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In this work, we exemplified the "copride" family of drug candidates able to both inhibit acetylcholinesterase and to activate 5-HT 4 receptors, with anti-amnesiant and promnesiant activities in mice. Twenty-one analogs of donecopride, the first-in class representative of the series, were synthesized exploring the influence on the biological activities of the substituents (methoxy, amine and chlorine) carried by its phenyl ring. This work was the support of an intensive structure-activity relationship study and allowed to obtain some interesting derivatives of donecopride. In this respect, the replacement of the methoxy group of the latter with a deuterated one led to deudonecopride. On the other hand, the replacement of the chlorine atom of donecopride by various halogen atoms was of particular interest, among which fluorine led to a potent analog, we called flucopride. The latter exhibited promising in vitro activities associated to excellent drugability parameters. Flucopride was consequently involved in in vivo studies such as a scopolamine-induced deficit model of working memory and in a novel object recognition test. Through these evaluations, flucopride demonstrated both its antiamnesiant and promnesiant capacities, which could make it a potential preclinical drug candidate for the treatment of Alzheimer's disease., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Patrick Dallemagne has patent #Acetylcholinesterase inhibitor compounds and 5-HT4 serotonergic receptor agonists with promnesia effect, their preparation and pharmaceutical compositions containing them pending to licensee. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Based on the structure of a previously identified hit, Gamhepathiopine 1, which showed promising antiplasmodial activity, but poor microsomal stability, several strategies were investigated to improve the metabolic stability of the compounds. This included the introduction of fluorine or deuterium atoms, as well as carbocyclic groups. Among the new compounds, the 2-aminocyclobutyl derivative 5g demonstrated enhanced microsomal stability compared to compound 1, while retaining antiplasmodial activity against erythrocytic and hepatic stages of Plasmodium, without significant cytotoxicity against primary hepatocytes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Alzheimer's disease (AD) is the most widespread form of senile dementia worldwide and represents a leading socioeconomic problem in healthcare. Although it is widely debated, the aggregation of the amyloid β peptide (Aβ) is linked to the onset and progression of this neurodegenerative disease. Molecules capable of interfering with specific steps in the fibrillation process remain of pharmacological interest. To identify such compounds, we have set up a small molecule screening process combining multiple experimental methods (UV and florescence spectrometry, ITC, and ATR-FTIR) to identify and characterise potential modulators of Aβ 1-42 fibrillation through the description of the biochemical interactions (molecule-membrane Aβ peptide). Three known modulators, namely bexarotene, Chicago sky blue and indomethacin, have been evaluated through this process, and their modulation mechanism in the presence of a biomembrane has been described. Such a well-adapted physico-chemical approach to drug discovery proves to be an undeniable asset for the rapid characterisation of compounds of therapeutic interest for Alzheimer's disease. This strategy could be adapted and transposed to search for modulators of other amyloids such as tau protein.

The increasing number of Plasmodium falciparum strains resistant to current treatments justifies the urgent need to discover new compounds active on several stages of the parasite development. Based on the structure of Gamhepathiopine, a 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one previously identified for its dual activity against the sexual and asexual stages of P. falciparum, 25 new 4-amino-substituted analogues were synthesized and evaluated on the erythrocytic and hepatic stages of Plasmodium. A promising compound, N 2 -(tert-butyl)-N [4]-(3-(dimethylamino)propyl)-6-(p-tolyl)thieno[3,2-d]pyrimidine-2,4-diamine, showed improved physicochemical properties, intestinal permeability (PAMPA model) and microsomal stability compared to Gamhepathiopine, while maintaining a good antiplasmodial activity on the erythrocytic stage of P. falciparum and on the hepatic stage of P. berghei., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

MCL-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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Gamhepathiopine (also known as M1), is a multi-stage acting antiplasmodial 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one hydrochloride that was first described in 2015. The development of this compound is limited by poor microsomal stability, insufficient aqueous solubility and low intestinal permeability. In order to obtain new optimized derivatives, we conducted a scaffold hopping strategy from compound M1, resulting in the synthesis of 20 new compounds belonging to six chemical series. All the compounds were tested on the K1 multi-resistant strain of Plasmodium falciparum and the human HepG2 cell-line, to evaluate their antiplasmodial activity and their cytotoxicity. Analogues' biological results also highlighted the mandatory presence of a heteroatom at position 5 of the thieno[3,2-d]pyrimidin-4(3H)-one moeity for the antiplasmodial activity. However, modifications at position 7 were detrimental for the antiplasmodial activity. We identified furane bioisostere 3j as a promising candidate, showing good blood stage antiplasmodial activity, better water solubility and highly improved intestinal permeability in the PAMPA assay., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

The overexpression of antiapoptotic members (BCL-2, BCL-xL, MCL-1, etc.) of the BCL-2 family contributes to tumor development and resistance to chemotherapy or radiotherapy. Synthetic inhibitors targeting these proteins have been developed, and some hematological malignancies are now widely treated with a BCL-2 inhibitor (venetoclax). However, acquired resistance to venetoclax or chemotherapy drugs due to an upregulation of MCL-1 has been observed, rendering MCL-1 an attractive new target for treatment. Six MCL-1 inhibitors (S64315, AZD-5991, AMG-176, AMG-397, ABBV-467 and PRT1419) have been evaluated in clinical trials since 2016, but some were affected by safety issues and none are currently used clinically. There is, therefore, still a need for alternative molecules. We previously described two drimane derivatives as the first covalent BH3 mimetics targeting MCL-1. Here, we described the characterization and biological efficacy of one of these compounds (NA1-115-7), isolated from Zygogynum pancheri, a plant belonging to the Winteraceae family. NA1-115-7 specifically induced the apoptosis of MCL-1-dependent tumor cells, with two hours of treatment sufficient to trigger cell death. The treatment of lymphoma cells with NA1-115-7 stabilized MCL-1, disrupted its interactions with BAK, and rapidly induced apoptosis through a BAK- and BAX-mediated process. Importantly, a similar treatment with NA1-115-7 was not toxic to erythrocytes, peripheral blood mononuclear cells, platelets, or cardiomyocytes. These results highlight the potential of natural products for use as specific BH3 mimetics non-toxic to normal cells, and they suggest that NA1-115-7 may be a promising tool for use in cancer treatment., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

An antileishmanial structure−activity relationship (SAR) study focused on positions 2 and 8 of the imidazo[1,2-a]pyridine ring was conducted through the synthesis of 22 new derivatives. After being screened on the promatigote and axenic amastigote stages of Leishmania donovani and L. infantum, the best compounds were tested against the intracellular amastigote stage of L. infantum and evaluated regarding their in vitro physicochemical and pharmacokinetic properties, leading to the discovery of a new antileishmanial6-chloro-3-nitro-8-(pyridin-4-yl)-2-[(3,3,3-trifluoropropylsulfonyl)methyl]imidazo[1,2-a]pyridine hit. It displayed low cytotoxicities on both HepG2 and THP1 cell lines (CC50 > 100 µM) associated with a good activity against the intracellular amastigote stage of L. infantum (EC50 = 3.7 µM versus 0.4 and 15.9 µM for miltefosine and fexinidazole, used as antileishmanial drug references). Moreover, in comparison with previously reported derivatives in the studied series, this compound displayed greatly improved aqueous solubility, good mouse microsomal stability (T1/2 > 40 min) and high gastrointestinal permeability in a PAMPA model, making it an ideal candidate for further in vivo studies on an infectious mouse model.

Background: In central sterile services departments (CSSD), the functionality of rigid endoscopes, which are complex and fragile reusable devices, is usually controlled visually and is considered a complex and subjective task. ScopeControl® was developed to provide an automated quality control of rigid endoscopes by measuring the value of six parameters: viewing angle (VA), field of view (FV), color correctness (CC), light transmission (LT), fibers transmission (FT), and focus (FC). The aim of the present study was to assess the ability of ScopeControl® to pre-emptively identify endoscope defects before the surgeon considers them as defective., Methods: The same endoscope was evaluated by surgeons during surgery using a scoring scale as well as the CSSD staff using the ScopeControl® during reprocessing. The ScopeControl® categorized the endoscope into 3 groups: "passed," "in danger," and "failed." Correlations between the surgeon's evaluation and results of the ScopeControl® were calculated., Results: One hundred sixty-six controls were carried out concerning 51 different endoscopes. According to the surgeon's evaluation, 78.9% and 80.7% of controls were considered as satisfactory for image and brightness quality, respectively. Results obtained using ScopeControl® found that 13.3% of controls were considered as "passed," 31.3% "in danger," and 55.4% "failed," with poor correlation with the surgeons' evaluation. LT and FT parameters represented 95.2% of the reasons for failures. The ability of the ScopeControl® to detect endoscope defects earlier than surgeons was validated by tracking the results of endoscopes used and controlled several times., Conclusion: The ScopeControl® achieved an objective and consistent quality control of endoscopes and showed poor correlation with the surgeon's opinion. In practice, the ScopeControl® could avoid the use of defective endoscopes in the surgery unit and thus improve the quality of the surgical procedure., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Purpose: The activation of 5-HT 4 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 C 18 /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.

Anxiety appears among the most frequent psychiatric disorders. During recent years, a growing incidence of anxiety disorders can be attributed, at least in part, to the modification of our eating habits. To treat anxiety disorders, clinicians use benzodiazepines, which unfortunately display many side effects. Herein, the anxiolytic-like properties of two natural products (αS1-casein hydrolysate and Gabolysat ® ) were investigated in rats and compared to the efficacy of benzodiazepine (diazepam). Thus, the conditioned defensive burying test was performed after a unique oral dose of 15 mg/kg, at two time-points (60 min and then 30 min post oral gavage) to show potential fast-onset of anxiolytic effect. Both natural products proved to be as efficient as diazepam to reduce the time rats spent burying the probe (anxiety level). Additionally, when investigated as early as 30 min post oral gavage, Gabolysat ® also revealed a fast-anxiolytic activity. To date, identification of bioactive peptide, as well as how they interact with the gut-brain axis to sustain such anxiolytic effect, still remains poorly understood. Regardless, this observational investigation argues for the consideration of natural compounds in care pathway.

Alzheimer's disease is the most common form of senile dementia in the world, and amyloid β peptide1-42 (Aβ 1-42 ) is one of its two principal biological hallmarks. While interactome concept was getting forward the scientific community, we proposed that the study of the molecular interactions of amyloid β peptide with the biological membranes will allow to highlight underlying mechanisms responsive of AD. We have developed two simple liposomal formulations (phosphatidylcholine, cholesterol, phosphatidylglycerol) mimicking neuronal cell membrane (composition, charge, curvature radius). Interactions with Aβ 1-42 and mutant oG37C, a stable oligomeric form of the peptide, were characterized according to a simple multiparametric procedure based on ThT fluorescence, liposome leakage assay, ATR-FTIR spectroscopy. Kinetic aggregation, membrane damage and peptide conformation provided our first methodologic bases to develop an original model to describe interactions of Aβ peptide and lipids., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Beside acetylcholinesterase, butyrylcholinesterase could be considered as a putative target of interest for the symptomatic treatment of Alzheimer's disease (AD). As a result of complexity of AD, no molecule has been approved since 2002. Idalopirdine, a 5-HT 6 receptors antagonist, did not show its effectiveness in clinical trial despite its evaluation as adjunct to cholinesterase inhibitors. Pleiotropic molecules, known as multitarget directed ligands (MTDLs) are currently developed to tackle the multifactorial origin of AD. In this context, we have developed a pleiotropic carbamate 7, that behaves as a covalent inhibitor of BuChE (IC 50  = 0.97 μM). The latter will deliver after hydrolysis, compound 6, a potent 5-HT 6 receptors antagonist (K i  = 11.4 nM) related to idalopirdine. In silico and in vitro evaluation proving our concept were performed completed with first in vivo results that demonstrate great promise in restoring working memory., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Cognitive decline appears across aging. While some studies report beneficial effects of musical listening and practice on cognitive aging, the underlying neurobiological mechanisms remain unknown. This study aims to determine whether chronic (6 h/day, 3 times/week) and long-lasting (4-8 months) music exposure, initiated at middle age in rats (15 months old), can influence behavioral parameters sensitive to age effects and reduce age-related spatial memory decline in rats. Spontaneous locomotor, circadian rhythmic activity, and anxiety-like behavior as well as spatial working and reference memory were assessed in 14-month-old rats and then after 4 and 8 months of music exposure (19 and 23 months old, respectively). Spatial learning and reference memory data were followed up by considering cognitive status of animals prior to music exposure (14 months old) given by K-means clustering of individual Z-score. Hippocampal cell proliferation and brain-derived neurotrophic factor (BDNF) level in the hippocampus and frontal cortex were measured. Results show that music exposure differentially rescues age-related deficits in spatial navigation tasks according to its duration without affecting spontaneous locomotor, circadian rhythmic activity, and anxiety-like behavior. Hippocampal cell proliferation as well as hippocampal and frontal cortex BDNF levels was not affected by music across aging. Cognitive improvement by music in aging rats may require distinct neurobiological mechanisms than hippocampal cell proliferation and BDNF., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC 50  = 17 nM, SI = 2650 & E° = -0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T 1/2  > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T 1/2  = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

An 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 ≤ EC 50 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 (EC 50 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Direct nose-to-brain delivery has been raised as a non-invasive powerful strategy to deliver drugs to the brain bypassing the blood-brain barrier (BBB). This study aimed at preparing and characterizing an innovative composite formulation, associating the liposome and hydrogel approaches, suitable for intranasal administration. Thermosensitive gel formulations were obtained based on a mixture of two hydrophilic polymers (Poloxamer 407, P407 and Poloxamer 188, P188) for a controlled delivery through nasal route via liposomes of an active pharmaceutical ingredient (API) of potential interest for Alzheimer's disease. The osmolarity and the gelation temperature (T° sol-gel) of formulations, defined in a ternary diagram, were investigated by rheometry and visual determination. Regarding the issue of assays, a mixture composed of P407/P188 (15/1%, w/w ) was selected for intranasal administration in terms of T° sol-gel and for the compatibility with the olfactory mucosal (280 ± 20 mOsmol, pH 6). Liposomes of API were prepared by the thin film hydration method. Mucoadhesion studies were performed by using mucin disc, and they showed the good natural mucoadhesive characteristics of in situ gel formulations, which increased when liposomes were added. The study demonstrated successful pharmacotechnical development of a promising API-loaded liposomes in a thermosensitive hydrogel intended for nasal Alzheimer's disease treatment ., Competing Interests: The authors declare no conflict of interest.

An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1 H )-one pharmacophore. Fifteen new derivatives were synthesized and evaluated in vitro against L. infantum , T. brucei brucei , and T. cruzi , in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative 12 was revealed, presenting EC 50 values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC 50 ≤ 13 μM). Moreover, compound 12 was not genotoxic in the comet assay and showed high in vitro microsomal stability (half life >40 min) as well as favorable pharmacokinetic behavior in the mouse after oral administration. Finally, molecule 12 ( E ° = -0.37 V/NHE) was shown to be bioactivated by type 1 nitroreductases, in both Leishmania and Trypanosoma , and appears to be a good candidate to search for novel antitrypanosomal lead compounds., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Pyridoclax is considered a promising anticancer drug, acting as a protein-protein interaction disruptor, with potential applications in the treatment of ovarian, lung, and mesothelioma cancers. Eighteen sensibly selected structural analogues of Pyridoclax were synthesized, and their physicochemical properties were systematically assessed and analyzed. Moreover, considering that drug-membrane interactions play an essential role in understanding the mode of action of a given drug and its eventual toxic effects, membrane models were used to investigate such interactions in bulk (liposomes) and at the air-water interface. The measured experimental data on all original oligopyridines allowed the assessment of relative differences in terms of physicochemical properties, which could be determinant for their druggability, and hence for drug development., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But AChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central AChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects. We aim in this article to pave the road of this new avenue with an in vitro and in vivo study of pleiotropic prodrugs targeting both the 5-HT 4 receptor and AChE, in order to display a neuroprotective activity associated with a sustained restoration of the cholinergic neurotransmission and without the usual peripheral side effects associated with classic AChEI. This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits.

Lipophilicity must be necessarily determined in drug discovery since this physicochemical property will directly influence the pharmacokinetics of a drug as its pharmacodynamics profile. Pyridoclax is an original lead, recently identified as very promising in treatment of chemoresistant cancers. The partition coefficient (Kp) of this anticancer drug was determined by microplate assays, well adapted in drug discovery, since being rapid, and requiring only poor drug amounts. The analytical approach was performed either by UV derivative spectrophotometry after validation thanks to a set of basic, neutral and acid reference substances, or originally, by raw fluorescence spectrophotometry by taking advantage of the pyridoclax intrinsic fluorescence. Large unilamellar vesicles (LUVs) were formulated from soybean-, egg-, or dipalmitoyl-phosphatidylcholine, characterized in terms of granulometric properties, ζ potential (determined by DLS), and of phospholipid content (quantified by 1 H NMR, also in presence of cholesterol). Whatever the detection method used, log Kp of pyridoclax were in the same magnitude order, and pyridoclax appeared as a lipophilic compound. It was also established that interactions between this lead and biomimetic membranes were influenced by the relative fluidity of the membranes, as confirmed by results of a liposome leakage assay., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Herein we describe the drug design steps developed to increase the radical scavenging and β-amyloid aggregation inhibitory activities of a previously described series of benzylidenephenylpyrrolizinones. Among the newly synthesized derivatives, some benzylphenylpyrrolizinones exhibited interesting results in regard to those activities. Initial druggability parameters were measured, and suggest these compounds as a suitable starting point for potential alternatives in treating Alzheimer's disease., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The use of electrosurgery has expanded to a wide variety of surgical specialities, but it has also been accompanied by its share of complications, including thermal injuries to nontargeted tissues, caused by a break or defect in the insulation of the instrument's coat. The purpose of this study was to determine the prevalence and the location of insulation failures (IFs) in electrosurgical instruments, then to assess the necessity of routine IF testing., Methods: Electrosurgical instruments were visually inspected and checked for IF using a high-voltage detector. Two different detectors were used during two testing sessions: DTU-6 (Petel company) and DIATEG (Morgate company). Laparoscopic and non-laparoscopic instruments were determined to have IF if current crossed the instrument's insulation, signaled by an alarm sound., Results: A total of 489 instruments were tested. The overall prevalence of IFs was 24.1 % with only visual inspection and 37.2 % with the IF detector. Among the 489 instruments, 13.1 % were visually intact, but had an electric test failure. DTU-6 and DIATEG detectors showed comparable efficiency in detection of overall IFs and for laparoscopic and non-laparoscopic instruments. The median location of IFs was more pronounced for laparoscopic instruments (50.4 %) and the distal location for non-laparoscopic instruments (40.4 %)., Conclusion: Accidental burns are a hidden problem and can lead to patient complications. In Central Sterilization Service Department, prevention currently includes only visual control of electrosurgery instrumentation, but testing campaigns are now necessary in order to identify maximum instruments' defects.

The cuttlefish belongs to the mollusk class Cephalopoda, considered as the most advanced marine invertebrates and thus widely used as models to study the biology of complex behaviors and cognition, as well as their related neurochemical mechanisms. Surprisingly, methods to quantify the biogenic monoamines and their metabolites in cuttlefish brain remain sparse and measure a limited number of analytes. This work aims to validate an HPLC-ECD method for the simultaneous quantification of dopamine, serotonin, norepinephrine and their main metabolites in cuttlefish brain. In comparison and in order to develop a method suitable to answer both ecological and biomedical questions, the validation was also carried out on a phylogenetically remote species: mouse (mammals). The method was shown to be accurate, precise, selective, repeatable and sensitive over a wide range of concentrations for 5-hydroxyindole-3-acetic acid, serotonin, dopamine, 3,4-dihydroxyphenylacetic acid and norepinephrine in the both extracts of cuttlefish and mouse brain, though with low precision and recovery for 4-hydroxy-3-methoxyphenylethylene glycol. Homovanillic acid, accurately studied in rodents, was not detectable in the brain of cuttlefish. Overall, we described here the first fully validated HPLC method for the routine measurement of both monoamines and metabolites in cuttlefish brain. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Despite its implication in several physiological and pathological processes the serotonin subtype-4 receptor (5-HT4R) has seen limited effort for the development of radiolabeling agent especially concerning single photon emission computed tomography (SPECT). Bearing an ester function, the available ligands are rapidly susceptible to hydrolysis which limits their use in vivo. In this study the synthesis of iodinated benzamide and ketone analogs were described. Their affinity for the 5-HT4R and their lipophilicity were evaluated and the most promising derivatives were evaluated ex vivo for their binding to the receptor and for their ability to displace the reference ligand [(125)I]-SB207710., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: The treatment of newborns and infants with congenital toxoplasmosis is standard practice. Some observational studies have examined safety in newborns, but most of these failed to provide sufficient details for a provisional assessment of causality. The aim of this study was to evaluate the clinical and biological adverse effects of the combination of sulfadoxine-pyrimethamine., Methods: Sixty-five children treated for 1 year with a combination of sulfadoxine-pyrimethamine (1 dose every 10 days) for congenital toxoplasmosis were followed up to evaluate abnormal hematological values and potential adverse events using a standardized method of causality assessment., Results: Nine patients (13.8%) presented at least 1 adverse clinical event that was nonspecific, such as diarrhea on the day of drug administration, vomiting and agitation. In 1 patient, erythema appeared at the end of the treatment and resolved within 10 days. None of these events was attributed to the treatment. Six patients (9.2%) developed an adverse hematological event (neutropenia, n = 3; eosinophilia, n = 2 and both anemia and eosinophilia, n = 1) that was considered to be possibly related to the sulfadoxine-pyrimethamine combination. Four treatments were temporarily interrupted, and toxicity was observed after readministration of treatment in 1 case only. However, none of these adverse events was life threatening., Conclusions: According to our results and previously published data, the combination of sulfadoxine-pyrimethamine seems to be well tolerated. However, the sample size of our study was too small to rule out the risk of less frequent, but nevertheless severe, reactions and, in particular, of hypersensitivity reactions.

This work describes the synthesis and the biological evaluation of novel benzylidenephenylpyrrolizinones as potential antioxidant, metal chelating or amyloid β (βA) aggregation inhibitors. Some derivatives exhibited interesting results in regard to several of the performed evaluations and appear as valuable Multi-Target Directed Ligands with potential therapeutic interest in Alzheimer's disease. Among them, compound 29 particularly appears as a valuable radical and NO scavenger, a Cu(II) and Fe(II) chelating agent and exhibits moderate βA aggregation inhibition properties. These activities, associated to a good predictive bioavailability and a lack of cytotoxicity, design it as a promising hit for further in vivo investigation., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPα release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment of Alzheimer's disease.

RS67333 is a partial serotonin subtype 4 receptor (5-HT4R) agonist that has been widely studied for its procognitive effect. More recently, it has been shown that its ability to promote the nonamyloidogenic cleavage of the precursor of the neurotoxic amyloid-β peptide leads to the secretion of the neurotrophic protein sAPPα. This effect has generated great interest in RS67333 as a potential treatment for Alzheimer's disease (AD). We show herein that RS67333 is also a submicromolar acetylcholinesterase (AChE) inhibitor and therefore, could contribute, through this effect, to the restoration of the cholinergic neurotransmission that becomes altered in AD. We planned to pharmacomodulate RS67333 to enhance its AChE inhibitory activity to take advantage of this pleiotropic pharmacological profile in the design of a novel multitarget-directed ligand that is able to exert not only a symptomatic but also, a disease-modifying effect against AD. These efforts allowed us to select donecopride as a valuable dual (h)5-HT4R partial agonist (Ki = 10.4 nM; 48.3% of control agonist response)/(h)AChEI (IC50 = 16 nM) that further promotes sAPPα release (EC50 = 11.3 nM). Donecopride, as a druggable lead, was assessed for its in vivo procognitive effects (0.1, 0.3, 1, and 3 mg/kg) with an improvement of memory performances observed at 0.3 and 1 mg/kg on the object recognition test. On the basis of these in vitro and in vivo activities, donecopride seems to be a promising drug candidate for AD treatment.

Since the stimulatory effect of kisspeptin on gonadotropin secretion is blocked by a GnRH antagonist, it has been suggested that the effect of kisspeptin is manifest exclusively at the level of hypothalamic GnRH secretion. However, kisspeptins are present in ovine hypophysial portal blood suggesting that the pituitary gland may be a target of kisspeptin. Dual fluorescence labeling with a specific mouse monoclonal antibody against LHbeta demonstrates that KiSS-1 and GPR54 are expressed by the gonadotrophs. Different paradigms were designed in animals and in humans in vivo to elucidate its role. However, in vitro studies assessing the direct stimulatory effects of kisspeptins on gonadotropin secretion in the pituitary have given conflicting results, depending on the hormonal (GnRH and/or estradiol) environment of the cells. Kisspeptins alone seem unable to induce the LH surge. It is therefore likely that kisspeptin has a synergic effect with GnRH and estradiol, at both hypothalamic and pituitary levels. However, kisspeptin may also play another role, distinct from that restricted to the reproductive axis. In this paper, we shall also review data on the potential role of kisspeptin in the control of other pituitary functions, e.g. somatotroph and lactotroph. Finally, kisspeptins could act as endocrine/autocrine/paracrine signals in modulating hormonal secretions of the anterior pituitary.

Objectives: We report the first survey on French physicians and patients participating to assess motivations prior enrolment and benefits and constraints perceived after participation., Method: Twenty physicians were interviewed and 37 patients completed a questionnaire during clinical study participation., Results: If the main patient's motivation is altruistic, physician wish their own patient feel better. After participation, patient is satisfied with being part of a research effort and contributing to medical science. Effect of trial treatment on physical well-being seems less pronounced. Main constraint is the randomisation to placebo group. For physicians, the main benefit is getting research experience and training. Main constraints are logistical. Otherwise, perceptions on the same clinical trial depend on participant. In fact, physician usually overestimates constraints of clinical trial for patient., Conclusion: The knowledge of patients and physicians perceptions of clinical trials and its taking into account should probably reduce difficulties in the recruitment in France.

The role of estrogens is dual: they suppress basal expression of gonadotropins and enhance GnRH responsiveness at the time of the LH surge. Estrogens are synthesized by cytochrome P450 aromatase (P450arom), encoded by the cyp19 gene. We focused on the cyp19 gene in rat and showed that it is expressed in gonadotropes through promoters PII and PI.f, using RT-PCR and dual fluorescence labeling with anti-P450arom and -LH antibodies. Real-time PCR quantification revealed that aromatase mRNA levels varied during the estrous cycle and were significantly increased after ovariectomy. This effect is prevented by estradiol (E2) as well as GnRH antagonist administration, suggesting that GnRH may mediate the steroid effect. Interestingly, the long-acting GnRH agonist that induces LH desensitization does not modify aromatase expression in ovariectomized rats. Administration of E2 in ovariectomized rats receiving either GnRH agonist or GnRH antagonist clearly demonstrated that E2 also reduces cyp19 expression at the pituitary level. The selective estrogen receptor-alpha ligand propyl pyrazole triol and the selective estrogen receptor-beta ligand diarylpropionitrile both mimic the E2 effects. By contrast, propyl pyrazole triol reduces LH beta expression whereas diarylpropionitrile does not. In addition, using transient transfection assays in an L beta T2 gonadotrope cell line, we provided evidence that GnRH agonist stimulated, in a dose-dependant manner, cyp19 promoters PII and PI.f and that E2 decreased the GnRH stimulation. In conclusion, our data demonstrate that GnRH is an important signal in the regulation of cyp19 in gonadotrope cells. Both common and specific intracellular factors were responsible for dissociated variations of LH beta and cyp19 expression.

Unlabelled: OBJECTIVE - METHOD: The purpose of this review is to explore the expectations of patients and physicians prior to participate to a clinical trial and their positive or negative experiences after participating. A systematic review of Medline database from 1966 to 2005 identified 79 papers reported patients and physicians perceptions of clinical trials (only 3 in French), whom 27 English surveys conducted on patients and physicians., Results: If primary patients' motivation for enrolment was altruistic, physicians wish to help their patient. After enrolment, the most perceived positive benefit for patients and physicians are, respectively, the emotional improvement and the greater opportunity for personal benefit offered to enrolled patients. Most physicians' negative experience included logistical difficulties while patients are unease with randomisation and often uncomfortable with medical procedures. Unlike patients, all physicians' expectations seem to be fulfilled., Conclusion: The knowledge of patients' and physicians' perception of participation may improve recruitment in clinical trials.

Aromatase cytochrome P450, the key enzyme of estrogen biosynthesis from androgens, is encoded by CYP19. Its structure shows some peculiarities: exons II to X encode the protein, while multiple alternative exons I encode unique 5'-untranslated regions of the aromatase mRNA transcripts. Immunohistochemistry studies in the rat have shown that pituitary aromatase expression is sex-dependent and varies across the estrous cycle, suggesting that estrogens might be involved in the regulation of aromatase activity and might act locally as a paracrine or autocrine factor in the pituitary. In the present study, we used RT-PCR to characterize aromatase transcripts and real-time PCR to quantify the expression of the total aromatase mRNA at the different stages of the estrous cycle and from an ovariectomy and estradiol replacement model. We identified the two previously described aromatase transcripts with a specific 5'untranslated region of the brain 1f and the gonadal PII transcripts. Total aromatase mRNA expression in the pituitary varied significantly during the estrous cycle, with the highest level occurring on the day of metestrus. After ovariectomy, we observed an increase of aromatase mRNA levels, and this effect was completely prevented by estradiol administration. These results suggest that pituitary aromatase mRNA expression is downregulated by estrogens.

The population pharmacokinetics of pyrimethamine (PYR) and sulfadoxine (SDX) for a group of 32 children with congenital toxoplasmosis was investigated by nonparametric modeling analysis. A one-compartment model was used as the structural model, and individual pharmacokinetic parameters were estimated by Bayesian modeling. PYR (1.25 mg/kg of body weight) and SDX (25 mg/kg) were administered orally every 10 days for 1 year, with adjustment of the dose to body weight every 3 months. Drug concentrations were measured by high-performance liquid chromatography. A total of 101 measurements in serum were available for both drugs. Mean absorption rate constants, volumes of distribution, elimination rate constants, and half-lives were 0.915 h(-1), 4.379 liters/kg, 0.00839 h(-1), and 5.5 days for PYR and 1.659 h(-1), 0.392 liters/kg, 0.00526 h(-1), and 6.6 days for SDX, respectively. Wide interindividual variability was observed. The estimated minimum and maximum concentrations of PYR in serum differed 8- and 25-fold among patients, respectively, and those of SDX differed 4- and 5-fold, respectively. Increases in the concentration of PYR were observed for eight children, and increases in the SDX concentration were observed for seven children. Serum PYR-SDX concentrations are unpredictable even when the dose is standardized for body weight. The concentrations of the PYR-SDX combination that are most efficacious for children have not yet been established. A model such as ours, associated with long-term follow-up, is needed to study the correlation between exposure to these two drugs and clinical outcome in children.

Site-selective scission of ribonucleic acids (RNAs) has attracted considerable interest, since RNA is an intermediate in gene expression and the genetic material of many pathogenic viruses. Polyamine-imidazole conjugates for site-selective RNA scission, without free imidazole, were synthesized and tested on yeast phenylalanine transfer RNA. These molecules catalyze RNA hydrolysis non-randomly. Within the polyamine chain, the location of the imidazole residue, the numbers of nitrogen atoms and their relative distances have notable influence on cleavage selectivity. A norspermine derivative reduces the cleavage sites to a unique location, in the anticodon loop of the tRNA, in the absence of complementary sequence. Experimental results are consistent with a cooperative participation of an ammonium group of the polyamine moiety, in addition to it's binding to the negatively charged ribose-phosphate backbone, as proton source, and the imidazole moiety as a base. There is correlation between the location of the magnesium binding sites and the RNA cleavage sites, suggesting that the protonated nitrogens of the polycationic chain compete with some of the magnesium ions for RNA binding. Therefore, the cleavage pattern is specific of the RNA structure. These compounds cleave at physiological pH, representing novel reactive groups for antisense oligonucleotide derivatives or to enhance ribozyme activity.

Transfer-messenger RNA (tmRNA, 10Sa RNA or ssrA) acts to rescue stalled bacterial ribosomes while encoding a peptide tag added trans-translationally to the nascent peptide, targeting it for proteolysis. The understanding at molecular level of this ubiquitous quality control system in eubacteria requires structural information. Here, we describe the purification and structural analysis of a functional fragment of both Aquifex aeolicus and Escherichia coli tmRNA, recapitulating their tRNA-like domain, which were expressed in vivo from synthetic genes. Both recombinant RNA are correctly processed at both 5' and 3' ends and are produced in quantities suitable for structural analysis by NMR and/or X-ray crystallography. The sequence and solution structure of the tRNA-like domains were analysed by various methods including structural mapping with chemical and enzymatic probes and 2D NMR spectroscopy. The minimalist RNAs contain two post-transcriptional base modifications, 5-methyluridine and pseudouridine, as the full-length tmRNA. Both RNAs fold into three stems, a D-analogue, a T-loop and a GAAA tetra-loop. 2D NMR analysis of the imino proton resonances of both RNAs allowed the assignment of the three stems and of a number of tertiary interactions. It shows the existence of interactions between the TPsiC-loop and the D-analogue, exhibiting a number of similarities and also differences with the canonical tRNA fold, indicating that RNA tertiary interactions can be modulated according to the sequence and secondary structure contexts. Furthermore, the E.coli minimalist RNA is aminoacylatable with alanine with a catalytic efficiency an order of magnitude higher than that for full-length tmRNA.

Excluding all other costs or benefits of participation in clinical trials, the objective of this study was to evaluate and analyse the cost avoidance represented by the free supply of the investigational drug in place of paying for a marketed drug. The cost avoided was defined as money that would most likely have been spent, but not because of inclusion of the patient in the clinical study. Only studies for which a marketed alternative drug was available with a standard dosage have been analysed. The numbers of delivered doses or the treatment durations were tabulated from pharmacy dispensing records for each study, and were used to calculate the medication cost avoided. No marketed alternative drug was available for 10 of 56 clinical studies. In total, in 2000, the cost avoidance was estimated between [symbol: see text] 585,492 and [symbol: see text] 603,674, with a wide variability between studies or between patients (CV: 120-520%). The two disease categories associated with the largest cost avoidance were multiple sclerosis and growth hormone deficiency. The cost avoidance was essentially of benefit to the medical insurance or the patient (98%) and was lower than [symbol: see text] 10,000 for the hospital, because 91% of patients are not hospitalised. So, why are clinical studies involving ambulatory patients performed in hospital? Of the 56 studies analysed, 46 could be shown to be non-innovative, because a marketed alternative drug was available. Few studies appeared to permit free access to treatment with non-reimbursable marketed drugs.