Cardiotoxic principle in comfrey.
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Allantoin↗
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[Data on the composition of comfrey mucilage].
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Chemistry Techniques, Analytical↗
[A comfrey phytobezoar; a case report].
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Adult↗
Carcinogenic activity of Symphytum officinale.
The carcinogenicity of Symphytum officinale L., Russian comfrey, used as a green vegetable or tonic, was studied in inbred ACI rats. Three groups of 19--28 rats each were fed comfrey leaves for 480--600 days; four additional groups of 15--24 rats were fed comfrey roots for varying lengths of time. A control group was given a normal diet. Hepatocellular adenomas were induced in all experimental groups that received the diets containing comfrey roots and leaves. Hemangioendothelial sarcoma of the liver was infrequently induced.
Animals↗
Efficacy and safety of topically applied Symphytum herb extract cream in the treatment of ankle distortion: results of a randomized controlled clinical double blind study.
In a controlled, double blind, randomized multicentre study, the efficacy and safety of the topical comfrey product Traumaplant (10% active ingredient of a 2.5:1 aqueous ethanolic pressed juice of freshly harvested, cultivated comfrey herb (Symphytum x uplandicum NYMAN), corresponding to 25 g of fresh herb per 100 g of cream; n = 104) was tested against a 1% product (corresponding to 2.5 g of fresh comfrey herb in 100 g of cream; n = 99) in 203 patients with acute ankle distortion. With the high concentration, decrease of the scores for pain on active motion, pain at rest and functional impairment was highly significant and clinically relevant on days T3-4 as well as T7 (p < 0.001). Amelioration of swellings as compared to reference was also significant on day 3-4 (p < 0.01). Efficacy was judged good to excellent in 85.6% of cases with verum and in 65.7% of cases with reference on day 3-4. Overall tolerability was excellent.
Administration, Topical↗
Topical symphytum herb concentrate cream against myalgia: a randomized controlled double-blind clinical study.
The effectiveness and tolerability of the topical Symphytum product Traumaplant (Harras Pharma Curarina, München, Germany) (10% active ingredient of a 2.5:1 aqueous-ethanolic pressed concentrate of freshly harvested, cultivated comfrey herb [Symphytum uplandicum Nyman], corresponding to 25 g of fresh herb per 100 g of cream) in the treatment of patients with myalgia (n=104) were tested against a 1% reference product (corresponding to 2.5 g of fresh comfrey herb in 100 g of cream; n=111). The primary efficacy parameter in this double-blind, reference- controlled, randomized, multicenter study of 215 patients with pain in the lower and upper back was pain in motion, assessed with the aid of a visual analogue scale. Secondary efficacy parameters included pain at rest, pain on palpation, and functional impairment. With high concentrations of the treatment product, amelioration of pain on active motion (P<5 x 10 -9 ), pain at rest (P<.001), and pain on palpation (P=5 x 10 -5 ) was significantly more pronounced than that attained with the reference product and was clinically highly relevant. A number needed to treat of 3.2 was calculated from the study results. Global efficacy was significantly better (P=1 x 10 -8 ) and onset of effects was faster (P=4 x 10 -7 ) with the high-concentration product. Tolerability of the highly concentrated study product was good to excellent in all patients. Study results confirm the known anti-inflammatory and analgesic effects of topical (Symphytum cream. As a new finding, applicability in certain forms of back pain can be concluded.
Adult↗
Consumption of poisonous plants (Senecio jacobaea, Symphytum officinale, Pteridium aquilinum, Hypericum perforatum) by rats: chronic toxicity, mineral metabolism, and hepatic drug-metabolizing enzymes.
Effect of dietary tancy ragwort (Senecio jacobaea), comfrey (Symphytum officinale), bracken (Pteridium aquilinum) and alfalfa (Medicago sativa) on hepatic drug-metabolizing enzymes in rats were measured. Tansy ragwort and bracken increased (P less than 0.05) the activity of glutathione transferase and epoxide hydrolase. Comfrey and alfalfa increased (P less than 0.05) the activity of aminopyrine N-demethylase. Feeding bracken or St. John's wort (Hypericum perforatum) in conjunction with tansy ragwort did not influence chronic toxicity of tansy ragwort as assessed by rat survival time. Dietary tansy ragwort resulted in increased (P less than 0.05) hepatic copper levels; the other plants did not affect copper levels. The results do not suggest any major interaction in the toxicity of tansy ragwort with bracken or St. John's wort.
Animals↗
Formation of DHP-derived DNA adducts in vivo from dietary supplements and chinese herbal plant extracts containing carcinogenic pyrrolizidine alkaloids.
We recently determined that the metabolism of a series of tumorigenic pyrrolizidine alkaloids resulted in the formation of a set of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts. These DHP-derived DNA adducts have been proposed as potential biomarkers of pyrrolizidine alkaloid tumorigenicity, as well as pyrrolizidine alkaloid exposure. In this paper, we report that DHP-derived DNA adducts are formed in the liver of female F344 rats, gavaged with three dietary supplements (comfrey root extract, comfrey compound oil, and coltsfoot root extract), or an extract of a Chinese herbal plant, flos farfara (Kuan Tong Hua).
Animals↗
The Budd-Chiari syndrome and hepatic veno-occlusive disease. Recognition and treatment.
In a review of 29 patients who were surgically treated by combined hepatic and portal decompression for intractable ascites, 18 were identified as falling into the category of the Budd-Chiari syndrome, with varying causes. Of this group, 2 patients were distinguished by the classical hepatic venous endophlebitis described by Chiari and later by Bras et al. Recently, this disease entity has been recognized as being due to the toxic effects of pyrrolizidine alkaloids contained in the Senecio and Crotolaria plants. In the first of these two cases the patient had emigrated from Jamaica and was exposed to "bush trees," but no chemical measurements were done. The second patient had consumed a large amount of comfrey teas, which were shown to contain high levels of pyrrolizidine alkaloids. These two cases add further weight to the existing evidence of the toxic effect of these alkaloids, and also demonstrate the effectiveness of hepatic and portal decompression.
Beverages↗
Foraging bumblebees avoid flowers already visited by conspecifics or by other bumblebee species
Honey bees, Apis mellifera, use short-lived repellent scent marks to distinguish and reject flowers that have recently been visited by themselves or by siblings, and so save time that would otherwise be spent in probing empty flowers. Conversely, both honey bees and bumblebees, Bombus spp., can mark rewarding flowers with scent marks that promote probing by conspecifics. We examined detection of recently visited flowers in a mixed community of bumblebees foraging on comfrey, Symphytum officinale, in southern England. When foraging among inflorescences on a plant, three abundant species of Bombus probed fewer inflorescences more than once than would be expected from random foraging. Bees frequently encountered inflorescences but departed without probing them for nectar. Examination of the incidence of such rejections in the two most common species, B. terrestris and B. pascuorum, revealed that the low incidence of multiple probing visits was due to two factors: bees both foraged systematically and selectively rejected inflorescences that they had previously visited. When presented with inflorescences of known history, bees selectively rejected those that had been recently visited by themselves or by conspecifics compared with randomly selected inflorescences. They were also able to distinguish inflorescences that had been visited by other Bombus species. Bees were unable to distinguish and reject inflorescences from which the nectar had been removed artificially. We conclude that these Bombus species are probably using scent marks left by previous visitors. The significance of deposition and detection of interspecific scent marks for competitive interactions between species is discussed. Copyright 1998 The Association for the Study of Animal Behaviour.
Journal Article↗
Toxicokinetics of riddelliine, a carcinogenic pyrrolizidine alkaloid, and metabolites in rats and mice.
Riddelliine is a representative pyrrolizidine alkaloid, a class of naturally occurring toxic phytochemicals present in plant species worldwide. Human exposure to pyrrolizidine alkaloids occurs through consumption of herbal dietary supplements, including comfrey, and through contaminated livestock products (e.g., milk). A recently completed 2-year bioassay of riddelliine carcinogenicity showed that male and female rats and male mice, but not female mice, developed liver tumors. The toxicokinetics of riddelliine and two metabolites, the N-oxide and retronecine, were determined in serum following an oral gavage dose in male and female rats and mice using a validated liquid chromatography-electrospray mass spectrometric method. The results are consistent with extensive metabolism of riddelliine and its more polar metabolites prior to excretion. It is concluded that factors other than toxicokinetics are responsible for the observed species/sex specificity of gross toxicity or liver tumor induction in rats and mice.
Animals↗
An evaluation of acetone extracts from six plants in the Ames mutagenicity test.
Acetone extracts from six plants were evaluated for mutagenic activity with the Salmonella/mammalian-microsome mutagenicity test (Ames) utilizing tester strains TA98 and TA100 and in the presence and absence of induced rat liver microsomes. Extracts from alfalfa (Medicago sativa), lettuce (Lactuca sativa) and thread-leaf groundsel (Senecio longilobus) produced only negative responses. Comfrey (Symphytum officinale) and tansy ragwort (Senecio jacobaea) extracts produced toxic responses that were abolished in the presence of the microsomal bioactivation system. Bracken (Pteridium aquilinum) and tansy ragwort extracts produced positive responses following bioactivation with the liver microsomal system. The results suggest that the Ames mutagenicity test may be of some value in initial evaluations for potential toxic effects of plants consumed by animals and man.
Acetone↗
Hepatic venocclusive disease associated with the consumption of pyrrolizidine-containing dietary supplements.
Venocclusive disease, a form of Budd-Chiari syndrome, was diagnosed in a 49-yr-old woman. The patient had portal hypertension associated with obliteration of the smaller hepatic venules. A liver biopsy specimen showed centrilobular necrosis and congestion. Analysis of food supplements the woman regularly consumed showed the presence of pyrrolizidine alkaloids. The major source was a powder purporting to contain ground comfrey root (Symphytum sp). We calculated that during the 6 mo before the woman was hospitalized, she had consumed a minimum of 85 mg of pyrrolizidine alkaloids (15 micrograms/kg body wt X day). The clinical and analytic findings were consistent with chronic pyrrolizidine intoxication, indicating that low-level, chronic exposure to such alkaloids can cause venocclusive disease.
Budd-Chiari Syndrome↗
Simultaneous determination of N-oxides and free bases of pyrrolizidine alkaloids by cation-exchange solid-phase extraction and ion-pair high-performance liquid chromatography.
Cation-exchange solid-phase extraction using LiChrolut SCX (Merck, Darmstadt) cartridges filled with polymeric strong cation-exchanger enabled efficient isolation of both N-oxides and free bases of pyrrolizidine alkaloids (PAs). The recoveries were about 80% for retrorsine-N-oxide, 90% for retrorsine and 100% for senkirkine and were assessed both by TLC-densitometry and ion-pair high-performance liquid chromatography (HPIPC) on Hypersil BDS C8 stationary phase and hexane-l-sulfonic acid as ion-pairing agent. The applied HPIPC gradient procedure was suitable for separation of PAs with various types of structures (N-oxides, free bases, otonecine-PAs). The method limits of detection and quantitation, respectively, ranged from 0.06 ng/microl (senecionine) and 0.2 ng/microl (senkirkine) to 0.1 and 0.35 ng/microl for retrorsine-N-oxide. For each component calibrated by linear regression method, correlation coefficients were higher than 0.9995 (six-point calibration from 4 to 100 microg/ml). The elaborated procedure was used in searching for PAs in plant derived samples from Symphytum sp. (comfrey), Petasites hybridus and Petasites albus (butterbur), Tussilago farfara (coltsfoot), Emilia coccinea (tassel flower) and Doronicum columnae (leopard's bane). For the last three samples macrocyclic PAs (senecionine, senecionine-N-oxide. senkirkine) have been detected for the first time. Details of precision of the analyses are also included.
Cation Exchange Resins↗
Screening botanical extracts for quinoid metabolites.
Botanical dietary supplements represent a significant share of the growing market for alternative medicine in the USA, where current regulations do not require assessment of their safety. To help ensure the safety of such products, an in vitro assay using pulsed ultrafiltration and LC-MS-MS has been developed to screen botanical extracts for the formation of electrophilic and potentially toxic quinoid species upon bioactivation by hepatic cytochromes P450. Rat liver microsomes were trapped in a flow-through chamber by an ultrafiltration membrane, and samples containing botanical extracts, GSH and NADP(H), were flow-injected into the chamber. Botanical compounds that were metabolized to reactive intermediates formed stable GSH adducts mimicking a common in vivo detoxification pathway. If present in the ultrafiltrate, GSH conjugates were detected using LC-MS-MS with precursor ion scanning followed by additional characterization using product ion scanning and comparison to standard compounds. As expected, no GSH adducts of reactive metabolites were found in extracts of Trifolium pratense L. (red clover), which are under investigation as botanical dietary supplements for the management of menopause. However, extracts of Sassafras albidum (Nutt.) Nees (sassafras), Symphytum officinale L. (comfrey), and Rosmarinus officinalis L. (rosemary), all of which are known to contain compounds that are either carcinogenic or toxic to mammals, produced GSH adducts during this screening assay. Several compounds that formed GSH conjugates including novel metabolites of rosmarinic acid were identified using database searching and additional LC-MS-MS studies. This assay should be useful as a preliminary toxicity screen during the development of botanical dietary supplements. A positive test suggests that additional toxicological studies are warranted before human consumption of a botanical product.
Animals↗
Rat toxicogenomic study reveals analytical consistency across microarray platforms.
To validate and extend the findings of the MicroArray Quality Control (MAQC) project, a biologically relevant toxicogenomics data set was generated using 36 RNA samples from rats treated with three chemicals (aristolochic acid, riddelliine and comfrey) and each sample was hybridized to four microarray platforms. The MAQC project assessed concordance in intersite and cross-platform comparisons and the impact of gene selection methods on the reproducibility of profiling data in terms of differentially expressed genes using distinct reference RNA samples. The real-world toxicogenomic data set reported here showed high concordance in intersite and cross-platform comparisons. Further, gene lists generated by fold-change ranking were more reproducible than those obtained by t-test P value or Significance Analysis of Microarrays. Finally, gene lists generated by fold-change ranking with a nonstringent P-value cutoff showed increased consistency in Gene Ontology terms and pathways, and hence the biological impact of chemical exposure could be reliably deduced from all platforms analyzed.
Animals↗
Unsafe and potentially safe herbal therapies.
Unsafe and potentially safe herbal therapies are discussed. The use of herbal therapies is on the rise in the United States, but most pharmacists are not adequately prepared educationally to meet patients' requests for information on herbal products. Pharmacists must also cope with an environment in which there is relatively little regulation of herbal therapies by FDA. Many herbs have been identified as unsafe, including borage, calamus, coltsfoot, comfrey, life root, sassafras, chaparral, germander, licorice, and ma huang. Potentially safe herbs include feverfew, garlic, ginkgo, Asian ginseng, saw palmetto, St. John's wort, and valerian. Clinical trials have been used to evaluate feverfew for migraine prevention and rheumatoid arthritis; garlic for hypertension, hyperlipidemia, and infections; ginkgo for circulatory disturbances and dementia; ginseng for fatigue and cancer prevention; and saw palmetto for benign prostatic hyperplasia. Also studied in formal trials have been St. John's wort for depression and valerian for insomnia. The clinical trial results are suggestive of efficacy of some herbal therapies for some conditions. German Commission E, a regulatory body that evaluates the safety and efficacy of herbs on the basis of clinical trials, cases, and other scientific literature, has established indications and dosage recommendations for many herbal therapies. Pharmacists have a responsibility to educate themselves about herbal therapies in order to help patients discern the facts from the fiction, avoid harm, and gain what benefits may be available.
Drug Interactions↗
Drug-induced liver disease.
Although the year 2001 did not see any prescription drugs withdrawn because of drug-induced liver disease, the US Food and Drug Administration requested that dietary supplements containing comfrey be taken off the market because of the danger of hepatic injury. The Food and Drug Administration remains very involved in the process by which drug-induced liver disease can be detected early in drug development and in the determination of how best to prevent hepatotoxicity after drug approval. A workshop on drug-induced liver disease cosponsored by the Food and Drug Administration, the Pharmaceutical Research and Manufacturers Association, and the American Association for the Study of Liver Diseases was held in Washington, DC, in February 2001, and the resulting white paper outlined several areas for research. A number of agents were newly described as causing various forms of liver injury, and several others had drug-induced liver disease confirmed by additional reports. Several investigators dealt with the difficulties inherent in establishing causality of drug-induced liver disease and the potential negative consequences of wrongly attributing hepatotoxicity to a particular agent. In one recent series, more than half the instances of alleged drug-induced liver disease were found to have other causes, often leading to a delay in the actual diagnosis and appropriate management. Case reports in particular were often misleading. Although several drug assessment scales have been developed, none appears to be foolproof.
Journal Article↗