Real-time measurements of ATP dynamics via ATeams in Plasmodium falciparum reveal drug-class-specific response patterns.

Malaria tropica, caused by the parasite Plasmodium falciparum (P. falciparum), remains one of the greatest public health burdens for humankind. Due to its pivotal role in parasite survival, the energy metabolism of P. falciparum is an interesting target for drug design. To this end, analysis of the central metabolite adenosine triphosphate (ATP) is of great interest. So far, only cell-disruptive or intensiometric ATP assays have been available in this system, with various drawbacks for mechanistic interpretation and partly inconsistent results. To address this, we have established fluorescent probes, based on Förster resonance energy transfer (FRET) and known as ATeam, for use in blood-stage parasites. ATeams are capable of measuring MgATP2- levels in a ratiometric manner, thereby facilitating in cellulo measurements of ATP dynamics in real-time using fluorescence microscopy and plate reader detection and overcoming many of the obstacles of established ATP analysis methods. Additionally, we established a superfolder variant of the ratiometric pH sensor pHluorin (sfpHluorin) in P. falciparum to monitor pH homeostasis and control for pH fluctuations, which may affect ATeam measurements. We characterized recombinant ATeam and sfpHluorin protein in vitro and stably integrated the sensors into the genome of the P. falciparum NF54attB cell line. Using these new tools, we found distinct sensor response patterns caused by several different drug classes. Arylamino alcohols increased and redox cyclers decreased ATP; doxycycline caused first-cycle cytosol alkalization; and 4-aminoquinolines caused aberrant proteolysis. Our results open up a completely new perspective on drugs' mode of action, with possible implications for target identification and drug development.

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.

Pyrroloquinoline quinone supplementation attenuates inflammatory liver injury by STAT3/TGF-ß1 pathway in weaned piglets challenged with lipopolysaccharide.

This study is aimed to evaluate the effect and underling mechanism of dietary supplementation with pyrroloquinoline quinone (PQQ) disodium on improving inflammatory liver injury in piglets challenged with lipopolysaccharide (LPS). A total of seventy-two crossbred barrows were allotted into four groups as follows: the CTRL group (basal diet + saline injection); the PQQ group (3 mg/kg PQQ diet + saline injection); the CTRL + LPS group (basal diet + LPS injection) and the PQQ + LPS group (3 mg/kg PQQ diet + LPS injection). On days 7, 11 and 14, piglets were challenged with LPS or saline. Blood was sampled at 4 h after the last LPS injection (day 14), and then the piglets were slaughtered and liver tissue was harvested. The results showed that the hepatic morphology was improved in the PQQ + LPS group compared with the CTRL + LPS group. PQQ supplementation decreased the level of serum inflammatory factors, aspartate aminotransferase and alanine transaminase, and increased the HDL-cholesterol concentration in piglets challenged with LPS; piglets in the PQQ + LPS group had lower liver mRNA level of inflammatory factors and protein level of α-smooth muscle actin than in the CTRL + LPS group. Besides, mRNA expression of STAT3/TGF-ß1 pathway and protein level of p-STAT3(Tyr 705) were decreased, and mRNA level of PPARα and protein expression of p-AMPK in liver were increased in the PQQ + LPS group compared with the CTRL + LPS group (P < 0·05). In conclusion, dietary supplementation with PQQ alleviated inflammatory liver injury might partly via inhibition of the STAT3/TGF-ß1 pathway in piglets challenged with LPS.

Mosquitoes do not Like Bitter.

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.

Fluorescent Probe-Based Fiber Optic Sensor for Real-Time Monitoring of Chloride Ions in Coastal Concrete Structures.

Coastal concrete structures, such as cross-sea bridges and tunnels, are susceptible to the penetration of chloride ions, which can lead to the deterioration of the passive film on the rebar surface, consequently accelerating the corrosion process. Conventional methods for monitoring chloride ions typically require in situ drilling for sample collection, thereby compromising efficiency and accuracy. Additionally, real-time monitoring and early warning cannot be achieved. To address these challenges, this work introduces a fluorescent-probe-based fiber optic sensor for monitoring chloride levels in concrete structures. Quinine sulfate was chosen as the fluorescent material due to its exceptional sensitivity to chloride ions and its stability in concrete environments. The proposed sensor was manufactured using sol-gel and 3D-printing techniques. Tests were conducted using concrete simulation fluid and cement mortar specimens. The results demonstrate that the sensitivity of the proposed sensor is greater than 0.01 M, and its accuracy in penetration depth measurement is better than 3 mm. The findings confirm that the designed fiber optic sensor based on quinine sulfate enables real-time monitoring of chloride ions in concrete structures, offering high sensitivity (0.1% in concentration and 2.7 mm in terms of penetration depth), unique selectivity (as it is immune to other ions whose concentrations are 10 times higher than those of Cl-), and a compact size (10 × 20 mm). These attributes render it promising for practical engineering applications.

CuAAC-Based Synthesis, Copper-Catalyzed Aldehyde-Forming Hydrolytic Fission and Antiproliferative Evaluation of Novel Ferrocenoylamino-Substituted Triazole-Tethered Quinine-Chalcone Hybrids.

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.

Blackwater Fever Treated with Steroids in Nonimmune Patient, Italy.

Causes of blackwater fever, a complication of malaria treatment, are not completely clear, and immune mechanisms might be involved. Clinical management is not standardized. We describe an episode of blackwater fever in a nonimmune 12-year-old girl in Italy who was treated with steroids, resulting in a rapid clinical resolution.

Palatability profile in spontaneously hypertensive rats.

The spontaneously hypertensive rats (SHRs) have enhanced palatability for NaCl taste as measured by the increased number of hedonic versus aversive responses to intraoral infusion (1 mL/1 min) of 0.3 M NaCl, in a taste reactivity test in euhydrated condition or after 24 h of water deprivation + 2 h of partial rehydration (WD-PR). SHRs also ingested more sucrose than normotensive rats, without differences in quinine hydrochloride intake. Here, we investigated the palatability of SHRs (n = 8-10) and normotensive Holtzman rats (n = 8-10) to sucrose and quinine sulphate infused intraorally in the same conditions that NaCl palatability was increased in SHRs. SHRs had similar number of hedonic responses to 2% sucrose in euhydrated condition (95 ± 19) or after WD-PR (142 ± 25), responses increased when compared with normotensive rats in euhydrated condition (13 ± 3) or after WD-PR (21 ± 6). SHRs also showed increased number of aversive responses to 1.4 mM quinine sulphate compared with normotensive rats, whether in euhydrated condition (86 ± 6, vs. normotensive: 54 ± 7) or after WD-PR (89 ± 9, vs. normotensive: 40 ± 9). The results suggest that similar to NaCl taste, sweet taste responses are increased in SHRs and resistant to challenges in bodily fluid balance. They also showed a more intense aversive response in SHRs to bitter taste compared with normotensives. This suggests that the enhanced response of SHRs to taste rewards does not correspond to a decreased response to a typical aversive taste.

In paired preference tests, domestic chicks innately choose the colour green over red, and the shape of a frog over a sphere when both stimuli are green.

Many animals express unlearned colour preferences that depend on the context in which signals are encountered. These colour biases may have evolved in response to the signalling system to which they relate. For example, many aposematic animals advertise their unprofitability with red warning signals. Predators' innate biases against these warning colours have been suggested as one of the potential explanations for the initial evolution of aposematism. It is unclear, however, whether unlearned colour preferences reported in a number of species is truly an innate behaviour or whether it is based on prior experience. We tested the spontaneous colour and shape preferences of dark-hatched, unfed, and visually naive domestic chicks (Gallus gallus). In four experiments, we presented chicks with a choice between either red (a colour typically associated with warning patterns) or green (a colour associated with palatable cryptic prey), volume-matched spheres (representing a generalised fruit shape) or frogs (representing an aposematic animal's shape). Chicks innately preferred green stimuli and avoided red. Chicks also preferred the shape of a frog over a sphere when both stimuli were green. However, no preference for frogs over spheres was present when stimuli were red. Male chicks that experienced a bitter taste of quinine immediately before the preference test showed a higher preference for green frog-shaped stimuli. Our results suggest that newly hatched chicks innately integrate colour and shape cues during decision making, and that this can be augmented by other sensory experiences. Innate and experience-based behaviour could confer a fitness advantage to novel aposematic prey, and favour the initial evolution of conspicuous colouration.

Photoexcited triplet state and singlet oxygen generation of quinine, an antimalarial drug.

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.

Chemosensory representation of first-time oral exposure to ethanol in the orbitofrontal cortex of mice.

Intermittent ethanol consumption changes the neuronal activity of the orbitofrontal cortex (OFC) in rodents, which has been attributed to important participation in the development of addiction, particularly alcoholism. The OFC participates in gustatory sensory integration. However, it is unknown whether this region can encode chemosensory elements of oral ethanol administration independently of the consumption movement (orofacial motor response) when administered for the first time (naïve mice). To answer this question, we used a sedated mouse model and a temporary analysis protocol to register extracellular neuronal responses during the oral administration of ethanol. Our results show an increase in neuronal frequency (in the first 500 ms) when low (0.6, 1, and 2.1 M) and high (3.2, 4.3, and 8.6 M) concentrations of ethanol are orally administered. The modulatory effect of ethanol was observed from low and high concentrations and differed from the tastants. There was consistent neuronal activity independent of the concentration of ethanol. Our results demonstrate a sensory representation of oral ethanol stimulation in the OFC neurons of naïve mice under sedation.

The Study of the Effect of Dimethylsulfoxide (or Diethylsulfoxide) on Quinine Sulfate-DNA Binding by UV-Vis and Steady-State Fluorescence Spectroscopies.

The effect of dimethylsulfoxide (DMSO) and diethylsulfoxide (DESO) on binding between quinine sulfate (QS) and DNA was studied by virtue of UV-Vis absorption, steady-state fluorescence spectroscopies, and fluorescence polarization measurements. The binding constant was determined at three different temperatures and the values of standard Gibbs energy change, enthalpy and entropy of binding were determined. The mechanism of binding and the effect of sulfoxides on this process was revealed. The values of binding constant, fluorescence polarization and iodide quenching studies confirmed that the main binding mode in QS-DNA system is groove binding. Addition of sulfoxides does not change the binding mechanism. Moreover, with addition of sulfoxides binding constant increases due to the removal of water molecules from DNA grooves making them more available for QS molecules. To explain the effect of DMSO and DESO on QS-DNA binding the photophysical properties of QS in aqueous solutions of DMSO and DESO were also studied. On the basis of quantum yield of QS in water, DMSO and DESO the types of intermolecular interactions were discussed. The obtained results show that quantum yield of QS in sulfoxides is lower compared with that in water and aqueous solution of 0.1 M H2SO4. QS forms ground state complexes with both DMSO and DESO that are stronger fluorophores compared with free QS molecules.

Mouth rinsing and ingesting salty or bitter solutions does not influence corticomotor excitability or neuromuscular function.

PURPOSE: To explore the effect of tasting unpleasant salty or bitter solutions on lower limb corticomotor excitability and neuromuscular function. METHODS: Nine females and eleven males participated (age: 27 ± 7 years, BMI: 25.3 ± 4.0 kg m-2). Unpleasant salty (1 M) and bitter (2 mM quinine) solutions were compared to water, sweetened water, and no solution, which functioned as control conditions. In a non-blinded randomized cross-over order, each solution was mouth rinsed (10 s) and ingested before perceptual responses, instantaneous heart rate (a marker of autonomic nervous system activation), quadricep corticomotor excitability (motor-evoked potential amplitude) and neuromuscular function during a maximal voluntary contraction (maximum voluntary force, resting twitch force, voluntary activation, 0-50 ms impulse, 0-100 impulse, 100-200 ms impulse) were measured. RESULTS: Hedonic value (water: 47 ± 8%, sweet: 23 ± 17%, salt: 71 ± 8%, bitter: 80 ± 10%), taste intensity, unpleasantness and increases in heart rate (no solution: 14 ± 5 bpm, water: 18 ± 5 bpm, sweet: 20 ± 5 bpm, salt: 24 ± 7 bpm, bitter: 23 ± 6 bpm) were significantly higher in the salty and bitter conditions compared to control conditions. Nausea was low in all conditions (< 15%) but was significantly higher in salty and bitter conditions compared to water (water: 3 ± 5%, sweet: 6 ± 13%, salt: 7 ± 9%, bitter: 14 ± 16%). There was no significant difference between conditions in neuromuscular function or corticomotor excitability variables. CONCLUSION: At rest, unpleasant tastes appear to have no influence on quadricep corticomotor excitability or neuromuscular function. These data question the mechanisms via which unpleasant tastes are proposed to influence exercise performance.

Design, Synthesis, and Docking Study of Quinine-9-Triazolyl Conjugates.

To develop a better chemotherapeutically potential candidate for lung cancer treatment and cure with repurposed motifs, quinine has been linked with biocompatible CuAAC-inspired regioselective 1,2,3-triazole linker and a series of ten novel 1,2,3-triazolyl-9-quinine conjugates have been developed by utilizing click conjugation of glycosyl ether alkynes with 9-epi-9-azido-9-deoxy-quinine under standard click conditions. In parallel, the docking study indicated that the resulting conjugates have an overall appreciable interaction with ALK-5 macromolecules. Moreover, the mannose-triazolyl conjugate exhibited the highest binding interactions of -7.6 kcal/mol with H-bond interaction with the targeted macromolecular system and indicate the hope for future trials for anti-lung cancer candidates.

Mouth Rinsing and Ingestion of Unpleasant Salty or Bitter Solutions Does Not Improve Cycling Sprint Performance in Trained Cyclists.

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.

A Novel Equipment-Free Paper-Based Fluorometric Method for the Analytical Determination of Quinine in Soft Drink Samples.

A simple, equipment-free, direct fluorometric method, employing paper-based analytical devices (PADs) as sensors, for the selective determination of quinine (QN) is described herein. The suggested analytical method exploits the fluorescence emission of QN without any chemical reaction after the appropriate pH adjustment with nitric acid, at room temperature, on the surface of a paper device with the application of a UV lamp at 365 nm. The devices crafted had a low cost and were manufactured with chromatographic paper and wax barriers, and the analytical protocol followed was extremely easy for the analyst and required no laboratory instrumentation. According to the methodology, the user must place the sample on the detection area of the paper and read with a smartphone the fluorescence emitted by the QN molecules. Many chemical parameters were optimized, and a study of interfering ions present in soft drink samples was carried out. Additionally, the chemical stability of these paper devices was considered in various maintenance conditions with good results. The detection limit calculated as 3.3 S/N was 3.6 mg L-1, and the precision of the method was satisfactory, being from 3.1% (intra-day) to 8.8% (inter-day). Soft drink samples were successfully analyzed and compared with a fluorescence method.

Synthesis of (R)-(6-Methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methanol Tetraphenylborate Ion-Pair Complex: Characterization, Antimicrobial, and Computational Study.

The (R)-(6-Methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methanol (quinine)-tetraphenylborate complex was synthesized by reacting sodium tetraphenyl borate with quinine in deionized water at room temperature through an ion-pair reaction (green chemistry) at room temperature. The solid complex was characterized by several physicochemical methods. The formation of ion-pair complex between bio-active molecules and/or organic molecules is crucial to comprehending the relationships between bioactive molecules and receptor interactions. The complex under study was examined for antimicrobial activity. All theoretical calculations were carried out in vacuum and water using the B3LYP level 6-311G(d,p) levels of theory. The theoretical computation allowed for the prediction and visualization of ionic interactions, which explained the complex's stability. The results of energy optimization showed that the Q-TPB complex is stable with a negative complexation energy. The obtained geometries showed that the boron (B-) and nitrogen (N+) in piperidine of the two molecules tetraphenylborate and quinine are close to each other, which makes it possible for ions to interact. The modest energy gap between HOMO and LUMO showed that the compound was stable. The computation of the electron transitions of the two models by density functional theory (TD-DFT) in the solvent at the theoretical level B3LYP/6-311G(d,p) allowed for the detection of three UV/visible absorption bands for both models and the discovery of a charge transfer between the host and the guest. The UV absorption, infrared, and H NMR are comparable with the experimental part.

Need for optimized dosages in the design of comparative clinical trials of anti-malarial drugs.

We read with interest the publication on malaria treatment by Obonyo et al. (Malaria J 21:30, 2022). This commentary questions the methodology, especially the chosen time points of treatment outcome measures.

Alcohol solution strength preference predicts compulsive-like drinking behavior in rats.

BACKGROUND: Understanding compulsive drinking behavior is key to improving outcomes in the treatment of addiction. In the present study, we investigated compulsive-like drinking in alcohol-addicted rats using the alcohol deprivation effect (ADE) model of relapse behavior, which involves repeated deprivation and reintroduction phases; the latter approximate relapse. METHODS: High-resolution longitudinal drinking and locomotor data were measured while rats (n = 30) underwent a four-bottle (water, 5%, 10%, 20% alcohol v/v) free-choice ADE paradigm. Alcohol bottles were adulterated with the bitter compound quinine during a reintroduction phase to test for compulsive behavior. We characterized how drinking and locomotor behavior during ADE + quinine differed from a regular ADE and how, at the individual level, behavioral parameters extracted from the regular ADE related to compulsive-like drinking. Associations of drinking with locomotor activity were also examined. RESULTS: In the ADE with quinine, we observed reduced consumption of alcohol and a shift to preference for stronger alcohol. Quinine acted by decreasing both the access size and frequency of drinking of 5% alcohol while increasing the frequency of consumption of 20% alcohol. Preference for higher alcohol concentrations prior to the quinine challenge was associated with greater compulsive-like drinking behavior; higher baseline consumption of 20% alcohol correlated with more drinking of quinine-adulterated solutions while high frequency and amount of 5% alcohol consumption at baseline were correlated with being more strongly affected by quinine. Associations between locomotor activity and drinking behavior were observed at the hourly level. These associations reflected changing preferences across experimental phases. CONCLUSION: Drinking patterns, and specifically solution preference, may offer insights into the presentation of compulsive-like drinking. The findings provide a preclinical basis for observations from epidemiological studies that link higher risk and burden of alcohol-related disease to stronger alcohol concentrations and encourage further translational studies to better understand the underlying mechanisms.

Clinical pharmacokinetics of quinine and its relationship with treatment outcomes in children, pregnant women, and elderly patients, with uncomplicated and complicated malaria: a systematic review.

BACKGROUND: Standard dosage regimens of quinine formulated for adult patients with uncomplicated and complicated malaria have been applied for clinical uses in children, pregnant women, and elderly. Since these populations have anatomical and physiological differences from adults, dosage regimens formulated for adults may not be appropriate. The study aimed to (i) review existing information on the pharmacokinetics of quinine in children, pregnant women, and elderly populations, (ii) identify factors that influence quinine pharmacokinetics, and (iii) analyse the relationship between the pharmacokinetics and treatment outcomes (therapeutic and safety) of various dosage regimens of quinine. METHODS: Web of Sciences, Cochrane Library, Scopus, and PubMed were the databases applied in this systematic search for relevant research articles published up to October 2020 using the predefined search terms. The retrieved articles were initially screened by titles and abstracts to exclude any irrelevant articles and were further evaluated based on full-texts, applying the predefined eligibility criteria. Excel spreadsheet (Microsoft, WA, USA) was used for data collection and management. Qualitative data are presented as numbers and percentages, and where appropriate, mean + SD or median (range) or range values. RESULTS: Twenty-eight articles fulfilled the eligibility criteria, 19 in children, 7 in pregnant women, and 2 in elderly (14 and 7 articles in complicated and uncomplicated malaria, respectively). Severity of infection, routes of administration, and nutritional status were shown to be the key factors impacting quinine pharmacokinetics in these vulnerable groups. CONCLUSIONS: The recommended dosages for both uncomplicated and complicated malaria are, in general, adequate for elderly and children with uncomplicated malaria. Dose adjustment may be required in pregnant women with both uncomplicated and complicated malaria, and in children with complicated malaria. Pharmacokinetics studies relevant to clinical efficacy in these vulnerable groups of patients with large sample size and reassessment of MIC (minimum inhibitory concentration) should be considered.