A Biomimetic Multiparametric Assay to Characterise Anti-Amyloid Drugs.

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 ß peptide (Aß) 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 Aß1-42 fibrillation through the description of the biochemical interactions (molecule-membrane Aß 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.

Implementation of clinical medication review in a geriatric ward to reduce potentially inappropriate prescriptions among older adults.

PURPOSE: The impact of several pharmaceutical interventions to reduce the use of potentially inappropriate medications (PIMs) and potentially omitted medications (POMs) has been recently studied. We aimed to determine whether clinical medication review (CMR) (i.e. a systematic and patient-centred clinical assessment of all medicines currently taken by a patient) performed by a geriatrician and a pharmacist added to standard pharmaceutical care (SPC) (i.e. medication reconciliation and regular prescription review by the pharmacist) resulted in more appropriate prescribing compared to SPC among older inpatients. METHODS: A retrospective observational single-centre study was conducted in a French geriatric ward. Six criteria for appropriate prescribing were chosen: the number of PIMs and POMs as defined by the STOPP/STARTv2 list, the total number of drugs prescribed, the number of administrations per day and the number of psychotropic and anticholinergic drugs. These criteria were compared between CMR and SPC group using linear and logistic regression models weighted on propensity scores. RESULTS: There were 137 patients included, 66 in the CMR group and 71 in the SPC group. The mean age was 87 years, the sex ratio was 0.65, the mean number of drugs prescribed was 9, the mean MMSE was 21 and at admission 242 POMs, and 363 PIMs were prescribed. Clinical medication review did not reduce the number of PIMs at discharge compared to SPC (beta = - 0.13 [- 0.84; 0.57], p = 0.71) nor did it reduce the number of drugs prescribed (p = 0.10), the number of psychotropic drugs (p = 0.17) or the anticholinergic load (p = 0.87). Clinical medication review resulted in more POMs being prescribed than in standard pharmaceutical care (beta = - 0.39 [- 0.72; - 0.06], p = 0.02). Cardiology POMs were more implemented in the medication review group (p = 0.03). CONCLUSION: Clinical medication review did not reduce the number of PIMs but helped clinicians introduce underused drugs, especially cardiovascular drugs, which are known to be associated with morbidity and mortality risk reduction.

Disproportionality analysis in VigiBase as a drug repositioning method for the discovery of potentially useful drugs in Alzheimer's disease.

Drug repositioning aims to propose new indications for marketed drugs. Although several methods exist, the utility of pharmacovigilance databases for this purpose is unclear. We conducted a disproportionality analysis in the World Health Organization pharmacovigilance database VigiBase to identify potential anticholinesterase drug candidates for repositioning in Alzheimer's disease (AD). METHODS: Disproportionality analysis is a validated method for detecting significant associations between drugs and adverse events (AEs) in pharmacovigilance databases. We applied this approach in VigiBase to establish the safety profile displayed by the anticholinesterase drugs used in AD and searched the database for drugs with similar safety profiles. The detected drugs with potential activity against acetylcholinesterase and butyrylcholinesterases (BuChEs) were then evaluated to confirm their anticholinesterase potential. RESULTS: We identified 22 drugs with safety profiles similar to AD medicines. Among these drugs, 4 (clozapine, aripiprazole, sertraline and S-duloxetine) showed a human BuChE inhibition rate of over 70% at 10-5  M. Their human BuChE half maximal inhibitory concentration values were compatible with clinical anticholinesterase action in humans at their normal doses. The most active human BuChE inhibitor in our study was S-duloxetine, with a half maximal inhibitory concentration of 1.2 µM. Combined with its ability to inhibit serotonin (5-HT) reuptake, the use of this drug could represent a novel multitarget directed ligand therapeutic strategy for AD. CONCLUSION: We identified 4 drugs with repositioning potential in AD using drug safety profiles derived from a pharmacovigilance database. This method could be useful for future drug repositioning efforts.

Desirable drug-drug interactions or when a matter of concern becomes a renewed therapeutic strategy.

Drug-drug interactions are sometimes considered to be detrimental and responsible for adverse effects. In some cases, however, some are stakeholders of the efficiency of the treatment and this combinatorial strategy is exploited by some drug associations, including levodopa (L-Dopa) and dopadecarboxylase inhibitors, ß-lactam antibiotics and clavulanic acid, 5-fluorouracil (5-FU) and folinic acid, and penicillin and probenecid. More recently, some drug-drug combinations have been integrated in modern drug design strategies, aiming to enhance the efficiency of already marketed drugs with new compounds acting not only as synergistic associations, but also as real boosters of activity. In this review, we provide an update of examples of such strategies, with a special focus on microbiology and oncology.

Noncellular screening for the discovery of protein-protein interaction modulators.

Protein-protein interactions (PPIs) constitute many potential therapeutic targets for the discovery of new drugs. Given their specificity, PPIs are more challenging to target than other ligands. Thus, finding the best screening process can be difficult. Moreover, PPIs often have no direct accessible activity readout. Therefore, it can be unclear which test to choose for the screening of small molecules targeting PPIs. Given that noncellular assays are the most suitable both as first screening assays and for high-throughput screening (HTS), here we focus on noncellular screening assays. For each assay, we discuss the principles and advantages/drawbacks and provide a recent example. We also highlight the crucial parameters to take into account to select the most suitable assays to screen PPI modulators.

Drug repositioning: a brief overview.

OBJECTIVES: Drug repositioning, that is, the use of a drug in an indication other than the one for which it was initially marketed, is a growing trend. Its origins lie mainly in the attrition experienced in recent years in the field of new drug discovery. KEY FINDINGS: Despite some regulatory and economic challenges, drug repositioning offers many advantages, and a number of recent successes have confirmed both its public health benefits and its commercial value. The first examples of successful drug repositioning mainly came about through serendipity like acetylsalicylic acid, thalidomide, sildenafil or dimethylfumarate. CONCLUSION: The history of great-repositioned drugs has given some solutions to various pathologies. Serendipity is not yet useful to find repositioning drugs. Drug repositioning is of growing interest. Nowadays, a more rational approach to the identification of drug candidates for repositioning is possible, especially using data mining.

Impact of pharmacist interventions on clinical outcome and cost avoidance in a university teaching hospital.

Background A significant number of clinical pharmacy services have shown to improve in-hospital medication safety and patient outcome. Prescription review and pharmacist interventions are a fundamental part of hospital clinical pharmacy activities. In a context of restricted financial resources, proving the economic and clinical impact of this activity seems necessary. Objective The aim of this study was to assess the clinical impact on patient outcomes and economic benefit of prescription review by pharmacists. Setting 1624-bed tertiary French university teaching hospital. Method Prospective single center study evaluating prescriptions for which a pharmacist intervention was issued over a 6-month period. The clinical impact of every pharmacist intervention was evaluated by a multidisciplinary experts committee. Economic benefit was evaluated from the public health care system spending standpoint. Main outcome measures Number of avoided hospitalization days and associated public health care system cost-avoidance. Results Prescription review and interventions by pharmacists prevented 73 intensive care unit hospitalization days, 74 continuous monitoring unit hospitalization days and 66 days of conventional hospitalization. €252,294.00 in public health expenditure were thus prevented. For every Euro invested in the prescription review activity, €5.09 of public health spending were potentially saved. Conclusion Our study shows that prescription review and clinical pharmacists' interventions had an impact on clinical outcomes which translated into prevented hospitalization days. Prescription optimization through pharmacist interventions allows significant health care cost savings which makes this service highly efficient.

Benzylphenylpyrrolizinones with Anti-amyloid and Radical Scavenging Effects, Potentially Useful in Alzheimer's Disease Treatment.

Herein we describe the drug design steps developed to increase the radical scavenging and ß-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.

Novel benzylidenephenylpyrrolizinones with pleiotropic activities potentially useful in Alzheimer's disease treatment.

This work describes the synthesis and the biological evaluation of novel benzylidenephenylpyrrolizinones as potential antioxidant, metal chelating or amyloid ß (ßA) 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 ßA 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.

Near-Death Experiences in patients with locked-in syndrome: Not always a blissful journey.

Memories of Near-Death Experiences (NDEs) most often are recounted as emotionally positive events. At present, no satisfactory explanatory model exists to fully account for the rich phenomenology of NDEs following a severe acute brain injury. The particular population of patients with locked-in syndrome (LIS) provides a unique opportunity to study NDEs following infratentorial brain lesions. We here retrospectively characterized the content of NDEs in 8 patients with LIS caused by an acute brainstem lesion (i.e., "LIS NDEs") and 23 NDE experiencers after coma with supratentorial lesions (i.e., "classical NDEs"). Compared to "classical NDEs", "LIS NDEs" less frequently experienced a feeling of peacefulness or well-being. It could be hypothesized that NDEs containing less positive emotions might have a specific neuroanatomical substrate related to impaired pontine/paralimbic connectivity or alternatively might be related to the emotional distress caused by the presence of conscious awareness in a paralyzed body.

Near-death experiences in non-life-threatening events and coma of different etiologies.

BACKGROUND: Near death experiences (NDEs) are increasingly being reported as a clearly identifiable physiological and psychological reality of clinical significance. However, the definition and causes of the phenomenon as well as the identification of NDE experiencers is still a matter of debate. To date, the most widely used standardized tool to identify and characterize NDEs in research is the Greyson NDE scale. Using this scale, retrospective and prospective studies have been trying to estimate their incidence in various populations but few studies have attempted to associate the experiences' intensity and content to etiology. METHODS: This retrospective investigation assessed the intensity and the most frequently recounted features of self-reported NDEs after a non-life-threatening event (i.e., "NDE-like" experience) or after a pathological coma (i.e., "real NDE") and according to the etiology of the acute brain insult. We also compared our retrospectively acquired data in anoxic coma with historical data from the published literature on prospective post-anoxic studies using the Greyson NDE scale. RESULTS: From our 190 reports who met the criteria for NDE (i.e., Greyson NDE scale total score >7/32), intensity (i.e., Greyson NDE scale total score) and content (i.e., Greyson NDE scale features) did not differ between "NDE-like" (n = 50) and "real NDE" (n = 140) groups, nor within the "real NDE" group depending on the cause of coma (anoxic/traumatic/other). The most frequently reported feature was peacefulness (89-93%). Only 2 patients (1%) recounted a negative experience. The overall NDE core features' frequencies were higher in our retrospective anoxic cohort when compared to historical published prospective data. CONCLUSIONS: It appears that "real NDEs" after coma of different etiologies are similar to "NDE-like" experiences occurring after non-life threatening events. Subjects reporting NDEs retrospectively tend to have experienced a different content compared to the prospective experiencers.