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Clinical Toxicology (Philadelphia, Pa.) Dec 2022The genus is composed of plants containing a diverse set of steroidal alkaloids. plant material has been utilized for centuries as herbal medicines, however the...
INTRODUCTION
The genus is composed of plants containing a diverse set of steroidal alkaloids. plant material has been utilized for centuries as herbal medicines, however the alkaloids have such a low therapeutic index that they are not used in modern medicine. Here we report an incident of inadvertent ingestion of by hikers in Georgia that allowed detection, and in several instances identification of alkaloids from the plant, and correlated their presence within patient blood and breast milk specimens.
CASE HISTORY
Eight patients, three male and five female, presented in the spring of 2020 and 2021 with symptoms requiring emergent medical attention after ingestion of All patients believed the plants to be a local native species of wild leek, , locally known as ramps. Plants were identified using photographs as well as fresh and cooked plant material provided by patients, in consultation with botanists at the University of Georgia Herbarium. Written consent was obtained from all patients for collection of blood and breast milk specimens for laboratory identification of alkaloids.
METHODS
plant material, and patient serum and breast milk were analyzed by high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-QTOF) to identify steroidal alkaloids.
RESULTS
The extract was confirmed to contain cyclopamine, veratramine, jervine, and muldamine. Two out of the eight patients had detectable concentrations of alkaloids. Of the alkaloids identified in the plant, cyclopamine and jervine were detected within patient serum, and cyclopamine and veratramine were observed to be present in breast milk.
DISCUSSION
Toxicity resulting from steroidal alkaloids has primarily been reported from and . This is the second report of poisoning. The present work reports for the first time the presence of muldamine and jervine within . This work provides the first instance of identification of alkaloids in breast milk. Thus, the findings presented herein add to literature record causative agents contributing to the toxicity of when ingested and potential for secondary poisoning through breastfeeding.
CONCLUSION
toxicity was observed to cause nausea, vomiting, hypotension, bradycardia, abdominal pain, light-headedness, blurred vision, and tingling in the arms. Patients experiencing mild symptoms improved with supportive care, IV fluids, and antiemetics, but hemodynamically unstable patients required atropine and vasopressors. This study demonstrated that more lipophilic alkaloids can be passed along in breast milk, which suggests additional precautions may be critical to limit further poisonings.
Topics: Female; Humans; Veratrum; Milk, Human; Veratrum Alkaloids; Alkaloids; Plant Poisoning
PubMed: 36301078
DOI: 10.1080/15563650.2022.2132166 -
Science (New York, N.Y.) Jun 2009Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of...
Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibition of the Hedgehog cellular signaling pathway. The combination therapy produced a transient increase in intratumoral vascular density and intratumoral concentration of gemcitabine, leading to transient stabilization of disease. Thus, inefficient drug delivery may be an important contributor to chemoresistance in pancreatic cancer.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Disease Models, Animal; Drug Resistance, Neoplasm; Hedgehog Proteins; Humans; Kruppel-Like Transcription Factors; Mice; Neoplasm Transplantation; Neovascularization, Pathologic; Pancreatic Neoplasms; Receptors, G-Protein-Coupled; Signal Transduction; Smoothened Receptor; Stromal Cells; Veratrum Alkaloids; Zinc Finger Protein GLI1; Gemcitabine
PubMed: 19460966
DOI: 10.1126/science.1171362 -
International Journal of Molecular... Oct 2021Basal cell carcinoma is one of the most common types of non-melanoma skin cancers, which can be locally destructive despite low-rate metastasis. Surgery is the treatment... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Basal cell carcinoma is one of the most common types of non-melanoma skin cancers, which can be locally destructive despite low-rate metastasis. Surgery is the treatment of choice, but it lacks of efficacy on advanced cases. Hedgehog pathway inhibitors are a class of drugs providing a new therapeutic option for patients affected by advanced disease. Besides systemic therapy, such as vismodegib and sonidegib, also topical inhibitors have been developed. Patidegib is able to decrease tumor burden, reducing the adverse effects induced by systemic targeted therapies.
METHODS
We performed comprehensive research to summarize the use of patidegib in advanced and recurrent aggressive basal cell carcinomas. Only English language human studies were included in the search.
RESULTS
Seven trials reported the application of patidegib. Both topical and systemic patidegib demonstrated safety, tolerability, and efficacy in naïve patients with stage II and III basal cell carcinomas, while stage IV disease and not-naïve patients did not show any benefit.
CONCLUSION
Unlike systemic Hedgehog pathway inhibitors, patidegib 2% gel is not associated with systemic adverse effects and allows a better patient management. Considering the multidisciplinary management of neoplasia, in the era of precision medicine, it is mandatory to confide in pharmacogenomics to obtain personalized combined or sequential therapies.
Topics: Antineoplastic Agents; Biphenyl Compounds; Clinical Trials as Topic; Dermatology; Hedgehog Proteins; Humans; Molecular Targeted Therapy; Prognosis; Pyridines; Signal Transduction; Skin Neoplasms; Treatment Outcome; Veratrum Alkaloids
PubMed: 34639065
DOI: 10.3390/ijms221910725 -
British Heart Journal May 1991
PubMed: 18610390
DOI: 10.1136/hrt.65.5.286 -
Scientific Reports May 2023Veratrum (Melanthiaceae; Liliales) is a genus of perennial herbs known for the production of unique bioactive steroidal alkaloids. However, the biosynthesis of these...
Veratrum (Melanthiaceae; Liliales) is a genus of perennial herbs known for the production of unique bioactive steroidal alkaloids. However, the biosynthesis of these compounds is incompletely understood because many of the downstream enzymatic steps have yet to be resolved. RNA-Seq is a powerful method that can be used to identify candidate genes involved in metabolic pathways by comparing the transcriptomes of metabolically active tissues to controls lacking the pathway of interest. The root and leaf transcriptomes of wild Veratrum maackii and Veratrum nigrum plants were sequenced and 437,820 clean reads were assembled into 203,912 unigenes, 47.67% of which were annotated. We identified 235 differentially expressed unigenes potentially involved in the synthesis of steroidal alkaloids. Twenty unigenes, including new candidate cytochrome P450 monooxygenases and transcription factors, were selected for validation by quantitative real-time PCR. Most candidate genes were expressed at higher levels in roots than leaves but showed a consistent profile across both species. Among the 20 unigenes putatively involved in the synthesis of steroidal alkaloids, 14 were already known. We identified three new CYP450 candidates (CYP76A2, CYP76B6 and CYP76AH1) and three new transcription factor candidates (ERF1A, bHLH13 and bHLH66). We propose that ERF1A, CYP90G1-1 and CYP76AH1 are specifically involved in the key steps of steroidal alkaloid biosynthesis in V. maackii roots. Our data represent the first cross-species analysis of steroidal alkaloid biosynthesis in the genus Veratrum and indicate that the metabolic properties of V. maackii and V. nigrum are broadly conserved despite their distinct alkaloid profiles.
Topics: Veratrum; Transcriptome; Alkaloids; Gene Expression Profiling; Veratrum Alkaloids; Steroids; Cytochrome P-450 Enzyme System
PubMed: 37211560
DOI: 10.1038/s41598-023-35429-5 -
Toxins Jul 2022Jervine, protoveratrine A (proA), and protoveratrine B (proB) are alkaloids that are presented in some remedies obtained from , such as . This paper reports on a...
Jervine, protoveratrine A (proA), and protoveratrine B (proB) are alkaloids that are presented in some remedies obtained from , such as . 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 Na1.5, and machine learning-based structure-activity relationship modeling. HPLC-MS/MS method in combination with clinical events were used to analyze alkaloid cardiotoxicity in patients. Jervine demonstrates the highest docking score (-10.8 kcal/mol), logP value (4.188), and p value (9.64) compared with proA and proB. Also, this compound is characterized by the lowest calculated IC. In general, all three analyzed alkaloids show the affinity to Na1.5 that highly likely results in cardiotoxic action. The clinical data of seven cases of intoxication by 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 Na1.5 inhibition.
Topics: Alkaloids; Cardiotoxicity; Humans; Molecular Docking Simulation; Pilot Projects; Tandem Mass Spectrometry; Veratrum; Veratrum Alkaloids
PubMed: 35878228
DOI: 10.3390/toxins14070490 -
Phytomedicine : International Journal... Nov 2023Hypertension is a serious global public health issue. Blood pressure (BP) is still not effectively controlled in about 20 - 30% of hypertensive patients. Therefore, it...
BACKGROUND
Hypertension is a serious global public health issue. Blood pressure (BP) is still not effectively controlled in about 20 - 30% of hypertensive patients. Therefore, it is imperative to develop new treatments for hypertension. Veratrum alkaloids were once used for the clinical treatment of hypertension, the mechanism of which is still unclear. It was gradually phased out due to adverse reactions.
PURPOSE
This study aimed to investigate the short-term and long-term hypotensive profiles of different components of Veratrum alkaloids in spontaneously hypertensive rats (SHRs) to unveil their mechanisms of action.
RESULTS
Total Veratrum alkaloid (V), component A (A), and veratramine (M) quickly decreased BP within 30 min of treatment, reduced renal and cardiovascular damage, and improved relevant biochemical indicators (nitric oxide [NO], endothelin-1 [ET-1], angiotensin II [Ang II)], noradrenaline [NE], etc) in SHRs to delay stroke occurrence. Thereinto, A exhibited excellent protective effects in cardiovascular disease. The metabolomic profiles of SHRs treated with V, A, and M were significantly different from those of SHRs treated with vehicle. Thirteen metabolites were identified as potential pharmacodynamic biomarkers. Through Kyoto Encyclopedia of Genes and Genomes analysis, V, A, and M-induced hypotension was mainly related to alterations in nicotinate and nicotinamide metabolism, GABAergic synapses, linoleic acid metabolism, ketone body synthesis and degradation, arginine and proline metabolism, and urea cycle, of which nicotinate and nicotinamide metabolism was the key metabolic pathway to relieve hypertension.
CONCLUSION
This work shows that A is an effective and promising antihypertensive agent for hypertension treatment to reduce BP and hypertensive target organ damage, which is mainly mediated through modulating nicotinate and nicotinamide metabolism, RAS, and NO-ET homeostasis.
Topics: Humans; Animals; Rats; Antihypertensive Agents; Niacin; Veratrum Alkaloids; Hypertension; Data Analysis; Niacinamide
PubMed: 37647672
DOI: 10.1016/j.phymed.2023.155033 -
The Journal of General Physiology Nov 1960The interactions of veratridine, cevadine, veracevine, and veratramine with monolayers of stearic acid show marked differences. Veratridine and cevadine, at...
The interactions of veratridine, cevadine, veracevine, and veratramine with monolayers of stearic acid show marked differences. Veratridine and cevadine, at concentrations that are known from potential, ionic flux, and other measurements to affect living membranes, react strongly with the film and appear to cause an "interfacial dissolution" whereby both the alkaloid and the stearate leave the surface. Veracevine at the same concentration does not interact with the film. The veratramine reaction is weak, much like that of the local anesthetic procaine. The veratridine and cevadine effects are antagonized by 10(-3)M Ca(++), low pH, and 3.7 and 7.4 x 10(-3)M procaine. These differences among the veratrum alkaloids and the antagonisms parallel effects observed in living systems. Such parallelism suggests that similar physical interactions are involved in the stearate film and in natural membranes.
Topics: Anesthetics, Local; Calcium; Procaine; Stearates; Stearic Acids; Veratrine; Veratrum; Veratrum Alkaloids
PubMed: 13750673
DOI: 10.1085/jgp.44.2.345 -
Zeitschrift Fur Naturforschung. C,... 2010Twelve steroidal alkaloids were isolated from four populations of Veratrum lobelianum Bernh. and Veratrum nigrum L. Full NMR data for veralosinine (1), and extensive 1H...
Twelve steroidal alkaloids were isolated from four populations of Veratrum lobelianum Bernh. and Veratrum nigrum L. Full NMR data for veralosinine (1), and extensive 1H NMR data for veralosine (3) and teinemine (5) are presented here for the first time. (+/-)-15-O-(2-Methylbutyroyl)germine (10) is undescribed up to now. The antiproliferative activities of veranigrine, veralosinine, and neogermitrine have shown that they are a perspective for further studies.
Topics: Animals; Bulgaria; Cell Division; Leukemia L5178; Magnetic Resonance Spectroscopy; Medicine, Traditional; Mice; Models, Molecular; Mongolia; Phytosterols; Veratrum; Veratrum Alkaloids
PubMed: 20469637
DOI: 10.1515/znc-2010-3-405 -
British Medical Journal Feb 1954
Topics: Hypersensitivity; Hypertension; Immune System Diseases; Veratrum Alkaloids
PubMed: 13115709
DOI: 10.1136/bmj.1.4857.316