Active Targeted Nanoemulsions for Repurposing of Tegaserod in Alzheimer’s Disease Treatment

Background and Purpose: The activation of 5-HT4 receptors with agonists has emerged as a valuable therapeutic strategy to treat Alzheimer’s disease (AD) by enhancing the nonamyloidogenic pathway. Here, the potential therapeutic effects of tegaserod, an effective agent for irritable bowel syndrome, were assessed for AD treatment. To envisage its efficient repurposing, tegaserod-loaded nanoemulsions were developed and functionalized by a blood–brain barrier shuttle peptide. Results: The butyrylcholinesterase inhibitory activity of tegaserod and its neuroprotective cellular effects were highlighted, confirming the interest of this pleiotropic drug for AD treatment. In regard to its drugability profile, and in order to limit its peripheral distribution after IV administration, its encapsulation into monodisperse lipid nanoemulsions (Tg-NEs) of about 50 nm, and with neutral zeta potential characteristics, was performed. The stability of the formulation in stock conditions at 4 °C and in blood biomimetic medium was established. The adsorption on Tg-NEs of peptide-22 was realized. The functionalized NEs were characterized by chromatographic methods (SEC and C18/HPLC) and isothermal titration calorimetry, attesting the efficiency of the adsorption. From in vitro assays, these nanocarriers appeared suitable for enabling tegaserod controlled release without hemolytic properties. Conclusion: The developed peptide-22 functionalized Tg-NEs appear as a valuable tool to allow exploration of the repurposed tegaserod in AD treatment in further preclinical studies

Mort probable, mort certaine. Réflexions en paléodémographie à partir de squelettes modernes et contemporains

Die 1982 von Claude Masset entwickelte « Methode der Wahrscheinlichkeitsvektoren « ermöglicht es, ein Bild der wahrscheinlichen Verteilung des Sterbealters einer bestatteten adulten Bevôlkerungsgruppe zu zeichnen. Die paläode- mographische Auswertung der Ergebnisse beschränkt sich jedoch auf Vergleiche zwischen Bestattungsensembles, für die man eine gleiche Auswahl annimmt. Die schwache Korrelation zwischen den Knochenmerkmalen und dem wirklichen Alter der Betroffenen lässt eine Bestimmung des individuellen Sterbealters nicht zu, die es erlauben würde, mittels Hypothesen die Paläodemographie zu rekonstruieren. Ist hingegen die Zusammensetzung einer Friedhofsbevölkerung nach Geschlecht und Alter bekannt, so ist es möglich ohne Umwege die Verteilung des Sterbealters einzuschätzen. Claude Masset hat dies an Beispielen aus der historischen Demographie uberpruft und regte dazu an, diese Berechnung an archâologischen Bevôlkerungen durch-zuführen. Die ausgewählten Beispiele gehören zu Bevölkerungen, deren demographische Struktur bekannt ist : die Nonnen der Abtei von Maubuisson aus dem 17-18. Jhdt und die Bewohner von Antibes vom Ende des 19. Jhdts. Die Methode der Wahrscheinlichkeitsvektoren erzielt sehr annehmbare Ergebnisse, es darf jedoch nicht vergessen werden, dass die Vektoren eine wahrscheinliche aber keine sichere Verteilung des Sterbealters angeben.The « probability vectors method » proposed by Claude Masset in 1982 makes it possible to obtain an image of the probable distribution of deaths according to age group in a buried adult population. However, the paleodemographic exploitation of the results is limited to comparisons between funerary sets for which an identical selection criterion is supposed. Indeed, the poor correlation between the osseous indicator and the actual age of the subjects does not allow the individual age of the adults at death to be determined, which would, making certain assumptions, enable the demography of the populations of the past to be reconstructed. Yet, if the breakdown by sex and by age of the population of recruitment of the cemetery is known at the outset, it is possible to estimate, without skew, the age distribution at death of the population buried. Claude Masset has verified this on the basis of examples from historical demography : it was instructive to do it similarly for archaeological populations. The selected sets belong to populations for which the demographic structure is known : nuns of the abbey of Maubuisson, 17th-18th centuries, and inhabitants of Antibes dating from the end of the 19th century. The « probability vectors method » yielded very acceptable results ; however, it should be borne in mind that the vectors provide a probable, and not certain, distribution of deaths.La méthode des « vecteurs de probabilités », proposée par Claude Masset en 1982, permet d'obtenir une image de la répartition probable des décès par groupes d'âges dans une population adulte inhumée. Toutefois, l'exploitation paléodémographique des résultats se limite à des comparaisons entre ensembles funéraires dont on suppose le mode de recrutement identique. En effet, la médiocre corrélation entre l'indicateur osseux et l'âge réel des sujets n'autorise pas une détermination de l'âge individuel au décès des adultes qui permettrait de reconstituer, moyennant certaines hypothèses, la démographie des populations du passé. Pourtant, si l'on connaît au préalable la composition par sexes et par âges de la population de recrutement du cimetière, il est possible d'estimer, sans biais, la répartition par âges au décès de la population inhumée. Claude Masset l'a vérifié sur des exemples de la démographie historique, il était instructif de le faire sur des populations archéologiques. Les ensembles choisis appartiennent à des populations dont la structure démographique est connue : religieuses de l'abbaye de Maubuisson, XVIIe-XVIIIe siècles, et habitants d'Antibes, fin XIXe siècle. La méthode des « vecteurs de probabilités » a donné des résultats très acceptables ; toutefois, il ne faut jamais oublier que les vecteurs fournissent une probable répartition et non une répartition certaine des décès.Buchet Luc, Séguy Isabelle, Boulle Eve-Line, Gallien Véronique, Wabont Monique. Mort probable, mort certaine. Réflexions en paléodémographie à partir de squelettes modernes et contemporains. In: Revue archéologique de Picardie. Numéro spécial 21, 2003. Sens dessus dessous. La recherche du sens en Préhistoire. Recueil d'études offert à Jean Leclerc et Claude Masset. pp. 101-111

Design of Non-Haemolytic Nanoemulsions for Intravenous Administration of Hydrophobic APIs

Among advanced formulation strategies, nanoemulsions are considered useful drug-delivery systems allowing to improve the solubility and the bioavailability of lipophilic drugs. To select safe excipients for nanoemulsion formulation and to discard any haemolytic potential, an in vitro miniaturized test was performed on human whole blood. From haemolysis results obtained on eighteen of the most commonly used excipients, a medium chain triglyceride, a surfactant, and a solubilizer were selected for formulation assays. Based on a design of experiments and a ternary diagram, the feasibility of nanoemulsions was determined. The composition was defined to produce monodisperse nanodroplets with a diameter of either 50 or 120 nm, and their physicochemical properties were optimized to be suitable for intravenous administration. These nanoemulsions, stable over 21 days in storage conditions, were shown to be able to encapsulate with high encapsulation efficiency and high drug loading, up to 16% (w/w), two water practically insoluble drug models: ibuprofen and fenofibrate. Both drugs may be released according to a modulable profile in sink conditions. Such nanoemulsions appear as a very promising and attractive strategy for the efficient early preclinical development of hydrophobic drugs

Active Targeted Nanoemulsions for Repurposing of Tegaserod in Alzheimer’s Disease Treatment

International audienceBackground and Purpose: The activation of 5-HT4 receptors with agonists has emerged as a valuable therapeutic strategy to treat Alzheimer’s disease (AD) by enhancing the nonamyloidogenic pathway. Here, the potential therapeutic effects of tegaserod, an effective agent for irritable bowel syndrome, were assessed for AD treatment. To envisage its efficient repurposing, tegaserod-loaded nanoemulsions were developed and functionalized by a blood–brain barrier shuttle peptide.Results: The butyrylcholinesterase inhibitory activity of tegaserod and its neuroprotective cellular effects were highlighted, confirming the interest of this pleiotropic drug for AD treatment. In regard to its drugability profile, and in order to limit its peripheral distribution after IV administration, its encapsulation into monodisperse lipid nanoemulsions (Tg-NEs) of about 50 nm, and with neutral zeta potential characteristics, was performed. The stability of the formulation in stock conditions at 4 °C and in blood biomimetic medium was established. The adsorption on Tg-NEs of peptide-22 was realized. The functionalized NEs were characterized by chromatographic methods (SEC and C18/HPLC) and isothermal titration calorimetry, attesting the efficiency of the adsorption. From in vitro assays, these nanocarriers appeared suitable for enabling tegaserod controlled release without hemolytic properties.Conclusion: The developed peptide-22 functionalized Tg-NEs appear as a valuable tool to allow exploration of the repurposed tegaserod in AD treatment in further preclinical studies

In vitro evaluation of NA1-115-7-loaded nanoemulsions, an MCL-1-specific inhibitor of natural origin, intended to treat B-cell lymphoproliferative disorders after oral administration

International audienceMCL-1, an anti-apoptotic member of the BCL-2 protein family, is overexpressed in many types of cancer and contributes to chemotherapy resistance. The drimane derivative NA1-115-7 is a natural compound isolated from Zygogynum pancheri that can be considered as a very promising lead for treating MCL-1-dependent hematological malignancies. As this drug suffers from low stability in acidic conditions and poor aqueous solubility, we evaluated the potential oral use of NA1-115-7 by encapsulating it in lipid nanoemulsions (NA-NEs) prepared by spontaneous emulsification. NA-NEs showed a particle size of 41.9 ± 2.2 nm, PDI of 0.131 ± 0.016, zeta potential of-5.8 ± 3.4 mV, encapsulation efficiency of approximately 100 % at a concentration of 24 mM. The stability of NA-1-115-7 was sixfold higher than that of the unencapsulated drug in simulated gastric fluid. NA-NEs significantly restored apoptosis and halved the effective doses of NA1-115-7 on BL2, a Burkitt lymphoma cell line, without toxicity in normal cells. Such a drug-delivery system appears to be particularly interesting for the oral administration of NA1-115-7, as it improves its solubility and stability, as well as efficacy, by reducing the therapeutic dose, making it possible to further consider in-vivo studies of this promising drug in BL2 xenografted mice

A winning strategy to improve the anticancer properties of Cisplatin and Quercetin based on the nanoemulsions formulation

The aim of the present study was the proposal of a strategy to permit the safe use of the powerful antitumor agent Cisplatin. Considering the possibility of reducing the oxidative stress responsible for the Cisplatin induced nephrotoxicity by using antioxidants, such as flavonoids, we proposed the concomitant therapeutic association of Cisplatin with Quercetin. Considering the poor solubility of Quercetin, nanoemulsions have been proposed to encapsulate and facilitate the use of the drug. Originally, the concomitant encapsulation of Quercetin with Cisplatin has been also assessed. The obtained formulations have been characterized and tested against two human cell models, namely the human breast cancer MDA-MB-231 and the normal HEK-293 renal cells. We demonstrated that the new formulated nanoemulsions have improved the anticancer properties of both the molecules and, most importantly, the synergistic effect of the Cisplatin/Quercetin against the MDA-MB-231. Moreover, the dramatic cytotoxic effects of Cisplatin against the human renal HEK-293 cells have been significantly diminished by the use of nanoemulsions containing both the molecules, whereas the antioxidant properties of encapsulated Quercetin have been improved. Finally, the simple process used to obtain the nanoemulsions and the physico-chemical properties compatible with parenteral administration, the stability and the improved pharmaceutical effects contribute to the high potential of this strategy to be studied in future in vivo studies

NA1—115—7, from Zygogynum pancheri, is a new selective MCL-1 inhibitor inducing the apoptosis of hematological cancer cells but non-toxic to normal blood cells or cardiomyocytes

International audienc

8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi

International audienceAn antikinetoplastid pharmacomodulation study was done at position 8 of a previously identified pharmacophore in 3-nitroimidazo[1,2-a]pyridine series. Twenty original derivatives bearing an alkynyl moiety were synthesized via a Sonogashira cross-coupling reaction and tested in vitro, highlighting 3 potent (40 nM ≤ EC50 blood stream form≤ 70 nM) and selective (500 ≤ SI ≤ 1800) anti-T. brucei brucei molecules (19, 21 and 22), in comparison with four reference drugs. Among these hit molecules, compound 19 also showed the same level of activity against T. cruzi (EC50 amastigotes = 1.2 μM) as benznidazole and fexinidazole. An in vitro comet assay showed that nitroaromatic derivative 19 was not genotoxic. It displayed a low redox potential value (-0.68 V/NHE) and was shown to be bioactivated by type 1 nitroreductases both in Leishmania and Trypanosoma. The SAR study indicated that an alcohol function improved aqueous solubility while maintaining good activity and low cytotoxicity when the hydroxyl group was at position beta of the alkyne triple bond. Hit-compound 19 was also evaluated regarding in vitro pharmacokinetic data: 19 is BBB permeable (PAMPA assay), has a 16 min microsomal half-life and a high albumin binding (98.5%). Moreover, compound 19 was orally absorbed and was well tolerated in mouse after both single and repeated administrations at 100 mg/kg. Its mouse plasma half-life (10 h) is also quite encouraging, paving the way toward further efficacy evaluations in parasitized mouse models, looking for a novel antitrypanosomal lead compound