oxygen species involved in atherosclerotic disease. The investigators developed an ELISA to evaluate serum levels of soluble-gp91phox, the catalytic core of phagocyte NADPH oxidase. Recently the investigators showed that statins (30 days treatment) exert an antioxidant effect via inhibition of soluble gp91phox expression.
The exact mechanism by which atorvastatin reduces NADPH oxidase, however, is unclear. Recent study showed that statin treatment inhibits leukocyte ROCK activity, a protein kinase implicated in the activation of NADPH oxidase, with a mechanism that seems to be independent from lowering cholesterol. To further study the mechanism(s) implicate in gp91phox downregulation by statin the investigators planned the present study in patients with high risk of vascular events such as hypercholesterolemic and Type 2 Diabetes mellitus patients.
In addition the investigators want to evaluate the synergistic role of atorvastatin with aspirin treatment.
Přehled studie
Postavení
Intervence / Léčba
Detailní popis
Primary and secondary prevention trials with statins, as well as with antiplatelet, clearly demonstrated that these drugs are able to reduce cardiovascular events. Even if the principal mechanism of action of statins is to lower cholesterol, other effects, the so-called pleiotropic effects, have been considered as adjunctive properties potentially accounting for the antiatherosclerotic effect of statins.
Inhibition of oxidative stress may be considered an intriguing pleiotropic effect in view of the fact that oxidative stress is thought to be a key event in the initiation and progression of atherosclerotic disease. Reduction of several markers of oxidative stress including isoprostanes, 8-hydroxydeoxyguanosine (8-OHdG), and nitrotyrosine have been observed after statin treatment. NADPH oxidase is among the most important sources of reactive oxygen species involved in atherosclerotic disease. The investigators developed an ELISA to evaluate serum levels of soluble-gp91phox, the catalytic core of phagocyte NADPH oxidase. Recently the investigators showed that statins (30 days treatment) exert an antioxidant effect via inhibition of soluble gp91phox expression.
The exact mechanism by which atorvastatin reduces NADPH oxidase, however, is unclear. Recent study showed that statin treatment inhibits leukocyte ROCK activity, a protein kinase implicated in the activation of NADPH oxidase, with a mechanism that seems to be independent from lowering cholesterol.
Accelerated atherosclerosis is a typical feature of type 2 diabetes mellitus (T2DM). Thus, patients with T2DM have a 2- to 4-fold increased risk of cardiovascular diseases (CAD) and 2- to 6-fold increased risk of stroke.
Platelets play a major role in the etiology of atherosclerotic disease, as shown by the significant decrease of cardiovascular events in patients treated with aspirin, an inhibitor of COX1 that prevents platelet thromboxane (Tx) A2 formation. Despite this, interventional trials with aspirin in diabetic patients failed to show a beneficial effect. It has been previously demonstrated that COX1 inhibition determines a shift in arachidonic acid metabolism towards other pathways, such as the lipooxygenase system. The investigators speculate that COX1 inhibition could also be associated with increased conversion of arachidonic acid to platelet isoprostane formation; the increase of platelet isoprostanes would balance the inhibition of TxA2, thus hampering the antiplatelet effect of aspirin. As reported above, statins have been reported to down-regulate systemic isoprostanes with a mechanism that may involve inhibition of NADPH oxidase,therefore it could be interesting to examine if statins improve the antiplatelet effect of aspirin via inhibition of platelet isoprostanes.
To further study the mechanism(s) implicate in gp91phox downregulation by statin the investigators planned the present study in patients with hypercholesterolemia.
Furthermore, the second part of the study will be addressed to evaluate the synergistic role of atorvastatin with aspirin treatment in Type 2 Diabetes mellitus patients.
Typ studie
Zápis (Očekávaný)
Fáze
- Fáze 4
Kontakty a umístění
Studijní místa
-
-
-
Rome, Itálie, 00161
- Stefania Basili
-
-
Kritéria účasti
Kritéria způsobilosti
Věk způsobilý ke studiu
Přijímá zdravé dobrovolníky
Pohlaví způsobilá ke studiu
Popis
For Hypercholesterolemic patients:
Inclusion Criteria:
- Patients with polygenic hypercholesterolemia (LDL-C > 160 mg/dl)
- Males and Females
- White race
- Sign of the informed consent
Exclusion Criteria:
- Liver insufficiency
- Serious renal disorders
- Diabetes mellitus
- Arterial hypertension
- History or evidence of previous myocardial infarction or other atherothrombotic diseases
- Any autoimmune diseases
- Cancer
- Present or recent infections
- Patients were taking nonsteroidal antiinflammatory drugs, drugs interfering with cholesterol metabolism, or vitamin supplements
For T2 Diabetic patients:
Inclusion Criteria:
- Patients with T2DM diagnosed according to the American Diabetes Association definition
- Treatment with 100 mg/day aspirin from at least 30 days
- Males and Females
- White race
- Sign of the informed consent
Exclusion Criteria:
- recent history (< 3 months) of acute vascular events
- clinical diagnosis of type 1 DM
- serum creatinine level greater than 2.5 mg/dl
- active infection or malignancy
- cardiac arrhythmia or congestive heart failure
- use of non-steroidal anti-inflammatory drugs, vitamin supplements, or other antiplatelet drugs such as clopidogrel in the previous 30 days
Studijní plán
Jak je studie koncipována?
Detaily designu
- Primární účel: Léčba
- Přidělení: Randomizované
- Intervenční model: Paralelní přiřazení
- Maskování: Žádné (otevřený štítek)
Zbraně a zásahy
Skupina účastníků / Arm |
Intervence / Léčba |
---|---|
Aktivní komparátor: Atorvastatin
Each day accordingly to randomization patients allocated to Atorvastatin received a pill of 40 mg of atorvastatin. In diabetic patients the concomitant aspirin treatment include a previous 30 days treatment with 100 mg daily of aspirin. All patients followed the diet used in the placebo group. |
Atorvastatin 40 mg day
Ostatní jména:
|
Komparátor placeba: Diet
Low-fat diet with mean macronutrient profiles that were close to the present Adult Treatment Panel III guidelines (7% energy from saturated fat and, 200 mg dietary cholesterol per day)
|
Diet
|
Co je měření studie?
Primární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
---|---|---|
Evaluation of effect of Atorvastatin Therapy in Hypercholesterolemic Patients (n=30) and Diabetic Patients (n=30)
Časové okno: Baseline, 2 hours, 24 hours, 3 days, 7 days, 30 days
|
In Hypercholesterolemic patients (n=30) and in Diabetic patients (n=30) under chronic treatment with low dose aspirin (100 mg daily for at least 30 days), blood and urine samples were taken at each above reported time to evaluate the effect of atorvastatin or no treatment (Diet) on platelet recruitment, platelet and serum isoprostanes, platelet and serum thromboxane A2, platelet and serum NOX2 activation indexes, thrombin activation indexes, urinary excretion of thromboxane and isoprostanes.
|
Baseline, 2 hours, 24 hours, 3 days, 7 days, 30 days
|
Spolupracovníci a vyšetřovatelé
Sponzor
Vyšetřovatelé
- Vrchní vyšetřovatel: Stefania Basili, Prof., Sapienza-Univerity of Rome
Publikace a užitečné odkazy
Obecné publikace
- Carnevale R, Pignatelli P, Di Santo S, Bartimoccia S, Sanguigni V, Napoleone L, Tanzilli G, Basili S, Violi F. Atorvastatin inhibits oxidative stress via adiponectin-mediated NADPH oxidase down-regulation in hypercholesterolemic patients. Atherosclerosis. 2010 Nov;213(1):225-34. doi: 10.1016/j.atherosclerosis.2010.08.056. Epub 2010 Aug 19.
- Pignatelli P, Carnevale R, Cangemi R, Loffredo L, Sanguigni V, Stefanutti C, Basili S, Violi F. Atorvastatin inhibits gp91phox circulating levels in patients with hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):360-7. doi: 10.1161/ATVBAHA.109.198622. Epub 2009 Dec 3. Erratum In: Arterioscler Thromb Vasc Biol. 2014 Sep;34(9):e20.
- Pignatelli P, Carnevale R, Pastori D, Cangemi R, Napoleone L, Bartimoccia S, Nocella C, Basili S, Violi F. Immediate antioxidant and antiplatelet effect of atorvastatin via inhibition of Nox2. Circulation. 2012 Jul 3;126(1):92-103. doi: 10.1161/CIRCULATIONAHA.112.095554. Epub 2012 May 21.
Termíny studijních záznamů
Hlavní termíny studia
Začátek studia
Primární dokončení (Očekávaný)
Dokončení studie (Očekávaný)
Termíny zápisu do studia
První předloženo
První předloženo, které splnilo kritéria kontroly kvality
První zveřejněno (Odhad)
Aktualizace studijních záznamů
Poslední zveřejněná aktualizace (Odhad)
Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality
Naposledy ověřeno
Více informací
Termíny související s touto studií
Klíčová slova
Další relevantní podmínky MeSH
- Poruchy metabolismu glukózy
- Metabolické choroby
- Onemocnění endokrinního systému
- Diabetes Mellitus
- Poruchy metabolismu lipidů
- Hyperlipidemie
- Dyslipidemie
- Diabetes mellitus, typ 2
- Hypercholesterolémie
- Molekulární mechanismy farmakologického působení
- Inhibitory enzymů
- Antimetabolity
- Anticholesteremická činidla
- Hypolipidemická činidla
- Látky regulující lipidy
- Inhibitory hydroxymethylglutaryl-CoA reduktázy
- Atorvastatin
Další identifikační čísla studie
- ATORVASA
Tyto informace byly beze změn načteny přímo z webu clinicaltrials.gov. Máte-li jakékoli požadavky na změnu, odstranění nebo aktualizaci podrobností studie, kontaktujte prosím register@clinicaltrials.gov. Jakmile bude změna implementována na clinicaltrials.gov, bude automaticky aktualizována i na našem webu .
Klinické studie na Diabetes mellitus 2. typu
-
Hoffmann-La RocheDokončenoDiabetes 2. typu, Diabetes 1. typuRakousko, Spojené království
-
Services Hospital, LahoreDokončeno
-
Griffin HospitalCalifornia Walnut CommissionDokončenoDIABETES MELLITUS TYP 2Spojené státy
-
West China HospitalDokončeno
-
University of Roma La SapienzaNeznámýDiabetes Mellitus Typ 2 Reaktivita krevních destiček StatinItálie
-
Bristol-Myers SquibbDokončenoDiabetes, typ 2Spojené státy, Kanada, Mexiko, Portoriko, Austrálie, Polsko, Tchaj-wan
-
Universidade Federal de Ouro PretoDokončeno
-
Kyowa Kirin Co., Ltd.Dokončeno
-
Novo Nordisk A/SNáborDiabetes, typ 2Spojené státy, Indie, Španělsko, Polsko, Jižní Afrika, Bulharsko, Německo, Japonsko, Portoriko
-
Pfizer's Upjohn has merged with Mylan to form Viatris...Churchill HospitalDokončenoDiabetes, typ 2Spojené království