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Introduction: Antitussive and expectorant drugs such as aminophylline (APL), doxofylline (DXL), bromhexine hydrochloride (BXH), and ambroxol hydrochloride (AXH), either individually or in combination, are widely used in the prevention and treatment of respiratory diseases. The study aimed to establish a high-performance liquid chromatography (HPLC) method for the simultaneous determination of these four drugs and to investigate their stability in 0.9% sodium chloride injection or 5% glucose injection over 48 hours. Methods: An InertSustain C 18 column (150 mm × 4.6 mm, 5 μm) was used. The mobile phase consisted of acetonitrile and 50 mmol·L -1 potassium dihydrogen phosphate solution (pH 4.0) with gradient elution. The flow rate was 0.8 mL·min -1 , and the column temperature was maintained at 30°C. The stability of APL, DXL, BXH, and AXH in 0.9% sodium chloride and 5% glucose injections over 48 h was determined using HPLC. Results: APL, DXL, BXH, and AXH showed good linearity within the ranges of 0.01 to 0.20, 0.003-0.06, 0.015-0.30, and 0.016-0.16 mg·mL -1 , respectively (r > 0.999). The intraday and interday relative standard deviations were <2%, with recovery rates between 98.4% and 102.2%. The four drugs remained colorless and clear in infusion mixtures. The pH value fluctuated within ±0.3 over 48 hours, and the relative percentage content of the drugs ranged from 95.0% to 105.0%. Conclusion: The established HPLC method is simple, reliable, and stable, allowing for the simultaneous determination of the four antitussive and expectorant drugs. APL, DXL, BXH, and AXH were stable within 48 hours when mixed with 0.9% sodium chloride and 5% glucose injections., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

A quantitative testing method was developed for the analysis of low molecular weight (small molecules) nitrosamine impurities in cough syrups using solid phase extraction (SPE) on strong cation-exchange functionalized polymeric sorbent cartridges followed by gas chromatography-mass spectrometry. The matrix spike recoveries of the nitrosamine impurities from the cough syrup samples was observed to be within the range of 90 %-120 %. Limit of detection (LOD) achieved for NNitrosodimethylamine (NDMA) and NNitroso morpholine (NMOR) was about 0.1 ng/mL while the LOD for NNitrosodiethylamine (NDEA), NNitrosodiisopropylamine (NDIPA) and NNitrosoisopropylethylamine (NIPEA) impurities was about 0.02 ng/mL. The method was evaluated and found to meet the acceptable criteria as per the ICH Q2 guidelines for a working concentration range of 0.02 ng/mL to 1.2 ng/mL for the analyzed impurities. The selectivity of the nitrosamine impurities against the presence of drug product was established using multiple reaction monitoring (MRM) transitions during analysis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A quick, simple, sensitive, efficient and stability-indicating reverse-phase ultraperformance liquid chromatographic method for the estimation of propylparaben, methylparaben and sodium benzoate in a pharmaceutical liquid oral formulation was developed. A Waters Acquity UPLC BEH C 18 , 50 × 2.1 mm, 1.7 μm i.d. column was used to perform chromatographic separation with a 0.1% perchloric acid mobile phase used as solvent A and a mixture of 0.1 % perchloric acid and methanol in the ratio 20:80 (v/v), respectively, as solvent B. The experiments were carried out at a flow rate of 0.4 ml/min and the detection wavelength was 240 nm. The compartment temperature of the column was set at 40°C and the injection volume was set at 2 μl. The main aim of the research was to develop a single UPLC assay method for promethazine (active ingredient) and preservatives in the oral solution of promethazine HCl and dextromethorphan HBr that contains promethazine (active ingredient) and methylparaben, propylparaben and sodium benzoate (preservatives). An assay of dextromethorphan HBr was developed and validated by another HPLC method. The drug and preservatives were eluted at retention times of 19.3 min for promethazine HCl, 9.3 min for methylparaben, 18.9 min for propylparaben and 8.9 min for sodium benzoate. Validation of the developed method was carried out as stated by the International Conference on Harmonization guidelines ICH Q2B and under USP<1225>. The analytical parameters verified specificity/selectivity, linearity, accuracy, ruggedness and robustness. The linearity ranges of promethazine HCL, methylparaben, propylparaben and sodium benzoate were 10-100, 10-80, 1.0-8.0 and 10-80 μg/ml, respectively, with a correlation coefficient of active ingredients and preservatives of 1.00. Percentage recoveries of promethazine, propylparaben, methylparaben, and sodium benzoate were 100.0-100.2, 99.0-100.3, 99.5-98.0 and 99.0-100.0%. The validated analytical method proves that the method is specific, precise, linear, accurate, sensitive, rugged and stable, indicating the quantification of the active ingredient and all preservatives in liquid oral formulations., (© 2024 John Wiley & Sons Ltd.)

Dextromethorphan (DXM) is an over-the-counter antitussive that is commonly used worldwide. Recently, DXM has become popular among young individuals because of its euphoric, hallucinogenic, and dissociative properties. Despite an increasing number of patients with DXM addiction, fatal cases of DXM poisoning are rare, and patients with fatalities often ingest DXM along with other drugs. Here, we report an autopsy case in which DXM was detected without multidrug ingestion. A man in his early twenties was found dead at home; no external injuries or obvious internal lesions were found during the autopsy. The toxicological analyses revealed extremely high concentrations of DXM, and no drugs other than DXM were detected. To the best of our knowledge, this is the first case report to describe a death caused by a single overdose of DXM in Japan. Public awareness regarding the risks associated with a massive ingestion of DXM should be increased., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Zhi-Ke-Bao pills (ZKB), a traditional Chinese medicine preparation composed of 13 herbs, is generally used to treat cough caused by external wind cold, phlegm, etc in clinical applications, and it plays a core role in relieving cough caused by COVID-19 and influenza in China. Till now, the understanding of its chemical constituents was dramatically limited due to its chemical complexity, restricting its clinical application or development. In this work, a developed ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF MS) method, a targeted and non-targeted strategy and network pharmacology were used to comprehensively characterize the chemical compositions in ZKB and predict its mechanism against cough. A total of 164 compounds (148 targeted compounds and 16 non-targeted ones) were identified or tentatively characterized in ZKB, including 65 flavonoids, 25 alkaloids, 19 organic acids, 41 saponins, 9 coumarins, 2 phenylpropanoids, 2 anthraquinones, and 1 other types. Among them, 37 compounds were unambiguously identified by comparison to reference standards. Meanwhile, the fragmentation behaviors of five main chemical structure types were also summarized. 309 targets and two core signaling pathways of ZKB against cough were predicted by network pharmacology, including MAPK and PI3K-Akt signaling pathways. It was the first time to characterize the chemical compounds of ZKB and reveal its potential mechanism against cough, providing the material basis for further quality control or pharmacodynamic evaluation of ZKB., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Feng-Xiang Zhang reports financial support was provided by Teyi Pharmaceutical Group Co., Ltd. Qing-Min Zhang reports a relationship with Teyi Pharmaceutical Group Co., Ltd that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: A synergic antihistamine, cough suppressant, and decongestant combination of chlorpheniramine, dextromethorphan, and phenylephrine is used to treat acute respiratory infections caused by seasonal viruses. The effective qualitative and quantitative methods require the simultaneous measurement of a ternary combination in the pharmaceutical syrup dosage form. Therefore, a new, simple, fast and robust high performance thin layer chromatographic (HPTLC) method has been developed and validated for chlorpheniramine maleate (CPM), dextromethorphan hydrobromide (DEXO) and phenylephrine hydrochloride (PE)., Material and Methods: The chromatographic separation was carried out on precoated aluminium plates with silica gel 60 F254 as the stationary phase. Mobile phase used was chloroform: methanol: ammonia (2.5:7.5:0.3, v/v/v) for proper separation. The detection was carried out at 270nm wavelength in absorbance mode. Developed method was validated as per International Council for Harmonization (ICH) Q2 (R1) guideline., Results: The linearity range is 400 to 1400ng/band for CPM, 3000 to 11500ng/band for DEXO and 1000 to 3500ng/band for PE with correlation coefficient ≥ 0.995. The consistent lower values of relative standard deviation (RSD, %) for precision and robustness study indicate the method reliability. The percent recovery ranged from 97.82 to 102.03% indicates the good accuracy of the method., Conclusion: The proposed method was complying for the analytical method validation parameters suggested by the ICH Q2 (R1) guideline. The method was found to be simple, rapid and reliable for the simultaneous estimation of CPM, DEXO and PE from its pharmaceutical syrup dosage form. The method was successfully applied to quantify these analytes from the several pharmaceutical syrup dosage form., (Copyright © 2024 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Dextromethorphan (DXM) is a widely utilized central antitussive agent, which is frequently abused by individuals seeking its recreational effect. But DXM overdose can cause some adverse effects, including brain damage, loss of consciousness, and cardiac arrhythmias, and hence its detection is significant. Herein, an electrochemical sensor based on a Cu-coordinated molecularly imprinted polymer (Cu-MIP) was fabricated for its detection. For constructing the sensor, nitrogen-doped carbon nanosheets (CCNs) were prepared through calcining chitin under an argon atmosphere, and molybdenum disulfide (MoS 2 ) was allowed to grow on their surface. Subsequently, the obtained MoS 2 /CCNs composite was employed to modify a glassy carbon electrode (GCE), and the Cu-MIP was electrodeposited on the electrode in a Cu-1,10-phenanthroline (Cu-Phen) solution containing DXM, where Cu 2+ played a role in facilitating electron transfer and binding DXM. Due to the large specific surface area, good electrocatalytic properties and recognition of the resulting composite, the resulting Cu-MIP/MoS 2 /CCNs/GCE showed high selectivity and sensitivity. Under optimized experimental conditions, the peak current of DXM and its concentration exhibited a good linear relationship over the concentration range of 0.1-100 μM, and the limit of detection (S/N = 3) was 0.02 μM. Furthermore, the electrochemical sensor presented good stability, and it was successfully used for the determination of DXM in pharmaceutical, human serum and urine samples.

Farfarae Flos is a commonly used traditional herb for the treatment of respiratory disorders. In this study, ultra-high-performance liquid chromatography coupled with time-of-flight mass spectrometry combined with the mass defect filter method was used for the qualitative analysis of Farfarae Flos metabolites in the lung tissues. Then a method for the simultaneous determination of 14 Farfarae Flos metabolites was developed and validated in terms of specificity, linearity, precision and accuracy, matrix effect and recovery. The method was applied to compare the lung tissue of Farfarae Flos treated mice, and 10 caffeoylquinic acid metabolites were higher in the mice with better antitussive effect. Further network pharmacology analysis and molecular docking results showed that these metabolites played an important role in the antitussive effect of Farfarae Flos. This study presented a novel strategy for deciphering the active compounds of herbal medicine by inter-individual variability of bioactivities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To develop the method for identification of mebeverine and its metabolites in biological materials (urine and hair) for solution of the problem of possible cross-reaction with psychoactive substances during preliminary studies by immunochromatographic method., Material and Methods: The study was carried out using «Mebeverine» tablets (NAO «Severnaya Zvezda», Russia), enzymes, namely trypsin, chymotrypsin and hyaluronidase, papain. The obtained extracts were analyzed using HELC-MS/MS on a modular liquid Nexera XR chromatograph with a tandem LCMS-8050 (Shimadzu) mass spectrometer. Guinea pigs weighing about 500 gr were used in modelling the long-term use of mebeverine. The drug was administered per os, once to 5 guinea pigs at a dosage of 200 mg calculated as an animal weighing 500 gr and daily urine was collected. The wool was collected 30 days after regular administration., Results and Conclusion: The main mebeverine's metabolites have been determined and native mebeverine and its marker metabolites (mebeverine and veratric acids) have been found in urine while taking this medicine in therapeutic doses for medical purposes. The application of enzymatic hydrolysis of hair method allowed to establish that hair tissue accumulates only a native molecule of mebeverine, therefore, only by results of hair analysis it is possible to conclude, if there was pharmacological use of this medicine or psychoactive substances from the group of phenylalkilamines. The effectiveness of enzymatic hydrolysis by hyaluronidase to isolate mebeverine from hair has been shown.

In this study, the inter-individual variability of antitussive effect of Farfarae Flos was observed, and then the Farfarae Flos treated mice were divided into the mice with good or poor antitussive effect. Then a UHPLC-Q TOF-MS method was developed and validated to quantify 13 fecal metabolites of Farfarae Flos, and the results showed concentrated differences between the two subgroups. The results of 16 S rRNA gene sequencing analysis showed that mice with good or poor antitussive effects were also different at the structure of gut microbiota in phylum and genus, as well as the related 6 pathways. In addition, the differential fecal metabolites of Farfarae Flos between the two subgroups were probably related with 5 bacterial that participating in the CQAs and flavonoids metabolism. This study explained the inter-individual variability of the antitussive effect of Farfarae Flos from the perspective of gut microbiota. However, the specific bacterial that participate in the metabolism of Farfarae Flos as well as the antitussive effects of Farfarae Flos need to be further validated., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: Three simple, sensitive, precise, reproducible and validated spectrophotometric methods have been developed for the quantification of pipazethate HCl as antitussive drug in pure and dosage forms., Methods: The methods are based on utilization of N-bromosuccinimide as an oxidant and three dyes, amaranth, methylene blue, and indigo carmine, as auxiliary reagents. The proposed methods are based on oxidation reaction of pipazethate HCl with a known excess of N-bromosuccinimide in acid medium, followed by determination of unreacted N-bromosuccinimide by the reaction with a fixed amount of dyes, amaranth, methylene blue, and indigo carmine followed by the measurement of the absorbance at 520, 663 and 610nm, respectively. The optimization of the reaction conditions was investigated., Results: Under the optimum conditions, linear relationships with good correlation coefficients (0.9998-0.9999) were found over the concentration ranges of 0.3-9.0, 0.5-12 and 0.5-10μgmL -1 with a limit of detection (LOD) of 0.1, 0.15 and 0.15μgmL -1 using amaranth, methylene blue, and indigo carmine methods, respectively. Intra-day and inter-day accuracy and precision of the methods have been evaluated. No interference was observed from the common tablet excipients., Conclusion: The developed methods were validated in accordance with ICH guidelines and successfully applied to the analysis of pipazethate HCl in dosage forms with good accuracy and precision. The reliability of the methods was further ascertained by performing recovery studies via the standard addition method. Statistical comparison of the results obtained by applying the proposed methods with those of the reported method by applying Student's t-test and variance ratio F-test at the 95% confidence level revealed good agreement and indicates no significant difference in accuracy and precision., (Copyright © 2021 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Dropropizine is a peripheral antitussive drug that acts by inhibiting cough reflex through its action on the peripheral receptors and their afferent conductors. It is marketed in a racemic form or its pure enantiomer called levodropropizine and both are available worldwide in various drug dosage formulations such as tablets, sirup and oral solution. Due to the widespread use of antitussives in the clinic it is necessary to develop efficient analytical methodologies for quality control and also for pharmacokinetic, bioavailability and bioequivalence studies. This review presents a survey of the characteristics, properties and analytical methods used for drug determination, being carried out through scientific articles as well as in official compendia. From the analyzed studies, the majority reports the use of HPLC/UV techniques for drug determination, but also spectrophotometric UV/Vis methods as well as gas chromatography, and voltammetric, potentiometric and conductometric titration methods. In addition, the methodologies addressed the determination of dropropizine or levodropropizine in different types of matrices such as raw material, pharmaceutical formulations, plasma and urine. Despite the extensive clinical use of dropropizine, data from this review evidenced a still limited number of studies dealing with analytical methods for its determination in different matrices, which may be of concern since the applicability of these methods is important for quality assurance, efficacy and safety of the medicine.

Two chromatographic methods were developed for the assay of the FDA approved lozenges containing dextromethorphan hydrobromide (DXT) and menthol (MNT). The first was a green HPTLC method which uses a mobile phase of methanol-ammonia (10:0.1, v/v). The densitometric measurements of the spots which were retained at 0.28±0.01 for DXT and 0.76±0.02 for MNT was done at 210nm. The other method was RP-HPLC method with stability indicating merits at which a mixture of 20mM phosphate buffer pH 3 and acetonitrile as mobile phase in isocratic mode was used. The cited drugs were resolved in RP-HPLC method using isocratic elution using 20mM phosphate buffer: acetonitrile (65:35 v/v) with retention times of 2.21 and 3.47min for MNT and DXT, respectively and quantified using 215nm. Both methods were entirely validated and both methods were successfully able to analyze both drugs in presence of lozenges inactive ingredients. HPLC method had the advantage of being stability indicating at which resolution of the drugs from their forced degradation products was successfully attained. For HPTLC method, both drugs showed reasonable RF values when compared to rapidly eluted MNT in RP-HPLC; also it was more environmentally friendly than RP-HPLC as it used solvents which are less toxic and greener., (Copyright © 2020 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Kalimeris indica (L) Sch-Bip is a medicinal plant used by the Miao ethnic group in the Guizhou province of China. It is widely used as a fresh vegetable to treat colds, diarrhea and gastric ulcers. However, few studies have been conducted on the mechanism of its effect on colds, and its quality control. The anticomplement and antitussive activities of different polar extracts of K. indica were evaluated. Fifty-nine compounds, mainly including phenols and flavonoids, were identified in K. indica extract by ultra-high-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry. A method was established through ultra-high-performance liquid chromatography with a photodiode array to simultaneously determine the anticomplement and antitussive activity of five compounds in K. indica combining chemical identification with chemometrics for discrimination and quality assessment. Also, 3,5-dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid exhibited significantly higher anticomplementary activity than the other three compounds. The quantitative data were further analyzed by principal component analysis and orthogonal partial least-squares discriminant analysis. Heatmap visualization was conducted to clarify the distribution of the major compounds in different geographical origins. Screening pharmacological activities by a combination of chemometrics and chemical identification might be an effective method for the quality control of K. indica., (© 2020 John Wiley & Sons, Ltd.)

Identification and determination of diethylene glycol (DEG) in glycerin-based products was successfully achieved using FT-IR spectroscopy. Studied samples included 0.5% to 20% by mass DEGspiked into cough syrup, two paracetamol syrup formulations, and two food supplements. The characteristic DEGwavenumbers at 881 cm-1 and 1083 cm-1 were used for its quantitative determination in the studied samples. A very good accuracy in determining the DEG fraction was achieved with a mean error% of ±2.02% to ±7.69% upon using the corrected absorbance at 881 cm-1. The corrected absorbance at 1083 cm-1 band was used in the case of paracetamol formulations and resulted in a mean error% ranging from ±2.50% to ±10.28%. The values of limit of detection of the current method ranged from 0.051% to 0.068% DEG for all studied samples.

Suhuang antitussive capsule (SH), one of traditional Chinese patent medicines, has been widely used for treating cough variant asthma and postinfectious cough in clinic. The objective of this work is to identify the characteristic and active ingredients as the quality control markers for SH based on high performance liquid chromatography with photodiode array detector (HPLC-PDA) fingerprint and screening of anti-inflammatory components. Similarity analysis (SA), hierarchical clustering analysis (HCA) and principal component analysis (PCA) were used to evaluate 16 different batches of SH. 13 compounds accounting for 36% of the total components in the fingerprint were identified and semi-quantitatively analyzed, which anti-inflammatory activity was tested with the in vitro assay. The results showed that the established chemical fingerprint could clearly distinguish different batches of SH by SA, HCA, and PCA analysis. Furthermore, four known compounds (chlorogenic acid, schisandrin, angeloylgomisin H and praeruptorin A) were screened out to be the most discriminant variables, which could be applied to quality control of SH by quantitative analysis. The semi-quantitative results showed that six compounds were major components, i.e. arctiin (10.28 ± 3.18 mg/g), ephedrine (9.26 ± 1.58 mg/g), schisandrin (3.09 ± 0.83 mg/g), pseudoephedrine (2.34 ± 1.04 mg/g), schisandrin B (1.48 ± 0.16 mg/g), and 1-caffeoylquinic acid (1.36 ± 0.42 mg/g). The anti-inflammatory results showed that SH extract, praeruptorin A, schisandrin, arctigenin and pseudoephedrine could significantly inhibit inflammatory mediator NO production in LPS-stimulated RAW264.7 macrophages. These findings indicated that praeruptorin A, schisandrin, arctiin and pseudoephedrine could be proposed as the quality control markers for SH., Competing Interests: Declaration of Competing Interest The authors have declared no conflict of interest., (Copyright © 2019. Published by Elsevier B.V.)

Pentoxyverine citrate (PEN-citrate) is an antitussive (cough suppressant) drug used for cough associated with illnesses like common cold. In this work, PEN-citrate is quantified by applying a simple, direct and accurate spectrophotometric method in pure form, pharmaceutical formulation (Cabella®, 2.13 mg/mL) and human serum samples. The formation of a stable yellow ion-pair with sulfonephthalein dyes; bromocresol green (BCG), bromophenol blue (BPB), bromothymol blue (BTB), bromocresol purple (BCP), bromochlorophenol blue (BChPB) and bromoxylenol blue (BXB), in three nonpolar solvents (chloroform, dichloromethane, acetonitrile) is used as the basis for this method. This is the first assay method reported for the quantification of PEN-citrate using the sulfonephthaleins as coloring agents. Diverse parameters were investigated in order to optimize the calibration curve conditions. The strategy was validated with respect to linearity range, precision, accuracy, specificity, robustness and limits of detection (LOD) and quantification (LOQ). In addition, solvents of different polarities were utilized to investigate the color reaction, light absorption and to allow for increasing the method sensitivity. Beer's law is obeyed over a wide concentration range (up to 42.05 μg/mL in case of BTB method). LOD and LOQ values reached 0.22 and 0.72 μg/mL, respectively, upon using BChPB. The relative standard deviation (%RSD) was ≤1.91% while correlation coefficient values (r) were ≥ 0.9974. High molar absorptivity values and low values of Sandell's sensitivity were obtained indicating that the proposed methods are highly sensitive. The validated methods were applied to the analysis of PEN-citrate in the dosage form and human serum samples where the drug was successfully resolved from the pharmaceutical additives and serum components with recoveries ≥98.98%., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Two sensitive chromatographic methods have been developed, and validated for chlorpheniramine maleate (CM), phenylephrine (PE) and guaifenesin (GF) determination in their mixture and in presence of GF related substance guaiacol (GL) and preservative namely; sodium benzoate (NaB). The first method was based on thin layer chromatographic separation (TLC) followed by densitometric determination of the separated spots. The separation was achieved using silica gel 60 F254 TLC plates and ethyl acetate: methanol: toluene: ammonia (7:1.5:1:0.5, by volume) as a developing system. Densitometric quantification of the three drugs was carried by the reflectance mode at 270 nm. The second method was based on the use of high-performance liquid chromatography with diode array detection, by which the proposed components were separated on a reversed phase C18 analytical column using phosphate buffer pH 2.9 (containing 0.1 g Heptane-1-sulphonic acid sodium salt) and acetonitrile (85:15, v/v) at 0.8 mL/min for 4 minutes then 1 mL/min till end of the run using flow rate online switching technique. Both methods were validated according to the ICH guidelines and successfully applied for the determination of CM, PE, and GF in pure powder and in combined cough syrup without interference from the excipients., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The highly oriented modern detection techniques provide a precise and definite tool for investigation in natural medicines. Current study directed the standardization of eminent biomarker Vasicine in a natural cough syrup. A highly accurate and precise method of High-performance thin layer chromatography (HPTLC) has been developed to certify the quantity of vasicine inside the syrup. Ethyl acetate, chloroform, ethanol and ammonia (6:3:1: 1 v/v) were mobile phase for the study. The TLC plate silica gel G60F254 was used with CAMAG Scanner III and CAMAG Linomate 5. The detected Rf value was 0.51 in both sample and reference standard at 254 nm. International conference of Harmonization (ICH) guidelines were followed for the validation of the developed method. Linearity was achieved in the range of 200μg to 1600μg with co-efficient correlation r2=0.9995. Accuracy was found in between 98.9 to 101.4% however precision was good at both inter and intra-day. As per the standardization of ICH, the developed method was found to be reproducible and showed sharp similar peak with high resolution.

Ethnopharmacological Relevance: Clitoria ternatea flower is traditionally used in the treatment of respiratory disorders including bronchitis and is one of the ingredients in different Ayurvedic preparations that are used in respiratory disorders. However, till date there is no scientific report on the anti-asthmatic activity of this flower., Aim of the Study: Ethanolic extract of Clitoria ternatea flowers (ECT) was evaluated for its anti-allergy and anti-tussive potential in experimental animals. Additionally, the anti-inflammatory potential of ECT was carried out to draw a plausible mechanism of action of the drug., Materials and Methods: In-vitro anti-asthmatic activity of ECT was evaluated in goat tracheal chain and isolated guinea pig ileum preparations. Acute and chronic anti-asthmatic activity of ECT (100, 200 and 400 mg/kg; p.o.) was estimated in histamine aerosol exposed guinea pigs and in OVA sensitized and challenged mice respectively. Anti-tussive activity of ECT (100, 200 and 400 mg/kg; p.o.) was evaluated against sulfur dioxide- and citric acid-induced cough in experimental animals. Moreover, the anti-inflammatory activity of ECT (100, 200 and 400 mg/kg; p.o.) was evaluated against carrageenan- and acetic acid-induced inflammation in rats., Results: ECT attenuated histamine-induced contraction in both goat tracheal chain and isolated guinea pig ileum preparations. ECT (400 mg/kg) attenuated histamine-induced dyspnoea and OVA-induced changes in differential cell count in broncheoalveolar fluid, levels of interleukins (IL-1beta and IL-6) and immunoglobulin (OVA-sensitive IgG1) in animals. ECT (400 mg/kg) further ameliorated sulfur dioxide- and citric acid-induced cough in experimental animals. Additionally, ECT (400 mg/kg) attenuated inflammation in carrageenan and acetic acid challenged rodents., Conclusions: Standardized ECT could be considered as a potential therapeutic alternative in the management of allergy-induced asthma., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The presence of coloring matters in syrups usually interferes with the spectrophotometric determination of active pharmaceutical ingredients. A novel approach was introduced to eliminate the interference of sunset yellow (coloring matter) in Cyrinol syrup. Smart, simple, accurate, and selective spectrophotometric methods were developed and validated for the simultaneous determination of a ternary mixture of carbinoxamine maleate, pholcodine, and ephedrine hydrochloride in syrup. Four of the applied methods used ratio spectra: successive derivative subtraction coupled with constant multiplication, successive derivative of ratio spectra, ratio subtraction coupled with ratio difference, and ratio spectra continuous wavelet transforms zero-crossing. In addition, a method that was based on the presence of an isosbestic point, the amplitude summation method, was also established. A major advantage of the proposed methods is the simultaneous determination of the mentioned drugs without prior separation steps. These methods were successfully applied for the determination of laboratory-prepared mixtures and a commercial pharmaceutical preparation without interference from additives, thus proving the selectivity of the methods. No significant difference regarding both accuracy and precision was observed upon statistical comparison of the results obtained by the proposed methods with each other and with those of official or reported ones.

Multi-energy calibration (MEC) is a novel strategy that explores the capacity of several analytes of generating analytical signals at many different wavelengths (transition energies). Contrasting with traditional methods, which employ a fixed transition energy and different analyte concentrations to build a calibration plot, MEC uses a fixed analyte concentration and multiple transition energies for calibration. Only two calibration solutions are required in combination with the MEC method. Solution 1 is composed of 50% v v -1 sample and 50% v v -1 of a standard solution containing the analytes. Solution 2 has 50% v v -1 sample and 50% v v -1 blank. Calibration is performed by running each solution separately and monitoring the instrument response at several wavelengths for each analyte. Analytical signals from solutions 1 and 2 are plotted on the x-axis and y-axis, respectively, and the analyte concentration in the sample is calculated from the slope of the resulting calibration curve. The method has been applied to three different atomic spectrometric techniques (ICP OES, MIP OES and HR-CS FAAS). Six analytes were determined in complex samples (e.g. green tea, cola soft drink, cough medicine, soy sauce, and red wine), and the results were comparable with, and in several cases more accurate than, values obtained using the traditional external calibration, internal standardization, and standard additions methods. MEC is a simple, fast and efficient matrix-matching calibration method. It may be applied to any technique capable of simultaneous or fast sequential monitoring of multiple analytical signals., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A generally applicable high-performance liquid chromatographic method for the qualitative and quantitative determination of pharmaceutical preparations containing phenylephrine hydrochloride, paracetamol, ephedrine hydrochloride, guaifenesin, doxylamine succinate, and dextromethorphan hydrobromide is developed. Optimization of chromatographic conditions was performed for the gradient elution using different buffer pH values, flow rates and two C18 stationary phases. The method was developed using a Kinetex® C18 column as a core-shell stationary phase with a gradient profile using buffer pH 5.0 and acetonitrile at 2.0 mL/min flow rate. Detection was carried out at 220 nm and linear calibrations were obtained for all components within the studied ranges. The method was fully validated in agreement with ICH guidelines. The proposed method is specific, accurate and precise (RSD% < 3%). Limits of detection are lower than 2.0 μg/mL. Qualitative and quantitative responses were evaluated using experimental design to assist the method robustness. The method was proved to be highly robust against 10% change in buffer pH and flow rate (RSD% < 10%), however, the flow rate may significantly influence the quantitative responses of phenylephrine, paracetamol, and doxylamine (RSD% > 10%). Satisfactory results were obtained for commercial combinations analyses. Statistical comparison between the proposed chromatographic and official methods revealed no significant difference., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The majority of the population in the Philippines relies on herbal products as their primary source for their healthcare needs. After the recognition of Vitex negundo L. (lagundi) as an important and effective alternative medicine for cough, sore throat, asthma and fever by the Philippine Department of Health (DOH), there was an increase in the production of lagundi-based herbal products in the form of teas, capsules and syrups. The efficiency of these products is greatly reliant on the use of authentic plant material, and to this day no standard protocol has been established to authenticate plant materials. DNA barcoding offers a quick and reliable species authentication tool, but its application to plant material has been less successful due to (1) lack of a standard DNA barcoding loci in plants and (2) poor DNA yield from powderised plant products. This study reports the successful application of DNA barcoding in the authentication of five V. negundo herbal products sold in the Philippines. Also, the first standard reference material (SRM) herbal library for the recognition of authentic V. negundo samples was established using 42 gene accessions of ITS, psbA-trnH and matK barcoding loci. Authentication of the herbal products utilised the SRM following the BLASTn and maximum-likelihood (ML) tree construction criterion. Barcode sequences were retrieved for ITS and psbA-trnH of all products tested and the results of the study revealed that only one out of five herbal products satisfied both BLASTn and ML criterion and was considered to contain authentic V. negundo. The results prompt the urgent need to utilise DNA barcoding in authenticating herbal products available in the Philippine market. Authentication of these products will secure consumer health by preventing the negative effects of adulteration, substitution and contamination.

Dextromethorphan (DXM) and diphenhydramine (DPH) are two commonly used over-the-counter non-narcotic antitussive drugs. Recent reports reveal the widespread abuse of DXM and DPH due to their euphoric and alcohol-like effects. Due to their medicinal importance as well as the apparent increase in their use as abused drugs, it has become critical to determine them in samples of biological, clinical and pharmaceutical interest. The electrochemical techniques for drug analysis have gathered considerable attention due to their pronounced selectivity, sensitivity and simplicity. The given review presents a compilation of published voltammetric and potentiometric methods developed for determination of DXM and DPH. It critically highlights the analytical performances, revealing the recent trends and progress in the specified approach for their analysis. The review forms a basis for further progress in this field and development of improved electrochemical sensors to determine the drug., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Accurate detection and quantification of microbiological contaminations remains an issue mainly due the lack of rapid and precise analytical techniques. Standard methods are expensive and time-consuming being associated to high economic losses and public health threats. In the context of pharmaceutical industry, the development of fast analytical techniques able to overcome these limitations is crucial and spectroscopic techniques might constitute a reliable alternative. In this work we proved the ability of Fourier transform near infrared spectroscopy (FT-NIRS) to detect and quantify bacteria (Bacillus subtilis, Escherichia coli, Pseudomonas fluorescens, Salmonella enterica, Staphylococcus epidermidis) from 10 to 10(8) CFUs/mL in sterile saline solutions (NaCl 0.9%). Partial least squares discriminant analysis (PLSDA) models showed that FT-NIRS was able to discriminate between sterile and contaminated solutions for all bacteria as well as to identify the contaminant bacteria. Partial least squares (PLS) models allowed bacterial quantification with limits of detection ranging from 5.1 to 9 CFU/mL for E. coli and B. subtilis, respectively. This methodology was successfully validated in three pharmaceutical preparations (contact lens solution, cough syrup and topic anti-inflammatory solution) proving that this technique possess a high potential to be routinely used for the detection and quantification of bacterial contaminations., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: The root of Aster tataricus L. f., recorded in all versions of Chinese Pharmacopoeia, is a traditional Chinese medicine with the function of dispelling phlegm and relieving cough for more than 2000 years. This study was designed to evaluate the expectorant, antitussive, and anti-inflammatory activities of the root of A. tataricus and to explore the chemical substances responsible for these activities., Materials and Methods: The 70% ethanol extract of the root of A. tataricus (RA-70) was divided into three fractions, Fr-0, Fr-50 and Fr-95. They were all orally administrated to the mice to investigate their potential expectorant activities by a tracheal phenol red secretion method. The most effective fraction, together with shionone, was evaluated the expectorant, antitussive and anti-inflammatory activities by the mouse models of phenol red secretion, ammonia-induced cough, and xylene-induced ear swelling. Furthermore, the chemical components of the effective fraction were analyzed and identified by an HPLC-Q-TOF/MS method., Results: Treatment with RA-70, Fr-0 and Fr-50 increased the amount of phenol red secretion by 65.3%, 56.5%, and 76.9%, respectively. Fr-50 was chosen for the further investigation and the results showed that Fr-50 at 40, 80 mg/kg significantly enhanced the phenol red secretion of tracheas, increased the latent period and decreased the frequency of cough and inhibited the ear edema in mice. Shionone at 80 mg/kg showed the trend of enhancing sputum secreting, but had no effect on ammonia-induced cough and xylene-induced ear edema. HPLC-Q-TOF/MS analysis indicated that Fr-50 was mainly composed of 12 caffeoylquinic acids (40.8%, in relative peak area), 7 astersaponins (12.0%) and 13 astins/asterinins (pentapeptides, 26.5%)., Conclusions: The root of A. tataricus has significant expectorant, antitussive and anti-inflammatory effects. Caffeoylquinic acids, astersaponins, and aster peptides, rather than shionone, may be the main constituents responsible for the expectorant and antitussive activities of A. tataricus and act in a synergistic way., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The purpose of the present study is to determine the role of lidocaine, caffeine and dextromethorphan, used as adulterant substances, in five cases of drug overdose which have come to our attention. Taking into account the pharmacological mechanism, blood concentration and route of administration (intravenous) we evaluated the hypothesis that these substances could act with a synergistic effect - or at least additive - with the illicit drugs on the central nervous system and cardiovascular system., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

This study aims to find metabolites responsible for antitussive and expectorant activities of Tussilago farfara L. by metabolomic approach. Different parts (roots, flower buds, and leaves) of the title plant were analyzed systematically. The in vivo study revealed that the leaves and flower buds had strong antitussive and expectorant effects. Then ¹H NMR spectrometry together with principal component analysis (PCA) and partial least squares discriminant (PLS-DA) analysis were used to investigate the compounds responsible for the bioactivities. PCA was used to find the differential metabolites, while PLS-DA confirmed a strong correlation between the observed effects and the metabolic profiles of the plant. The result revealed that chlorogenic acid, 3,5-dicaffeoylquinic acid, and rutin may be closely related with the antitussive and expectorant activities. The overall results of this study confirm the benefits of using metabolic profiling for screening active principles in medicinal plants., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Dimemorfan was extracted from human plasma samples (100 μL) using MonoTip C(18) tips, which were packed with a C(18)-bonded monolithic silica gel attached to the inside of the tip. The samples, which contained dimemorfan and trimeprazine as an internal standard (IS), were mixed with 300 μL of distilled water and 50 μL of 1M glycine-sodium hydroxide buffer (pH 10). The mixture was extracted onto the C(18) phase of the tip by 20 sequential aspirating/dispensing cycles using a manual micropipettor. The analytes retained on the C(18) phase were then eluted with methanol by five sequential aspirating/dispensing cycles. The eluate was injected directly into a gas chromatograph and detected by a mass spectrometer with selected ion monitoring in positive electron ionization mode. An Equity-5 fused silica capillary column (30 m × 0.32 mm i.d., film thickness 0.25 μm) gave adequate separation of the dimemorfan, IS, and impurities. The recoveries of dimemorfan and the IS spiked into plasma were ≥83%. The regression equation for dimemorfan showed excellent linearity from 0.25 to 32.0 ng/100 μL of plasma, and the limit of detection was 0.125 ng/100 μL of plasma. The maximum intra-day and inter-day relative standard deviations were 13%, while accuracy ranged from 88% to 105%. Dimemorfan was stable for at least 12 h at 4°C, 4 weeks at -80°C, and three freeze-thaw cycles in plasma. This new method is expected to have application as a pretreatment for the rapid, simple, and quantitative determination of dimemorfan in plasma samples., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Pediatric liquid medicaments (PLM) are popular and are easily accepted by both parents and children. They are widely prescribed and easily available. However the sugar content and properties of these preparations determines their cariogenic potential., Aims and Objectives: This study assessed the pH and viscosity of pediatric liquid medicaments, type and concentration of sugars present in them and their effect on the growth of Streptococcus mutans., Methodology: PLM included two each of the most commonly prescribed analgesics, antibiotics, nutritional supplements, antitussive and antiepileptic preparations. The endogenous pH was measured using a digital pH meter and the viscosity was measured using a digital Brookefield viscometer. Analysis of sugars (sucrose, glucose and sorbitol) was performed using High Performance Liquid Chromatography. The effect of PLM on Streptococcus mutans was done by ditch plate method., Results: The pH of PLM ranged from 3.70 to 7.04 and viscosity varied from 307.33cP to 2408.33cP. Fifty percent of the PLM contained sucrose, glucose and sorbitol, and sucrose was present in nine of the PLM. The antibiotic preparations showed zones of inhibition against growth of Streptococcus mutans., Conclusions: The physical properties of Pediatric Liquid Medicaments as well as the type and concentration of sugars present in them can be indicative of their cariogenic potential.

Derivative and derivative ratio methods are presented for the determination of butamirate citrate, formoterol fumarate, montelukast sodium, and sodium cromoglycate. Using the second derivative ultraviolet (UV) spectrophotometry, butamirate citrate and formoterol fumarate were determined by measuring the peak amplitude at 260.4 and 261.8 nm, respectively, without any interference of their degradation products. Butamirate citrate degradation product, 2-phenyl butyric acid, was determined by the measurement of its second derivative amplitude at 246.7 nm where butamirate citrate displays zero crossing. Formoterol fumarate degradation product, desformyl derivative, could be evaluated through the use of the first derivative at peak amplitude of 264.8 nm where interference of formoterol fumarate is negligible. In the first mode, the zero-crossing technique was applied at 305 nm for the determination of montelukast sodium in the presence of its photodegradation product, cis-isomer. The derivative of ratio spectra of montelukast sodium and its cis- isomer were used to determine both isomers using the first derivative of the ratio spectra by measuring the amplitudes of the trough at 305 nm and the peak at 308 nm, respectively. The later technique was also used for the determination of a ternary mixture of sodium cromoglycate and its two degradation products using zero-crossing method. In the derivative ratio spectra of the ternary mixture, trough depths were measured at 271.6, 302.8 and 302.2 nm, using the second, the first, and the second mode to evaluate sodium cromoglycate, degradation product (1) and degradation product (2), respectively. All the methods were applied successfully to the pharmaceutical preparation and were validated according to ICH guidelines., (Copyright © 2011 John Wiley & Sons, Ltd.)

A liquid chromatographic method was applied for the analysis of two sustained-release mixtures containing dextromethorphane hydrobromide, carbinoxamine maleate with either phenylephrine hydrochloride in pharmaceutical capsules (Mix 1) or phenyl-propanolamine, methylparaben, and propylparaben, which bonds as a drug base to ion exchange resin in pharmaceutical syrup (Mix 2). The method was used for their simultaneous determination using a CN column with a mobile phase consisting of acetonitrile-12 mM ammonium acetate in the ratio of 60:40 (v/v, pH 6.0) for Mix 1 and 45:55 (v/v, pH 6.0) for Mix 2.

Herein, we present the solution-state NMR studies on dextromethorphan (1) under both isotropic and anisotropic conditions. From the measurement of 22 residual dipolar couplings using a stretched polystyrene gel (PS), we show that accurate and detailed structural information is readily determined including the relative stereochemical assignments of chiral centers, validation of diastereomer configuration, and the stereospecific assignment of the seven pairs of prochiral protons. This utility of PS gels is thus showcased to obtain rapid, accurate conformational, and relative configuration information in this important class of compounds without recourse to X-ray analysis., (Copyright 2009 Wiley-Liss, Inc.)

This work presents two cases of codeine intoxication in 3-year-old monozygotic twin brothers while treated with a codeine slow-release formulation. One child had to be admitted to the hospital, whereas the other one died at home after aspiration of gastric content. The concentrations of codeine and major metabolites including morphine and corresponding glucuronide conjugates were measured by liquid chromatography-tandem mass spectrometry in serum, urine, cerebrospinal fluid, and brain tissue, respectively. A genetic polymorphism study was carried out in order to determine the ability of the children to metabolize codeine by O-demethylation. A pharmacokinetic calculation was also performed to estimate the administered dose of codeine in question. High concentrations of all substances were found in samples of both children. The pharmacokinetic estimate suggests an overdose of codeine, and the possible reasons for the high opiate concentrations are discussed. Furthermore, the postmortem distribution--during and after resuscitation--might play a major role in the interpretation of postmortem concentration levels.

The case of a 13-month-old boy with a diagnosis of unclear unconsciousness is reported on. As the physical examination did not lead to any explanation of his condition, the administration of drugs in the context of Munchausen syndrome by proxy was suspected. Complex forensic-toxicological analyses using HPLC/UV, LC/MS/MS, and GC/MS identified ambroxol and clobutinol, two drugs that are indicated for acute respiratory diseases. No other central active compounds were detected. The accusation of intentional bodily injury raised against the parents could be rebutted, since the boy's unconsciousness could be explained with a rare but harmful side effect of the antitussive clobutinol.

A sensitive, selective, precise and stability-indicating thin-layer chromatographic (TLC) method was developed and validated for the analysis of noscapine, both as a bulk drug and in its formulation. The method employed TLC aluminium plates precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of chloroform-methanol (10:0.5 v/v). Densitometric analysis of noscapine and its degradation products was carried out in the absorbance mode at 254 nm. This system was found to give compact symmetrical spots for noscapine (R(f) value 0.85 +/- 0.04). Noscapine was subjected to acid and alkali hydrolysis, oxidation and photo degradation. The drug undergoes photo degradation and also degrades under acidic and basic conditions. The prepared degradation products were identified and verified through infrared (IR) and mass spectral analyses. The degraded products were also well resolved from the pure drug with significantly different R(f) values and they were quantitatively determined. The method was validated for linearity, precision, robustness, limit of detection (LOD), limit of quantitation (LOQ), specificity and accuracy. Linearity was found to be in the 1.0-10.0 microg, 0.4-3.2 microg, 1.0-9.0 microg and 0.5-5.0 microg/band ranges for noscapine, cotarnine, meconine and opionic acid, respectively. The polynomial regression analysis for the calibration plots showed a good polynomial relationship with r(2) of 0.9998, 9989, 9996 and 0.9997 for noscapine and its three degradation products, cotarnine, meconine and opionic acid, respectively. Statistical analysis proves that the method is repeatable and specific for the estimation of noscapine. As this approach could effectively separate the drug from its degradation products it can be employed as a stability-indicating method in Quality Control laboratories.

A new simple, rapid and sensitive liquid chromatographic method has been developed and validated for the simultaneous determination of pseudoephdrine, pheniramine, guaifenisin, pyrilamine, chlorpheniramine and dextromethorphan in cough and cold pharmaceuticals. The separation of these compounds was achieved within 13 min on a Kromasil C18 column using an isocratic mobile phase consisting of methanol-dihydrogenphosphate buffer at pH 3 (45:55, v/v). The analysis was performed at a flow rate of 1 mL min(-1) and at a detection wavelength of 220 nm. The selectivity, linearity of calibration, accuracy, within and between-days precision and recovery were examined as parts of the method validation. The concentration-response relationship was linear over a concentration range of 5-50 microg mL(-1) for pseudoephdrine, pheniramine, chlorpheniramine and 50-600 microg mL(-1) for guaifenisin, pyrilamine, dextromethorphan, methylparaben and sodium benzoate with correlation coefficients better than 0.998. The standard deviations of the intraday and interday were all less than 2%. The proposed liquid chromatographic method was successfully applied for the routine analysis of these compounds in different cough and cold pharmaceutical preparations such as syrups, capsules, tablets and sachets. The presence of preservatives (sodium benzoate and methylparaben) and other excipients did not show any significant interference on the determination of these compounds.

Adenophora triphylla is commonly used in food materials and oriental medicine as an analgesic, anti-inflammatory, and antitussive. In the present study, the leaves and roots of A. triphylla were extracted with water and ethanol, respectively, to examine the extracts' in vitro antioxidant activities and total phenolic contents, as well as A. triphylla's potential as a new functional food source and safe and inexpensive supply of antioxidants. Different antioxidant tests were employed and the results were compared with ascorbic acid as a standard antioxidant. The total extractable contents of phenolic compounds and flavonoids, which relate to antioxidant activity in medicinal plants, were also measured. The leaf extracts had notable levels of total phenolics and flavonoids and showed high radical and nitrite scavenging activities as well as inhibition activity against enzymes that induce oxidation. These results suggest that A. triphylla leaves are a potential ingredient for food supplements and a natural source of antioxidants.

The authors report on two cases of suspected Munchausen by proxy syndrome. In a 3-year-old boy, clinical toxicological analyses produced suspicious clues that an antidepressant had been administered, which could not be verified by forensic toxicological investigations. In a 13-month-old boy, the mother was also suspected of having poisoned the child. Initial clinical toxicological examinations failed to explain the observed symptoms (unclear unconsciousness, narrowed pupils). While in the first case, the incorrect interpretation of findings by a laboratory without forensic experience resulted in suspicions against the mother, the cause for the observed symptoms in the second case could be proved by complex analyses not performed before and the suspicion that the clinical picture had been intentionally brought about could be cleared up (use of an antitussive containing clobutinol). The two reports show that especially in cases with a potential forensic background, adequately qualified forensic laboratories with a broad spectrum of analytical methods should be involved.

Objective: In September 2006, a Panamanian physician reported an unusual number of patients with unexplained acute renal failure frequently accompanied by severe neurological dysfunction. Twelve (57%) of 21 patients had died of the illness. This paper describes the investigation into the cause of the illness and the source of the outbreak., Methods: Case-control and laboratory investigations were implemented. Case patients (with acute renal failure of unknown etiology and serum creatinine > 2 mg/dl) were individually matched to hospitalized controls for age (+/- 5 years), sex and admission date (< 2 days before the case patient). Questionnaire and biological data were collected. The main outcome measure was the odds of ingesting prescription cough syrup in cases and controls., Findings: Forty-two case patients and 140 control patients participated. The median age of cases was 68 years (range: 25-91 years); 64% were male. After controlling for pre-existing hypertension and renal disease and the use of angiotensin-converting enzyme inhibitors, a significant association was found between ingestion of prescription cough syrup and illness onset (adjusted odds ratio: 31.0, 95% confidence interval: 6.93-138). Laboratory analyses confirmed the presence of diethylene glycol (DEG) in biological samples from case patients, 8% DEG contamination in cough syrup samples and 22% contamination in the glycerin used to prepare the cough syrup., Conclusion: The source of the outbreak was DEG-contaminated cough syrup. This investigation led to the recall of approximately 60 000 bottles of contaminated cough syrup, widespread screening of potentially exposed consumers and treatment of over 100 affected patients.

A simple, effective, and sensitive online concentration method for the detection of dextromethorphan hydrobromide (Dex), chlorphenamine hydrogen maleate (Chl), pseudoephedrine hydrochloride (Pse) and paracetamol (Par) based on flow injection-capillary electrophoresis (FI-CE) analysis with head-column field-amplified sample stacking and large-volume sample stacking was developed. The background electrolyte (BGE) was a solution composed of 55 mM borate-15% (v/v) acetonitrile (ACN) (pH 9.3). The sample was injected electrokinetically between plugs of water. Under the optimum conditions, about a 30-fold improvement in the concentration sensitivity relative to normal CE methods was achieved, giving low limits of detection (LOD) of 1.94 x 10(-5), 0.64 x 10(-5), 1.16 x 10(-5) and 2.84 x 10(-5) mg/mL for Dex, Chl, Pse and Par, respectively. The repeatability (defined as RSD) was 1.01, 1.91, 0.89 and 0.92% with the peak-area evaluation and 1.94, 3.98, 2.66 and 3.27% with the peak-height evaluation for Dex, Chl, Pse and Par, respectively. This method has been successfully applied to the analysis of commercial pharmaceutical preparations containing Dex, Chl, Pse and Par.

The development of a highly sensitive enzyme-linked immunosorbent assay and gas chromatography-mass spectrometry confirmation method for the detection of dextromethorphan and its major metabolite dextrorphan in urine and oral fluid is described. For the screening assay, the intraday precision was less than 8% for urine and less than 5% for oral fluid. The interday precision was less than 10% for both drugs in urine and oral fluid. For the confirmatory procedure, both inter- and intraday precision was less than 5% for both matrices. The detection limit for both methods was 1 ng/mL. The quantifying ions chosen from the full scan mass spectra were m/z 271 for dextromethorphan, m/z 329 for dextrorphan, and m/z 332 for tri-deuterated dextrorphan-d(3). A high recovery yield (> 93%) from the Quantisal oral fluid collection device was achieved, and the drugs were stable in the collection device for at least 10 days at room temperature. The extracted drugs from both matrices were stable for at least 48 h while kept at room temperature. Both screening and confirmatory procedures were applied to authentic urine and oral fluid specimens obtained from volunteers following therapeutic ingestion of dextromethorphan.

A simple and reliable high-performance liquid chromatographic method was developed for the simultaneous determination of mixture of phenylephrine hydrochloride (PHENYL), guaifenesin (GUAIF), and chlorpheniramine maleate (CHLO) either in pure form or in the presence of methylparaben and propylparaben in a commercial cough syrup dosage form. Separation was achieved on a C8 column using 0.005 M heptane sulfonic acid sodium salt (pH 3.4 +/- 0.1) and acetonitrile as a mobile phase by gradient elution at different flow rates, and detection was done spectrophotometrically at 210 nm. A linear relationship in the range of 30-180, 120-1800, and 10-60 microg/mL was obtained for PHENYL, GUAIF, and CHLO, respectively. The results were statistically analyzed and compared with those obtained by applying the British Pharmacopoeia (2002) method and showed that the proposed method is precise, accurate, and can be easily applied for the determination of the drugs under investigation in pure form and in cough syrup formulations.

Multivariate spectrophotometric calibration and liquid chromatographic (LC) methods were applied to the determination of 2 multicomponent mixtures containing diprophylline, guaiphenesin, methylparaben, and propylparaben (Mixture 1), or clobutinol, orciprenaline, saccharin sodium, and sodium benzoate (Mixture 2). For the multivariate spectrophotometric calibration methods, principal component regression (PCR) and partial least-squares regression (PLS-1), a calibration set of the mixtures consisting of the components of each mixture was prepared in 0.1 M HCl. Analytical figures of merit such as sensitivity, selectivity, limit of quantitation, and limit of detection were determined for both PLS-1 and PCR. The LC separation was achieved on a reversed-phase C18 analytical column by using isocratic elution with 20 mM potassium dihydrogen phosphate, pH 3.3-acetonitrile (55 + 45, v/v) as the mobile phase and UV detection at 260 and 220 nm for Mixture 1 and Mixture 2, respectively. The proposed methods were validated and successfully applied to the analysis of pharmaceutical formulations and laboratory-prepared mixtures containing the 2 multicomponent combinations.

A high-performance liquid chromatography coupled with diode array detection and evaporative light scattering detection (HPLC-DAD-ELSD) method was developed to simultaneously quantify six major bioactive alkaloids belonging to different structure types in Radix Stemonae, Bai-Bu in Chinese, a traditionally used antitussive and insecticidal medicinal material in China and other countries of Southeast Asia. Diode array detector (DAD) with the wavelengths at 307 and 260 nm was used to monitor the conjugated system of protostemonine (2) and maistemonine (4), respectively, whereas evaporative light scattering detector (ELSD) was employed to detect croomine (1), stemoninine (3), neotuberostemonine (5) and tuberostemonine (6), the other four analytes with no or poor chromophores. The assay was validated to be sensitive, precise and accurate, with a detection limit of 3.64-0.04 microg/mL depending on the individual analytes. The overall intra- and inter-day variations were less than 9.3%, and the overall recoveries higher than 91.2%, respectively. The correlation coefficients of the calibration curves were better than 0.996 for all analytes. The newly established method was successfully utilized to determine six major components in the genuine sources of Radix Stemonae: Stemona japonica, S. sessilifolia and S. tuberosa. Significant variations of contents of these components were demonstrated in samples of these three species. This simple, rapid, low-cost and reliable method is suitable for the routine quality control of herbal medicines containing bioactive components with different structure types such as Radix Stemonae., (2007 John Wiley & Sons, Ltd)

A new flow injection chemiluminescence (CL) system was used for the determination of noscapine. This technique is based on the reduction effect of noscapine on the Ru(phen)3(3+), which is produced by reaction between Ru(phen)3(2+) and acidic Ce(IV) solutions, and this rapid reduction produces strong CL. Calibration plots were linear over the range of 3.0 x 10(-7) - 2.0 x 10(-6) mol L(-1) and 2.0 x 10(-6) - 2.0 x 10(-4) mol L(-1). The CL intensity was so high, that it is able to produce a detection limit of 6.6 x 10(-8) M noscapine (3sigma). The relative standard deviation of 2.0 x 10(-6) M noscapine was 1.0% (n=10). The proposed method was successfully applied for the flow injection determination of noscapine in cough and Tonin syrup samples. The results of real sample analyses show good recovery percentages (97.3-102.4%). The minimum sampling rate was 100 samples per hour.

A simple, accurate and highly sensitive spectrophotometric method is proposed for the rapid determination of pipazethate hydrochloride, dextromethorphan hydrobromide and drotaverine hydrochloride using chromotrope 2B (C2B) and chromotrope 2R (C2R). The method consists of extracting the formed ion-associates into chloroform in the case of pipazethate HCl and dextromethorphan HBr or into methylene chloride in the case of drotaverine HCl. The ion-associates exhibit absorption maxima at 528, 540 and 532 nm with C2B and at 526, 517 and 522 nm with C2R for pipazethate HCl, dextromethorphan HBr and drotaverine HCl, respectively. The calibration curves resulting from the measurements of absorbance-concentration relations (at the optimum reaction conditions) of the extracted ion-pairs are linear over the concentration range 4.36-52.32 microg mL(-1) for pipazethate, 3.7-48.15 microg mL(-1) for dextromethorphan and 4.34-60.76 microg mL(-1) for drotaverine, respectively. The effect of acidity, reagent concentration, time, solvent and stoichiometric ratio of the ion-associates were estimated. The molar absorptivity and Sandell sensitivity of the reaction products were calculated. Statistical treatment of the results reflects that the procedure is precise, accurate and easily applied for the determination of the drugs under investigation in pure form and in their pharmaceutical preparations.

A simple, rapid and accurate method for the separation and determination of paracetamol (Par), pseudoephedrine hydrochloride (Pse), dextromethorphan hydrobromide (Dex) and chlorphenamine hydrogen maleate (Chl) was developed by combination of flow injection and capillary zone electrophoresis for the first time. The analysis was carried out using an unmodified fused-silica capillary (75 mm x 75 microm i.d. x 375 microm o.d., effective separation length of 45 mm) and direct ultraviolet detection at 214 nm, 1.0 kV applied voltage. The optimized running buffer composed of 75 mM sodium borate-15% (v/v) acetonitrile (ACN) (pH* 9.30) was applied for the separation of the four analytes. The separation was achieved in 4.5 min. The sample throughput rate could reach up to 19 h(-1). The repeatability (defined as relative standard deviation) was 0.6%, 1.0%, 2.1%, 1.9% with peak height evaluation and 0.7%, 1.8%, 0.7%, 1.1% with peak area evaluation for Par, Pse, Dex and Chl, respectively. The limits of detection (S/N=3) were 0.22 microg/ml, 0.29 microg/ml, 0.42 microg/ml and 0.70 microg/ml for Par, Pse, Dex and Chl, respectively. The method was successfully applied to determine the four compounds in three cold medicines with recoveries in the range of 97.18-105.15%.