Insights into the Cardiotoxic Effects of Veratrum Lobelianum Alkaloids: Pilot Study.

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.

Veratrum Alkaloid Determination in Four Cases of Veratrum Aqua Poisonings.

Veratrum poisonings are described in 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), which is topically used for the 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 V. lobelianum alkaloids (jervine, protoveratrine A (proA) 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 proA quantification. A simple and rapid liquid-liquid extraction with methyl tert-butyl ether was utilized for analyte extraction. Chromatographic separation was achieved using a 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 proA (concentration range: 0-0.67 ng/mL). At this time, proA already reached maximum concentrations in urine (concentration range: 0.15-37.70 ng/mL). Maximum concentrations of jervine in urine were observed 24 h 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.