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Pietri, Sylvia; Seguin, J; D’Arbigny, Pierre; Drieu, Katy; Culcasi, Marcel

doi:10.1023/a:1007728729844

Cited by 77 publications

(14 citation statements)

References 45 publications

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“…In preclinical in vivo studies, TRO40303 was prepared as an emulsion in IL30, at ~6 mg/mL. Aqueous stock solutions of the nitrone 5,5-dimethyl-1-pyrroline N -oxide (DMPO) were purified and checked for diamagnetism as previously described [16]. For the clinical study, TRO40303 was administered as a 20 mg/mL solution in liposomes (Northern Lipids Inc, Burnaby, Canada).…”

Section: Methodsmentioning

confidence: 99%

Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial

et al. 2014

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BackgroundAlthough reperfusion injury has been shown to be responsible for cardiomyocytes death after an acute myocardial infarction, there is currently no drug on the market that reduces this type of injury. TRO40303 is a new cardioprotective compound that was shown to inhibit the opening of the mitochondrial permeability transition pore and reduce infarct size after ischemia-reperfusion in a rat model of cardiac ischemia-reperfusion injury.MethodsIn the rat model, the therapeutic window and the dose effect relationship were investigated in order to select the proper dose and design for clinical investigations. To evaluate post-ischemic functional recovery, TRO40303 was tested in a model of isolated rat heart. Additionally, TRO40303 was investigated in a Phase I randomized, double-blind, placebo controlled study to assess the safety, tolerability and pharmacokinetics of single intravenous ascending doses of the compound (0.5 to 13 mg/kg) in 72 healthy male, post-menopausal and hysterectomized female subjects at flow rates from 0.04 to 35 mL/min (EudraCT number: 2010-021453-39). This work was supported in part by the French Agence Nationale de la Recherche.ResultsIn the vivo model, TRO40303 reduced infarct size by 40% at 1 mg/kg and by 50% at 3 and 10 mg/kg given by intravenous bolus and was only active when administered before reperfusion. Additionally, TRO40303 provided functional recovery and reduced oxidative stress in the isolated rat heart model.These results, together with pharmacokinetic based allometry to human and non-clinical toxicology data, were used to design the Phase I trial. All the tested doses and flow rates were well tolerated clinically. There were no serious adverse events reported. No relevant changes in vital signs, electrocardiogram parameters, laboratory tests or physical examinations were observed at any time in any dose group. Pharmacokinetics was linear up to 6 mg/kg and slightly ~1.5-fold, hyper-proportional from 6 to 13 mg/kg.ConclusionsThese data demonstrated that TRO40303 can be safely administered by the intravenous route in humans at doses expected to be pharmacologically active. These results allowed evaluating the expected active dose in human at 6 mg/kg, used in a Phase II proof-of-concept study currently ongoing.

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Section: Methodsmentioning

confidence: 99%

Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial

et al. 2014

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“…The most important ones are flavonols glycosides (24% to 25%, i.e. quercetin, kaempferol, and myricetin) and terpenoids (6%), which have free radical scavenging activity [109,110]. Ginkgo biloba extract is widely used in the treatment of acute ischemic stroke in China and is occasionally used in Europe.…”

Section: Ginkgo Bilobamentioning

confidence: 99%

Dietary Antioxidants as Potential Pharmacological Agents for Ischemic Stroke

Cherubini¹,

Ruggiero²,

Morand³

et al. 2008

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Acute ischemic stroke is a leading cause of death and severe disability in industrialised countries and also in many developing countries. An excessive amount of free radicals is generated during cerebral ischemia, which significantly contributes to brain damage. Therefore, an increasing interest has been devoted to the potential benefits of antioxidant compounds in ischemic stroke patients. In this review, we examined the most relevant observational studies concerning the relationship between dietary antioxidants and ischemic stroke as well as clinical trials investigating the effects of single or multiple antioxidant supplementation in the prevention or treatment of acute ischemic stroke. Furthermore, we reviewed the most promising antioxidant compounds, i.e. dehydroascorbic acid, alpha-tocotrienol, gamma-tocopherol, flavonoids, resveratrol and gingko biloba, tested in animal models of acute ischemic stroke. Finally, we carefully evaluated the reasons for the discrepancy between experimental and clinical studies, and provided recommendations to improve the translation of the results obtained in animal models to patients with acute ischemic stroke.

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“…Chlorogenic, as a natural antioxidants, is able to chelate iron [56] and protect against oxidative stress [57] and DNA damage [58]. Quercetin, the main representative of the flavonol, found in high concentration in onions, apple, red wine, Ginkgo biloba, influences some carcinnogenosis markers [59][60][61][62][63][64][65][66]. Quercetin and its derivatives, as the principal polyphenol of Ginkgo biloba, might be partly responsible for its medicinal function of decrease in blood pressure [59].…”

Section: Potential Beneficial Effects Of Consuming Ulam Rajamentioning

confidence: 99%