Veratrum poisonings are known to the toxicology literature as multiple Veratrum species grow in different parts of the Northern Hemisphere and are occasionally ingested by mistake. Veratrum toxicity is attributed to the steroidal alkaloids contained in all parts of the plant. In Russia Veratrum poisonings are more common since there is an over-the-counter Veratrum Lobelianum-based tincture, Veratrum Aqua (VA), that is topically used for treatment of lice infestation. Despite its toxicity, VA is misused in traditional medicine as a remedy for alcohol use disorder. We describe four cases of VA poisoning that occurred in Moscow, Russia. Three main Veratrum Lobelianum alkaloids (jervine, protoveratrine A and protoveratrine B), were determined in patient plasma and urine samples using liquid chromatography tandem mass-spectrometry (LC-MS/MS). Here we describe a novel validated LC-MS/MS method for jervine and protoveratrine A quantification. Simple and rapid liquid-liquid extraction with methyl tert-butyl ether was utilized for analyte extraction. Chromatographic separation was achieved using Poroshell 120 EC-C18 column, and the total run time was 14 min. The lower limit of quantification was 0.1 ng/mL for jervine and proA in both plasma and urine. Biological samples were obtained upon hospital admission and during treatment, thus enabling to get a better understanding of the alkaloid elimination profile. Upon admission plasma concentrations of jervine (concentration range: 0.10–5.01 ng/mL) prevailed over protoveratrine A (concentration range: 0–0.67 ng/mL). At this time, protoveratrine A already reached maximum concentrations in urine (concentration range: 0.15–37.70 ng/mL). Maximum concentrations of jervine in urine were observed 24 hours after admission (concentration range: 0.10–9.55 ng/mL). In all cases plasma concentrations of Veratrum alkaloids correlated with condition severity. Since none of the patients confirmed VA intake, instrumental analysis was the basis for the definitive diagnosis of VA poisoning.
Introduction. According to the XIV Edition of the Russian Federation State Pharmacopoeia, the quality control of the «Veratrum Lobelianum rhizome and roots» herbal substance is carried out through the determination of the alkaloid sum by means of the titration-based method. There are no selective and sensitive instrumental methods for the quantitative analysis of veratrum aqua active ingredients either. Veratrum aqua is produced from the mentioned above herbal substance. Therefore, the study of veratrum aqua alkaloid composition is relevant, as well as the development of a modern analytical method for individual alkaloid determination that can be implemented in veratrum aqua standardization.Aim. To develop an approach to the quantitative analysis in Veratrum Aqua standardization.Materials and methods. Two analytical methods were developed: one for the veratrum alkaloid determination in veratrum aqua samples by means of high performance liquid chromatography coupled with tandem mass-spectrometry (HPLC-MS/MS), another – for jervine, the main veratrum aqua alkaloid, quantitation by means of HPLC with diode-array detector (HPLC-DAD).Results and discussion. Three main alkaloids, namely jervine, protoveratrine A and protoveratrine B, were identified in veratrum aqua. Jervine was found to be the most abundant one, hence it was chosen for the further development of a more affordable HPLC-DAD method. This method was validated for specificity, linearity, accuracy and precision. Jervine concentrations were measured in seven veratrum aqua samples produced by different manufacturers.Conclusion. The highest jervine concentration among the examined samples was found to be 170 µg/ml, the lowest – 136 µg/ml. It is proposed to implement the following quantitative content parameter in veratrum aqua standardization: «Quantitative test. Jervine content should be not lessthan 136 µg/ml». This parameter is to be determined by HPLC-DAD.
Jervine, protoveratrine A (proA), and protoveratrine B (proB) are Veratrum alkaloids that are presented in some remedies obtained from Veratrum lobelianum, such as Veratrum aqua. This paper reports on a single-center pilot cardiotoxic mechanism study of jervine, proA, and proB in case series. The molecular aspects were studied via molecular dynamic simulation, molecular docking with cardiac sodium channel NaV1.5, and machine learning-based structure–activity relationship modeling. HPLC-MS/MS method in combination with clinical events were used to analyze Veratrum alkaloid cardiotoxicity in patients. Jervine demonstrates the highest docking score (−10.8 kcal/mol), logP value (4.188), and pKa value (9.64) compared with proA and proB. Also, this compound is characterized by the lowest calculated IC50. In general, all three analyzed alkaloids show the affinity to NaV1.5 that highly likely results in cardiotoxic action. The clinical data of seven cases of intoxication by Veratrum aqua confirms the results of molecular modeling. Patients exhibited nausea, muscle weakness, bradycardia, and arterial hypotension. The association between alkaloid concentrations in blood and urine and severity of patient condition is described. These experiments, while primary, confirmed that jervine, proA, and proB contribute to cardiotoxicity by NaV1.5 inhibition.
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