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The purpose of this study was to investigate the influence of mouth rinsing and ingesting unpleasant salty or bitter solutions on cycling sprint performance and knee extensor force characteristics. Eleven male and one female trained cyclists (age: 34 ± 9 years, maximal oxygen uptake 56.9 ± 3.9 ml·kg−1·min−1) completed a ramp test and familiarization followed by four experimental trials. In each trial, participants completed an all-out 30-s cycling sprint with knee extensor maximal voluntary contractions before and immediately after the sprint. In a randomized, counterbalanced, cross-over order, the four main trials were: a no solution control condition, water, salty (5.8%), or bitter (2 mM quinine) solutions that were mouth rinsed (10 s) and ingested immediately before the cycling sprint. There were no significant differences between conditions in mean power (mean ± SD, no solution: 822 ± 115 W, water: 818 ± 108 W, salt: 832 ± 111 W, bitter: 818 ± 105 W); peak power (no solution: 1,184 ± 205 W, water: 1,177 ± 207 W, salt: 1,195 ± 210 W, bitter: 1,184 ± 209 W); or fatigue index (no solution: 51.5% ± 5.7%, water: 50.8% ± 7.0%, salt: 51.1% ± 5.9%, bitter: 51.2% ± 7.1%) during the sprint. Maximal force and impulse declined postexercise; however, there were no significant differences between conditions in knee extensor force characteristics. The present data do not support the use of unpleasant salty or bitter solutions as an ergogenic aid to improve sprint exercise performance. [ABSTRACT FROM AUTHOR]

The post-oral sensing of bitter compounds by a family of bitter taste receptors (TAS2Rs) is suggested to regulate postprandial glycemia in humans. However, reports are inconsistent. This systematic review used meta-analysis to synthesise the impact of bitter compound interventions on the postprandial glycaemic response in humans. Electronic databases (Medline, PubMed, and Web of Science) were systematically searched from inception to April 2024 to identify randomised controlled trials reporting the effect of interventions utilising post-oral bitter compounds vs. placebo on postprandial plasma glucose levels at t = 2 h (2 h-PPG), and area under the curve (AUC) of glucose, insulin, and c-peptide. The random-effect and subgroup analysis were performed to calculate pooled weighted mean differences (WMD), overall and by predefined criteria. Forty-six studies (within 34 articles) were identified; 29 and 17 studies described chronic and acute interventions, respectively. The chronic interventions reduced 2 h-PPG (n = 21, WMD = −0.35 mmol/L, 95%CIs = −0.58, −0.11) but not AUC for glucose or insulin. Subgroup analysis showed the former was particularly evident in individuals with impaired glycemia, interventions longer than three months, or quinine family administration. The acute interventions did not improve the postprandial glycemia response, but subgroup analysis revealed a decrease in AUC-glucose after quinine family administration (n = 4 WMD = −90.40 (nmol × time/L), 95%CIs = −132.70, −48.10). Chronic bitter compound interventions, particularly those from the quinine family, may have therapeutic potential in those with glycemia dysregulation. Acute intervention of the quinine family may also improve postprandial glucose. Given the very low quality of the evidence, further investigations with more rigorous methods are still required. [ABSTRACT FROM AUTHOR]

All new drugs must go through preclinical screening tests to determine their proarrhythmic potential. While these assays effectively filter out dangerous drugs, they are too conservative, often misclassifying safe compounds as proarrhythmic. In this study, we attempt to address this shortcoming with a novel, medium‐throughput drug‐screening approach: we use an automated patch‐clamp system to acquire optimized voltage clamp (VC) and action potential (AP) data from human induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) at several drug concentrations (baseline, 3×, 10× and 20× the effective free plasma concentrations). With our novel method, we show correlations between INa block and upstroke slowing after treatment with flecainide or quinine. Additionally, after quinine treatment, we identify significant reductions in current during voltage steps designed to isolate If and IKs. However, we do not detect any IKr block by either drug, and upon further investigation, do not see any IKr present in the iPSC‐CMs when prepared for automated patch experiments (i.e. in suspension) – this is in contrast to similar experiments we have conducted with these cells using the manual patch setup. In this study, we: (1) present a proof‐of‐concept demonstration of a single‐cell medium‐throughput drug study, and (2) characterize the non‐canonical electrophysiology of iPSC‐CMs when prepared for experiments in a medium‐throughput setting. Key points: Human induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) offer potential as an in vitro model to study the proarrhythmic potential of drugs, but insights from these cells are often limited by the low throughput of manual patch‐clamp.In this study, we use a medium‐throughput automated patch‐clamp system to acquire action potential (AP) and complex voltage clamp (VC) data from single iPSC‐CMs at multiple drug concentrations.A correlation between AP upstroke and INa transients was identified and drug‐induced changes in ionic currents found.We also characterize the substantially altered physiology of iPSC‐CMs when patched in an automated system, suggesting the need to investigate differences between manual and automated patch experiments. [ABSTRACT FROM AUTHOR]

The year 2024 marks the 80th anniversary of the landmark formal synthesis of (±)‐quinine completed by Woodward and Doering. This article examines the evolution of approaches to access this storied Cinchona alkaloid natural product which represent a microcosm the progress that has been made in organic synthesis over the past ~170 years. Seminal contributions led by Pasteur, Rabe, Woodward, Uskoković, Stork, Jacobsen, Hayashi, Maulide and others are discussed. [ABSTRACT FROM AUTHOR]

Quantum chemical modeling using the Hartree–Fock theory level HF-3c/MINIS/MINIS11 (d)(Cl)/def2-SV(P) ECP(Pt) considering intermolecular interaction within the ORCA 5.03 software package was employed to study the electronic structure and binding energy of cisplatin, quinine, and fullerenol adducts and their three-component systems. Analysis of the total energies of the systems and the calculated energy diagrams of the highest occupied and lowest unoccupied molecular orbitals for the initial components and the molecular ensembles formed by them indicated the probable stability of their combinations. The synergistic effects were examined and the prospects for using the three-component cisplatin–quinine–fullerenol C60(OH)24 system in cancer chemotherapy were discussed. [ABSTRACT FROM AUTHOR]

Previous experiments found that acceptance of saccharin by rats was reduced if they had prior experience of sucrose or some other highly palatable solution. This study tested whether such successive negative contrast (SNC) effects involve acquisition of an aversion to the new taste. In three experiments, rats were switched from sucrose exposure in Stage 1 to a less palatable solution containing a new taste in Stage 2. In Experiments 1 and 2, a novel flavor was added to a saccharin solution at the start of Stage 2. In Experiment 1, preference tests revealed a weak aversion to the added vanilla flavor in the Suc-Sacch group, while in Experiment 2 an aversion was found in the Suc-Sacch group to the salty flavor that was used, compared with controls given access either saccharin or water in Stage 1. In Experiment 3, the Suc-Quin group, given quinine solution in Stage 2, displayed a greater aversion to quinine than a Water-Quin control group. These results support the suggestion that taste aversion learning plays a role in the initial suppression of intakes in a qualitative consummatory SNC effect. However, in the light of other evidence, it seems that the unusual persistence of successive negative contrast when rats are switched from sucrose to saccharin is not due to a long-lasting reduction in the value of saccharin. [ABSTRACT FROM AUTHOR]

Abstract Disorders of gallbladder motility can lead to serious pathology. Bitter tastants acting upon bitter taste receptors (TAS2R family) have been proposed as a novel class of smooth muscle relaxants to combat excessive contraction in the airways and other organs. To explore whether this might also emerge as an option for gallbladder diseases, we here tested bitter tastants for relaxant properties and profiled Tas2r expression in the mouse gallbladder. In organ bath experiments, the bitter tastants denatonium, quinine, dextromethorphan, and noscapine, dose-dependently relaxed the pre-contracted gallbladder. Utilizing gene-deficient mouse strains, neither transient receptor potential family member 5 (TRPM5), nor the Tas2r143/Tas2r135/Tas2r126 gene cluster, nor tuft cells proved to be required for this relaxation, indicating direct action upon smooth muscle cells (SMC). Accordingly, denatonium, quinine and dextromethorphan increased intracellular calcium concentration preferentially in isolated gallbladder SMC and, again, this effect was independent of TRPM5. RT-PCR revealed transcripts of Tas2r108, Tas2r126, Tas2r135, Tas2r137, and Tas2r143, and analysis of gallbladders from mice lacking tuft cells revealed preferential expression of Tas2r108 and Tas2r137 in tuft cells. A TAS2R143-mCherry reporter mouse labeled tuft cells in the gallbladder epithelium. An in silico analysis of a scRNA sequencing data set revealed Tas2r expression in only few cells of different identity, and from in situ hybridization histochemistry, which did not label distinct cells. Our findings demonstrate profound tuft cell- and TRPM5-independent relaxing effects of bitter tastants on gallbladder smooth muscle, but do not support the concept that these effects are mediated by bitter receptors.

Disorders of gallbladder motility can lead to serious pathology. Bitter tastants acting upon bitter taste receptors (TAS2R family) have been proposed as a novel class of smooth muscle relaxants to combat excessive contraction in the airways and other organs. To explore whether this might also emerge as an option for gallbladder diseases, we here tested bitter tastants for relaxant properties and profiled Tas2r expression in the mouse gallbladder. In organ bath experiments, the bitter tastants denatonium, quinine, dextromethorphan, and noscapine, dose-dependently relaxed the pre-contracted gallbladder. Utilizing gene-deficient mouse strains, neither transient receptor potential family member 5 (TRPM5), nor the Tas2r143/Tas2r135/Tas2r126 gene cluster, nor tuft cells proved to be required for this relaxation, indicating direct action upon smooth muscle cells (SMC). Accordingly, denatonium, quinine and dextromethorphan increased intracellular calcium concentration preferentially in isolated gallbladder SMC and, again, this effect was independent of TRPM5. RT-PCR revealed transcripts of Tas2r108, Tas2r126, Tas2r135, Tas2r137, and Tas2r143, and analysis of gallbladders from mice lacking tuft cells revealed preferential expression of Tas2r108 and Tas2r137 in tuft cells. A TAS2R143-mCherry reporter mouse labeled tuft cells in the gallbladder epithelium. An in silico analysis of a scRNA sequencing data set revealed Tas2r expression in only few cells of different identity, and from in situ hybridization histochemistry, which did not label distinct cells. Our findings demonstrate profound tuft cell- and TRPM5-independent relaxing effects of bitter tastants on gallbladder smooth muscle, but do not support the concept that these effects are mediated by bitter receptors. [ABSTRACT FROM AUTHOR]

This account summarizes the author's endeavors in target-oriented synthesis at Seoul National University since 2011. A collection of the most celebrated molecules in total synthesis are revisited and the author's solutions to these historical challenges are presented. In particular, the unique perception of their molecular frameworks and unprecedented bond-forming sequences form the basis of the newly developed strategies. Together with a 'personal touch' on these selected stories, the author hopes that this account will offer new insights and fresh perspectives for all levels of enthusiasts of target-oriented total synthesis. 1 Introduction 2.1 Synthesis of Strychnine 2.2 Synthesis of Actinophyllic Acid 2.3 Synthesis of Dendrobine 2.4 Synthesis of Communesin 2.5 Synthesis of Morphinans 2.6 Synthesis of Reserpine 2.7 Synthesis of Quinine and Quinidine 2.8 Synthesis of Haouamine 2.9 Future Work 3 Summary and Outlook 4 Abbreviations [ABSTRACT FROM AUTHOR]

Malaria was a major cause of casualties during World War II in the Southwest Pacific, and drug supply issues were acute strategic concerns. The capture of the cinchona plantations of Indonesia by the Japanese Imperial Army and the lack of manufacturing capacity for synthetic substitutes were significant logistical constraints that limited Allied combat operations in the Indo-Pacific Region. Tens of thousands of soldiers were infected with malaria due to inadequate treatment and chemoprophylaxis. In Milne Bay, Papua New Guinea, military operations halted for several months at the end of 1942 due to poor malaria discipline compounded by inadequate medications. Sufficient drug supplies only became available in 1943 when daily quinacrine suppression was enforced. Drug supply disruptions during the COVID-19 pandemic are a reminder that specialist anti-infective medications could have an outsized, modern impact on military operations. [ABSTRACT FROM AUTHOR]

Aims Continued alcohol consumption despite negative consequences is a core symptom of alcohol use disorder. This is modeled in mice by pairing negative stimuli with alcohol, such as adulterating alcohol solution with quinine. Mice consuming alcohol under these conditions are considered to be engaging in aversion-resistant intake. Previously, we have observed sex differences in this behavior, with females more readily expressing aversion-resistant consumption. We also identified three brain regions that exhibited sex differences in neuronal activation during quinine-alcohol drinking: ventromedial prefrontal cortex (vmPFC), posterior insular cortex (PIC), and ventral tegmental area (VTA). Specifically, male mice showed increased activation in vmPFC and PIC, while females exhibited increased activation in VTA. In this study, we aimed to identify what specific type of neurons are activated in these regions during quinine-alcohol drinking. Method We assessed quinine-adulterated alcohol intake using the two-bottle choice procedure. We also utilized RNAscope in situ hybridization in the three brain regions that previously exhibited a sex difference to examine colocalization of Fos, glutamate, GABA, and dopamine. Result Females showed increased aversion-resistant alcohol consumption compared to males. We also found that males had higher colocalization of glutamate and Fos in vmPFC and PIC, while females had greater dopamine and Fos colocalization in the VTA. Conclusions Collectively, these experiments suggest that glutamatergic output from the vmPFC and PIC may have a role in suppressing, and dopaminergic activity in the VTA may promote, aversion-resistant alcohol consumption. Future experiments will examine neuronal circuits that contribute to sex differences in aversion resistant consumption. [ABSTRACT FROM AUTHOR]

The ICH E14/S7B Q&As highlighted the need for best practices concerning the design, execution, analysis, interpretation, and reporting of the in vivo non‐rodent QT assay as a component of the integrated risk assessment to potentially support a TQT waiver or substitute. We conducted a dog telemetry study to assess the effects on QTc of six reference compounds (five positive and one negative) previously evaluated by Darpo et al. (2015) in humans. The sensitivity of the assay to detect QTc increases was determined, and exposure–response analysis was performed, as done in clinical practice. By‐timepoint analysis showed QTc prolongation induced by moxifloxacin, dofetilide, dolasetron, ondansetron, and quinine within human relevant plasma exposures ranges. Moreover, a hysteresis was observed for quinine. As expected, levocetirizine showed no statistically significant effect on QTc across a range of exposure, well exceeding the therapeutic Cmax. Power analyses confirmed the study ability to detect statistically significant QTc changes of less than 10 milliseconds with 80% probability, even with a sample size as low as n = 4 animals. Finally, concentration‐QTc modeling enabled to predict the minimal plasma concentration needed to detect a 10 milliseconds QTc prolongation, including for quinine. The comparison with clinical available data supported the relevance of dogs under these experimental conditions as a robust translational predictor of drug‐induced QTc prolongation in humans as a key pillar of the integrated risk assessment. [ABSTRACT FROM AUTHOR]

BACKGROUND: One characteristic of alcohol use disorder is compulsive drinking or drinking despite negative consequences. When quinine is used to model such aversion-resistant drinking, female rodents typically are more resistant to punishment than males. Using an operant response task where C57BL/6J responded for ethanol mixed with quinine, we previously demonstrated that female mice tolerate higher concentrations of quinine in ethanol than males. Here, we aimed to determine whether this female vulnerability to aversion-resistant drinking behavior is similarly observed with footshock punishment. METHODS: Male and female C57BL/6J mice were trained to respond for 10% ethanol in an operant task on a fixed-ratio three schedule. After consistent responding, mice were tested in a punishment session using either a 0.25 mA or 0.35 milliamp (mA) footshock. To assess footshock sensitivity, a subset of mice underwent a flinch, jump, and vocalize test in which behavioral responses to increasing amplitudes of footshock (0.05 to 0.95 mA) were assessed. In a separate cohort of mice, males and females were trained to respond for 2.5% sucrose and responses were punished using a 0.25 mA footshock. RESULTS: Males and females continued to respond for 10% ethanol when paired with a 0.25 mA footshock. Females alone continued to respond for ethanol when a 0.35 mA footshock was delivered. Both males and females reduced responding for 2.5% sucrose when punished with a 0.25 mA footshock. Footshock sensitivity in the flinch, jump, and vocalize test did not differ by sex. CONCLUSIONS: Females continue to respond for 10% ethanol despite a 0.35 mA footshock, and this behavior is not due to differences in footshock sensitivity between males and females. These results show that female C57BL/6J mice are generally more resistant to punishment in an operant self-administration paradigm. The findings add to the literature characterizing aversion-resistant alcohol-drinking behaviors in females.

BACKGROUND: Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisinin-based treatment (ABT) versus non-ABTs in the first trimester of pregnancy. METHODS: For this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase, and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021, containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this search were added to those of a previous systematic review that included publications published up until November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO, number CRD42015032371. FINDINGS: We identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including 34 178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5·7%) of 736 ABT-exposed pregnancies compared with 96 (8·9%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio [aHR] 0·71, 95% CI 0·49-1·03). Similar results were seen for the individual components of miscarriage (aHR=0·74, 0·47-1·17), stillbirth (aHR=0·71, 0·32-1·57), and major congenital anomalies (aHR=0·60, 0·13-2·87). The risk of adverse pregnancy outcomes was lower with artemether-lumefantrine than with oral quinine in the first trimester of pregnancy (25 [4·8%] of 524 vs 84 [9·2%] of 915; aHR 0·58, 0·36-0·92). INTERPRETATION: We found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with artemether-lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the known superior tolerability and antimalarial effectiveness of ACTs, artemether-lumefantrine should be considered the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether-lumefantrine is unavailable, other ACTs (except artesunate-sulfadoxine-pyrimethamine) should be preferred to quinine. Continued active pharmacovigilance is warranted. FUNDING: Medicines for Malaria Venture, WHO, and the Worldwide Antimalarial Resistance Network funded by the Bill & Melinda Gates Foundation.

Creating an expedient method for synthesizing biologically significant functionally rich octahydroquinoline is a highly sought‐after yet challenging endeavour. In this report, we document an unprecedented approach to the construction of novel spirooctahydroquinoline oxindole architectures. The reaction proceeds through Pd (II) catalyzed cycloisomerisation and quinine catalyzed [4+2]‐addition sequence to afford the desired adduct in moderate to excellent yield (up to 89%) in a single diastereomer with three contiguous stereocenters including one spirocenter. An overwhelming number of libraries were generated (35 examples) reflecting the synthetic versatility and functional groups/substituents tolerance. Further, the adduct is transformed into medicinally important fluoro‐decahydroepoxyethanoquinoline spirooxindole scaffold with five contiguous stereocenters in excellent yield and selectivity (95% yield and >99:1 dr) through a three steps sequence which signifies the synthetic utility of the developed methodology. [ABSTRACT FROM AUTHOR]

We describe the efficient synthesis of novel dehydroxyquinines by arylation of quincorine bromide using Ni‐catalysed cross electrophile coupling. The method demonstrates robust compatibility with (hetero)aryl bromides bearing diverse functional groups. Oxidation at C‐9 of the dehydroxyquinines expediently provided quinine‐inspired pseudo‐natural products ('quinalogs'). Investigation of the compound collection against Plasmodium falciparum revealed a new insight into the structure activity relationship of quinine. Analogs bearing specifically functionalised pyridines, in place of the 6‐methoxyquinoline ring of quinine, retained activity at the same order of magnitude, albeit not exceeding the activity of the natural product. This synthetic strategy conveniently enables iteration of the aromatic component of quinine for the first time, and holds promise for the development of effective new antimalarials. [ABSTRACT FROM AUTHOR]

Chemical repellents play a crucial role in personal protection, serving as essential elements in reducing the transmission of vector-borne diseases. A biorational perspective that extends beyond the olfactory system as the classical target may be a promising direction to move. The taste system provides reliable information regarding food quality, helping animals to discriminate between nutritious and potentially harmful food sources, often associated with a bitter taste. Understanding how bitter compounds affect feeding in blood-sucking insects could unveil novel molecules with the potential to reduce biting and feeding. Here, we investigated the impact of two naturally occurring bitter compounds, caffeine and quinine, on the feeding decisions in female Aedes aegypti mosquitoes at two distinctive phases: (1) when the mosquito explores the biting substrate using external taste sensors and (2) when the mosquito takes a sip of food and tastes it using internal taste receptors. We assessed the aversiveness of bitter compounds through both an artificial feeding condition (artificial feeder test) and a real host (arm-in-cage test). Our findings revealed different sensitivities in the external and internal sensory pathways responsible for detecting bitter taste in Ae. aegypti. Internal detectors exhibited responsiveness to lower doses compared to the external sensors. Quinine exerted a more pronounced negative impact on biting and feeding activity than caffeine. The implications of our findings are discussed in the context of mosquito food recognition and the potential practical implications for personal protection. [ABSTRACT FROM AUTHOR]

Drug-induced thrombotic microangiopathy (DITMA) is a life-threatening condition which may be immune or nonimmune mediated. Quinine is the most implicated drug in immune-mediated DITMA. However, the optimal treatment is unclear. Complement inhibition by eculizumab has demonstrated success in many DITMA (e.g., carfilzomib, gemcitabine, and tacrolimus), but there are limited data in DITMA, including quinine-associated cases. A 55-year-old female was diagnosed with quinine-associated thrombotic microangiopathy (TMA), as confirmed by a positive quinine-dependent platelet-associated antibody. This was successfully treated with eculizumab with complete resolution of thrombocytopenia and anemia by 1 and 6 weeks. She required hemodialysis for a month and gained full recovery of renal function. We discuss various challenges with the diagnosis and management of DITMA. We also review published data on the use of eculizumab in various DITMA. Our case demonstrates successful treatment of quinine-induced TMA with eculizumab. We recommend further studies to assess the efficacy of complement inhibition in quinine and other DITMA. [ABSTRACT FROM AUTHOR]

In the search of potential multi-target medicinal agents, new NOO-tridentate hydrazone ligands (H2L1–H2L4) (1–4) and their transition metal(II) complexes (5–20) were synthesized from salicylaldehyde derivatives and xanthene-9-carboxylic acid hydrazide. The synthesized compounds were well characterized by different techniques, such as FT-IR, (1H, 13C) NMR, mass spectrometry, UV–Vis, ESR, TG–DTA, powder-XRD, SEM-EDAX and molar conductivity measurements. The spectral techniques confirmed the tridentate nature of hydrazones and coordination of ligands with metal ion via Nazomethine, Ophenolic and Oenolic (NOO) which suggested octahedral stereochemistry of the complexes. The complexes were obtained in good yield, non-electrolytic in nature and stable up to 150 °C. The compounds (1–20) were screened for in vitro anti-malarial activity against Plasmodium falciparum 3D7 strain and the Co(II) complex (5) (IC50 = 0.94 ± 0.03 nM) exhibited comparable potency to quinine (IC50 = 0.826 ± 0.02 nM), whereas, Cu(II) complex (19) (IC50 = 0.65 ± 0.05 nM) have excellent potency to control malarial infection. Furthermore, the in vitro antimicrobial activity against six strains revealed that the compounds 5 and 19 demonstrated greater efficacy to inhibit the growth of microbial strains among the tested compounds (1–20). The most potent anti-malarial compounds (1, 5, 19) were examined by molecular docking study against Dihydroorotate dehydrogenase protein receptor (PDB ID: 1TV5) to accomplish the acquired biological results through binding energy and interaction mode. [ABSTRACT FROM AUTHOR]

Pharmacy personnel that manipulate cytotoxic drugs are under continuous exposure risk. Therefore, training and strict adherence to recommended practices should always be promoted. The main objective of this study was to develop and apply a safe, effective and low-cost method for the training and assessment of the safe handling of cytotoxic drugs, using commercially available tonic water. To evaluate the potential of tonic water as a replacement marker for quinine hydrochloride, deliberate spills of 1 mL of four different tonic waters (one coloured and three non-coloured) were analysed under ultraviolet light (300–400 nm). The pigmented sample did not produce fluorescence under ultraviolet (UV) light. The three commercially available tonic waters that exhibited fluorescence were further analysed by UV/Vis spectrophotometry (300–500 nm). Afterwards, a protocol of simulated manipulation of cytotoxic drugs was developed and applied to 12 pharmacy technicians, that prepared 24 intravenous bags according to recommended routine procedures using tonic water. Participants responded to a brief questionnaire to evaluate the adequacy and applicability of the activity. Seven of the participants had spillages during manipulation, the majority of which recorded during manipulation with needles. All participants scored the tonic water manipulation simulation with 4 or 5 points for simplicity, efficiency and feasibility. The obtained results suggest that tonic water can be used to simulate the manipulation of cytotoxic drugs in training and assessment programs. By using this replacement marker for quinine hydrochloride, it is possible to perform a more cost-effective, yet equally effective, assessment. [ABSTRACT FROM AUTHOR]

Introduction: Compounding robots are increasingly being implemented in hospital pharmacies. In our hospital, the recent acquisition of a robot (RIVATM, ARxIUM) for intravenous cancer drug compounding obliged us to replace the previously used infusion devices. The objective of the present study was to assess and qualify the new intravenous sets prior to their use in our hospital and prior to the implementation of the compounding robot. Materials and Methods: The ChemoLockTM (ICU Medical) was compared with the devices used previously for compounding (BD PhaSealTM, Becton-Dickinson) and infusion (Connect-ZTM, Codan Medical). The connection/disconnection of infusion devices to/from 50 mL infusion bags was tested with a dynamometer (Multitest-i, Mecmesin). Leakage contamination was visualized by a methylene blue assay and was quantified in simulated pump infusions with 20 mg/mL quinine sulfate (N = 36/group); after the analytical assay had been validated, quinine was detected by UV-spectrophotometry at 280 and 330 nm. Groups were compared using chi-squared or Mann–Whitney U tests. Results: The connection/disconnection test showed that although all the devices complied with the current standard, there was a statistically significant difference in the mean ± standard deviation compression force (51.5 ± 11.6 for the Connect-ZTM vs. 60.3 ± 11.7 for the ChemoLockTM; p = 0.0005). Leaks were detected in 32 (29.1%) of the 110 tests of the ChemoLockTM. The contamination rates were also significantly different: 13.9% for the BD PhaSealTM versus 75.0% for the ChemoLockTM; p < 0.0001). Discussion/conclusion: Our results showed that the new infusion device complied with current standards. However, the presence of contamination emphasizes the need for operators to use the recommended personal protective equipment. Further studies of contamination with cancer drugs are required. [ABSTRACT FROM AUTHOR]

Plants produce secondary metabolites for defense against herbivorous insects. In this study, the effects of different concentrations of quinine, nicotine, and tannic acid on food consumption and pupal parameters of the larva of a severe pest, Malacosoma neustria L. (Lepidoptera: Lasiocampidae), were investigated in 2007. Artificial diets containing 0.125%, 0.25%, and 0.5% concentrations of quinine or nicotine were prepared. In addition, diets containing 1.25%, 2.5%, and 5% tannin and a control diet without secondary metabolite were prepared. The feeding experiments revealed that the food consumption and pupal parameters of male and female larvae were different, and all parameters of female individuals were higher than those of male larvae. It has been determined that tannins cause more reductions in food consumption and pupal parameters than alkaloids in male and female individuals. We observed an increase in male larvae's pupal mass with increased concentration of nicotine to 0.5%. Nicotine did not cause a decrease in pupal parameters of larvae compared to quinine. In addition, all parameters of female individuals decreased with the addition of secondary metabolite. Although food consumption in alkaloid-containing diets was less than in the control group, there was a positive relationship between food consumption and pupal lipid and protein content. However, quinine had a more significant effect on triggering protein storage than nicotine. In diets containing tannins, more lipids were stored. A decrease was observed in the food consumption and pupal parameters of all individuals in the tannin-containing diets compared to the other diets. [ABSTRACT FROM AUTHOR]

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Quinine, a bitter compound, can act as an agonist to activate the family of bitter taste G protein-coupled receptor family of proteins. Previous work from our laboratory has demonstrated that quinine causes activation of RalA, a Ras p21-related small G protein. Ral proteins can be activated directly or indirectly through an alternative pathway that requires Ras p21 activation resulting in the recruitment of RalGDS, a guanine nucleotide exchange factor for Ral. Using normal mammary epithelial (MCF-10A) and non-invasive mammary epithelial (MCF-7) cell lines, we investigated the effect of quinine in regulating Ras p21 and RalA activity. Results showed that in the presence of quinine, Ras p21 is activated in both MCF-10A and MCF-7 cells; however, RalA was inhibited in MCF-10A cells, and no effect was observed in the case of MCF-7 cells. MAP kinase, a downstream effector for Ras p21, was activated in both MCF-10A and MCF-7 cells. Western blot analysis confirmed the expression of RalGDS in MCF-10A cells and MCF-7 cells. The expression of RalGDS was higher in MCF-10A cells in comparison to the MCF-7 cells. Although RalGDS was detected in MCF-10A and MCF-7 cells, it did not result in RalA activation upon Ras p21 activation with quinine suggesting that the Ras p21-RalGDS-RalA pathway is not active in the MCF-10A cells. The inhibition of RalA activity in MCF-10A cells due to quinine could be as a result of a direct effect of this bitter compound on RalA. Protein modeling and ligand docking analysis demonstrated that quinine can interact with RalA through the R79 amino acid, which is located in the switch II region loop of the RalA protein. It is possible that quinine causes a conformational change that results in the inhibition of RalA activation even though RalGDS is present in the cell. More studies are needed to elucidate the mechanism(s) that regulate Ral activity in mammary epithelial cells. [ABSTRACT FROM AUTHOR]

The development of a portable device created by 3D printing for fluorimetric measurements is an efficient tool for analytical applications in situ or in the laboratory presenting a wide field of applications in the environmental and food field. This device uses a light-emitting diode (LED) as a radiation source and a digital microscope as a detector. Digital images obtained by the interaction between the radiation source and the sample were analyzed with the help of the YouCam software, the images were filed in JPEG format and processed with the Chemostat software.The entire system is connected to a notebook, which serves as an LED and detector power supply without the need for any additional power source. The proposed device was used for the determination in situ of quinine in water and beverage samples, respectively. For the validation of the developed system, the results obtained were compared with a conventional spectrofluorometer with a t-test at a 95% confidence level. The proposed system provides satisfactory precision and accuracy values. The proposed method presented detection and quantification limits of 0.99 and 1.46 mg·L−1, at a 95% confidence interval.

Spirocyclic compounds have always attracted attention due to their presence as a structural core in a wide variety of natural and bioactive molecules and to exhibit pharmaceutical properties. An asymmetric synthesis of spiro[indoline‐3,4′‐pyrano[2,3‐c]pyrazoles] via Michael addition of trifluoromethyl substituted pyrazolone to isatylidene ethyl cyanoacetate derivatives was conducted with excellent enantioselectivities up to 99 % and up to 97 % isolated yield at room temperature with using 2 mol % of bifunctional quinine derived squaramide organocatalysts. [ABSTRACT FROM AUTHOR]

A rapid, efficient, and precise RP-HPLC protocol has been developed to quantify dihydroquinine content in quinine sulfate pharmaceutical dosage form accurately. This reverse-phase high-performance liquid chromatography (RP-HPLC) method has been validated in compliance with the regulatory guidelines and has efficaciously met specified criteria. The RP-HPLC analysis utilized a Zorbax C18-column with an acetonitrile-buffer mobile phase. A constant 1.2 mL/min flow rate and a 20 µL injection volume were employed with a 316 nm detection wavelength. The linear range for standard solution concentrations was established at 48.7-193.87 µg/mL of quinine sulfate. Retention times were noted at 4.6 min for quinine and 6.9 min for dihydroquinine (impurity). The accuracy assessment of the dihydroquinine analysis revealed a recovery rate of 99.4%. In the present study, an analytical technique was devised and employed to quantify dihydroquinine in finished product tablets. The proposed technique is characterized by its precision, simplicity, and ease of adoption, demonstrating its robustness and applicability. [ABSTRACT FROM AUTHOR]

A series of novel triazole-tethered ferrocenoylamino-substituted cinchona–chalcone hybrids along with two representative benzoylamino-substituted reference compounds were prepared by three methods of CuAAC chemistry. In line with the limited success or complete failure of attempted conversions with low catalyst loadings, by means of DFT modeling studies, we demonstrated that a substantial part of the Cu(I) ions can be chelated and thus trapped in the aroylamino-substituted cinchona fragment and all of the accessible coordinating sites of the chalcone residues. Accordingly, increased amounts of catalysts were used to achieve acceptable yields; however, the cycloadditions with para-azidochalcones were accompanied by partial or complete aldehyde-forming hydrolytic fission of the enone C=C bond in a substituent-, solvent- and copper load-dependent manner. The experienced hydrolytic stability of the hybrids obtained by cycloadditions with ortho-azidochalcones was interpreted in terms of relative energetics, DFT reactivity indices and MO analysis of simplified models of two isomer copper–enone complexes. The novel hybrids were evaluated on HeLa, MDA-MB-231 and A2780 cell lines and showed substantial activity at low-to-submicromolar concentrations. An organometallic model carrying 3,4,5-trimethoxyphenyl residue in the enone part with a para-disubstituted benzene ring in the central skeletal region was identified as the most potent antiproliferative lead, characterized by submicromolar IC50 values measured on the three investigated cells. The biological assays also disclosed that this ferrocenoylamino-containing lead compound displays a ca. two- to five-fold more substantial antiproliferative effect than its benzoylamino-substituted counterpart. [ABSTRACT FROM AUTHOR]

Blackwater fever (BWF) is a severe syndrome occurring in patients with malaria upon antimalarial treatment, characterized by massive intravascular haemolysis and haemoglobinuria. BWF is a neglected condition and management recommendations are unavailable. We performed a scoping review to appraise available data on clinical picture, treatment and physiopathology of BWF, which could guide rationally its clinical management. MEDLINE, EMBASE, LILACS, Web of Science, and Scopus databases, and the reference list of relevant publications, were searched. Papers reporting original data on BWF cases or investigating the physiopathology of BWF were eligible. Data regarding case characteristics, trigger event, clinical management and outcome were extracted. For papers investigating the physiopathology of BWF, study design and principal findings were extracted. No quality assessment was performed. Data are presented as numbers and percentages, and summary of findings, grouped by paper focus (clinical description or physiopathology). 101 papers were included. The majority of BWF cases were observed in autochthonous children (75.7%) and adults (15.3%), in contrast with historical perception that BWF patients were typically expatriates. Clinical management was described for 794 cases; corticosteroids were used in 23. Outcome was reported for 535 patients, with 18.1% mortality. The trigger was reported for 552 (47.5%) cases; in 70.4% identified as quinine. However, two RCT comparing artesunate and quinine for falciparum malaria treatment did not find significant difference in BWF occurrence after their administration. Two case-control studies did not find significant difference in G6PDH deficiency between malaria patients with and without BWF. The physiopathology and optimal treatment of BWF remain similarly unknown as they were over a century ago. Empirical supporting treatment approach seems reasonable, while change of antimalarial drug and use of corticosteroids remain object of debate. [ABSTRACT FROM AUTHOR]

Mesolimbic dopamine signaling plays a major role in alcohol and substance use disorders as well as comorbidities such as anxiety and depression. Growing evidence suggests that alcohol drinking is modulated by the function of the dopamine transporter (DAT), which tightly regulates extracellular dopamine concentrations. Adult male rats on a Wistar Han background (DAT+/+) and rats with a partial DAT deletion (DAT+/−) were used in this study. First, using fast‐scan cyclic voltammetry in brain slices containing the nucleus accumbens core from ethanol‐naïve subjects, we measured greater evoked dopamine concentrations and slower dopamine reuptake in DAT+/− rats, consistent with increased dopamine signaling. Next, we measured ethanol drinking using the intermittent access two‐bottle choice paradigm (20% v/v ethanol vs. water) across 5 weeks. DAT+/− rats voluntarily consumed less ethanol during its initial availability (the first 30 min), especially after longer periods of deprivation. In addition, DAT+/− males consumed less ethanol that was adulterated with the bitter tastant quinine. These findings suggest that partial DAT blockade and concomitant increase in brain dopamine levels has potential to reduce drinking and ameliorate alcohol use disorder (AUD). [ABSTRACT FROM AUTHOR]

Rationale: Female rodents consume more ethanol (EtOH) than males and exhibit greater aversion-resistant drinking in some paradigms. Ovarian hormones promote EtOH drinking but the contribution of ovarian hormones to aversion-resistant drinking has not been assessed. Objectives: We aimed to investigate the role of ovarian hormones to aversion-resistant drinking in female mice in a drinking in the dark (DID) task. Methods: Female C57BL/6 J mice first underwent an ovariectomy (OVX, n = 16) or sham (SHAM, n = 16) surgery. Four weeks following surgery, mice underwent a DID paradigm where they were given access to water and 15% EtOH 3 h into the dark cycle for up to 4 h across 15 drinking sessions. To assess frontloading behavior, bottles were weighed at 30 min, 2 h, and 4 h. Aversion-resistance was tested by adding escalating concentrations of quinine (0, 100, 250, and 500 µM) to the 15% EtOH bottle on sessions 16 – 19. Results: Removal of the ovaries reduced EtOH consumption in OVX subjects. When assessing aversion-resistant EtOH drinking, mice with ovarian hormones (SHAM) reduced consumption of 250 and 500 µM quinine in EtOH, while OVX subjects exhibited aversion-resistance at all quinine concentrations. OVX mice had greater frontloading for quinine + EtOH at higher concentrations of quinine. Conclusions: These results indicate that circulating ovarian hormones may be protective against the development of aversion-resistant EtOH drinking and call for further investigation of the role of ovarian hormones in models of addictive behavior. [ABSTRACT FROM AUTHOR]

Energy transfer from the lowest excited triplet (T1) state of quinine (QN) to ground-state molecular oxygen produces singlet oxygen. In aqueous solutions, a neutral form QN, a singly protonated cation QNH+ and doubly protonated cation QNH22+ are present according to their pKa values. To the best of our knowledge, the pH dependence of QN-photosensitized singlet oxygen generation has not been reported. In the present study, the quantum yields of photosensitized singlet oxygen generation (ΦΔ) by QN, QNH+ and QNH22+ have been determined through the measurements of time-resolved near-IR phosphorescence. ΦΔ decreases in the following order: ΦΔ (QNH+) > ΦΔ (QNH22+) > ΦΔ (QN). The nature of the T1 states of QN, QNH+ and QNH22+ has been studied through the measurements of transient absorption, phosphorescence and EPR by changing the pH of the medium. This is the first report of EPR for the T1 state of QN. The photoexcited T1 state of 6-methoxyquinoline (6-MeOQL), a closely related component, has been studied for comparison. The observed zero-field splitting parameters, phosphorescence spectra and triplet lifetimes suggest that the nature of the T1 state of QN can be regarded as a locally excited 3ππ*state within 6-MeOQL. The two unpaired electrons localize mainly on 6-MeOQL. The nature of the T1 state of QN scarcely changes when the quinuclidine nitrogen site is protonated. Applying the Förster cycle to the T1 states of QN and its protonated cations, it was found that QNH+ becomes more basic when excited to its T1 state. [ABSTRACT FROM AUTHOR]

This article discusses the synthesis of C2'-sulfonylated quinine derivatives, which are novel organocatalysts. The authors successfully modified cinchona alkaloids at the quinoline moiety and synthesized various derivatives. These derivatives have the potential to be chiral organocatalysts and useful intermediates for further derivatization. The article provides detailed accounts of the synthetic routes used to produce specific compounds, along with their physical and spectroscopic properties. The information presented can be useful for researchers interested in the synthesis and potential uses of cinchona alkaloids. The authors of the article are Cheng-Yu Gu, Jie Zhou, Dong-Xing Tan, and Fu-She Han. [Extracted from the article]

This study presents techniques based on the use of fluorescent quinine as a visual tracer for surface flows, to assess surface flow velocities in channels and streams under low luminosity conditions. Fieldwork was conducted in three open channels, with different hydraulic characteristics. A quinine solution, in both liquid and solid (ice cube) forms, was applied on the water flow surface and an Unmanned Aerial System (UAS) was used to record the movement of the fluorescent quinine. The results were compared to the velocities estimated using the thermal tracer technique and flowmeter-based velocity maps. The findings show that the quinine solution, in both liquid and solid forms, can be used to estimate open-channel surface flow velocities under low luminosity conditions. While the solid form of the quinine tracer was applied in a smaller volume than the liquid tracer, its fluorescence effect persisted longer. By comparison, the liquid tracer had the advantage of continual availability and was devoid of the constraint of melting. HIGHLIGHTS Using a UAS for surface flow velocity measurements can improve data recording in hard-to-reach survey sites.; The new quinine-based tracer allows us to observe the spatiotemporal water movement in open channels and to estimate surface flow velocities under low luminosity conditions.; Quinine tracer has high visibility under UVA light in low luminosity conditions.;

After establishment of the pharmacokinetic and toxicological profile of quinine derivatives using in silico approaches, this study reports the synthesis of new acetyl and benzoyl esters of quinine bearing one or more fluorine or chlorine atoms on the acetyl/benzoyl moiety. The antimalarial activity of these compounds on Plasmodium falciparum 3D7 and K1 strains as well as the antiprotozoal activity on Trypanosoma brucei brucei and Trypanosoma cruzi were evaluated. Lastly, the cytotoxicity on MRC-5SV2 cells was established. The fluoroacetyl ester compounds were found to be more active in vitro against Plasmodium falciparum 3D7 strain than the reference compound quinine. All synthesized quinine derivatives were non-cytotoxic for MRC-5SV2 cells (CC50 > 64 µM). These results confirm that the introduction of one or more fluorine atoms into acetyl and benzoyl esters of quinine can sometimes improve the biological activity.