Search

Purpose: The present study investigated the effect of unpleasant salty or bitter tastes on cycling sprint performance and knee-extensor force characteristics in different fatigue states. Methods: Following a familiarization session, 11 trained male cyclists completed 3 experimental trials (salty, bitter, and water) in a randomized crossover order. In each trial, participants cycled at 85% of the respiratory compensation point for 45 minutes and then, after a 5-minute rest, completed a 1-minute sprint. Muscle-force characteristics were assessed using 2 knee-extensor maximal voluntary contractions immediately before, between, and after the cycling efforts. Participants mouth-rinsed and ingested 25 mL of test solution (salty, bitter, and water) immediately before each maximal voluntary contractions and the 1-minute sprint. Results: There were no significant differences in mean and peak power output during the 1-minute sprint between conditions (mean power: 528 [71] W, 524 [70] W, and 521 [80] W in the water, salt, and bitter conditions, respectively). Muscle-force production was impaired in all conditions after the heavy-intensity cycling, evidenced by a decline in maximum force production (P =.01, effect size = 0.32) and 100- to 200-millisecond impulse (P =.04, effect size = 0.27). However, there were no significant differences between conditions in maximal force or impulse measures at rest or after exercise. Conclusion: These data question whether unpleasant tastes can influence muscle-force production and do not support that they may be used as an ergogenic aid for a cycling sprint performed under fatigued conditions. [ABSTRACT FROM AUTHOR]

This study successfully optimized two advanced extraction methods, microwave-assisted extraction (MAE) and ultrasound-assisted extraction (UAE), for the efficient and rapid recovery of quinine from Cinchona officinalis. Among the evaluated parts of the plant, the bark consistently yielded the highest quinine concentration, highlighting its significance as the primary source for alkaloid extraction. The optimized conditions for MAE (65% ethanol, 130 °C, 34 min) achieved a maximum yield of 3.93 ± 0.11 mg/g, while UAE (61% ethanol, 25 °C, 15 min) provided a faster but slightly lower yield of 2.81 ± 0.04 mg/g. These findings confirm the superiority of MAE and UAE over conventional methods like Soxhlet extraction in terms of time efficiency and sustainability. The quantification of quinine using high-performance liquid chromatography (HPLC) coupled with advanced detection methods further validated the reliability and reproducibility of the results. While this study focused on optimizing extraction and quantification parameters, it sets the groundwork for future research into the sustainable utilization and potential valorization of C. officinalis byproducts. These findings not only provide a standardized protocol for extracting quinine but also contribute to the broader application of green chemistry principles in pharmaceutical production. [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]

Context: Dietary zinc oxide (ZnO) (a bitter antimicrobial chemical) in pigs is being gradually phased out due to pollution and antibiotic resistance. Bitter compounds like quinine hydrochloride (HCl) have shown potential to enhance growth and feed efficiency by slowing gastric emptying and intestinal passage rates in pigs. Aims: This study aimed to evaluate quinine's ability to improve performance in weanling pigs without ZnO. Methods: Two experiments were conducted. Experiment 1: 120 Landrace (LD) × Large White (LW) weaned piglets (initial BW 6.8 ± 0.1 kg) were randomly assigned to one of four diets in a 2 × 2 factorial design: with/without ZnO and copper sulfate (CuSO4) (3000 and 250 ppm, respectively) and two quinine levels (0 and 500 ppm). Parameters measured included average daily feed intake (ADFI), average daily gain (ADG), gain to feed ratio (G:F), and faecal score. Experiment 2: 1440 LD × LW piglets (initial BW 7.4 ± 0.2 kg) were housed in groups of 18 per pen and assigned the same four dietary treatments as in Experiment 1. Key results: Growth performance parameters were recorded and analysed, showing that ZnO/CuSO4 supplement improved growth and feed efficiency (P < 0.05) compared to the ZnO/CuSO4-free diet group. In Experiment 1, pigs supplemented with quinine in non-ZnO/CuSO4 diets showed similar (P > 0.05) performance levels to the ZnO/CuSO4 fed group. In addition, an interaction (P < 0.05) was found, indicating that adding quinine improved or worsened ADG and G:F depending on the absence or presence of ZnO/CuSO4 in the diet, respectively. In Experiment 2, quinine inclusions in non-ZnO diets improved (P < 0.05) ADG but did not affect (P > 0.05) ADFI and G:F. Conclusion: Our findings suggest that the anticipated deleterious effects of phasing out the use of dietary ZnO can be partially compensated by includingquinine in the diet of post-weaning pigs. The negative effect of quinine when provided together with ZnO is compatible with a competitive exclusion mechanism linked to both stimulating bitterness, a mechanism that warrants further investigation. Implications: Quinine shows potential as a partial replacement for ZnO in post-weaning pig diets, providing a promising alternative to maintain piglet health and growth while transitioning away from ZnO. Quinine shows promise in improving the sustainability of pig farming by enhancing piglet growth while addressing environmental concerns linked to zinc oxide. Our studies revealed that quinine, comparable to traditional supplements, not only boosts piglet growth but also does so independently of zinc oxide showing promise as a viable alternative. This finding suggests that quinine could play a crucial role in promoting more sustainable pig nutrition practices. [ABSTRACT FROM AUTHOR]

The extensive use of the alkaloid quinine (QN) in the cosmetic and food industries has induced major concerns relating to its impact on human health, considering its potential toxicity. Therefore, developing sensitive and selective electrochemical sensors is crucial for monitoring QN in environmental, food, and pharmaceutical samples. To respond to this need, a surfactant-supported green synthesis approach, based on a straightforward, organic solvent-free hydrothermal method was employed to synthesize highly crystalline pseudospherical bismuth oxychloride (BiOCl) nanoparticles. This material was used for the enrichment of carbon paste electrodes and its further utilization for the detection and quantification of quinine. They have superior electrocatalytic performance, due to their size and morphology, and facilitate the interactions of the target with the electrode surface. Under optimal operating conditions, differential pulse voltammetry demonstrated a remarkable feature: a broad linear working range of 10 to 140 μM, a detection limit of 0.14 μM, and a high sensitivity of 1.995 μA μM−1 cm−2. The suggested method's satisfactory sensitivity, along with its good stability, repeatability, and reproducibility, strongly point to a possible use for identifying quinine in real samples. [ABSTRACT FROM AUTHOR]

The natural product quinine has been known to humankind for centuries, and in that time has played a pivotal role in the treatment of malaria. Quinine, and the related cinchona alkaloids, have seen widespread contemporary use across chemical and biological disciplines, owing in part to the plethora of functional groups and stereochemical information contained within their scaffold. This review focuses on site‐selective synthetic modifications of the cinchona alkaloids. Our comparative analysis may act as a 'user manual' for the selective functionalisation of the cinchona alkaloids, and aims to promote consideration of remarkable and lesser‐understood aspects of cinchona chemistry. [ABSTRACT FROM AUTHOR]

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]

Envenomations by snakes represent a neglected health problem in tropical and subtropical countries. In South America, Lachesis muta occasionally causes severe human envenomation, with treatment being conditioned to an unspecific antivenom. In this work, we examined the neutralizing ability of Coutarea hexandra stem bark hydroalcoholic extract (Ch‐E), including the commercial phytochemicals coumarin and quinine, on the neuromuscular blockade induced by L. m. muta venom in mouse phrenic nerve‐diaphragm preparation. Biological assays were performed following conventional myographic technique ex vivo. Ch‐E was phytochemically characterized to detect the presence of coumarin and quinine using analytical methods. Ch‐E and commercial phytochemicals were tested separately or combined under pre‐ and post‐venom incubation protocols. Ch‐E attenuated the venom‐induced neuromuscular blockade only under the pre‐venom incubation protocol. Quinine was not detected in Ch‐E. Commercial coumarin and quinine exhibited a concentration‐dependent counteracting effect on the venom‐induced neuromuscular blockade. The pre‐venom incubation protocol showed to be efficient in attenuating the L. m. muta venom–induced neuromuscular blockade, most likely due to the presence of coumarin derivatives and unknown alkaloids in this extract. [ABSTRACT FROM AUTHOR]

Quinine is a historically important natural product containing a methoxy group that has been assumed to be incorporated at a late pathway stage. Here we show that the methoxy group in quinine and related alkaloids is introduced onto the starting substrate tryptamine. Feeding studies definitively show that 5‐methoxytryptamine is utilized as a quinine biosynthetic intermediate in planta. We discover the biosynthetic genes that encode the responsible oxidase and methyltransferase, and we use these genes to reconstitute the early steps of the alkaloid biosynthetic pathway in Nicotiana benthamiana to produce a mixture of methoxylated and non‐methoxylated alkaloid intermediates. Importantly, we show that the co‐occurrence of both tryptamine and 5‐methoxytryptamine substrates, along with the substrate promiscuity of downstream pathway enzymes, enable parallel formation of both methoxylated and non‐methoxylated alkaloids. [ABSTRACT FROM AUTHOR]

Modulation of predatory behaviors based on prey profitability can improve overall foraging efficiency by allocating energy reserves towards more valuable prey. Should the value of prey vary predictably across the landscape, predators could also benefit from the utilization of environmental cues to inform their foraging decisions. Here, we present data on context-dependent foraging behaviors of the wolf spider Pardosa milvina (Araneae: Lycosidae). Spiders underwent testing during which subjects were alternately provided cricket prey coated with either a favorable (sucrose) or unfavorable (quinine) solution. Each prey type was paired with 1 of 2 environmental odors such that one odor was always predictive of unfavorable prey and the other was always predictive of favorable prey. We found that P. milvina reduced their attacks over time while differing significantly in behavior towards the 2 prey types. The rate of nonresponses towards the unfavorable prey increased significantly over time compared to the favorable prey, suggesting that spiders were avoiding the former. Our findings indicate that P. milvina can differentiate between environmental odor cues associated with prey type. Additionally, we report on a novel prey handling behavior where spiders would repeatedly drag unfavorable prey along the arena floor between bouts of cheliceral grooming. We propose this behavior may have served to remove quinine from the prey. [ABSTRACT FROM AUTHOR]

Objectives: Investigating how nanoparticle systems interact in whole blood (WB) is critical to evaluating the effectiveness of malaria therapy. Methods: We decided to establish a pharmacokinetic/pharmacodynamic (PK/PD) model of the quinine population in WB using Plasmodium berghei-infected mice, with a subsequent model comparison for nanocapsules coated with polysorbate (NCP80) or prepared with Eudragit® RS (NCEUD). The WB quinine population pharmacokinetic model in rats was developed using plasma and partition coefficients for rat erythrocytes. Mouse WB quinine population PK/PD modeling was developed using allometrically scaled literature-free mouse quinine pharmacokinetic data and covariate values to obtain a WB population pharmacokinetic model for quinine and nanocapsules in mice. This allowed for PK/PD modeling of the quinine population with the WB concentration and parasitemia data in mice. All models were built in NONMEN. Results: The WB quinine concentration profiles in rats were characterized using a two-compartment model. Nanoencapsulation reduced clearance and central compartment volume and increased peripherical compartimental volume. A maximum effect model described the PK/PD of the quinine WB population in mice, demonstrating that NCEUD enhances the antimalarial effect. Conclusions: Quinine WB is a good surrogate for describing the response to exposure in malaria. NCEUD outperformed NCP80 and free quinine, suggesting that cationic surfaces improve the potential for treating malaria. [ABSTRACT FROM AUTHOR]

Background: Nicotine is largely responsible for the initiation and maintenance of tobacco dependence and contributes to a global health problem. Aims: This study characterizes nicotine oral consumption and preference in male and female mice of several Diversity Outbred (DO) founder strains: C57BL/6J, A/J, 129S1/SvImJ, PWK/PhJ, NOD/ShiLtJ, and CAST/EiJ. It assesses the impact of nicotine concentration on intake and preference, the potential interaction of strain with sex, and estimates the degree of heritable variation in nicotine consumption. Methods: Two-bottle choice oral self-administration paradigm was used to assess nicotine intake, nicotine preference, and total fluid intake in male and female mice of each strain in a concentration-response manner. A conditioned place preference (CPP) test was performed to evaluate the rewarding and aversive effects of nicotine in certain strains after systemic administration of the drug. Results: The highest nicotine-consuming strain was found to be 129S1/SvlmJ, and the lowest nicotine-consuming strain was A/J. Strain differences in nicotine intake were not due to differences in bitter and sweet tastes as shown in the saccharine and quinine two-bottle choice tests. A/J strain showed no significant CPP for nicotine while the 129S1/SvImJ strain showed a significant CPP for nicotine and a higher preference when compared to the C57BL/6J strain. Heritability estimates of nicotine intake were sex dependent and concentration dependent. Conclusions: Data support that nicotine consumption patterns are heritable with an influence of genotype in a voluntary oral self-administration paradigm. Results pave the way for future studies with the highly recombinant DO mice that might lead to the identification of novel genetic loci and genes influencing nicotine consumption. [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]

Measuring quinine is critical for the detection of its overdose, understanding its pharmacological and toxicological effects, and monitoring its pollution. While a previously reported aptamer named MN4 can bind quinine, it was not selected for it, leading to compromised binding affinity and specificity. In this work, a new quinine aptamer was isolated using the library immobilization capture‐SELEX technique. The Q1 aptamer has a Kd value of 10 nM determined by an isothermal titration calorimetry experiment and 45 nM in a fluorescence binding assay. A 3.5 nM quinine limit of detection was obtained based on the aptamer binding‐induced quenching of the intrinsic fluorescence of quinine. A large blue shift in fluorescence was observed for quinine upon binding to Q1, whereas binding to MN4 led to a very small red shift, indicating different ways of quinine binding by these two aptamers. Q1 did not bind cocaine based on NMR spectroscopy and fluorescence assays also indicated excellent selectivity against other tested molecules. This work has supplied a high affinity aptamer for quinine that can be useful for its detection and fundamental aptamer binding studies. It also highlights the advantages of using capture‐SELEX to isolate aptamers for small molecules. [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]

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]

Quinine Ester of Naproxen was obtained for the first time by O-acylation of quinine with naproxen [(S)-6-methoxy-α-methyl-2-naphthaleneacetic acid] chloride under alkaline conditions. The structure of the product was proved by 1H NMR. The photophysical properties of the resulting compound were studied, an intense fluorescent response to picric acid with a Stern–Volmer constant Ksv ≈ 1×106 M–1 was shown. [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.

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.

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]

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]

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]

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: 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.

This study successfully optimized two advanced extraction methods, microwave-assisted extraction (MAE) and ultrasound-assisted extraction (UAE), for the efficient and rapid recovery of quinine from Cinchona officinalis. Among the evaluated parts of the plant, the bark consistently yielded the highest quinine concentration, highlighting its significance as the primary source for alkaloid extraction. The optimized conditions for MAE (65% ethanol, 130 °C, 34 min) achieved a maximum yield of 3.93 ± 0.11 mg/g, while UAE (61% ethanol, 25 °C, 15 min) provided a faster but slightly lower yield of 2.81 ± 0.04 mg/g. These findings confirm the superiority of MAE and UAE over conventional methods like Soxhlet extraction in terms of time efficiency and sustainability. The quantification of quinine using high-performance liquid chromatography (HPLC) coupled with advanced detection methods further validated the reliability and reproducibility of the results. While this study focused on optimizing extraction and quantification parameters, it sets the groundwork for future research into the sustainable utilization and potential valorization of C. officinalis byproducts. These findings not only provide a standardized protocol for extracting quinine but also contribute to the broader application of green chemistry principles in pharmaceutical production.

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]

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]

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]