Recurrent Ventricular Arrhythmia Caused by Ingestion of Aconitum (Monkshood) Flowers.

We report the case of a patient who presented with respiratory failure, recurrent ventricular fibrillation, ventricular arrhythmias, and hypotension after an intentional ingestion of aconite flowers. Significant ingestion of this plant can produce life-threatening cardio- and neurotoxicity that may require evacuation from the wilderness to a medical facility capable of advanced treatment and intensive care monitoring.

[Data-mining characteristics of adverse drug reactions and pharmacovi-gilance of Chinese patent drugs including Aconitum herbs].

The common Aconitum herbs in clinical application mainly include Aconiti Radix(Chuanwu), Aconiti Kusnezoffii Radix(Caowu) and Aconiti Lateralis Radix Praeparaia(Fuzi), all of which have toxicity. Therefore, the safety of using Chinese patent drugs including Aconitum herbs has become an hot topic in clinical controversy. Based on the data-mining methods, this study explored the characteristics and causes of adverse drug reactions/events (ADR/ADE) of the Chinese patent drugs including Aconitum, in order to provide pharmacovigilance and rational drug use suggestions for clinical application. The detailed ADR/ADE reports about the Chinese patent drugs including Aconitum herbs were retrieved in the domestic literature databases since 1984 to now. The information extraction and data-mining were conducted based on the platforms of Microsoft office Excel 2016, Clementine 12.0 and Cytoscape 3.3.0. Finally, 78 detailed ADR/ADE reports involving a total of 30 varieties were included. 92.31% ADR/ADE were surely or likely led by the Chinese patent drugs including Aconitum, mostly involving multiple system/organ damages with good prognosis, and even 1 case of death. The incidence of included ADRs/ADEs was associated with various factors such as the patient idiosyncratic, drug toxicity, as well as clinical medication. The patient age was most closely related to ADR/ADEs, and those aged from 60 to 69 were more easily suffered from the ADRs/ADEs of Chinese patent drugs including Aconitum. The probability of ADR/ADEs for the drugs including Chuanwu or Caowu was greater than that of Fuzi, and the using beyond the instructions dose was the most important potential safety hazard in the clinical medication process. For the regular and characteristics of ADR/ADEs led by Chinese patent drugs including Aconitum, special attention shall be paid to the elder patients or with the patients with allergies; strictly control the dosage and course of treatment, strengthen the safety medication education to public, and avoid misuse or abuse to ensure rational drug use.

Establishment of one-step approach to detoxification of hypertoxic aconite based on the evaluation of alkaloids contents and quality.

Aconite is a valuable drug and also a toxic material, which can be used only after detoxification processing. Although traditional processing methods can achieve detoxification effect as desired, there are some obvious drawbacks, including a significant loss of alkaloids and poor quality consistency. It is thus necessary to develop a new detoxification approach. In the present study, we designed a novel one-step detoxification approach by quickly drying fresh-cut aconite particles. In order to evaluate the technical advantages, the contents of mesaconitine, aconitine, hypaconitine, benzoylmesaconine, benzoylaconine, benzoylhypaconine, neoline, fuziline, songorine, and talatisamine were determined using HPLC and UHPLC/Q-TOF-MS. Multivariate analysis methods, such as Clustering analysis and Principle component analysis, were applied to determine the quality differences between samples. Our results showed that traditional processes could reduce toxicity as desired, but also led to more than 85.2% alkaloids loss. However, our novel one-step method was capable of achieving virtually the same detoxification effect, with only an approximately 30% alkaloids loss. Cluster analysis and Principal component analysis analyses suggested that Shengfupian and the novel products were significantly different from various traditional products. Acute toxicity testing showed that the novel products achieved a good detoxification effect, with its maximum tolerated dose being equivalent to 20 times of adult dosage. And cardiac effect testing also showed that the activity of the novel products was stronger than that of traditional products. Moreover, particles specification greatly improved the quality consistency of the novel products, which was immensely superior to the traditional products. These results would help guide the rational optimization of aconite processing technologies, providing better drugs for clinical treatment.

Assessment of in vitro cardiotoxicity of extract fractions and diterpene alkaloids from Aconitum leucostomum Worosch: A short communication.

Aconitum leucostomum Worosch is a traditional Chinese medicine (TCM) and has a broad spectrum of health effects, but with a narrow therapeutic window. It is important to identify both the therapeutic ingredients and the toxic components to better utilize this TCM. The present study investigated the cardiotoxicity of the selected compounds in Aconitum leucostomum Worosch. The effects of extract of A. leucostomum Worosch and the isolated compounds on cardiocardiomyocytes were evaluated in vitro. Five known compounds in this TCM, including three C18-diterpene alkaloids, lappaconitine (2), N-deacetyllappaconitine (3), and ranaconitine (5), and two C19-diterpene alkaloids, delvestidine (1) and anthranoyllycoctonine (4), were isolated from A. leucostomum Worosch. The cardiotoxicity of these components and extract fractions, as measured by lactate dehydrogenase release and apoptosis, was ranked as follows, in descending order: delvestidine>anthranoyllycoctonine>pH 4 fraction>pH 8 fraction>aconitine>N-deacetyllappaconitine>ranaconitine>lappaconitine. The cytotoxicity of these compounds was shown to be dose-dependent, with delvestidine (1) and anthranoyllycoctonine (4) being the two most toxic compounds to cardiomyocytes in our assays. These results provide a basis for future rational use of this TCM, reducing side effects while retaining therapeutic effects.

[Study on effect of aqueous extracts from aconite on "dose-time-toxicity" relationships in mice hearts].

OBJECTIVE: To study the effect of single administration of aqueous extracts from aconite on "dose-toxicity" relationship and "time-toxicity" relationship of mice hearts, through changes in electrocardiogram (ECG) and serum biochemical indexes. METHOD: Mice were grouped according to different drug doses and time points, and orally administered with water extracts from aconite for once to observe the changes of mice ECG before and after the administration, calculate visceral indexes heart, liver and kidney, and detect levels of CK, LDH, BNP and CTn-I in serum. RESULT: According to the "time-toxicity" relationship study, at 5 min after oral administration with aqueous extracts from aconite in mice, the heart rate of mice began rising, reached peak at 60 min and then slowly reduced; QRS, R amplitude, T duration and amplitude and QT interval declined at 5 min, reduced to the bottom at 60 min and then gradually elevated. The levels of CK, LDH, BNP and CTn-I in serum elevated at 5 min and reached the peak at 60 min, with no significant change in ratios of organs to body at different time points. On the basis of the "dose-toxicity" relationship, with the increase in single dose of aqueous extracts from aconite, the heart rate of mice. QRS, T duration and amplitude and QT interval declined gradually, and levels of CK, LDH, BNP and CTn-I in serum slowly elevated, with a certain dose dependence and no significant change in ratios of organs to body in mice. CONCLUSION: Single oral administration of different doses of aqueous extracts from aconite could cause different degrees of heart injury at different time points, with a certain dose dependence. Its peak time of toxicity is at 60 min after the administration of aqueous extracts from aconite.

Transient A-V dissociation and severe hypotension due to consumption of Ayurvedic medicine--Vatsanabha (aconitum ferox).

A 24 year old married, well educated, female patient presented with complaints of giddiness and blackouts. On evaluation, patient had hypotension and bradycardia. ECG findings were suggestive of complete A-V dissociation. On detailed history patient revealed consumption. of Ayurvedic medicine Vatsanabha for arthritis. This study impresses upon the need for complete history talking and generating awareness regarding the correct and observed use of any drug including alternative medicines.

Serum metabolomics reveals betaine and phosphatidylcholine as potential biomarkers for the toxic responses of processed Aconitum carmichaelii Debx.

We recently reported that processed Aconitum carmichaelii Debx (Bai-Fu-Pian in Chinese, BFP) elicits differential toxic responses in rats under various health conditions. The present study aimed to determine the graded toxicity of BFP so as to derive a safe therapeutic rationale in clinical practice. Sensitive and reliable biomarkers of toxicity were also identified, with the corresponding metabolic pathways being unveiled. Thirty male Sprague-Dawley rats were divided into five groups (n = 6) and received oral administration of BFP extract (0.32, 0.64, 1.28 or 2.56 g kg(-1) per day) or an equal volume of drinking water (control) for 15 days. The metabolomic profiles of rat serum were analyzed by liquid chromatography quadruple time-of-flight mass spectrometry (LC-Q-TOF-MS). Linear regression analysis and Ingenuity Pathway Analysis (IPA) were used to elucidate the differentiated altered metabolites and associated network relationships. Results from biochemical and histopathological examinations revealed that BFP could induce prominent toxicity in the heart, liver and kidneys at a dose of 2.56 g kg(-1) per day. Betaine up-regulation and phosphatidylcholine down-regulation were detected in the serum samples of drug-treated groups in a dose-dependent manner. In summary, betaine and phosphatidylcholine could be regarded as sensitive biomarkers for the toxic responses of BFP. Perturbations of RhoA signaling, choline metabolism and free radical scavenging were found to be partly responsible for the toxic effects of the herbal drug. Based on the metabolomics findings, we could establish a safe therapeutic range in the clinical use of BFP, with promising predictions of possible drug toxicity.

Ultra-fast LC-ESI-MS/MS method for the simultaneous determination of six highly toxic Aconitum alkaloids from Aconiti kusnezoffii radix in rat plasma and its application to a pharmacokinetic study.

A fast, sensitive, and efficient ultra-fast LC-ESI-MS/MS method was developed for the simultaneous quantitation of six highly toxic Aconitum alkaloids, that is, aconitine, mesaconitine, hypaconitine, benzoylaconine, benzoylmesaconine, and benzoylhypaconine, in rat plasma after oral administration of crude ethanol extracts from Aconiti kusnezoffii radix by ultrasonic extraction, reflux extraction for 1 h, and reflux extraction for 3 h, respectively. The separation of six Aconitum alkaloids and aminopyrine (internal standard) was performed on an InertSustain® C18 column, and the quantification of the analytes was performed on a 4000Q ultra-fast LC-MS/MS system with turbo ion spray source in the positive ion and multiple-reaction monitoring mode. Absolute recoveries ranged within 65.06-85.1% for plasma samples. The intra- and interday precision and accuracy of analytes were satisfactory. The methods were validated with sensitivity reaching the lower LOQ for aconitine, mesaconitine, hypaconitine, benzoylaconine, benzoylmesaconine, and benzoylhypaconine, which were 0.025, 0.025, 0.050, 0.025, 0.025, and 0.100 ng/mL, respectively. The method was successfully applied to a pharmacokinetic study of six Aconitum alkaloids in rat plasma after oral administration of crude ethanol extracts from the raw root of Aconitum kusnezoffii Reichb. by three different extraction processes.

[Evaluation on efficacy-toxicity correlation of aqueous extracts from Aconiti Lateralis Radix Praeparata on diarrheal model rats based on "warmly invigorating spleen Yang" efficacy].

The diarrheal rat model was established by orally administering senna. The preventive experiment was concurrent for 6 days. The treatment experiment modeling had lasted for 12 days. The administration started at the 7th day, and lasted for 6 days. During the experiment, efforts were made in symptom score and weighing. After the experiment, hearts, livers, spleens, kidneys, brains, adrenals and thymuses were collected and weighed, lactic dehydrogenase (LDH) and cardiac troponin-I (cTn-I) in serum were detected. The efficacy of aqueousextracts from Aconiti Lateralis Radix Praeparata in preventing and treating rats with diarrheal and its accompanying toxicity were respectively studied. The result shows that aqueous extracts from Aconiti Lateralis Radix Praeparata could improve syndromes of rats with diarrheal. The 50% effective doses (ED50) of preventive and treatment administrations were 1.420 4 g · kg(-1) and 1.048 9 g · kg(-1), respectively. Aqueous extracts from Aconiti Lateralis Radix Praeparata could decrease the ratio of heart to body weight, and increase serum LDH and cTn-I. It was concluded that aqueous extracts from Aconiti Lateralis Radix Praeparata had a specific preventive and treatment effect on rats with diarrheal caused by senna, but with specific toxicity on heart.

Aconite poisoning following the percutaneous absorption of Aconitum alkaloids.

In vitro experiment using the modified Franz-type diffusion cell has demonstrated that the human skin is permeable to aconitine and mesaconitine. To characterise the risk of systemic toxicity following the topical applications of aconite tincture and raw aconite roots, relevant reports of percutaneous absorption of Aconitum alkaloids and aconite poisoning are reviewed. Published reports indicate that aconite tincture and raw aconite roots can be absorbed through the skin into systemic circulation to cause fatal and non-fatal aconite poisoning. Both aconite tincture and raw aconite roots contain very high concentrations of Aconitum alkaloids, which allow penetration of the stratum corneum along the diffusion gradient. The risk of systemic toxicity is even higher if Aconitum alkaloids are held in occlusive contact with the skin and the epidermis (stratum corneum) is already damaged. The public should be warned of the danger in using these topical aconite preparations and the risk of systemic toxicity following percutaneous absorption of Aconitum alkaloids.

Toxicological risks of Chinese herbs.

As traditional Chinese medicine (TCM) has become more popular there have been increasing concerns about safety and potential toxicity of the Chinese materia medica (CMM) comprising plants, animal parts and minerals. The potential toxicity of many CMM is well recognised in TCM and to reduce risks use of some herbs is restricted whilst specific processing methods have been developed to modify the activities/toxicity of others. However adverse reactions have been reported, many of these are due misuse or abuse of Chinese medicine. The main problem remains products adulterated with pharmaceuticals for weight loss or erectile dysfunction. But some herbs have narrow therapeutic ranges (e.g., Aconitum species) so toxic effects are frequently reported. Toxic effects from chronic or cumulative dosing are difficult to detect in the traditional setting and recent reports have demonstrated the health problems from Aristolochia species. Despite safety concerns, Chinese medicine appears to be relatively safe with comparatively few reports of adverse reactions compared with overall drug reports. The wealth of information in the Chinese literature needs to be more widely available. As TCM is widely used by patients, improved pharmacovigilance and pharmacoepidemiology can contribute valuable safety information, relevant to clinical use.

Ventricular tachycardia after ingestion of ayurveda herbal antidiarrheal medication containing aconitum.

Ayurveda is an East Indian tradition involving the treatment of medical ailments through the use of herbal medications. A previously asymptomatic 62-year-old man with a history of hypertension and stable coronary artery disease developed paresthesias and fascicular and ventricular tachycardia after ingestion of an Ayurveda bowel regimen containing substrates from the Aconitum species, which is a known neurotoxin and cardiotoxin. Findings of electrophysiologic study and cardiac magnetic resonance imaging were within normal limits, pointing to the ingestion of Aconitum as the most likely source of his arrhythmia.

Bradycardia, reversible panconduction defect and syncope following self-medication with a homeopathic medicine.

Alkaloid extracts from the plant Aconitum species have been used in various forms of herbal remedies predominantly as anti-inflammatory and analgesic agents. Many of these alkaloids are extremely potent cardiotoxins and documented cases of various arrhythmias with fatal outcomes have been reported. We report a case of self-medication with 'tincture of aconite' resulting in severe bradycardia, reversible panconduction defect evidenced by sinus inactivity, atrioventricular dissociation with idiojunctional rhythm and left bundle branch block pattern resulting in hypotension and syncope. Complete reversal of ECG findings with marked improvement in symptoms was noted within a few hours. Herbal medicines containing aconite alkaloids may result in severe cardiotoxicity, and strict regulatory measures are warranted to curb unsupervised use for therapeutic purposes.