Presence Of Quinine Research Articles

Asymmetric S‐Michael Reaction: Synthesis of CF2H−Containing S‐Ether Compounds through Isosteric Replacement

AbstractOptical pharmaceutical important compounds which bring CF2H to mimic the role of –SH were synthesized through the asymmetric S‐Michael addition reaction in the presence of quinine–a derived squaramide catalyst. Various sulfhydryl compounds including Benzyl mercaptan, phenthiol, alkyl thiophenol, mercaptoacetate, methyl 3‐mercaptoacrylate, and 1,4‐dithiane‐2,5‐diol were tested. The broad substrate scope, good functional group tolerance, and easy derivatization make this synthesis method very attractive.

Regulation of Ras p21 and RalA GTPases activity by quinine in mammary epithelial cells.

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.

Aptamer-based nanotrains and nanoflowers as quinine delivery systems

In this study, we designed aptamer-based self-assemblies for the delivery of quinine. Two different architectures were designed by hybridizing quinine binding aptamers and aptamers targeting Plasmodium falciparum lactate dehydrogenase (PfLDH): nanotrains and nanoflowers. Nanotrains consisted in controlled assembly of quinine binding aptamers through base-pairing linkers. Nanoflowers were larger assemblies obtained by Rolling Cycle Amplification of a quinine binding aptamer template. Self-assembly was confirmed by PAGE, AFM and cryoSEM. The nanotrains preserved their affinity for quinine and exhibited a higher drug selectivity than nanoflowers. Both demonstrated serum stability, hemocompatibility, low cytotoxicity or caspase activity but nanotrains were better tolerated than nanoflowers in the presence of quinine. Flanked with locomotive aptamers, the nanotrains maintained their targeting ability to the protein PfLDH as analyzed by EMSA and SPR experiments. To summarize, nanoflowers were large assemblies with high drug loading ability, but their gelating and aggregating properties prevent from precise characterization and impaired the cell viability in the presence of quinine. On the other hand, nanotrains were assembled in a selective way. They retain their affinity and specificity for the drug quinine, and their safety profile as well as their targeting ability hold promise for their use as drug delivery systems.

In vitro effects of quinine on the antibacterial activity of erythromycin against bacteria of clinical relevance

The study investigated the in vitro effects of quinine on the antibacterial activity of erythromycin for possible interactions. The antibacterial activities of each drug and their combinations were investigated by agar diffusion, agar and macrobroth dilution methods. While 100 µl of 1000 µg/ml of erythromycin produced inhibition zones ranging between 13 and 31 ± 1.0 mm in all the isolates except K. pneumoniae and P. aeruginosa ATCC 19582, combining the highest concentration of erythromycin with 35 µg/ml of quinine produced inhibition zones ranging between 14 and 34 ± 1.0 mm with the exception of S. flexneri KZN. Though quinine had no antibacterial effects on the isolates, erythromycin was effective at minimum inhibitory concentrations (MICs) ranging between 25 and 100 µg/ml while their combinations resulted in reduction of MICs of most of the isolates to 12.5 µg/ml except those against A. calcaoceuticus anitratus CSIR, Ps. aeruginosa ATCC 15442, P. shigelloides ATCC 51903, A. hydrophila ATCC 35654, Ps. aeruginosa ATCC 19582 and E. faecalis KZN that remained unchanged in agar dilution. While the MICs of erythromycin ranged between 25 and 50 µg/ml, the MICs of this antibiotic was reduced to concentrations ranging between 12.5 and 50 µg/ml indicating 50% to 75% in the presence of quinine. The combination of erythromycin and quinine, in vitro, resulted in synergistic (50%), additive/indifference (44.44%) and antagonistic (11.11%) interactions while quinine at concentrations lower than plasma quinine concentrations was inhibitory to the antibacterial activity of erythromycin. The synergistic effect may serve as remedy for bacterial infections in which the test bacteria have been implicated.

Membrane hyperpolarization and depolarization of rat thymocytes by azoxystrobin, a post harvest fungicide

Azoxystrobin, a broad-spectrum fungicide, has been increasingly used in the agricultural industry. In Japan in 2018, azoxystrobin at five times the normal limit was detected in a shipment of Australian barley that had been used in food products. Therefore, the effects of azoxystrobin need to be carefully examined to predict potential adverse reactions in humans. In this study, the effects of azoxystrobin on the membrane potential and intracellular Ca2+ levels of thymocytes have been photochemically examined using flow cytometry. Azoxystrobin hyperpolarized plasma membrane potential. This hyperpolarization appeared to be due to the activation of Ca2+-dependent K+ channels, as both the removal of extracellular Ca2+ and addition of charybdotoxin attenuated the observed hyperpolarization. In the presence of quinine, an anti-malarial drug that blocks Ca2+-dependent K+ channels, azoxystrobin depolarized the membranes instead. Azoxystrobin increased intracellular Ca2+ levels in a concentration-dependent manner through the influx of extracellular Ca2+ and intracellular release of Ca2+, as confirmed by reduction in azoxystrobin-induced response in the absence of extracellular Ca2+. It appears likely that azoxystrobin at micromolar concentrations modifies membrane ion permeability in thymocytes. Since changes in membrane potential and intracellular Ca2+ levels occur during typical physiological lymphocyte responses, azoxystrobin may disturb lymphocyte function.

Optimization of Curcuma Oil/Quinine-Loaded Nanocapsules for Malaria Treatment.

Quinine, a treatment used in chloroquine-resistant falciparum malaria, was loaded into poly(ɛ-caprolactone) or Eudragit® RS100 nanocapsules using Curcuma oil as the oil-based core. Until now, the effect of cationic nanocapsules on malaria has not been reported. A 24 factorial design was adopted using, as independent variables, the concentration of Curcuma oil, presence of quinine, type of polymer, and aqueous surfactant. Diameter, zeta potential, and pH were the responses studied. The formulations were also evaluated for drug content, encapsulation efficiency, photostability, and antimalarial activity against Plasmodium berghei-infected mice. The type of polymer influenced all of the responses studied. Quinine-loaded Eudragit® RS100 (F13) and PCL nanocapsules (F9), both with polysorbate 80 coating, showed nanometric particle size, positive zeta potential, neutral pH, high drug content, and quinine photoprotection ability; thus, these nanocapsules were selected for in vivo tests. Both formulations showed lower levels of parasitemia from the beginning of the experiment (5.78±3.60 and 4.76±3.46% for F9 and F13, respectively) and highest survival mean time (15.3±2.0 and 14.9±5.6days for F9 and F13, respectively). F9 and F13 showed significant survival curve compared to saline, thus demonstrating that nanoencapsulation improved bioefficacy of QN and co-encapsulated curcuminoids, regardless of the surface charge.

New insight into the stereoselective interactions of quinine and quinidine, with bovine serum albumin

Quinine (QN) and quinidine (QD), the chief quinoline alkaloids of various species of cinchona bark, are stereoisomers to each other. In this study, a series of appropriate and efficient methods have been applied to compare the binding modes of QN and QD with bovine serum albumin (BSA). The isothermal titration calorimetry and room temperature phosphorescence results show that both QN and QD can interact with BSA at one binding site to form drug-protein complexes, mainly through enthalpic driving force with the binding affinity order: QN > QD. The fluorescence resonance energy transfer and time-resolved fluorescence spectroscopy exhibits that QN has a larger energy transfer and more intensified binding capacity for BSA than QD. Data of dynamic light scattering reveal that the aggregate state of BSA is changed during this binding process, and the particle size distribution of QN-BSA bioconjugate is larger than that of QD. Nuclear magnetic resonance analysis indicates that aromatic protons make more contribution during ligand-protein complexation than that of aliphatic protons. The circular dichroism spectra exhibit different degrees of changes in BSA secondary structures in the presence of QN and QD, respectively.

CYP450 phenotyping and metabolite identification of quinine by accurate mass UPLC-MS analysis: a possible metabolic link to blackwater fever

BackgroundThe naturally occurring alkaloid drug, quinine is commonly used for the treatment of severe malaria. Despite centuries of use, its metabolism is still not fully understood, and may play a role in the haemolytic disorders associated with the drug.MethodsIncubations of quinine with CYPs 1A2, 2C9, 2C19, 2D6, and 3A4 were conducted, and the metabolites were characterized by accurate mass UPLC-MSE analysis. Reactive oxygen species generation was also measured in human erythrocytes incubated in the presence of quinine with and without microsomes.ResultsThe metabolites 3-hydroxyquinine, 2’-oxoquininone, and O-desmethylquinine were observed after incubation with CYPs 3A4 (3-hydroxyquinine and 2’-oxoquininone) and 2D6 (O-desmethylquinine). In addition, multiple hydroxylations were observed both on the quinoline core and the quinuclidine ring system. Of the five primary abundance CYPs tested, 3A4, 2D6, 2C9, and 2C19 all demonstrated activity toward quinine, while 1A2 did not. Further, quinine produced robust dose-dependent oxidative stress in human erythrocytes in the presence of microsomes.ConclusionsTaken in context, these data suggest a CYP-mediated link between quinine metabolism and the poorly understood haemolytic condition known as blackwater fever, often associated with quinine ingestion.

Digestive cells from Mytilus galloprovincialis show a partial regulatory volume decrease following acute hypotonic stress through mechanisms involving inorganic ions

The response of isolated digestive cells of the digestive gland of Mytilus galloprovincialis to hypotonic shock was studied using videometric methods. The isolated cells exposed to a rapid change (from 1100 to 800 mosmol kg(-1) ) of the bathing solution osmolality swelled but thereafter underwent a regulatory volume decrease (RVD), tending to recover the original size. When the hypotonic stress was applied in the presence of quinine and glibenclamide, known inhibitors of swelling activated ion channels, the cells did not exhibit an RVD response; in addition, they showed a larger increase in size in respect to control cells. These observations suggest that the digestive cells of the digestive gland have the machinery to cope with the hyposmotic shock allowing them to exhibit a small but significant RVD preventing an excessive increase in cell size. The pharmacological treatment of digestive cells during the RVD experiments suggests that cell volume is regulated by K(+) and Cl(-) efflux followed by an obliged water efflux from the cell. The involvement of organic osmolytes such as taurine and betaine seems to be excluded by NMR measurement on digestive cells.

Quinine-induced thrombocytopenia: drug-dependent GPIb/IX antibodies inhibit megakaryocyte and proplatelet production in vitro

AbstractThe development of immune cytopenias is a well-recognized side effect of many drugs. Quinine- and quinidine-dependent antibodies are classic examples of drug-induced effects that cause severe, life-threatening thrombocytopenia. Whereas the effects of drug-dependent antibodies on platelets have been well documented, their effects on megakaryocyte (Mk) biology are still unclear. We analyzed sera from several quinine-induced thrombocytopenia (QITP) patients on highly pure Mks (98% glycoprotein IIb-positive [GPIIb+]; 92% GPIX+) derived from human CD34+ cells cultured with human thrombopoietin. We demonstrate by flow cytometry and confocal microscopy that QITP IgGs bind Mks efficiently in the presence of quinine. Incubation of day-4 Mks with QITP sera or purified IgG resulted in induction of apoptosis, a significant decrease in cell viability, and an increase in cell death. Furthermore, QITP sera preferentially reduced the number of late GPIX+/GPIbα+ Mks and the number of receptors per cell in the surviving population. Ploidy distribution, lobularity, and average cell size of Mks remained unchanged after treatment. In addition, treated Mks showed a marked decrease in their proplatelet production capacity, suggesting that drug-dependent antibodies hinder platelet production. Therefore, QITP antibodies considerably reduce the proplatelet production capabilities of Mks despite undetectable effects on DNA content, morphology, and cell size.

A method of determining binary mixtures by distribution measurements, and its application to the assay of strychnine in the presence of quinine.

A method of determining binary mixtures by distribution measurements, and its application to the assay of strychnine in the presence of quinine.

Membrane Lipid Peroxidation of HbAA Erythrocyte of Non-Malarious Participants Administered with Quinine

The erythrocyte membrane is susceptible to lipid peroxidation due to its high content of polyunsaturated lipids. The present study ascertained levels of lipid peroxidation of non-parasitized erythrocytes of non-malarious male participants administered with quinine. Determination of erythrocyte lipid peroxidation was by a monitor of levels of thiobarbituric acid reactive substances, measured spectrophotometrically by taking the sample absorbance at 432 nm against a reagent blank at 24 °C. Fifteen (15) non-malarious male (59–79 kg) participants of confirmed HbAA genotype between the age brackets of 21–34 yr enrolled for this study. Three (3) participants per group were administered with quinine according to the corresponding doses: 1.5, 3.0, 4.5 and 6.0 mg/kg (control; n = 3). At regular time interval of 3 h for 12 h, blood samples were withdrawn for determination of erythrocyte membrane lipid peroxidation. Erythrocyte membrane of participants administered with quinine exhibited relatively high levels of lipid peroxidation in a dose dependent manner. Generally, within 0–6 h, the four adminstered doses of quinine caused a time dependent elevation of lipid peroxidation. Further increase in time (t > 6 h) showed decreasing levels of lipid peroxidation in participants administered with quinine. Generally, the levels of erythrocyte lipid peroxidation in the presence of quinine showed 2 phase profile. The first stage showed increasing levels of lipid peroxidation at t < 6 h after drug administration, followed by the second phase which showed decreasing levels of lipid peroxidation. The results showed that administration of quinine to non-malarious individuals elicited flux in erythrocyte lipid peroxidation.

Comparative in vitro Osmotic Stability of Three Human Erythrocyte Genotypes in the Presence of Quinine and Chloroquine Phosphate

Comparative in vitro Osmotic Stability of Three Human Erythrocyte Genotypes in the Presence of Quinine and Chloroquine Phosphate

Swelling-Induced Ca2+ Influx and K+ Efflux in American Alligator Erythrocytes

The American alligator can hibernate during winter, which may lead to osmotic imbalance because of reduced kidney function and lack of food consumption during this period. Accordingly, we hypothesized that their red blood cells would have a well-developed regulatory volume decrease (RVD) to cope with the homeostatic challenges associated with torpor. Osmotic fragility was determined optically, mean cell volume was measured by electronic sizing, and changes in intracellular Ca²+ concentration were visualized using fluorescence microscopy and fluo-4-AM. Osmotic fragility increased and the ability to regulate volume was inhibited when extracellular Na+ was replaced with K+, or when cells were exposed to the K+ channel inhibitor quinine, indicating a requirement of K+ efflux for RVD. Addition of the ionophore gramicidin to the extracellular medium decreased osmotic fragility and also potentiated volume recovery, even in the presence of quinine. In addition, hypotonic shock (0.5 x Ringer) caused an increase in cytosolic Ca²+, which resulted from Ca²+ influx because it was not observed when extracellular Ca²+ was chelated with EGTA (ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid). Furthermore, cells loaded with BAPTA-AM (1,2-bis(2-aminophenoxymethyl)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl) ester) or exposed to a low Ca²+-EGTA hypotonic Ringer had a greater osmotic fragility and also failed to recover from cell swelling, indicating that extracellular Ca²+ was needed for RVD. Gramicidin reversed the inhibitory effect of low extracellular Ca²+. Finally, and surprisingly, the Ca²+ ionophore A23187 increased osmotic fragility and inhibited volume recovery. Taken together, our results show that cell swelling activated a K+ permeable pathway via a Ca²+-dependent mechanism, and this process mediated K+ loss during RVD.

Effect of an early bitter taste experience on subsequent feather-pecking behaviour in laying hens

Recent studies showed that laying hens learn not to peck at bitter-tasting feathers from conspecifics. In the present experiment, feathers of newly hatched chicks were made distasteful by spraying them with a bitter-tasting substance (quinine). It was hypothesized that chicks could detect quinine and learn to avoid the downy feathers and the feathers of conspecifics later in life. Six groups of 10 high feather-pecking birds and six groups of 10 low feather-pecking birds were kept on litter. Half of each of these groups was quinine treated. Each bird in the quinine-treated groups was individually sprayed on a weekly basis for 25 weeks with a quinine solution. It was investigated whether the presence of quinine on the birds’ feather cover affected gentle and severe feather pecking. The result indicated that feathers made distasteful with quinine reduced severe feather pecking in young and adult birds as long as it was detected on birds feather cover.

ChemInform Abstract: Andersen Chemistry with an α,β-Unsaturated Sulfinyl Chloride: Synthesis and Grignard Reactions of Homochiral Cholesteryl (R)s-(E)-t-Butylethenesulfinate.

Abstract (−)-Cholesteryl ( R ) S -( E )- t -butylethenesulfinate 2 was prepared in enantiopure form through the reaction of ( E )- t -butylethenesulfinyl chloride and (−)-cholesterol in the presence of quinine (ca. 36% yield). Diastereomerically enriched versions of ( S )- 2 were prepared with d.e.s up to 75%. Grignard substitution reactions of 2 proceed with high stereospecificity to provide a new access to enantiomerically enriched ( E )-2- t -butylethenylaralkyl sulfoxides in good yield and excellent e.e.

Mitochondrial matrix K+ flux independent of large-conductance Ca2+-activated K+ channel opening

Large-conductance Ca(2+)-activated K(+) channels (BK(Ca)) in the inner mitochondrial membrane may play a role in protecting against cardiac ischemia-reperfusion injury. NS1619 (30 microM), an activator of BK(Ca) channels, was shown to increase respiration and to stimulate reactive oxygen species generation in isolated cardiac mitochondria energized with succinate. Here, we tested effects of NS1619 to alter matrix K(+), H(+), and swelling in mitochondria isolated from guinea pig hearts. We found that 30 microM NS1619 did not change matrix K(+), H(+), and swelling, but that 50 and 100 microM NS1619 caused a concentration-dependent increase in matrix K(+) influx (PBFI fluorescence) only when quinine was present to block K(+)/H(+) exchange (KHE); this was accompanied by increased mitochondrial matrix volume (light scattering). Matrix pH (BCECF fluorescence) was decreased slightly by 50 and 100 microM NS1619 but markedly more so when quinine was present. NS1619 (100 microM) caused a significant leak in lipid bilayers, and this was enhanced in the presence of quinine. The K(+) ionophore valinomycin (0.25 nM), which like NS1619 increased matrix volume and increased K(+) influx in the presence of quinine, caused matrix alkalinization followed by acidification when quinine was absent, and only alkalinization when quinine was present. If K(+) is exchanged instantly by H(+) through activated KHE, then matrix K(+) influx should stimulate H(+) influx through KHE and cause matrix acidification. Our results indicate that KHE is not activated immediately by NS1619-induced K(+) influx, that NS1619 induces matrix K(+) and H(+) influx through a nonspecific transport mechanism, and that enhancement with quinine is not due to the blocking of KHE, but to a nonspecific effect of quinine to enhance current leak by NS1619.

Taste aversion learning to eliminate feather pecking in laying hens, Gallus gallus domesticus

Feather pecking in laying hens is a redirection of normal pecking behaviour. There is clear evidence that severe feather pecking is influenced by the motivational system of foraging and feeding. Feather pecking is positively associated with feather eating, indicating that feathers are seen as a feeding substrate by laying hens. Feed choice may be affected by many factors, including learning processes. In this experiment, feathers of other birds were made distasteful by adding a bitter taste (quinine). We investigated whether laying hens could detect quinine and learn to avoid the feather cover of conspecifics. We also examined the effects of quinine on birds' own feather-related activity (preening). Six groups of 10 high feather-pecking birds and six groups of 10 low feather-pecking birds were kept on litter. Half of these groups were quinine treated. Each bird of the quinine-treated groups was individually sprayed with a quinine solution. We investigated whether the presence of quinine on birds' feather cover affected severe and gentle feather pecking, aggressive pecking and preening. In the present study, severe and gentle feather pecking decreased when feathers were made distasteful, suggesting that learning occurred. Furthermore, the results suggest that quinine is an effective reinforcing agent to alter feather-pecking behaviour. Distasteful feathers did not influence preening, whereas aggressive behaviour was reduced. Our experiment showed that birds in the quinine treatment were able to learn that feathers from conspecifics were not attractive to peck at and they learned to avoid them for a period of time.

Two-pore-domain potassium channels contribute to neuronal potassium release and glial potassium buffering in the rat hippocampus

Two-pore-domain potassium (K2P) channels have been suggested to be involved in neuronal K + release and glial K + uptake. We studied effects of the K2P channel blockers quinine (200 or 500 μM), quinidine (500 μM), and bupivacaine (200 μM) on stimulus-induced and iontophoretically induced transient increases of the extracellular potassium concentration ([K +] o) in area CA1 of rat hippocampal slices, always in presence of AMPA/kainate and NMDA receptor antagonists. Increases in [K +] o evoked by repetitive alvear stimulation (20 Hz) were blocked by quinine and quinidine but amplitudes of population spikes were only modestly reduced. Bupivacaine suppressed both rises in [K +] o and population spikes. In contrast, iontophoretically induced rises in [K +] o were moderately augmented by quinine and quinidine while bupivacaine had no effect. Barium at concentrations of 2 mM which should block both potassium inward rectifier (Kir) and some K2P channels doubled iontophoretically induced rises in [K +] o also in presence of quinine, quinidine, and bupivacaine. The data suggest that quinine/quinidine-sensitive K2P channels mediate K + release from neurons and possibly contribute to glial K + buffering.

Relationship of Cytoplasmic Droplets to Motility, Migration in Mucus, and Volume Regulation of Human Spermatozoa

A significantly greater percentage of motile than immotile spermatozoa bore droplets at the osmolality of semen and cervical mucus. The percentage of spermatozoa with droplets was not significantly correlated with the osmolality of semen or the extent of cell swelling in response to quinine in hypotonic medium. Droplets appeared slightly more frequently (ie, were more obvious) in the presence of quinine, which blocks regulatory volume decrease, indicating that they are the major site of volume expansion. There was no selection for or against droplet-bearing spermatozoa migrating through viscous surrogate mucus at high or low osmolality. Sperm swelling in response to quinine at mucus osmolality was significantly greater in fathers than in patients whose partners had no fertility problem. Therefore, cytoplasmic droplets are not deleterious to sperm motility and may be related to physiological volume regulation, which may be predictive of some forms of human male infertility.