Portable and benchtop Raman spectrometers coupled to cluster analysis to identify quinine sulfate polymorphs in solid dosage forms and antimalarial drug quantification in solution by AuNPs-SERS with MCR-ALS.

This paper proposes for the first time: (a) a qualitative analytical method based on portable and benchtop backscattering Raman spectrometers coupled to hierarchical cluster analysis (HCA) and multivariate curve resolution - alternating least-squares (MCR-ALS) to identify two polymorphs of antimalarial quinine sulfate in commercial pharmaceutical tablets in their intact forms and (b) a quantitative analytical method based on gold nanoparticles (AuNPs) as active substrates for surface-enhanced Raman scattering (SERS) in combination with MCR-ALS to quantify quinine sulfate in commercial pharmaceutical tablets in solution. The pure concentration and spectral profiles recovered by MCR-ALS proved that both formulations present different polymorphs. These results were also confirmed by two clusters observed in the HCA model, according to their similarities within and among the samples that provided useful information about the homogeneity of different pharmaceutical manufacturing processes. AuNPs-SERS coupled to MCR-ALS was able to quantify quinine sulfate in the calibration range from 150.00 to 200.00 ng mL-1 even with the strong overlapping spectral profile of the background SERS signal, proving that it is a powerful ultrahigh sensitivity analytical method. This reduced linearity was validated throughout a large calibration range from 25.00 to 175.00 µg mL-1 used in a reference analytical method based on high performance liquid chromatography with a diode array detector (HPLC-DAD) coupled to MCR-ALS for analytical validation purposes, even in the presence of a coeluted compound. The analytical methods developed herein are fast, because second-order chromatographic data and first-order SERS spectroscopic data were obtained in less than 6 and 2 min, respectively. Concentrations of quinine sulfate were estimated with low root mean square error of prediction (RMSEP) values and a low relative error of prediction (REP%) in the range 1.8-4.5%.

Cuando tomarse un gin-tonic se convierte en una mala experiencia: exantema fijo medicamentoso por quinina / When a Gin Tonic Can Mean Trouble: Fixed Drug Eruption Due to Quinine

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A bioelectronic taste sensor based on bioengineered Escherichia coli cells combined with ITO-constructed electrochemical sensors.

In this study, we developed a novel bioelectronic taste sensor for the detection of specific bitter substances. A human bitter taste receptor, hT2R4, was efficiently expressed in Escherichia coli (E. coli), which was used as the primary recognition element. A simple and low-cost electrochemical device based on ITO-based electrolyte-semiconductor (ES) structure was innovatively employed as the transducer to assess bacterial metabolic consequences of receptor activation in real time. An apparent increase in extracellular acidification rate was observed, which was resulted from the triggering of hT2R4 receptors by their target ligand of denatonium. The sensor showed dose-dependent responses to denatonuim ranging from 50 nM to 500 nM, while non-bioengineered bacteria without hT2R4 receptors exhibited negligible responses to the same stimulus. In addition, the specificity of the proposed taste biosensor was verified using other typical bitter substances such as quinine and alpha-naphthylthiourea (ANTU). This research provides a simple and inexpensive approach for the construction of bioelectronic taste sensors.

Evaluation of molecularly imprinted polymers for chlorpromazine and bromopromazine prepared by multi-step swelling and polymerization method-The application for the determination of chlorpromazine and its metabolites in rat plasma by column-switching LC.

Monodisperse molecularly imprinted polymers (MIPs) for chlorpromazine (CPZ) and bromopromazine (BPZ), MIPCPZ and MIPBPZ, were prepared using methacrylic acid as a functional monomer and ethylene glycol dimethacrylate as a crosslinker by multi-step swelling and polymerization. The retention and molecular-recognition properties of MIPCPZ and MIPBPZ were evaluated using a mixture of potassium phosphate buffer and acetonitrile or a mixture of water and acetonitrile including ammonium formate as a mobile phase in reversed-phase LC. On MIPBPZ, CPZ, BPZ and imipramine (IMP) gave the maximal retention factors at a mobile-phase pH 8, while the maximal imprinting factors were obtained at a mobile-phase pH 7. Each MIP recognized a template molecule the most, while CPZ metabolites, desmethyl CPZ (DM-CPZ), CPZ sulfoxide (CPZ-SO) and 7-hydroxy CPZ (7-OH-CPZ), were moderately recognized on MIPCPZ and MIPBPZ. Furthermore, both MIPs gave the similar retention and molecular-recognition for CPZ and its metabolites. For avoiding the template-leakage problems, MIPBPZ was used as the pretreatment column for the determination of CPZ and its metabolites in rat plasma in column-switching LC with UV detection. In addition to DM-CPZ and CPZ-SO, didesmethyl CPZ (DDM-CPZ) and CPZ N-oxide (CPZ-NO) were speculated as the metabolite in rat plasma after administration of CPZ using LC-ESI-TOF-MS, while 7-OH-CPZ was not detected. The column-switching LC method was validated and applied for the determination of CPZ and its metabolites, DM-CPZ, DDM-CPZ, CPZ-SO and CPZ-NO, in rat plasma after intravenous and oral administration of CPZ using IMP as an internal standard.

Detection of Cutting Agents in Drug-Positive Seized Exhibits within the United States.

The following report summarizes a study performed on seized drug exhibits collected in two U.S. states to evaluate the presence and identification of cutting agents. Aliquots of seized drug materials from Kentucky (n = 200) and Vermont (n = 315) were prepared using a dilute-and-shoot procedure. Initial analysis was performed using gas chromatography-mass spectrometry (GC-MS) followed by analysis using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF). Active compounds detected overall included caffeine (31.0%), quinine/quinidine (24.7%), levamisole (11.6%), acetaminophen, (8.2%) and procaine (8.2%). These compounds were found with several drugs of abuse, such as heroin, fentanyl, methamphetamine, and cocaine. This novel information about cutting agents used to dilute or alter drugs of abuse is important to criminal investigations and in the management of acute intoxications at health centers. However, common methodologies for analysis and standard reporting practices frequently do not include cutting agents, resulting in lacking or inadequate information regarding prevalence of these substances.

Quantitative determination of major alkaloids in Cinchona bark by Supercritical Fluid Chromatography.

Chinoline alkaloids found in Cinchona bark still play an important role in medicine, for example as antimalarial and antiarrhythmic drugs. For the first time Supercritical Fluid Chromatography has been utilized for their separation. Six respective derivatives (dihydroquinidine, dihydroquinine, quinidine, quinine, cinchonine and cinchonidine) could be resolved in less than 7 min, and three of them quantified in crude plant extracts. The optimum stationary phase showed to be an Acquity UPC2 Torus DEA 1.7 µm column, the mobile phase comprised of CO2, acetonitrile, methanol and diethylamine. Method validation confirmed that the procedure is selective, accurate (recovery rates from 97.2% to 103.7%), precise (intra-day ≤2.2%, inter-day ≤3.0%) and linear (R2 ≥ 0.999); at 275 nm the observed detection limits were always below 2.5 µg/ml. In all of the samples analyzed cinchonine dominated (1.87%-2.30%), followed by quinine and cinchonidine. Their total content ranged from 4.75% to 5.20%. These values are in good agreement with published data, so that due to unmatched speed and environmental friendly character SFC is definitely an excellent alternative for the analysis of these important natural products.

Rapid voltammetric method for quinine determination in soft drinks.

A novel voltammetric assay for quinine (QN) determination using an electrochemically pretreated pencil graphite electrode is described. The detection limit of QN was 2 × 10-7 M. The method possesses some obvious advantages including extreme simplicity, rapid response, and low cost.

An advanced technique using an electronic taste-sensing system to evaluate the bitterness of orally disintegrating films and the evaluation of model films.

Taste detection systems using electronic sensors are needed in the field of pharmaceutical design. The aim of this study was to propose an advanced technique using a taste-sensing system to evaluate the bitterness of an orally disintegrating film (ODF) samples. In this system, a solid film sample is kept in the test medium with stirring, and the sensor output is recorded. Model films were prepared using a solution-casting method with a water-soluble polymer such as pullulan, HPMC, HPC or PVP as film formers, and donepezil hydrochloride and quinine hydrochloride as model bitter-tasting active pharmaceutical ingredients (APIs). The results showed that this advanced techniques could detect the emergence of bitterness along the time course. Increasing the amount of donepezil hydrochloride increased the sensor output. The sensor output was suppressed at the very early stage of the test, and then increased. Both the film thickness and the use of additives markedly affected the delay of the sensor output. The profile of the sensor output was accurately related to the release of APIs. It was concluded that this advanced technique could detect the onset of bitterness during the initial stage of ODF administration.

Sweeping of hydrophobic amines under inhomogeneous electric field and low surfactant concentration in micellar electrokinetic chromatography.

The influence of sample matrix on sample sweeping in MEKC was examined in the presented manuscript. Significant focusing effect was observed for relatively hydrophobic cationic compounds (emetine, strychnine and quinine) using high ionic strength sample matrix (900 mM H3 PO4 /720 mM Tris) which conductivity was about ninefold higher than utilized BGE. Moreover, the results were obtained using BGE composed of comparatively low surfactant concentration (10 mM SDS) and 40 mM H3 PO4 /32 mM Tris buffer solution. About 200 to 300-fold preconcentration of analytes was reached with the presented method. Basing on experimental results and computer simulation using Simul5 software, hypothetical mechanism of observed phenomenon was proposed.

Significant Pharmacokinetic Interactions Between Quinine and Ampicillin-Cloxacillin Combination.

INTRODUCTION: The co-existence of malaria with bacterial infections is common in the tropics, hence the concurrent use of antimalarials and antibiotics. OBJECTIVE: This study aimed to investigate the effect on pharmacokinetics and antimicrobial activity of co-administration of quinine and combined ampicillin-cloxacillin. METHODS: In total, 14 healthy adults received single oral doses of ampicillin-cloxacillin combination alone and with quinine in a randomized crossover manner. Urine samples collected at predetermined intervals over 48 h were analysed. The effect of quinine on minimum inhibitory concentrations (MICs) of ampicillin and cloxacillin were determined against Staphylococcus aureus by agar diffusion, agar dilution, and broth dilution. RESULTS: Quinine significantly reduced the rate and extent of excretion of ampicillin and cloxacillin (p < 0.0002). The total amounts of ampicillin and cloxacillin excreted unchanged (Du(∞)) alone were 217.10 ± 53.82 and 199.0 ± 64.29 mg versus 126.40 ± 50.63 and 135.20 ± 52.24 mg, respectively, with quinine. Respective maximum excretion rates (dDu/dt max) for ampicillin and cloxacillin were 43.55 ± 19.41 and 77.64 ± 29.65 mg/h alone versus 18.01 ± 8.52 and 53.16 ± 20.72 mg/h with quinine. This indicates a significant reduction in Du(∞)and dDu/dt max by 41.78 and 58.65 % for ampicillin and 32.06 and 31.53 % for cloxacillin. Conversely, the disposition of quinine was unaffected by ampicillin-cloxacillin (p > 0.1). The MIC of antibiotics alone versus with quinine, respectively, were 0.11 ± 0.04 and 0.78 ± 0.1 µg/ml for ampicillin, and 0.18 ± 0.1 and 0.92 ± 0.4 µg/ml for cloxacillin, with a five- to sevenfold increase (p > 0.01); indicating a decrease in antimicrobial activity by quinine. CONCLUSIONS: Quinine therefore, reduced the bioavailability and the antimicrobial activity of ampicillin-cloxacillin upon co-administration, which may have therapeutic implications. Caution is required with the co-administration of these medicines.

Analytics of Quinine and its Derivatives.

The objective of this study was to perform a synthesis and analysis of the most important information on quinine and its derivatives, which are still very important in the treatment of malaria. The analysis of stereoisomers of quinine and its derivatives was conducted using two techniques, high-performance liquid chromatography and capillary electrophoresis. Particularly noteworthy is the technique used for the determination of isotachophoresis, referred to as one of the so-called green chemistry techniques. Particular attention was paid to properties and the use of quinine and its derivatives in the treatment of malaria. The analytical part will supplement knowledge about quinidine, quinine, and cinchonidine, and will contribute to the growth of research on the so-much-needed drugs against malaria.

[CAFFEINE AND QUININE IN SOFT DRINKS; CONTRIBUTION TO THE DIETARY INTAKE]. / CAFEÍNA Y QUININA EN BEBIDAS REFRESCANTES; CONTRIBUCIÓN A LA INGESTA DIETÉTICA.

INTRODUCTION: soft drinks are becoming increasingly consumed by society. They are composed by a great variety of components, some of which can produce adverse effects if they are frequently consumed in high levels. OBJECTIVES: determine caffeine and quinine concentration to prove that those concentration levels are lower than the legal limits allowed and calculate the contribution to dietary intake to obtain the Estimated Daily Intake. METHODS: levels of caffeine and quinine of the main brands of soft drinks were analyzed using High-Performance Liquid Chromatography technique. RESULTS: concentrations were obtained for all brands, and the medium level was estimated. CONCLUSIONS: it has been observed that in any case the maximum concentration limits are exceeded and the contribution to dietary intake doesn't mean adverse reaction.

Introducción: las bebidas refrescantes son cada vez más consumidas por la sociedad. Están compuestas por una gran variedad de sustancias, de las cuales algunas, si se consumen en dosis altas y con elevada frecuencia, pueden provocar efectos negativos. Objetivos: determinar la concentración de cafeína y quinina para comprobar si sus niveles se encuentran por debajo de los máximos permitidos por la reglamentación técnico-sanitaria vigente y calcular la contribución a la ingesta dietética obteniendo la Ingesta Diaria Estimada. Método: se analizaron las concentraciones de cafeína y quinina en las principales marcas comerciales de refrescos, usando para ello la técnica de cromatografía líquida de alta resolución. Resultados: se obtuvieron concentraciones para todas las marcas analizadas, que permitieron estimar la media en cada una. Conclusiones: se ha observado que en ningún caso se superan las concentraciones máximas y que la contribución a la ingesta no genera aparición alguna de reacción adversa.

Cafeína y quinina en bebidas refrescantes; contribución a la ingesta dietética / Caffeine and quinine in soft drinks; contribution to the dietary intake

Introducción: las bebidas refrescantes son cada vez más consumidas por la sociedad. Están compuestas por una gran variedad de sustancias, de las cuales algunas, si se consumen en dosis altas y con elevada frecuencia, pueden provocar efectos negativos. Objetivos: determinar la concentración de cafeína y quinina para comprobar si sus niveles se encuentran por debajo de los máximos permitidos por la reglamentación técnico-sanitaria vigente y calcular la contribución a la ingesta dietética obteniendo la Ingesta Diaria Estimada. Método: se analizaron las concentraciones de cafeína y quinina en las principales marcas comerciales de refrescos, usando para ello la técnica de cromatografía líquida de alta resolución. Resultados: se obtuvieron concentraciones para todas las marcas analizadas, que permitieron estimar la media en cada una. Conclusiones: se ha observado que en ningún caso se superan las concentraciones máximas y que la contribución a la ingesta no genera aparición alguna de reacción adversa (AU)

Introduction: soft drinks are becoming increasingly consumed by society. They are composed by a great variety of components, some of which can produce adverse effects if they are frequently consumed in high levels. Objectives: determine caffeine and quinine concentration to prove that those concentration levels are lower than the legal limits allowed and calculate the contribution to dietary intake to obtain the Estimated Daily Intake. Methods: levels of caffeine and quinine of the main brands of soft drinks were analyzed using High-Performance Liquid Chromatography technique. Results: concentrations were obtained for all brands, and the medium level was estimated. Conclusions: it has been observed that in any case the maximum concentration limits are exceeded and the contribution to dietary intake doesn’t mean adverse reaction (AU)

A Microfluidic Platform for the Rapid Determination of Distribution Coefficients by Gravity-Assisted Droplet-Based Liquid-Liquid Extraction.

The determination of pharmacokinetic properties of drugs, such as the distribution coefficient (D) is a crucial measurement in pharmaceutical research. Surprisingly, the conventional (gold standard) technique used for D measurements, the shake-flask method, is antiquated and unsuitable for the testing of valuable and scarce drug candidates. Herein, we present a simple microfluidic platform for the determination of distribution coefficients using droplet-based liquid-liquid extraction. For simplicity, this platform makes use of gravity to enable phase separation for analysis and is 48 times faster and uses 99% less reagents than performing an equivalent measurement using the shake-flask method. Furthermore, the D measurements achieved in our platform are in good agreement with literature values measured using traditional shake-flask techniques. Since D is affected by volume ratios, we use the apparent acid dissociation constant, pK', as a proxy for intersystem comparison. Our platform determines a pK' value of 7.24 ± 0.15, compared to 7.25 ± 0.58 for the shake-flask method in our hands and 7.21 for the shake-flask method in the literature. Devices are fabricated using injection molding, the batchwise fabrication time is <2 min per device (at a cost of $1 U.S. per device), and the interdevice reproducibility is high.

Macromolecular crowding-assisted fabrication of liquid-crystalline imprinted polymers.

A macromolecular crowding-assisted liquid-crystalline molecularly imprinted monolith (LC-MIM) was prepared successfully for the first time. The imprinted stationary phase was synthesized with polymethyl methacrylate (PMMA) or polystyrene (PS) as the crowding agent, 4-cyanophenyl dicyclohexyl propylene (CPCE) as the liquid-crystal monomer, and hydroquinidine as the pseudo-template for the chiral separation of cinchona alkaloids in HPLC. A low level of cross-linker (26%) has been found to be sufficient to achieve molecular recognition on the crowding-assisted LC-MIM due to the physical cross-linking of mesogenic groups in place of chemical cross-linking, and baseline separation of quinidine and quinine could be achieved with good resolution (R(s) = 2.96), selectivity factor (α = 2.16), and column efficiency (N = 2650 plates/m). In contrast, the LC-MIM prepared without crowding agents displayed the smallest diastereoselectivity (α = 1.90), while the crowding-assisted MIM with high level of cross-linker (80%) obtained the greatest selectivity factor (α = 7.65), but the lowest column efficiency (N = 177 plates/m).

Mouth rinsing with a bitter solution without ingestion does not improve sprint cycling performance.

PURPOSE: Recently, we have shown that combining mouth rinsing with the ingestion of a 2 mM quinine solution immediately before a 30-s cycling sprint significantly improves performance. However, the strong bitterness of such a solution produces an unpleasant taste and evokes nausea at higher concentrations. Given the possibility that mouth rinsing with quinine without ingesting it may not produce nausea, a mouth rinse only protocol may be a more practical approach to administer quinine for improving exercise performance. The purpose of the present study was to determine whether mouth rinsing with quinine without ingesting it improves 30-s sprint cycling performance. METHODS: Twelve competitive male cyclists performed a 30-s maximal cycling sprint immediately after rinsing their mouth for 10 s with either a 10 mM bitter quinine solution (QUI), plain water (WAT), a 7.1 % w/v sweet glucose solution (GLU), or no solution at all (control; CON). Sprint performance was assessed, and heart rate, ratings of perceived exertion and blood variables were measured pre- and post-exercise. RESULTS: Mean power output during the 30-s sprint (QUI 888 ± 38; CON 873 ± 39; WAT 885 ± 37; GLU 873 ± 42 W; p = 0.431) as well as peak power (QUI 1230 ± 61; CON 1,208 ± 65; WAT 1,220 ± 70; GLU 1,202 ± 59 W; p = 0.690) were similar between the four conditions. There were no significant differences in any other performance measures, heart rate, subjective ratings or blood variables between conditions. CONCLUSIONS: Mouth rinsing with a bitter tasting quinine solution without ingestion does not improve 30-s sprint cycling performance.

Assessment of field fluorometers.

Two field fluorometers, devoted either to natural organic matter (NOM) or to tryptophan-like fluorescing substances, were tested for the characterization of a large set of water samples (n = 263) impacted to various degrees by untreated or poorly treated urban sewage. Both fluorometers yielded consistent results when testing discrete samples. A nonlinear correlation (coefficient of determination = 0.98) was found between the tryptophan concentration given by the tryptophan field fluorometer and the fluorescence intensity given by a bench-top fluorometer (excitation = 285 nm, emission = 335 nm), corresponding to tryptophan-like fluorescing substances. A linear correlation with a mediocre coefficient of determination (0.63) was found between the NOM concentration given by the NOM field fluorometer and the fluorescence intensity given by the bench-top fluorometer (excitation = 355 nm, emission = 405 nm). This could be related to the diversity of NOM present, as illustrated by the different shapes of synchronous fluorescence spectra collected for the same samples.

Quality of antimalarial drugs and antibiotics in Papua New Guinea: a survey of the health facility supply chain.

BACKGROUND: Poor-quality life-saving medicines are a major public health threat, particularly in settings with a weak regulatory environment. Insufficient amounts of active pharmaceutical ingredients (API) endanger patient safety and may contribute to the development of drug resistance. In the case of malaria, concerns relate to implications for the efficacy of artemisinin-based combination therapies (ACT). In Papua New Guinea (PNG), Plasmodium falciparum and P. vivax are both endemic and health facilities are the main source of treatment. ACT has been introduced as first-line treatment but other drugs, such as primaquine for the treatment of P. vivax hypnozoites, are widely available. This study investigated the quality of antimalarial drugs and selected antibiotics at all levels of the health facility supply chain in PNG. METHODS AND FINDINGS: Medicines were obtained from randomly sampled health facilities and selected warehouses and hospitals across PNG and analysed for API content using validated high performance liquid chromatography (HPLC). Of 360 tablet/capsule samples from 60 providers, 9.7% (95% CI 6.9, 13.3) contained less, and 0.6% more, API than pharmacopoeial reference ranges, including 29/37 (78.4%) primaquine, 3/70 (4.3%) amodiaquine, and one sample each of quinine, artemether, sulphadoxine-pyrimethamine and amoxicillin. According to the package label, 86.5% of poor-quality samples originated from India. Poor-quality medicines were found in 48.3% of providers at all levels of the supply chain. Drug quality was unrelated to storage conditions. CONCLUSIONS: This study documents the presence of poor-quality medicines, particularly primaquine, throughout PNG. Primaquine is the only available transmission-blocking antimalarial, likely to become important to prevent the spread of artemisinin-resistant P. falciparum and eliminating P. vivax hypnozoites. The availability of poor-quality medicines reflects the lack of adequate quality control and regulatory mechanisms. Measures to stop the availability of poor-quality medicines should include limiting procurement to WHO prequalified products and implementing routine quality testing.