Clinical and genomic safety of treatment with Ginkgo biloba L. leaf extract (IDN 5933/Ginkgoselect®Plus) in elderly: a randomised placebo-controlled clinical trial [GiBiEx]

Stefano Bonassi, Giulia Prinzi, Palma Lamonaca, Patrizia Russo, Irene Paximadas, Giuseppe Rasoni, Raffaella Rossi, Marzia Ruggi, Salvatore Malandrino, Maria Sánchez-Flores, Vanessa Valdiglesias, Barbara Benassi, Francesca Pacchierotti, Paola Villani, Martina Panatta, Eugenia Cordelli, Stefano Bonassi, Giulia Prinzi, Palma Lamonaca, Patrizia Russo, Irene Paximadas, Giuseppe Rasoni, Raffaella Rossi, Marzia Ruggi, Salvatore Malandrino, Maria Sánchez-Flores, Vanessa Valdiglesias, Barbara Benassi, Francesca Pacchierotti, Paola Villani, Martina Panatta, Eugenia Cordelli

Abstract

Background: Numerous health benefits have been attributed to the Ginkgo biloba leaf extract (GBLE), one of the most extensively used phytopharmaceutical drugs worldwide. Recently, concerns of the safety of the extract have been raised after a report from US National Toxicology Program (NTP) claimed high doses of GBLE increased liver and thyroid cancer incidence in mice and rats. A safety study has been designed to assess, in a population of elderly residents in nursing homes, clinical and genomic risks associated to GBLE treatment.

Methods: GiBiEx is a multicentre randomized clinical trial, placebo controlled, double blinded, which compared subjects randomized to twice-daily doses of either 120-mg of IDN 5933 (also known as Ginkgoselect®Plus) or to placebo for a 6-months period. IDN 5933 is extracted from dried leaves and contains 24.3% flavone glycosides and 6.1% of terpene lactones (2.9% bilobalide, 1.38% ginkgolide A, 0.66% ginkgolide B, 1.12% ginkgolide C) as determined by HPLC. The study was completed by 47 subjects, 20 in the placebo group and 27 in the treatment group. Clinical (adverse clinical effect and liver injury) and genomic (micronucleus frequency, comet assay, c-myc, p53, and ctnnb1 expression profile in lymphocytes) endpoints were assessed at the start and at the end of the study.

Results: No adverse clinical effects or increase of liver injury markers were reported in the treatment group. The frequency of micronuclei [Mean Ratio (MR) = 1.01, 95% Confidence Intervals (95% CI) 0.86-1.18), and DNA breaks (comet assay) (MR = 0.91; 95% CI 0.58-1.43), did not differ in the two study groups. No significant difference was found in the expression profile of the three genes investigated.

Conclusions: None of the markers investigated revealed a higher risk in the treatment group, supporting the safety of IDN 5933 at doses prescribed and for duration of six months.

Trial registration: ClinicalTrials.gov Identifier: NCT03004508 , December 20, 2016. Trial retrospectively registered.

Keywords: DNA cell maintenance; Genomic stability; Ginkgo biloba Extract; Safety.

Conflict of interest statement

Ethics approval and consent to participate

All questionnaires and materials were processed anonymously.

The study was approved by the Ethics Committee of the institutions involved: IRCCS San Raffaele Pisana (Reference Number 02/15) and ASL RM C (Reference Number 24164). The study was conducted in accordance with the International Conference on Harmonization of Good Clinical Practices guidelines and with the ethical principles of the Declaration of Helsinki. The study was registered to ClinicalTrials.govID (NCT03004508) [56]. IDN 5933 (also named Ginkgoselect®Plus) is a registered trademark of Indena S.p.A., Italy.

Written informed consent was obtained from all patients.

Consent for publication

Not applicable.

Competing interests

The authors have declared the following competing interests: The institutions of SB, GP, PL, IP, and GP have received research grant support from Indena SpA. SB received fees for consulting services from Indena SpA. All the other authors have declared no conflict of interest.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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