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The article explores the effectiveness of intrauterine mepivacaine instillation in reducing pain during intrauterine device (IUD) placement. Topics discussed include the design of a randomized controlled trial, comparison of pain scores between mepivacaine and placebo groups, and patient satisfaction with pain management techniques.

Background: Rimegepant, a novel oral calcitonin gene-related peptide receptor antagonist, has been recently approved for the acute migraine treatment. While its efficacy was confirmed in randomized clinical trials, no data is available regarding real-life effectiveness and tolerability. GAINER, a prospective, multicentric study, aimed to evaluate rimegepant effectiveness and tolerability in the real-world setting. Methods: Our study involved 16 headache centers across Italy. The main outcomes were: i) 2 h pain freedom, and ii) occurrence of treatment-emergent adverse events after administration. Participants were instructed to treat one migraine attack with rimegepant 75 mg orally disintegrating tablet. Using an ad hoc diary, participants prospectively collected migraine attack features at baseline and every 30 min after rimegepant administration, up to 2 h post dose. A 24 h follow up was also collected. Results: We enrolled 103 participants with migraine (74.8% female, mean age 44.4 [42.0 – 46.7] years, 24.3% with chronic migraine of whom 44.0% presented a concomitant diagnosis of medication overuse headache). The number of previously failed preventive classes was 2.7 [2.3 – 3.2]. Participants presented a mean of 9.6 [8.2 – 10.9] monthly migraine days at baseline. At rimegepant intake, 40.8% of patients rated migraine intensity as severe. Pain freedom 2 h post dose was reported in 44.7% (46/103) of individuals. Pain freedom 2 h post dose was not influenced by baseline pain severity (p = 0.316), but it was associated with timing of intake (p = 0.032) with a higher rate of 2 h pain freedom when rimegepant was taken within 1 h from pain onset. Mild adverse events were reported in 15.5% total attacks (16/103), predominantly fatigue (n = 6), gastrointestinal symptoms (n = 6), somnolence (n = 4), and transient cognitive difficulties (n = 3). Tolerability was rated as good-to-excellent in 85.4% cases (88/103). Conclusions: Our data confirms rimegepant effectiveness and safety in the acute migraine treatment in a real-world setting in a cohort of participants that includes subjects with episodic or chronic migraine, medication overuse and a high number of prior preventive treatment failures. Trial registration: The study was preregistered on clinicaltrial.gov, NCT05903027. [ABSTRACT FROM AUTHOR]

Starting from an l-serine-derived multifunctional aminobutenolide as a common chiral building block, stereoselective synthetic routes to representative examples of di-, tri-, and tetrahydroxylated iminosugars have been developed. Key steps in the synthetic routes involved an intramolecular aminolysis protocol to form the azaheterocyclic core, and functionalization of a resident alkene moiety towards installation of the desired substituents at the various positions of the piperidine ring. The strategy and the approach described are expected to provide flexible synthetic routes to various iminosugar scaffolds of structural and medicinal chemical significance. [ABSTRACT FROM AUTHOR]

Purpose: SN-38, the active metabolite of irinotecan, may cause adverse events necessitating treatment discontinuation and management. Diarrhea, which is treated with loperamide, is one such event. However, loperamide may delay SN-38 elimination, causing more adverse events. Therefore, understanding the adverse events caused by symptomatic drugs is crucial for safe drug therapy. This study aimed to assess the association between loperamide and irinotecan-induced adverse events. Methods: We analyzed data up to December 2022 from VigiBase, the World Health Organization's adverse event database. The study used reporting odds ratios (RORs) to evaluate the associations between concomitant medications and irinotecan-induced adverse events. Fisher's exact probability test was used to analyze the adverse events. Logistic regression analysis was performed to identify associated adverse event signals. Results: Of the 32,520,983 cases analyzed, 57,454 involved the use of irinotecan. Among these, 1589 (2.8%) patients were co-treated with loperamide. Signals for neutropenia (ROR 1.37, 95% confidence interval (CI) 1.20–1.57, p < 0.001), anemia (ROR 1.81, 95% CI 1.43–2.30, p < 0.001), and alopecia (ROR 1.89, 95% CI 1.30–2.74, p < 0.01) were detected with concomitant loperamide. Multivariate logistic regression analysis confirmed that concomitant loperamide use was associated with signals for neutropenia, anemia, and alopecia. Conclusion: Our results suggest that loperamide increases the risk of irinotecan-induced adverse events and enhances irinotecan toxicity. The study methodology may be useful for predicting adverse event risk when choosing symptomatic therapy drugs during irinotecan use. [ABSTRACT FROM AUTHOR]

Four new alkaloids, arecatines A–D (1–4), were isolated from the peels of Areca catechu. Compound 1 is an unusual piperidine-pyridine hybrid alkaloid, whereas compounds 2–4 feature bis-piperidine alkaloids. Their structures were elucidated by UV, IR, HRESIMS, and NMR spectra analysis. The molecular docking analysis indicated that compound 3 exhibited the best binding affinity with the GABAA receptor, indicating its potential anti-epilepsy activity. [ABSTRACT FROM AUTHOR]

In the title molecule, C13H17N3O3, the substituents on the phenyl ring are rotated slightly out of the mean plane of the ring but the piperidine moiety is nearly perpendicular to that plane. In the crystal, C--H···O hydrogen bonds form chains of molecules extending along the c-axis direction, which are linked by C O···π(ring) interactions. A Hirshfeld surface analysis showed the majority of intermolecular interactions to be H···H contacts while O···H/H···O contacts are the second most numerous. [ABSTRACT FROM AUTHOR]

Novel tetrahydroisoquinoline and piperidine derivatives were selectively synthesized from substituted indenes or cyclopentenes. The process starts with an oxidative cleavage of the ring olefin bond, which gives reactive diformyl intermediates. By a ring‐closing step using chiral (R) or (S) α‐methylbenzylamine under a reductive amination protocol facilitated ring formation with ring expansion of the corresponding nitrogen‐containing heterocycles. The stereocontrolled methodology enabled accurate control of the stereochemistry of the final products. Additionally, the synthesized amino acid derivatives possessing an aryl moiety in their structure may be relevant building blocks for foldamer chemistry. [ABSTRACT FROM AUTHOR]

Modern medicinal chemists are targeting more complex molecules to address challenging biological targets, which leads to synthesizing structures with higher sp3 character (Fsp3) to enhance specificity as well as physiochemical properties. Although traditional flat, high-fraction sp2 molecules, such as pyridine, can be decorated through electrophilic aromatic substitution and palladium (Pd)–based cross-couplings, general strategies to derivatize three-dimensional (3D) saturated molecules are far less developed. In this work, we present an approach for the rapid, modular, enantiospecific, and diastereo-selective functionalization of piperidine (saturated analog of pyridine), combining robust biocatalytic carbon-hydrogen oxidation with radical cross-coupling. This combination is directly analogous to electrophilic aromatic substitution followed by Pd-couplings for flat molecules, streamlining synthesis of 3D molecules. This study offers a generalizable strategy for accessing complex architectures, appealing to both medicinal and process chemists. [ABSTRACT FROM AUTHOR]

Oligomeric materials combine advantageous properties of both their small molecule and polymeric counterparts. Utilizing oligomers as non‐fullerene acceptors (NFAs) has been shown to be extremely useful for the development of organic solar cells with high efficiency, reproducible performance and long‐term stability. Here we report on two series of synthetically simple acceptor‐terminated oligomers A−T2‐(NDI−T2)n‐A with naphthalene diimide (NDI) and bithiophene (T2) cores up to the trimer (n =1,2,3). Termination of the oligomers is done using the strong acceptors (A) dicyanomethylene‐indanone (IC) and rhodanine (RD). Upon acceptor termination in the presence of piperidine (pip) as base, oligomers with pip‐substituted tricyclic end groups are obtained in high yield. We investigate the effect of oligomer length and acceptor end group on opto‐electronic properties and crystallinity. Both IC‐ and RD‐termination increase electron affinity compared to the parent, non‐functionalized cores. UV‐vis absorption in solution slightly redshifts as the chain length increases without showing a distinct aggregation. Asymmetric termination with hexylphenyl‐substituted indacenodithiophene (IDT) and IC is also possible. All symmetric oligomers show a strong tendency for crystallization, with the oligomer having the tricyclic end group exhibiting the highest melting enthalpy and temperature. The asymmetric IDT−T2‐NDI−T2‐IC oligomer is amorphous. [ABSTRACT FROM AUTHOR]

Background and purpose: Alzheimer's disease is the most common form of dementia and the sixth most common cause of death in the US according to the Alzheimer's Association. As regards, to date, no effective treatments are available because of the multifactorial nature of the disease, therefore, a large body of recent research has been allocated to the design and development of multi-target-directed ligands that can become effective drug candidates. Experimental approach: A novel series of benzamide derivatives (5a-5l) containing piperidine core were synthesized in the current work. After identification of the chemical structures of the members of this series using 1 H NMR, IR, and MS spectra, their anti-acetylcholinesterase activity was assessed by the Ellman's test. Docking studies were also performed to investigate the binding mode and determine the interacting amino acids with the corresponding ligands. Finally, the pharmacokinetic (ADME parameters) of the most potent derivative (5d) was predicted and compared with donepezil. Findings/Results: Compound 5d possessing the fluorine atom substitution at position ortho was the most active compound in these series (IC50 = 13 ± 2.1 nM). This compound demonstrated superior activity than the reference drug donepezil (IC50 = 0.6 ± 0.05 µM). Molecular docking showed a significant hydrogen bonding of the carbonyl group of compounds 5d with tyrosine 121 into the active site of acetylcholinesterase. Fortunately, this compound showed better promising ADME properties than donepezil. Conclusion and implication: The benzamide derivatives introduced in this paper could be proposed as potential anti-acetylcholinesterase. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Herein, a method for the enantioselective reduction of unprotected 2‐alkylpyridines is reported for the first time. By using pinacolborane and an amide as reducing agents, a large number of 2‐alkylpiperidines were synthesized with high yields and excellent enantioselectivities via a cascade process involving 1,4‐hydroboration and subsequent transfer hydrogenation. The resulting products can be easily converted to natural alkaloids. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Herein, a method for the enantioselective reduction of unprotected 2‐alkylpyridines is reported for the first time. By using pinacolborane and an amide as reducing agents, a large number of 2‐alkylpiperidines were synthesized with high yields and excellent enantioselectivities via a cascade process involving 1,4‐hydroboration and subsequent transfer hydrogenation. The resulting products can be easily converted to natural alkaloids. [ABSTRACT FROM AUTHOR]

Abstract Compounds containing the piperidine group are highly attractive as building blocks for designing new drugs. Functionalized piperidines are of significant interest due to their prevalence in the pharmaceutical field. Herein, 3-oxo-3-(piperidin-1-yl) propanenitrile has been synthesized, and piperidine-based sodium alginate/poly(vinyl alcohol) films have been prepared. The polymeric films display potency and potential for application to fight against microbial infections. The films could also help maintain interaction with tissue to ensure the controlled release of therapeutic molecules. Thus, they are promising in developing drug delivery systems essential in the pharmaceutical industry. The structure of the 3-oxo-3-(piperidin-1-yl)propanenitrile was confirmed via spectroscopic and single crystal x-ray diffraction techniques. A homogenous solution of sodium alginate (SA) was used to prepare the film by the casting method in the presence of poly(vinyl alcohol) (PVA) and 3-oxo-3-(piperidin-1-yl)propanenitrile (PPN). The prepared films were characterized physiochemically via FTIR, XRD, and TGA. The film morphology was studied using SEM. The antimicrobial potency of the prepared films was assessed against various species of microorganisms. The physicochemical analysis indicated that the films were bound by chemical and physical bond formation between the cyano group of 3-oxo-3-(piperidin-1-yl)propanenitrile, methylene group of PVA, and the hydroxyl group of SA. The films showed smooth, homogenous surfaces and good mechanical properties. The results revealed that the films are bioactive, as indicated by promising antimicrobial potency against P. aeruginosa, S. aureus, E. coli, B. subtilis, and C. albicans, with high potency as well as moderate activity against A. niger. Polymeric films have promising potential to be utilized in drug delivery applications.

Abstract Dihydrofolate reductase (DHFR), an essential enzyme in folate metabolism, presents a promising target for drug development against various diseases, including cancer and tuberculosis. Herein, we present an integrated approach combining in vitro biochemical assays with in silico molecular docking analysis to evaluate the inhibitory potential of 4-piperidine-based thiosemicarbazones 5(a-s) against DHFR. In our in vitro study, a novel series of 4-piperidine-based thiosemicarbazones 5(a-s) were assessed for their inhibitory activity against DHFR enzyme. The synthesized compounds 5(a-s) exhibited potent inhibition with IC50 values in the range of 13.70 ± 0.25 µM to 47.30 ± 0.86 µM. Among all the derivatives 5p displayed highest inhibitory activity. Simultaneously, in silico analysis were performed and compared with standard drug (Methotrexate) to predict the binding affinity and interaction pattern of synthesized compounds with DHFR active site. SAR analysis was done to elucidate how structural modifications impact compound’s biological activity, guiding the rational design of potent and selective drug candidates for targeted diseases. These findings may provide a comprehensive assessment of 4-piperdine-based thiosemicarbazones as DHFR inhibitors and contribute to the development of novel therapeutics targeting DHFR-associated diseases.

In the past two decades, targeted anti‐cancer therapeutics have achieved remarkable success due to their exceptional advantages of selectivity towards cancer cells and safety. Targeted small molecule anti‐cancer therapies persisted in many barriers; majorly poor response to drug therapy. Piperidine, a heterocyclic moiety, exceeds twenty instances of other pharmaceutical classes and natural compounds in the form of alkaloids effective in anti‐cancer treatment. The current review focuses on recent advancements, mainly from 2017–2023, of piperidine‐containing small molecule development as anti‐cancer agents. Total 10 piperidine containing anti‐cancer drugs have been approved by USFDA since 2017 to till date and around 15 small molecule anti‐cancer inhibitors containing piperidine scaffold which are in their early discovery phase have been reviewed which are classified according to their biological target. It highlights the structural contribution of piperidine ring towards the enhancement of activity or pharmacokinetic properties of diverse biological target‐specific anti‐cancer inhibitors of angiogenesis, EGFR, VEGFR, ALK, AKT1, topoisomerase, CDK2 etc. The role of the piperidine ring in enhancing potency, selectivity and bioavailability of novel molecules has been discussed. This review will be helpful to researchers, especially medicinal chemists, for the designing of piperidine‐containing potent drugs for specific biological targets for cancer. [ABSTRACT FROM AUTHOR]

Faecal incontinence is a hidden problem that is often under-reported, under-diagnosed, under-investigated and under-treated. Faecal incontinence is more common in women and older people. Its prevalence also increases with age. Faecal incontinence occurs because of a complex interplay of contributing factors, some of which can be reversed in primary care without the need for specialist investigations and treatment. This article explores the reasons why adults develop faecal incontinence and how to identify and treat reversible causes in primary care. It also provides information on specialist treatment and the management of intractable faecal incontinence. A structured approach to assessment and management is key in identifying problems and offering primary care for timely treatment. [ABSTRACT FROM AUTHOR]

Sequential Knoevenagel condensation/cyclization using cyclic active methylene compounds such as Meldrum's acid have been studied. The reaction of 2-(1-phenylvinyl)benzaldehyde and Meldrum's acid, dimedone, or 1,3-indandione with piperidine/AcOH or L-proline at room temperature for 17–18 h gave cyclized indene derivatives in 63–80% yield. The reaction of 2-(3,5-dimethoxyphenyl)benzaldehyde and Meldrum's acid at room temperature for 17 h gave a fluorene derivative in 98% yield. Furthermore, the reaction of 2-(3,5-dimethoxybenzyl)benzaldehyde and Meldrum's acid with piperidine at room temperature for 18 h gave a dihydroanthracene derivative bearing Meldrum's acid in 83% yield. The reaction of 2-(3,5-dimethoxybenzyl)benzaldehyde and Meldrum's acid with piperidine at 110 °C for 2 h gave Meldrum's acid fragmentated dihydroanthracene derivative in 48% yield. The reaction mechanisms of the cyclization steps and Meldrum's acid fragmentation have been examined by the DFT calculations. [ABSTRACT FROM AUTHOR]

Piperidine derivatives are highly abundant in natural products and pharmaceutically relevant compounds. Aza‐Prins cyclization has emerged as a step‐ atom‐economical and stereoselective method for the preparation of such azacycles. The possibility of coupling aza‐Prins process with the formation of a second cycle in a one‐pot manner is even more powerful and makes the object of this review. Cascade/domino/tandem bis‐cyclizations involving an aza‐Prins process, for the rapid construction of complex small molecules, are discussed in detail. [ABSTRACT FROM AUTHOR]

Objective: USP14 (Ubiquitin‐specific‐processing protease 14) is a deubiquitinating enzyme with oncogenic effects in oral squamous cell carcinoma (OSCC). This study aims to identify new substrates of USP14 and elucidate their role in modulating cancer stem‐like cells (CSCs) in OSCC. Materials and Methods: Bioinformatics prediction and docking were performed using UbiBrowser 2.0 and HDOCK, respectively. OSCC cell lines and patient‐derived cells were used for experimental validation, employing co‐immunoprecipitation, cycloheximide chase assays, and tumor sphere formation to evaluate the effects of USP14 on SOX2 stability, ubiquitination, and CSC phenotypes. Results: USP14 upregulation was associated with worse overall survival and progression‐free interval in OSCC. USP14 interacted with SOX2 with its ubiquitin carboxyl‐terminal hydrolase domain. USP14 knockdown impaired SOX2 stability by increasing its polyubiquitination. Ectopic overexpression of wild‐type USP14, but not the hydrolase‐deficient‐mutant USP14C114A, enhanced SOX2 stability by reducing polyubiquitination. USP14 knockdown suppressed OSCC cell proliferation, colony formation, and tumor sphere formation in vitro and tumor growth in vivo. However, the reduction of CSC markers following USP14 knockdown was mitigated by overexpressing SOX2. These findings were verified in OSCC patient‐derived CSC cells. Conclusion: This study revealed a USP14‐SOX2 axis regulating the CSC properties of OSCC. [ABSTRACT FROM AUTHOR]

Dihydrofolate reductase (DHFR), an essential enzyme in folate metabolism, presents a promising target for drug development against various diseases, including cancer and tuberculosis. Herein, we present an integrated approach combining in vitro biochemical assays with in silico molecular docking analysis to evaluate the inhibitory potential of 4-piperidine-based thiosemicarbazones 5(a-s) against DHFR. In our in vitro study, a novel series of 4-piperidine-based thiosemicarbazones 5(a-s) were assessed for their inhibitory activity against DHFR enzyme. The synthesized compounds 5(a-s) exhibited potent inhibition with IC50 values in the range of 13.70 ± 0.25 µM to 47.30 ± 0.86 µM. Among all the derivatives 5p displayed highest inhibitory activity. Simultaneously, in silico analysis were performed and compared with standard drug (Methotrexate) to predict the binding affinity and interaction pattern of synthesized compounds with DHFR active site. SAR analysis was done to elucidate how structural modifications impact compound’s biological activity, guiding the rational design of potent and selective drug candidates for targeted diseases. These findings may provide a comprehensive assessment of 4-piperdine-based thiosemicarbazones as DHFR inhibitors and contribute to the development of novel therapeutics targeting DHFR-associated diseases. [ABSTRACT FROM AUTHOR]

Acute leukemia is characterized by abnormal white blood cell proliferation with rapid onset and severe complications. Natural compounds, which are alternative treatments, are widely used in cancer treatment. Piperine, an alkaloid compound from black pepper, exerts anticancer effects through the cell death signaling pathway. Autophagy and senescence signaling pathways are considered target signaling pathways for cancer treatment. In this study, we investigated the effects of piperine via autophagy and senescence signaling pathways in NB4 and MOLT-4 cells. The MTT assay results demonstrated that piperine significantly decreased the viability of NB4 and MOLT-4 cells. Piperine induced autophagy by increasing LC3, Beclin-1 and ULK1 and decreasing mTOR and NF-κB1 expression in NB4 and MOLT-4 cells. In addition, piperine increased senescence-associated beta-galactosidase fluorescence intensity by increasing p21 and IL-6 expression while decreasing CDK2 expression in NB4 and MOLT-4 cells. In conclusion, our study provides additional information about the induction of autophagy and senescence by piperine in acute leukemia. [ABSTRACT FROM AUTHOR]

Piperidines are widely present in small molecule drugs and natural products. Despite many methods have been developed for their synthesis, new approaches to polysubstituted piperidines are highly desirable. This work presents a radical (4+2) cycloaddition reaction for synthesis of piperidines featuring dense substituents at 3,4,5‐positions that are not readily accessible by known methods. Using commercially available diboron(4) compounds and 4‐phenylpyridine as the catalyst precursors, the boronyl radical‐catalyzed cycloaddition between 3‐aroyl azetidines and various alkenes, including previously unreactive 1,2‐di‐, tri‐, and tetrasubstituted alkenes, has delivered the polysubstituted piperidines in generally high yield and diastereoselectivity. The reaction also features high modularity, atom economy, broad substrate scope, metal‐free conditions, simple catalysts and operation. The utilization of the products has been demonstrated by selective transformations. A plausible mechanism, with the ring‐opening of azetidine as the rate‐limiting step, has been proposed based on the experimental and computational results. [ABSTRACT FROM AUTHOR]

Objective: Following recent changes to the German Narcotics Act, this article examines prehospital analgesia by paramedics using piritramide vs. nalbuphine + paracetamol. Material and methods: Prehospital analgesia administered by paramedics from the Fulda (piritramide) and Gütersloh (nalbuphine + paracetamol) emergency services was compared regarding pain intensity at the beginning and end of the mission, measured using the numeric rating scale (NRS). Additionally, an analysis of the resulting complications was carried out. Results: In this study 2429 administrations of analgesia were evaluated (nalbuphine + paracetamol: 1635, 67.3%, initial NRS: 8.0 ± 1.4, end of NRS: 3.7 ± 2.0; piritramide: 794, 32.7%, initial NRS: 8.5 ± 1.1, end of NRS: 4.5 ± 1.6). Factors influencing NRS change were initial NRS (regression coefficient, RC: 0.7075, 95% confidence interval, CI: 0.6503–0.7647, p < 0.001), treatment with nalbuphine + paracetamol (RC: 0.6048, 95% CI: 0.4396–0.7700, p < 0.001). Treatment with nalbuphine + paracetamol (n = 796 (48.7%)) compared to piritramide (n = 190 (23.9%)) increased the odds of achieving NRS < 4 (odds ratio, OR: 2.712, 95% CI: 2.227–3.303, p < 0.001). Complications occurred in n = 44 (5.5%) with piritramide and in n = 35 (2.1%) with nalbuphine + paracetamol. Risk factors for complications were analgesia with piritramide (OR: 2.699, 95% CI: 1.693–4.301, p < 0.001), female sex (OR: 2.372, 95% CI: 1.396–4.029, p = 0.0014), and age (OR: 1.013, 95% CI: 1.002–1.025, p = 0.0232). Conclusion: Compared with piritramide, prehospital analgesia with nalbuphine + paracetamol has favorable effects in terms of analgesic efficacy and complication rates and should therefore be considered in future recommendations for paramedics. [ABSTRACT FROM AUTHOR]

Background: Although the Lee Silverman Voice Treatment BIG® (LSVT BIG®) improves motor symptoms in patients with Parkinson's Disease, no reports exist for patients with Progressive Supranuclear Palsy (PSP). Objective: To describe the effect of LSVT BIG® on the motor symptoms of a participant with PSP. Case Description: The participant was a 74-year-old man with PSP. His goals were to improve limb movement, balance ability, and festinating gait over the 4-week LSVT BIG® program. Outcomes: All assessments of limb movement and balance ability showed improvements after intervention for the limb and gait subsections of the PSP rating scale. Scores improved from 9 to 5, and 8 to 6, respectively for the Unified Parkinson's Disease Rating Scale (UPDRS) Part 3, from 30 to 21 and for the Berg balance scale (BBS), from 45 to 50 points. The improvements in UPDRS Part 3 and BBS exceeded the minimum detectable change values (7–8 and 2 points, respectively). After intervention, improvements in festinating gait and rapid walking pace were noted on the UPDRS Part 3 (2 to 1 point) and 10-meter walk test (1.65 m/s to 1.10 m/s). Conclusion: The intervention was effective for the participant but further studies with diverse populations are needed. [ABSTRACT FROM AUTHOR]

The collection, storage, and transport of samples prior to and during analysis is of utmost importance, especially for highly potent analogs that may not be present in high concentrations and are susceptible to pH or thermally mediated degradation. An accelerated stability study was performed on 17 fentanyl analogs (fentalogs) over a wide range of pH (2–10) and temperature (20–60°C) conditions over 24 h. Dilute aqueous systems were used to investigate temperature and pH‐dependent kinetics using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Liquid chromatography‐quadrupole/time‐of‐flight‐mass spectrometry (LC‐Q/TOF–MS) was used for structural elucidation of degradants. With the exception of remifentanil, all fentalogs evaluated were stable at pH 6 or lower. Fentalogs were generally unstable in strongly alkaline environments and at elevated temperatures. Remifentanil was the least stable drug and N‐dealkylated fentalogs were the most stable. Fentanyl degraded to acetylfentanyl, norfentanyl, fentanyl N‐oxide, and 1‐phenethylpyridinium salt (1‐PEP). A total of 26 unique breakdown products were observed for 15 of the fentanyl derivatives studied. Common degradation pathways involved N‐dealkylation, oxidation of the piperidine nitrogen, and β‐elimination of N‐phenylpropanamide followed by oxidation/dehydration of the piperidine ring. Ester and amide hydrolysis, demethylation at the propanamide, and O‐demethylation were observed for selected fentalogs only. The potential for analyte loss should be considered during the pre‐analytical phase (i.e., shipping and transport) where environmental conditions may not be controlled, as well as during the analysis itself. [ABSTRACT FROM AUTHOR]

Bio‐based antioxidants have garnered attention for their sustainability and environmental benefits. In this study, we designed and synthesized three cardanol‐piperidine derivatives (HSs) by utilizing hydrogenated cardanol (HC) and piperidine derivatives to improve the aging inhibition of polypropylene (PP). These bio‐based antioxidants were intended as eco‐friendly alternatives to conventional synthetic antioxidants. The impact of these HSs on the thermal stability, thermo‐oxidative stability, and light stability of PP was thoroughly evaluated. The results unveiled that after 5 h of interaction with 2,2‐diphenyl‐1‐picrylhydrazyl free radical, HSs exhibited a remarkable over 5‐fold increase in free radical scavenging efficiency as compared to HC. Moreover, the addition of HSs significantly increased the oxidation induction time and the initial oxidation temperature compared to pristine PP. After photo‐oxidative aging and thermo‐oxidative aging, the HS‐dosed PP demonstrated remarkable retention of elongation at break, reaching more than 72% and 69%. From the comparison with physical mixtures and the density functional theory calculations, an intramolecular synergism mechanism is proposed. The intramolecular synergism between hydrogenated cardanol and piperidine derivatives may be the main reason for the inhibition of PP aging. Highlights: A method for constructing simultaneous efficient light, thermal, and oxygen stable polypropylene.The mechanism for achieving simultaneous stabilization of light, heat, and oxygen is the intramolecular synergy of phenol piperidine.The essence of intramolecular synergy of cardanol and piperidine derivatives is its' reduced hydrogen bond dissociation energy and energy gap. [ABSTRACT FROM AUTHOR]

The article in the "Analytical & Bioanalytical Chemistry" journal presents a challenge focused on the NMR spectra of substituted piperidines, which are important in natural products and biologically active compounds. Participants are asked to distinguish between cis and trans isomers of 3,4-disubstituted piperidines using only the g-HSQC NMR spectra provided. The challenge aims to test knowledge in analytical chemistry and offers a prize for the randomly selected winner. Readers are encouraged to participate by submitting their solutions by a specified deadline. [Extracted from the article]

An experimental and computational study (including DFT calculations and distortion/interaction analysis) was conducted to assess the effect of the nitrone structure in the outcome of dipolar 1,3‐cycloadditions with levoglucosenone, a biomass derived chiral enone. While B3LYP/6‐31G* (the most popular method for modeling these reactions according to our literature search) provides qualitatively good results, large outliers were found for some systems versus experimental data. An exhaustive exploration of other levels allowed us to determine the most appropriate ones to predict simultaneously reactivity and selectivity. The systematically predicted high exo selectivity by the majority of the levels led us to reconsider our initial assignment for the reaction with the nitrone derived from piperidine, which resulted in the discovery of an interesting case of conformational dynamics. [ABSTRACT FROM AUTHOR]

Aripiprazole is an atypical antipsychotic medication indicated for the treatment of schizophrenia and bipolar disorders. The drug has been shown to exhibit acceptable efficacy and is often preferred as a first‐line psychiatric treatment option owing to its lower incidence of adverse effects. While first‐generation antipsychotics are associated with extrapyramidal syndrome (EPS), atypical antipsychotics such as aripiprazole are generally associated with a lower frequency of EPS. In this case, we present a 31‐year‐old woman with a history of bipolar disorder who developed EPS after ingesting 200 mg of aripiprazole. Fortunately, her symptoms improved with the administration of biperiden, and she was discharged five days after ingestion. This case highlights the potential for significant consequences associated with aripiprazole, even within its therapeutic index. [ABSTRACT FROM AUTHOR]

Stoma patients require continuous support throughout their entire journey with a stoma. Although many Stoma Care Services across the UK offer patient follow-up pathways, there is not one unified pathway. Patients may not be prepared for life with a stoma because, depending on their stoma type, they will have specific needs, and if patients and healthcare professionals are not prepared to manage these stoma-specific needs, complications and hospital readmissions may occur, worsening patients' outcomes and quality of life. Ileostomy patients are known to be more likely to experience complications, including hospital readmissions, and therefore, special care should be taken when preparing these patients for life with a stoma. They should be informed and educated to prevent complications, and if this is not always possible, thye should at least be able to recognise and manage early signs and symptoms of complications. This will empower them to self-care and know when to seek medical attention. [ABSTRACT FROM AUTHOR]

Simple Summary: NSCLC is one of the most life-threatening forms of oncological diseases. Although targeted and immunotherapy treatments have improved NSCLC prognosis, the chance of surviving is still limited for many patients. Therefore, further efforts are required to improve NSCLC care. AdipoRon is emerging as an antineoplastic molecule in the treatment of different cancers, but its potential in NSCLC is yet to be explored. Herein, we demonstrated that AdipoRon strongly impairs viability, growth and stemness in NSCLC cells. We also recorded higher glucose consumption and lactate accumulation as a result of AdipoRon treatment. Remarkably, the employment of glycolytic-interfering agents enhanced its antiproliferative features. A signaling pathways analysis revealed a marked AMPK phosphorylation, while, in contrast, its abrogation by Compound-C significantly counteracted AdipoRon effectiveness. Altogether, these findings emphasize AdipoRon's anticancer feature even in NSCLC, supporting its endorsement as a future candidate in cancer and NSCLC therapy. Despite the countless therapeutic advances achieved over the years, non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. To this primacy contribute both non-oncogene addicted and advanced NSCLCs, in which conventional therapies are only partially effective. The adiponectin receptor agonist AdipoRon has revealed antiproliferative action in different cancers, including osteosarcoma and pancreatic cancer. Herein, we investigated its potential anticancer role in NSCLC for the first time. We proved that AdipoRon strongly inhibits viability, growth and colony formation in H1299 and A549 NSCLC cells, mainly through a slowdown in cell cycle progression. Along with the biological behaviors, a metabolic switching was observed after AdipoRon administration in NSCLC cells, consisting of higher glucose consumption and lactate accumulation. Remarkably, both 2-Deoxy Glucose and Oxamate glycolytic-interfering agents greatly enhanced AdipoRon's antiproliferative features. As a master regulator of cell metabolism, AMP-activated protein kinase (AMPK) was activated by AdipoRon. Notably, the ablation of AdipoRon-induced AMPK phosphorylation by Compound-C significantly counteracted its effectiveness. However, the engagement of other pathways should be investigated afterwards. With a focus on NSCLC, our findings further support the ability of AdipoRon in acting as an anticancer molecule, driving its endorsement as a future candidate in NSCLC therapy. [ABSTRACT FROM AUTHOR]

Objectives: Perennial allergic rhinitis (PAR) is common in Japan. Second-generation antihistamines (SGAs) are commonly used for its treatment; however, it remains unclear which SGA is the most cost-effective. Additionally, the pharmacoeconomics of Japanese Kampo shoseiryuto (which was traditionally prescribed to treat PAR in Japan) remains poorly understood. In this study, we aimed to investigate the effectiveness of various SGAs and shoseiryuto for the treatment of PAR in Japanese outpatients, from the healthcare payer's perspective. Methods: The most cost- and clinically effective SGAs were determined from a list of 6 SGAs (bepotastine, 10 mg; cetirizine, 10 mg; ebastine, 10 mg; epinastine, 20 mg; loratadine, 10 mg; and olopatadine, 5 mg) together with shoseiryuto, using the overall improvement rate through a model-based analysis. The time horizon was 28 days. Costs were determined based on the Medical Fee Index in 2020. Deterministic and probabilistic sensitivity analyses were conducted to address the uncertainty of the base-case results. Results: Overall, bepotastine (10 mg) and ebastine (10 mg) were cost-effective. Shoseiryuto was less cost-effective than ebastine (10 mg) (dominated). Ebastine (10 mg) was the most cost-effective option based on deterministic and probabilistic sensitivity analyses. Conclusions: Ebastine (10 mg) was the most cost-effective treatment strategy for PAR among the agents evaluated in this study. This insight could aid in establishing an appropriate formulary for treating PAR in hospitals and communities. [ABSTRACT FROM AUTHOR]

Despite the progress in comprehending molecular design principles and biochemical processes associated with thrombin inhibition, there is a crucial need to optimize efforts and curtail the recurrence of synthesis-testing cycles. Nitrogen and N-heterocycles are key features of many anti-thrombin drugs. Hence, a pragmatic analysis of nitrogen and N-heterocycles in thrombin inhibitors is important throughout the drug discovery pipeline. In the present work, the authors present an analysis with a specific focus on understanding the occurrence and distribution of nitrogen and selected N-heterocycles in the realm of thrombin inhibitors. A dataset comprising 4359 thrombin inhibitors is used to scrutinize various categories of nitrogen atoms such as ring, non-ring, aromatic, and non-aromatic. In addition, selected aromatic and aliphatic N-heterocycles have been analyzed. The analysis indicates that ~62% of thrombin inhibitors possess five or fewer nitrogen atoms. Substituted N-heterocycles have a high occurrence, like pyrrolidine (23.24%), pyridine (20.56%), piperidine (16.10%), thiazole (9.61%), imidazole (7.36%), etc. in thrombin inhibitors. The majority of active thrombin inhibitors contain nitrogen atoms close to 5 and a combination of N-heterocycles like pyrrolidine, pyridine, piperidine, etc. This analysis provides crucial insights to optimize the transformation of lead compounds into potential anti-thrombin inhibitors. [ABSTRACT FROM AUTHOR]

Coumarins, which are 2H-1-benzopiran-2-one compounds originating from some plants, have been proven to be anticancer, antibacterial, and anticancer agents. Around of these structures are currently accepted for the treatment of cardiovascular disease (warfarin), antibiotics (novobiocin or chlorobiocin), and anticancer medications (geiparvarin). We created 38 coumarin derivatives (2-50), 22 of which were novel, in this project by replacing the eighth carbon of the benzopiran ring with nearly aromatic and aliphatically substituted piperidine and piperazines. This was done because of the structure's great potential and the dearth of research on molecules resulting from the benzopiranone heterocycle. The produced compounds' cytotoxicity, analgesic, and anti-inflammatory qualities were evaluated. The targeted molecules were made in two steps. Using the Pechmann reaction, the 7-hydroxy-4-methyl-chromen-2-one coumarin scaffold was created in the first step. Another phase was the derivatization of the 7-hydroxy-4-methyl-chromen-2-one coumarin scaffold (compound 1) by addition of piperidine and aromatic and aliphatic substituted piperazine groups. In vitro tests were used to evaluate the cytotoxicity, analgesic, and anti-inflammatory properties. MTT assay was employed to assess the cytotoxicity of MCF-7 breast cancer cells and RAW264.7 macrophages. The nitrite inhibition test was employed to evaluate anti-inflammatory activity using RAW264.7 macrophage cells. The reference drugs for the cytotoxicity and anti-inflammatory tests were L-NAME and indomethacin (IND). PGE2 production for the painkilling effect was noted. The outcomes indicated that compounds 11, 23, and 31 have promising anti-inflammatory activity. Compound 11 produced better results than the reference drugs and were three times more active than IND. Moreover, compound 11 confirmed little cytotoxicity and a moderate analgesic effect. [ABSTRACT FROM AUTHOR]

When treated with cycloalkylamines (pyrrolidine, piperidine, morpholine, and N-methylpiperazine), polyfluoro-containing benzoic and salicylic acid esters undergo chemoselective nucleophilic aromatic substitution of a fluorine atom in the para position to form 4-(N-cycloalkylamino)-substituted derivatives. The hydrolysis of the latter compounds with alkali in aqueous methanol affords the corresponding acids. Methyl 3,5-difluoro-2-hydroxy-4-(piperidin-1-yl)benzoate exhibits high antibacterial activity against the N. gonorrhoeae strain, which is twice higher than that of the drug spectinomycin. N-Cycloalkyl-substituted polyfluorobenzoic acids do not show analgesic activity. The effect of the esters is comparable with the activity of the drug diclofenac. The studied compounds have a lower acute toxicity compared to the reference drug. [ABSTRACT FROM AUTHOR]

In this study, a highly effective microwave‐assisted method employing a multicomponent domino Knoevenagel/phospha‐Michael reaction has been established. This approach facilitates the synthesis of a novel set of pyrazolylphosphonate derivatives in good yields by combining aryl aldehydes with pyrazolones and trialkylphosphites, utilizing piperidine as a Bronsted base catalyst. All pyrazolylphosphonates have been characterized by means of IR, 1H‐NMR, 13C‐NMR, and HRMS analyses and physical methods. This protocol can be characterized by its eco‐friendly nature, exceptional efficiency in terms of product yields, and short reaction times. [ABSTRACT FROM AUTHOR]

A general and useful palladium‐catalyzed [4 + 2] cycloaddition of sulfamate‐derived cyclic imines with γ‐methylidene‐δ‐valerolactones (or 2‐methylidenetrimethylene carbonate) is described. The developed strategy generated diverse sulfamate‐fused piperidine derivatives (or sulfamate‐fused 1,3‐oxazinane rings) in good yields. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a severe endocrine disease that affects more and more people every year. Modern medical chemistry sets itself the task of finding effective and safe drugs against diabetes. This review provides an overview of potential antidiabetic drugs based on three heterocyclic compounds, namely morpholine, piperazine, and piperidine. Studies have shown that compounds containing their moieties can be quite effective in vitro and in vivo for the treatment of diabetes and its consequences. [ABSTRACT FROM AUTHOR]

Piperidine is an essential moiety of morphine, responsible for the analgesic activity. Among number of other analgesic targets, µ-opioid receptor is still the most focused and therapeutically important in the management of pain. In this study, a series of novel derivatives of 4 amino methyl piperidine were synthesized and explored for analgesic potential against mu opioid receptor. Their structures were elucidated by FT-IR, 1H NMR, and LC-MS followed by in vivo analgesic evaluation by tail-flick method and writhing test. Among all derivatives, HN58 showed excellent analgesic activity (100% inhibition) in writhing test. Furthermore, reduction of HN58 analgesic effect by naloxone suggests its involvement with µ-OR. Molecular docking approach was also utilized to compare the analgesic potential of synthesized derivatives in order to find potent µ-OR inhibitors, we designed five piperidine derivatives with analgesic activity. We have elucidated the binding affinities and binding modes of these piperidine derivatives including standard molecules Morphine, Fentanyl Pethidine and DAMGO revealed a well-known µ-O inhibitor (having binding affinity ranges from −8.13 to −13.37 kcal/mol). All novel derivatives exhibited the remarkable binding score and encapsulated in the binding pocket of transmembraneous helices engaged by the residues Q124, W133, I144, D147, Y148, M151, V236, I296, H297, W318, I322, and Y236. All derivatives revealed excellent binding scores and interaction mechanism as compared to morphine, pethidine, and fentanyl respectively. [ABSTRACT FROM AUTHOR]

The article focuses on hereditary hyperekplexia (HPX), a rare disorder characterized by exaggerated startle response and generalized muscle stiffness, often presenting in infancy. It discusses the standard treatment with clonazepam and explores the novel use of trihexyphenidyl to alleviate persistent generalized stiffness episodes in patients unresponsive to clonazepam.

The article discusses research which investigated physician approaches to the pharmacologic dystonia treatment in people with cerebral palsy. The study surveyed physician approaches regarding medications for dystonia in CP including baclofen, trihexyphenidyl, gabapentin, carbidopa/levodopa, clonazepam, diazepam, clonidine, tetrabenazine, clobazam and cannabidiol. It described physician's prescribing practices and choice of medications for dystonia.

Recent advancements in anion exchange membrane fuel cells (AEMFCs) have been primarily driven by improvements in anion exchange membranes (AEMs). Aryl ether bond‐free membranes have emerged as a promising avenue for enhancing the overall performance of AEMs. In this study, poly (binaphthyl triphenyl piperidine) with different side‐chain degree (PBTP‐s‐x), possesses double cationic groups, aiming at further enhancing overall performance for AEMs. The use of a twisted stereospecific backbone structure of polymerized binaphthyl and triple biphenyl monomer and grafted side chains of piperidine cationic groups not only improves the microphase separation structure of the membrane, but also improves the alkali resistance. Notably, the PBTP‐s‐100 AEMs exhibit exceptional OH− conductivity, reaching up to 138.21 mS cm−1, and show outstanding mechanical properties with a tensile strength of up to 28 MPa. Additionally, PBTP‐s‐100 displays excellent durability, proved by the NMR spectral consistency and over 80 % ion conductivity retention in 1 M NaOH at 60 °C for 4 weeks. And PBTP‐s‐100 exhibits a higher Lowest Unoccupied Molecular Orbital (LUMO) and a larger energy gap for LUMO and Highest Occupied Molecular Orbital (HOMO) by density functional theory calculation, which indicates it possesses sterling alkaline stability. These findings highlight the potential of PBTP‐s‐100 as a highly performing polymer structure suitable for anion exchange membranes, which is capable of significantly enhancing the performance of fuel cells. [ABSTRACT FROM AUTHOR]

The reactivity of complexes [Fe2(μ‐S2)(CO)4L2] (L=CO (1), PPh3 (2)), with lithium alkynylide reagents generated in situ, was investigated. The behavior of the S2‐bridge in these compounds depends on the substitution at the diiron core. The reaction with the hexacarbonyl derivative 1 leads to the formation of the 1,2‐dithiolene bridged complex [Fe2(μ‐SCH=C(R)S)(CO)6] (3R) while the molecule [Fe2(μ‐SH)(μ‐SC≡CR)(CO)4(PPh3)2] (5R), with an open butterfly structure, is isolated when reacting the disubstituted derivative 2. The disubstituted dithiolene complex [Fe2(μ‐SCH=C(Ph)S)(CO)4(PPh3)2] (4Ph) can only be obtained by substitution of carbonyls with PPh3 in 3R. In the presence of piperidine, 5R isomerizes into the 1,1'‐dithiolene bridged derivative 6Ph. The novel compounds 4–6 were synthesized and characterized by IR and NMR spectroscopies. X‐ray crystallographic studies of the dithiolene complexes 3Ph–4Ph allowed their structural analysis. [ABSTRACT FROM AUTHOR]