Pharmaceutical Libraries Research Articles

Programmed Heterocycle Synthesis Using Halomucononitriles as Pyridinimine Precursors.

Herein we report a method to convert primary amines, ubiquitous motifs found in pharmaceutical libraries, to either imidazo[1,2-a]pyridines or 7-alkyl azaindoles in two steps from known compounds. Using halomucononitrile reagents, we can directly access 5-bromo-6-imino-1-alkyl-1,6-dihydropyridine-2-carbonitriles (pyridinimines) in a single step from primary amines (25-93% yield) through the cyclization of transient aminomucononitrile intermediates. We then demonstrate that these compounds can be readily converted to 7-alkylazaindoles using Sonogashira cross-coupling conditions (13 examples, up to 91% yield). Under oxidative conditions, the pyridinimines serve as directing groups for C-H functionalization reactions to afford imidazo[1,2-a]pyridines. We also studied the mechanism of the cyclization event using DFT calculations and propose that this takes place via sequential base-mediated E/Z isomerization and cyclization steps.

Sample Size Requirements of a Pharmaceutical Material Library: A Case in Predicting Direct Compression Tablet Tensile Strength by Latent Variable Modeling.

The material library is an emerging, new data-driven approach for developing pharmaceutical process models. How many materials or samples should be involved in a particular application scenario is unclear, and the impact of sample size on process modeling is worth discussing. In this work, the direct compression process was taken as the research object, and the effects of different sample sizes of material libraries on partial least squares (PLS) modeling in the prediction of tablet tensile strength were investigated. A primary material library comprising 45 materials was built. Then, material subsets containing 5 × i (i = 1, 2, 3, …, 8) materials were sampled from the primary material library. Each subset underwent sampling 1000 times to analyze variations in model fitting performance. Both hierarchical sampling and random sampling were employed and compared, with hierarchical sampling implemented with the help of the tabletability classification index d. For each subset, modeling data were organized, incorporating 18 physical properties and tableting pressure as the independent variables and tablet tensile strength as the dependent variable. A series of chemometric indicators was used to assess model performance and find important materials for model training. It was found that the minimum R2 and RMSE values reached their maximum, and the corresponding values were kept almost unchanged when the sample sizes varied from 20 to 45. When the sample size was smaller than 15, the hierarchical sampling method was more reliable in avoiding low-quality few-shot PLS models than the random sampling method. Two important materials were identified as useful for building an initial material library. Overall, this work demonstrated that as the number of materials increased, the model's reliability improved. It also highlighted the potential for effective few-shot modeling on a small material library by controlling its information richness.

Medicine Related Problems (MRPs) in Adult Patients with Asthma and Chronic Obstructive Pulmonary Disease (COPD)

Asthma and Chronic Obstructive Pulmonary disease (COPD) have been classified as non-communicable diseases by the World Health Organization (WHO). These diseases contribute to the occurrence of around 4.2 million deaths globally. Medicine related problems (MRPs) refer to incidents associated with medicine therapy that interfere in the desired health outcomes. Patients with asthma and/or COPD are likely to encounter MRPs due to ineffective treatment, adverse drug reactions (ADRs), and/or medication errors (MEs). Therefore, the current study aimed to identify the prevalence, causes, and risk factors of MRPs among adult patients with asthma and/or COPD. A systematic literature review was conducted using 13 databases. These databases included PubMed, NELM, Embase, Scopus, ISI Web of Knowledge, ScienceDirect, PsycInfo, British Nursing Index, Global heath, International Pharmaceutical Abstracts, PsycExtra, and Cochrane Library. ‘Medicine related problems (MRPs)’ ‘adults’ ‘asthma’ ‘adverse drug reactions (ADRs)’ ‘drug related problems (DRPs)’ ‘adverse drug events (ADEs)’ ‘medication errors (MEs)’, and ‘Chronic Obstructive Pulmonary Disease’ ‘(COPD)’ were used as search items. Only quantitative studies, which investigated MRPs in adult patients with asthma and/or COPD, were included. The results of the review retrieved initially 1146338 titles that were considered. The analysis of the titles of these studies identified 55 relevant abstracts, of which, 15 were included in the review. The data extracted from these studies showed that the MRPs had a prevalence rate of 39.8%, ADRs 4.6%, while MEs had a prevalence rate of 66.9%. The comparison of these prevalence rates showed that MEs and MRPs had a higher prevalence than ADRs. Theophylline was reported to have the highest prevalence rate of MRPs which required special consideration to ensure its safe use by patients. The findings of the current study would potentially provide insights pertaining to the reduction of the high rate of MRPs.

Systematic review of the impact of medication synchronization on healthcare utilization, economic, clinical, and humanistic outcomes

AbstractMedication synchronization (med‐sync) or appointment‐based medication synchronization (ABMS) programs allow patients to have their chronic medication refills aligned to one pickup day. For patients on multiple chronic medications, it provides a more manageable way of picking up those medications. The objective of the study was to systematically characterize literature describing economic and healthcare utilization, clinical, and humanistic outcomes for patients enrolled in med‐sync. A literature search was conducted on PubMed, International Pharmaceutical Abstracts (Ovid), CINAHL (EBSCO), EMBASE (Elsevier), and Cochrane Library. Studies were included if they were conducted at a pharmacy in the United States, between January 2008 and October 2022, and evaluated the impact of med‐sync on at least one of the four outcomes of interest (utilization, economic, clinical, and humanistic). The title and abstracts were screened, followed by a full‐text review and final data extraction by two researchers. A data extraction template and Cochrane risk of bias tool were used for data collection and quality assessments, respectively. The search resulted in 1617 studies and finally, 27 studies were included in the systematic review. All studies included patients enrolled in either ABMS, med‐sync, or in conjunction with other pharmacy services. Across all studies evaluating medication adherence, proportion of days covered (PDC) increased. All studies that administered patient surveys showed a majority of patients were satisfied with their med‐sync program. One study showed a reduction in healthcare utilization and costs, while another study indicated no change. Med‐sync programs have shown clinical outcomes, specifically to improve adherence in patients taking chronic medications. In terms of humanistic outcomes, patient surveys have shown high rates of satisfaction with med‐sync programs. Additional studies are needed to determine if med‐sync can lead to improvements in healthcare utilization and cost outcomes.

Abstract 2684: Synergistic efficacy of HSP90 and PI3K inhibitors in adrenocortical carcinoma

Abstract Adrenocortical cancer (ACC) is a rare and aggressive cancer (0.5-2 cases/million/year) with poor 5-year survival. Most patients inevitably succumb to widespread metastasis due to a lack of effective systemic treatment; therefore, it is critically important to identify new therapies for clinical trials. In this direction, we identified a potent synergistic combination of Heat Shock Protein 90 (HSP90) and PI3K inhibitors via quantitative high-throughput drug screening (qHTS) for ACC, using a pharmaceutical library of ~5000 drugs (FDA approved or investigational), and evaluating the drug synergy by computerized drug combination matrix analysis. Preclinical in vitro studies were performed to validate the efficacy of HSP90 inhibitors (STA9090, AUY922, HSP990), with PI3K inhibitors; PIK75 (investigational) or clinically available BGT226, and their pairwise combinations, in NCI-H295R and SW13 ACC cells. The drug combination of STA9090 and PIK75 significantly inhibited cell proliferation (monolayer and 3-dimensional culture and induced apoptosis more effectively than the individual drugs, with simultaneous upregulation of apoptotic protein markers (cleaved-Caspase3, cleaved-PARP), inhibition of the phosphorylated members of PI3K signaling pathway (AKT1, mTOR, S6K, 4EB1 and GSK3α/β), and the G2/M phase cell cycle arrest in ACC cells. Additionally, the synergetic effect of the drug combination was effective in reducing the metastatic potential as revealed by invasion/migration assay, which was confirmed by the downregulation of the epithelial-to-mesenchymal transition proteins (Vimentin, N-cadherin, SNAIL and Zeb1). An inhibition of cortisol production and altered oncogenic proteomic profiling was also observed. We validated the synergy of BGT226 with STA9090 and observed similar phenotypic changes by the drug combination in ACC cells. Interestingly, RNA sequencing and pathway analysis further revealed distinct gene expression profiles of STA9090 combined with PIK75 or BGT226, indicating different mechanism of cell death in both the PI3K drug combination treatment groups. Consistent with our in vitro findings, observations from the gene expression data from TCGA revealed significant mRNA overexpression of genes in HSP90 and PI3K signaling pathways (HSP90AA1, HSP90AB1 HSP90B1, TRAP1, PI3KCA, PI3KCB, AKT2, CDK1, CDK4, NR3C1) in 64% (n=59/92) ACC samples, with a positive correlation of mesenchymal markers TWIST1, ZEB1, VIM with HSP90AB1 and PI3KCA, suggesting our drug combination can be applicable in patients with ACC. A similar pattern of gene expressions was confirmed in independent GEO datasets. Conclusively, combination of HSP90 and PI3K inhibitors demonstrated a promising in vitro synergistic efficacy by inhibiting the key oncogenic targets of ACC. Further validation of in vivo efficacy is warranted. Citation Format: Prachi Mishra, Dipranjan Laha, Brieann Sobieski, Min Shen, Ya-Qin Zhang, Matthew Hall, Naris Nilubol. Synergistic efficacy of HSP90 and PI3K inhibitors in adrenocortical carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2684.

Collaborative Virtual Screening Identifies a 2-Aryl-4-aminoquinazoline Series with Efficacy in an In Vivo Model of Trypanosoma cruzi Infection.

Probing multiple proprietary pharmaceutical libraries in parallel via virtual screening allowed rapid expansion of the structure-activity relationship (SAR) around hit compounds with moderate efficacy against Trypanosoma cruzi, the causative agent of Chagas Disease. A potency-improving scaffold hop, followed by elaboration of the SAR via design guided by the output of the phenotypic virtual screening efforts, identified two promising hit compounds 54 and 85, which were profiled further in pharmacokinetic studies and in an in vivo model of T. cruzi infection. Compound 85 demonstrated clear reduction of parasitemia in the in vivo setting, confirming the interest in this series of 2-(pyridin-2-yl)quinazolines as potential anti-trypanosome treatments.

SOLVENT-FREE RAPID MICROWAVE SYNTHESIS AND ANTIVIRAL ACTIVITY OF 2,4-(I H, 3H)PYRIMIDINEDIONE

Microwave-assisted method has wide application in combinatorial chemistry. It has become a powerful tool in building the bioactive and pharmaceutical important compounds library within a short time. In view of a pronounced effect of Microwave-assisted methods in synthetic chemistry and their importance in drug discovery, a systematic work on the solvent-free synthesis of 2,4-(IH,3H)Pyrimidinedione(uracil) was carried out. Comparison was made between classic (conventional) and Novel (microwave-assisted) methods and it was found that compounds synthesized by microwave-assisted method showed better yield and reduced reaction time under safe and environment-friendly conditions, while conventional methods were tedious and time consuming. The structure elucidation of synthesized compounds was done by its melting/boiling points, solubility, thin layer chromatography (TLC) techniques and spectral analysis i.e ultraviolet (UV), Fourier transform infrared spectroscopy (FTIR) and Gas chromatography–mass spectrometry (GC-MS) were used to get the results. The pharmacological evaluation of synthesized compound was investigated by its antiviral activities against Lasota strain of NDV (ranikhait disease virus) and it showed the positive activity

RF07 | PSUN356 Synergistic Combination of HSP90 and PI3K inhibitors in Adrenocortical Cancer

Abstract Adrenocortical cancer (ACC) is a rare and aggressive cancer (0.5-2 cases/ million/ year) with a poor 5-year survival (<40%). Most patients inevitably succumb to the wide-spread metastasis because of the lack of effective systemic treatment options or to complications from uncontrolled hypercortisolism. Therefore, it is critically important to identify new effective treatments that can be readily used in a clinical trial. In this direction, we identified a potent synergistic combination of Heat Shock Protein 90 (HSP90) and PI3K inhibitors via quantitative high-throughput drug screening (qHTS) for ACC, using a pharmaceutical library comprised of ∼5000 drugs (FDA approved or investigational), and evaluation of drug synergy by a computerized drug combination matrix analysis. The synergistic efficacy of HSP90 inhibitor STA9090 and PI3K inhibitor, PIK75 was validated in vitro, in ACC cell lines H295R and SW13, by proliferation assay, which also determined the most efficacious doses of individual and combinatorial drugs. The drug combination significantly induced apoptosis and disintegrated the 3D-ACC spheroids as compared to the individual drugs, with a simultaneous upregulation of apoptotic protein markers (cleaved-Caspase3, cleaved-PARP), inhibition of the phosphorylation of PI3K pathway members (AKT1, mTOR, S6K, 4EB1 and GSK3α/β), and alteration in the G2/M phase of the cell cycle, in ACC cells. The synergetic effect of the drug combination was also effective in reducing the metastatic potential as revealed by invasion/migration assay, which was confirmed by the downregulation of the mesenchymal protein (Vimentin, N-cadherin, SNAIL and Zeb1) markers. Consistent with our data, observations from the gene expression data from The Cancer Genome Analysis (TCGA) & Gene Expression Omnibus (GEO) databases, revealed significant mRNA overexpression of HSP90AA1, HSP90AB1 HSP90B1 and its clients AKT2, CDK1, CDK4, NR3C1 indicating both HSP90 and PI3K/AKT pathways are highly activated in ACC cohorts. Overexpression and a positive correlation of mesenchymal markers TWIST1, ZEB1, VIM with HSP90AB1 and PI3KCA, in GEO and TCGA respectively, was consistent with the invasive potential of the ACC cells. In conclusion, our studies on the combination of HSP90 and PI3K inhibitors demonstrated a promising preliminary synergistic efficacy by inhibiting proliferation and epithelial-to-mesenchymal transition of ACC. Our findings can lead to development of an efficient mechanism-specific novel combination therapy that can be expedited to clinical trial in advanced ACC patients. Presentation: Saturday, June 11, 2022 1:12 p.m. - 1:17 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Fragmentation of Polyfunctional Compounds Recorded Using Automated High-Throughput Desorption Electrospray Ionization.

Using desorption electrospray ionization (DESI) as part of an automated high-throughput system, tandem mass spectra of the compounds in a pharmaceutical library were recorded in the positive mode under standardized conditions. Quality control filtering yielded an MS/MS library of 16 662 spectra. Fragmentation of subsets of the compounds in the library chosen to contain a single instance of a particular functional group (amide, piperazine, sulfonamide) was predicted by experts, and the results were compared with the experimental data. Expert performance was good to excellent for all the cases evaluated. Substituents on the functional groups were found to exert important secondary control over the fragmentation, with the main effect observed being product ion stabilization by aromatic substitution, which was consistent across the different groups evaluated. These substituent effects are generally explicable in terms of standard physical organic chemistry considerations of product ion stability as controlling fragmentation. A somewhat unexpected feature was the incidence of homolytic cleavages, driven by the stability of substituted amine radical cations. The findings of this study are intended to lay the groundwork for machine learning approaches to performing MS/MS spectrum → structure and structure → MS/MS spectrum operations on the same experimental data set. The effort involved and the success achieved in computer-aided interpretation, now underway, will be compared with the expert performance as described here.

X-ray on chip: Quantifying therapeutic synergies between radiotherapy and anticancer drugs using soft tissue sarcoma tumor spheroids

PurposeRadioresistance, tumor microenvironment, and normal tissue toxicity from radiation limit the efficacy of radiotherapy in treating cancers. These challenges can be tackled by the discovery of new radiosensitizing and radioprotecting agents aimed at increasing the therapeutic efficacy of radiotherapy. The goal of this work was to develop a miniaturized microfluidic platform for the discovery of drugs that could be used in combination with radiotherapy. The microfluidic system will allow the toxicity testing of cancer spheroids to different combinations of radiotherapy and molecular agents. Materials and methodsAn orthovoltage-based technique was used to expose the devices to multiple X-ray radiation doses simultaneously. Radiation dose-dependent DNA double-strand breaks in soft tissue sarcoma (STS) spheroids were quantified using comet assays. Analysis of proliferative death using clonogenic assays was also performed, and synergy between treatments with Talazoparib, Pazopanib, AZD7762, and radiotherapy was quantified using dedicated statistical tests. ResultsThe developed microfluidic system with simple magnetic valves was capable of growing 336 homogeneous STS spheroids. The irradiation of the microfluidic system with an orthovoltage-based technique enabled the screening of sixteen drug-radiotherapy combinations with minimal reagent consumption. Using this framework, we predicted a therapeutic synergy between a novel anticancer drug Talazoparib and radiotherapy for STS. No synergy was found between RT and either Pazopanib or AZD7762, as the combinations were found to be additive. ConclusionThis methodology lays the basis for the systemic search for molecular agent/radiotherapy synergies among preexisting pharmaceutical compounds libraries, in the hope to identify failed drug candidates in monotherapy that, in the presence of radiotherapy, would make it through clinical trials.

Collaborative virtual screening to elaborate an imidazo[1,2-a]pyridine hit series for visceral leishmaniasis.

An innovative pre-competitive virtual screening collaboration was engaged to validate and subsequently explore an imidazo[1,2-a]pyridine screening hit for visceral leishmaniasis. In silico probing of five proprietary pharmaceutical company libraries enabled rapid expansion of the hit chemotype, alleviating initial concerns about the core chemical structure while simultaneously improving antiparasitic activity and selectivity index relative to the background cell line. Subsequent hit optimization informed by the structure–activity relationship enabled by this virtual screening allowed thorough investigation of the pharmacophore, opening avenues for further improvement and optimization of the chemical series.

Fluorescence-Based TNFR1 Biosensor for Monitoring Receptor Structural and Conformational Dynamics and Discovery of Small Molecule Modulators.

Inhibition of tumor necrosis factor receptor 1 (TNFR1) is a billion-dollar industry for treatment of autoimmune and inflammatory diseases. As current therapeutics of anti-TNF leads to dangerous side effects due to global inhibition of the ligand, receptor-specific inhibition of TNFR1 signaling is an intensely pursued strategy. To monitor directly the structural changes of the receptor in living cells, we engineered a fluorescence resonance energy transfer (FRET) biosensor by fusing green and red fluorescent proteins to TNFR1. Expression of the FRET biosensor in living cells allows for detection of receptor-receptor interactions and receptor structural dynamics. Using the TNFR1 FRET biosensor, in conjunction with a high-precision and high-throughput fluorescence lifetime detection technology, we developed a time-resolved FRET-based high-throughput screening platform to discover small molecules that directly target and modulate TNFR1 functions. Using this method in screening multiple pharmaceutical libraries, we have discovered a competitive inhibitor that disrupts receptor-receptor interactions, and allosteric modulators that alter the structural states of the receptor. This enables scientists to conduct high-throughput screening through a biophysical approach, with relevance to compound perturbation of receptor structure, for the discovery of novel lead compounds with high specificity for modulation of TNFR1 signaling.

Cu-Catalyzed C-N Coupling with Sterically Hindered Partners.

Copper, an earth-abundant metal, has reemerged as a viable alternative to the versatile Pd-catalyzed C-N coupling. Coupling sterically hindered reaction partners, however, remains challenging. Herein, we disclose the discovery and development of a pyrrole-ol ligand to facilitate the coupling of ortho-substituted aryl iodides with sterically hindered amines. The ligand was discovered through a library screening approach and highlights the value of mining heteroatom-rich pharmaceutical libraries for useful ligand motifs. Further evaluation revealed that this ligand is uniquely effective in these challenging transformations. The reaction enables the coupling of sterically hindered primary and secondary amines, anilines, and amides with broad functional group tolerance.

Nickel-Catalyzed Cross-Electrophile Reductive Couplings of Neopentyl Bromides with Aryl Bromides.

5-Cyanoimidazole was identified as an inexpensive ligand for nickel-catalyzed cross-electrophile couplings by screening a diverse set of pharmaceutical compound library. A strategic screening approach led to the discovery of this novel ligand, which was successfully applied in the preparation of various alkylated arene products with good to high yields. Furthermore, the properties of this ligand allowed expanding the scope of reductive couplings to challenging substrates, such as sterically hindered neopentyl halides, which are known to generate motifs that are prevalent in biologically active molecules.

Identification of Three Antimicrobials Activating Serotonin Receptor 4 in Colon Cells.

The serotonin receptor 4b (5-HTR4b) is expressed throughout the gastrointestinal tract, and its agonists are used in the treatment of irritable bowel syndrome with constipation (IBS-C). Today, there are no rapid assays for the identification of 5-HTR4b agonists. Here, we developed a luciferase-based 5-HTR4b assay capable of assessing one compound per second with a 38-fold dynamic range and nM limit of detection for serotonin. We used the assay to screen more than 1000 natural products and anti-infection agents and identified five new 5-HTR4b ligands: hordenine, halofuginone, proflavine, ethacridine, and revaprazan. We demonstrate that hordenine (antibiofilm), halofuginone (antiparasitic), and revaprazan (gastric acid reducer) activate 5-HTR4b in human colon epithelial cells, leading to increased cell motility or wound healing. The 5-HTR4b assay can be used to screen larger pharmaceutical libraries to identify novel treatments for IBS-C. This work shows that antimicrobials interact not only with the gut microbiota, but also with the human host.

Identification of an Oxalamide Ligand for Copper‐Catalyzed C−O Couplings from a Pharmaceutical Compound Library

AbstractA typical pharmaceutical compound library is stocked with molecular diversity and could provide a platform for the discovery of new ligand structures. Herein, we describe the use of this approach in combination with high throughput screening to identify N,N’‐bis(thiophene‐2‐ylmethyl)oxalamide as a ligand that is generally effective for copper‐catalyzed C−O cross‐couplings to prepare both biarylethers as well as phenols under mild conditions.

Machine learning-powered antibiotics phenotypic drug discovery

Identification of novel antibiotics remains a major challenge for drug discovery. The present study explores use of phenotypic readouts beyond classical antibacterial growth inhibition adopting a combined multiparametric high content screening and genomic approach. Deployment of the semi-automated bacterial phenotypic fingerprint (BPF) profiling platform in conjunction with a machine learning-powered dataset analysis, effectively allowed us to narrow down, compare and predict compound mode of action (MoA). The method identifies weak antibacterial hits allowing full exploitation of low potency hits frequently discovered by routine antibacterial screening. We demonstrate that BPF classification tool can be successfully used to guide chemical structure activity relationship optimization, enabling antibiotic development and that this approach can be fruitfully applied across species. The BPF classification tool could be potentially applied in primary screening, effectively enabling identification of novel antibacterial compound hits and differentiating their MoA, hence widening the known antibacterial chemical space of existing pharmaceutical compound libraries. More generally, beyond the specific objective of the present work, the proposed approach could be profitably applied to a broader range of diseases amenable to phenotypic drug discovery.

Inhibiting the stringent response blocks Mycobacterium tuberculosis entry into quiescence and reduces persistence.

The stringent response enables Mycobacterium tuberculosis (Mtb) to shut down its replication and metabolism under various stresses. Here we show that Mtb lacking the stringent response enzyme RelMtb was unable to slow its replication rate during nutrient starvation. Metabolomics analysis revealed that the nutrient-starved relMtb -deficient strain had increased metabolism similar to that of exponentially growing wild-type bacteria in nutrient-rich broth, consistent with an inability to enter quiescence. Deficiency of relMtb increased the susceptibility of mutant bacteria to killing by isoniazid during nutrient starvation and in the lungs of chronically infected mice. We screened a pharmaceutical library of over 2 million compounds for inhibitors of RelMtb and showed that the lead compound X9 was able to directly kill nutrient-starved M. tuberculosis and enhanced the killing activity of isoniazid. Inhibition of RelMtb is a promising approach to target M. tuberculosis persisters, with the potential to shorten the duration of TB treatment.

Health Outcomes of Deprescribing Interventions Among Older Residents in Nursing Homes: A Systematic Review and Meta-analysis

ObjectivesDeprescribing is effective in addressing concerns relating to polypharmacy in residents of nursing homes. However, the clinical outcomes of deprescribing interventions among residents in nursing homes are not well understood. We evaluated the impact of deprescribing interventions by health care professionals on clinical outcomes among the older residents in nursing homes. DesignSystematic review and meta-analysis of randomized controlled trials. CINAHL, International Pharmaceutical Abstracts, MEDLINE, EMBASE, and Cochrane Library were searched from inception until September 2017; manual searches of reference lists of systematic reviews identified in the electronic search; and online trial registries for unpublished, ongoing, or planned trials. (PROSPERO CRD42016050028). Setting and ParticipantsRandomized controlled trials in a nursing home setting that included participants of at least 60 years of age. MeasuresFalls, all-cause mortality, hospitalization, and potentially inappropriate medication were assessed in the meta-analysis. ResultsA total of 41 randomized clinical studies (18,408 residents) that examined deprescribing (defined as either medication discontinuation, substitution, or reduction) in nursing were identified. Deprescribing interventions significantly reduced the number of residents with potentially inappropriate medications by 59% (odds ratio [OR] 0.41, 95% confidence interval [CI] 0.19–0.89). In subgroup analysis, medication review–directed deprescribing interventions reduced all-cause mortality by 26% (OR 0.74, 95% CI 0.65–0.84), as well as the number of fallers by 24% (OR 0.76, 95% CI 0.62–0.93). ConclusionsCompared to other deprescribing interventions, medication review–directed deprescribing had significant benefits on older residents in nursing homes. Further research is required to elicit other clinical benefits of medication review–directed deprescribing practice.

New development in the enantioselective synthesis of spiro compounds.

The enantioselective synthesis of spirocycles has long been pursued by organic chemists. Despite their unique 3D properties and presence in several natural products, the difficulty in their enantioselective synthesis makes them underrepresented in pharmaceutical libraries. Since the first pioneering reports of the enantioselective construction of spirosilanes by Tamao et al., significant effort has been devoted towards the development of new promising asymmetric methodologies. Remarkably, with the advent of organocatalysis, particularly over six years, the reported methodologies for the synthesis of spirocycles have increased exponentially. The aim of this review is to summarize the latest trends and developments in the enantioselective synthesis of spirocompounds during these last six years.