Herbal Science Research - toxicology

Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): A review [...]

Site Editor — Fri, 02 Nov 2007 15:49:24 -0700

Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): A review of recent research.: Food Chem Toxicol. 2007 Sep 18; Ali BH, Blunden G, Tanira MO, Nemmar A

Ginger (Zingiber officinale Roscoe, Zingiberacae) is a medicinal plant that has been widely used in Chinese, Ayurvedic and Tibb-Unani herbal medicines all over the world, since antiquity, for a wide array of unrelated ailments that include arthritis, rheumatism, sprains, muscular aches, pains, sore throats, cramps, constipation, indigestion, vomiting, hypertension, dementia, fever, infectious diseases and helminthiasis. Currently, there is a renewed interest in ginger, and several scientific investigations aimed at isolation and identification of active constituents of ginger, scientific verification of its pharmacological actions and of its constituents, and verification of the basis of the use of ginger in some of several diseases and conditions. This article aims at reviewing the most salient recent reports on these investigations. The main pharmacological actions of ginger and compounds isolated therefrom include immuno-modulatory, anti-tumorigenic, anti-inflammatory, anti-apoptotic, anti-hyperglycemic, anti-lipidemic and anti-emetic actions. Ginger is a strong anti-oxidant substance and may either mitigate or prevent generation of free radicals. It is considered a safe herbal medicine with only few and insignificant adverse/side effects. More studies are required in animals and humans on the kinetics of ginger and its constituents and on the effects of their consumption over a long period of time.

[Advances in studies on pharmacokinetics of aristolochic acid I]

Site Editor — Fri, 02 Nov 2007 15:29:34 -0700

[Advances in studies on pharmacokinetics of aristolochic acid I]: Zhongguo Zhong Yao Za Zhi. 2006 Oct;31(19):1573-5 Authors: Wang G, Wang ZM, Sun QS

Aristolochic acid I (AA-I) was absorbed and distributed quickly in vivo, the plasma concentration-time curve were fit with the open two-compartment model and one-compartment model, respectively. The elimination of AA-I has relationship with the dosage, the low dose group eliminates more quickly than the high dose group. The characters of pharmacokinetics of AA-I induce the cumulation of AA-I in vivo and the nephrotoxin to the kidney and other viscera.

PMID: 17165576 [PubMed - indexed for MEDLINE]

Black cohosh (Cimicifuga racemosa [L.] Nutt.): safety and efficacy for cancer patients.

Site Editor — Fri, 02 Nov 2007 05:52:36 -0700

Black cohosh (Cimicifuga racemosa [L.] Nutt.): safety and efficacy for cancer patients.: Support Care Cancer. 2007 Aug;15(8):913-21 Authors: Walji R, Boon H, Guns E, Oneschuk D, Younus J

GOALS OF WORK: Black cohosh is commonly used to treat hot flashes and other symptoms associated with menopause. It is thought to have multiple mechanisms of action, including potential phytoestrogenic properties. This has caused some concern about its use by patients with hormone-sensitive cancer. This paper will present the results of a systematic review of the safety and efficacy of black cohosh (Cimicifuga racemosa [L.] Nutt.) in patients with cancer. MATERIALS AND METHODS: A critical assessment of clinical (n = 5) and preclinical (n = 21) studies of black cohosh and cancer (breast and prostate) to treat hot flashes and other related symptoms is presented. In addition, clinical studies, case reports, animal studies, and in vitro assessments of the safety of black cohosh for patients with hormonally sensitive cancers is summarized and interpreted. MAIN RESULTS: In general, the research assessing efficacy of black cohosh for the treatment of hot flashes in women with breast cancer is inconclusive. There is laboratory evidence of antiproliferative properties but no confirmation from clinical studies for a protective role in cancer prevention. Black cohosh seems to have a relatively good safety profile. Concerns about liver toxicity are inconclusive. With relevance to cancer patients, black cohosh also seems not to exhibit phytoestrogenic activity and is in fact possibly an inhibitor of tumor growth. CONCLUSIONS: The use of black cohosh appears to be safe in breast cancer patients without risk for liver disease, although further research is needed in this and other populations.

PMID: 17602247 [PubMed - indexed for MEDLINE]

Epigallocatechin-3-gallate inhibits the invasion of human oral cancer cells [...]

Site Editor — Sun, 21 Oct 2007 05:54:24 -0700

Epigallocatechin-3-gallate inhibits the invasion of human oral cancer cells and decreases the productions of matrix metalloproteinases and urokinase-plasminogen activator.: J Oral Pathol Med. 2007 Nov;36(10):588-93 Authors: Ho YC, Yang SF, Peng CY, Chou MY, Chang YC

Background: Green tea polyphenols are considered beneficial to human health, especially as cancer chemopreventive agents in recent years. Epigallocatechin- 3-gallate (EGCG), the most abundant polyphenol in green tea, has been proven to suppress colonic tumorigenesis in animal and epidemiological studies, whereas its role in the oral carcinogenesis remains to be elucidated. Methods: Cytotoxicity, invasion, and migration assays were used to investigate the effects of human oral cancer cell line OC2 cells exposed to EGCG. To look at the precise involvement of EGCG in cancer metastasis, gelatin zymography and casein zymography were performed to evaluate the impacts of EGCG on matrix metalloproteinase (MMP)-2, MMP-9, and urokinase plasminogen activator (uPA) secretion in OC2 cells. Results: EGCG exhibited a dose-dependent inhibitory effect on the invasion and migration of OC2 cells in the absence of cytotoxicity (P < 0.05). EGCG was also found to decrease the expressions of MMP-2, MMP-9, and uPA in a concentration-dependent manner (P < 0.05). Conclusion: Taken together, these results suggest that EGCG could inhibit the invasion and migration of human oral cancer cells and that the effects may partially because of the decreased productions of MMP-2, MMP-9, and uPA.

PMID: 17944751 [PubMed - in process]

Metabolic activation of herbal and dietary constituents and its clinical and toxicological implications: an update.

Site Editor — Thu, 04 Oct 2007 06:07:49 -0700

Metabolic activation of herbal and dietary constituents and its clinical and toxicological implications: an update.: Curr Drug Metab. 2007 Aug;8(6):526-53 Authors: Zhou SF, Xue CC, Yu XQ, Wang G

In recent years, there has been a globally increasing application of herbal medicines and dietary supplements to treat various chronic diseases and to promote health. However, there are increasing clinical reports on the organ toxicities associated with consumption of herbal medicines. This review updates the knowledge on metabolic activation of herbal components and its clinical and toxicological implications. Like many synthetic drugs undergoing metabolic activation to form reactive metabolites which are often associated with drug toxicity, it is recognized that some herbal components may also be converted to toxic, or even mutagenetic and carcinogenic metabolites by cytochrome P450s (CYPs) and less frequently by Phase II conjugating enzymes. This is exemplified by aristolochic acids (AAs) in Aristolochia spp, which undergo reduction of the nitro group by hepatic CYP1A1/2 or peroxidases in extrahepatic tissues to generate highly reactive cyclic nitrenium ions. The latter can react with macromolecules (DNA and protein), resulting in activation of H-ras oncogene and gene mutation in renal cells and finally carcinogenesis of the kidneys. Some naturally occurring flavonoids (e.g. quercetin) and alkenylbenzenes (e.g. safrole, methyleugenol and estragole) can undergo metabolic activation by sequential 1-hydroxylation and sulfation, resulting in reactive intermediates capable of forming DNA adducts and finally genotoxicity. Additional examples are pulegone present in essential oils from many mint species; and teucrin A, a diterpenoid found in germander (Teuchrium chamaedrys) used as an adjuvant to slimming dietary supplements but caused severe hepatotoxicity. Extensive pulegone metabolism generated p-cresol that was a glutathione depletory, whereas the furan ring of the diterpenoids in germander was oxidized by CYP3A4 to reactive epoxide which can inactivate hepatic CYP3A and epoxide hydrolase through covalent binding. The hepatotoxic and carcinogenic species of plant pyrrolizidine alkaloids (e.g. echimidine and jacobine), namely pyrrole-type metabolites, are generated by hepatic CYP2B6 and CYP3A4. Potential mechanisms underlying the hepatotoxicity of kava have been related to intracellular glutathione depletion and/or quinone formation. Some herbal constituents (e.g. capsaicin from chili peppers, glabridin from licorice root, oleuropein in olive oil, dially sulfone in garlic, and resveratrol found in red wine) behave as mechanism-based inhibitors of various CYPs. This may provide an explanation for some reported herb-drug interactions. In addition, the inhibition of CYPs by herbal constituents may decrease the formation of toxic metabolites and thus inhibit carcinogenesis, as CYPs play an important role in procarcinogen activation. Due to the wide use and easy availability of herbal medicines, further research should be conducted to ensure the safety and quality of herbal medicine.

PMID: 17691916 [PubMed - indexed for MEDLINE]

The toxicology of cannabis and cannabis prohibition.

Site Editor — Sun, 30 Sep 2007 02:38:23 -0700

The toxicology of cannabis and cannabis prohibition.: Chem Biodivers. 2007 Aug;4(8):1744-69 Authors: Grotenhermen F

The acute side effects caused by cannabis use are mainly related to psyche and cognition, and to circulation. Euphoria, anxiety, changes in sensory perception, impairment of memory and psychomotor performance are common effects after a dose is taken that exceeds an individually variable threshold. Cannabis consumption may increase heart rate and change blood pressure, which may have serious consequences in people with heart disease. Effects of chronic use may be induction of psychosis and development of dependency to the drug. Effects on cognitive abilities seem to be reversible after abstinence, except possibly in very heavy users. Cannabis exposure in utero may have negative consequences on brain development with subtle impairment of cognitive abilities in later life. Consequences of cannabis smoking may be similar to those of tobacco smoking and should be avoided. Use by young people has more detrimental effects than use by adults. There appear to be promising therapeutic uses of cannabis for a range of indications. Use of moderate doses in a therapeutic context is usually not associated with severe side effects. Current prohibition on cannabis use may also have harmful side effects for the individual and the society, while having little influence on prevalence of use. Harm is greatest for seriously ill people who may benefit from a treatment with cannabis. This makes it difficult to justify criminal penalties against patients.

PMID: 17712818 [PubMed - indexed for MEDLINE]

Influence of aqueous extract of Hibiscus sabdariffa L. petal on cadmium toxicity in rats.

Site Editor — Sat, 22 Sep 2007 17:07:36 -0700

Influence of aqueous extract of Hibiscus sabdariffa L. petal on cadmium toxicity in rats.: Biol Trace Elem Res. 2007 Jan;115(1):47-57 Authors: Asagba SO, Adaikpoh MA, Kadiri H, Obi FO

The effects of chronic exposure to cadmium (Cd) on some selected biochemical parameters, as well as the possible protective role of aqueous extracts of Hibiscus sabdariffa L petal were studied in 12-wk-old male Wistar albino rats. Exposure to Cd caused a significant increase in plasma Lalanine aminotransferases (ALT) only but with a corresponding decrease in liver L-alanine and L-aspartate aminotransferases (L-ALT, L-AST) when compared to the Cd-free control. Total superoxide dismutase activity was decreased in the liver, testis, and prostate of Cd-exposed rats, whereas malondialdehyde (MDA) concentrations were increased relative to the Cd-free control. The metal significantly increased prostatic acid phosphatase activity in the prostate, but decreased the body weight gain of the rats and organ/body weight ratio for prostate and testis compared to the Cd-free control. Pretreatment of rats with aqueous extract of H. sabdariffa resulted in significantly less hepatotoxicity than with Cd alone as measured by plasma ALT and liver ALT and AST activities. The extract also protected the rats against Cd-induced liver, prostate, and testis lipoperoxidation as evidenced by significantly reduced MDA values in these organs, as well as reduced prostatic acid phosphatase activity in the prostate, when compared to the Cd-only exposed rats. Also, when compared to the organ/body weight ratios obtained from rats exposed to Cd alone the prostate and testis were protected by the extract as shown by enhanced prostate/body weight and testis/body weight ratios of Cd- and extract-treated rats. These data suggest that H. sabdarrifa L might be protective in Cd toxicity.

PMID: 17406073 [PubMed - indexed for MEDLINE]

Use of Artemisinin (Qinghaosu) derivatives in the treatment of malaria.

Site Editor — Fri, 13 Jul 2007 18:05:01 -0700

Use of Artemisinin (Qinghaosu) derivatives in the treatment of malaria.: Afr J Health Sci. 1998 Feb;5(1):8-11 Authors: Kokwaro GO

Derivatives of the Chinese herbal remedy ginghaosu (artemisinin) are useful in the treatment of multiple-drug resistant malaria. This review covers the discovery, development, clinical pharmacology and toxicology of these compounds, with emphasis on those derivatives currently in use in parts of Africa.

PMID: 17580987 [PubMed - in process]

Pediatric toxicology.

Site Editor — Fri, 13 Jul 2007 17:57:04 -0700

Pediatric toxicology.: Emerg Med Clin North Am. 2007 May;25(2):283-308; abstract vii-viii Authors: Eldridge DL, Van Eyk J, Kornegay C

Pediatric patients present unique concerns in the field of medical toxicology. First, there are medicines that are potentially dangerous to small children, even when they are exposed to very small amounts. Clinicians should be wary of these drugs even when young patients present with accidental ingestions of apparently insignificant amounts. Next, over-the-counter laxatives and syrup of ipecac, although not commonly considered abused substances, may be misused in both the setting of Munchausen's syndrome by proxy and in adolescents who have eating disorders. Their use should be considered in any gastrointestinal illness of uncertain origin. Finally, as the use of syrup of ipecac at home now has been discouraged by many, some have explored using activated charcoal at home as a new method of prehospital gastrointestinal decontamination. The literature examining activated charcoal and its use in this capacity is discussed.

PMID: 17482021 [PubMed - indexed for MEDLINE]

Herbal medicine in the treatment of liver diseases.

Site Editor — Sat, 23 Jun 2007 05:18:54 -0700

Herbal medicine in the treatment of liver diseases.:

Herbal medicine in the treatment of liver diseases.

Dig Liver Dis. 2007 Apr;39(4):293-304

Authors: Stickel F, Schuppan D

Herbal drugs have become increasingly popular and their use is widespread. Licensing regulations and pharmacovigilance regarding herbal products are still incomplete and clearcut proof of their efficacy in liver diseases is sparse. Nevertheless, a number of herbals show promising activity including silymarin for antifibrotic treatment, phyllantus amarus in chronic hepatitis B, glycyrrhizin to treat chronic viral hepatitis, and a number of herbal combinations from China and Japan that deserve testing in appropriate studies. Apart from therapeutic properties, reports are accumulating about liver injury after the intake of herbals, including those advertised for liver diseases. Acute and/or chronic liver damage occurred after ingestion of some Chinese herbs, herbals that contain pyrrolizidine alkaloids, germander, greater celandine, kava, atractylis gummifera, callilepsis laureola, senna alkaloids, chaparral and many others. Since the evidence supporting the use of botanicals to treat chronic liver diseases is insufficient and only few of them are well standardised and free of potential serious side effects, most of these medications are not recommended outside clinical trials. Particularly with regard to the latter, adequately powered randomised-controlled clinical trials with well-selected end points are needed to assess the role of herbal therapy for liver diseases.

PMID: 17331820 [PubMed - indexed for MEDLINE]

Amelioration of galactosamine-induced nephrotoxicity by a protein isolated from the leaves of the herb, Cajanus indicus L.

Site Editor — Mon, 11 Jun 2007 05:53:50 -0700

Amelioration of galactosamine-induced nephrotoxicity by a protein isolated from the leaves of the herb, Cajanus indicus L.: BMC Complement Altern Med. 2007;7:11 Authors: Sinha M, Manna P, Sil PC

BACKGROUND: Galactosamine (GalN), an established experimental toxin, mainly causes liver injury via the generation of free radicals and depletion of UTP nucleotides. Renal failure is often associated with end stage liver damage. GalN intoxication also induces renal dysfunction in connection with hepatic disorders. Present study was designed to find out the effect of a protein isolated from the leaves of the herb Cajanus indicus against GalN induced renal damage. METHODS: Both preventive as well as curative effect of the protein was investigated in the study. GalN was administered intraperitoneally at a dose of 800 mg/kg body weight for 3 days pre and post to protein treatment at an intraperitoneal dose of 2 mg/kg body weight for 4 days. The activities of antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) and glutathione-S-transferase (GST), levels of cellular metabolites, reduced glutathione (GSH), total thiols, oxidized glutathione (GSSG) and lipid peroxidation end products were determined to estimate the status of the antioxidative defense system. In addition, serum creatinine and urea nitrogen (UN) levels were also measured as a marker of nephrotoxicity. RESULTS: Results showed that GalN treatment significantly increased the serum creatinine and UN levels compared to the normal group of mice. The extent of lipid peroxidation and the level of GSSG were also enhanced by the GalN intoxication whereas the activities of antioxidant enzymes SOD, CAT, GR and GST as well as the levels of total thiols and GSH were decreased in the kidney tissue homogenates. Protein treatment both prior and post to the toxin administration successfully altered the effects in the experimental mice. CONCLUSION: Our study revealed that GalN caused a severe oxidative insult in the kidney. Protein treatment both pre and post to the GalN intoxication could protect the kidney tissue against GalN induced oxidative stress. As GalN induced severe hepatotoxicity followed by renal failure, the protective role of the protein against GalN induced renal damages is likely to be an indirect effect. Since the protein possess hepatoprotective activity, it may first ameliorate GalN-induced liver damage and consequently the renal disorders are reduced. To the best of our knowledge, this is probably the first report describing GalN-induced oxidative stress in renal damages and the protective role of a plant protein molecule against it.

Gynura root induces hepatic veno-occlusive disease: a case report and review of the literature.

Site Editor — Mon, 11 Jun 2007 05:52:02 -0700

Gynura root induces hepatic veno-occlusive disease: a case report and review of the literature.: World J Gastroenterol. 2007 Mar 14;13(10):1628-31 Authors: Dai N, Yu YC, Ren TH, Wu JG, Jiang Y, Shen LG, Zhang J

Gynura root has been used extensively in Chinese folk medicine and plays a role in promoting microcirculation and relieving pain. However, its hepatic toxicity should not be neglected. Recently, we admitted a 62-year old female who developed hepatic veno-occlusive disease (HVOD) after ingestion of Gynura root. Only a few articles on HVOD induced by Gynura root have been reported in the literature. It is suspected that pyrrolizidine alkaloids in Gynura root might be responsible for HVOD. In this paper, we report a case of HVOD and review the literature.

Study of the anticancer potential of Yemeni plants used in folk medicine.

Site Editor — Mon, 11 Jun 2007 05:48:39 -0700

Study of the anticancer potential of Yemeni plants used in folk medicine.: Pharmazie. 2007 Apr;62(4):305-7 Authors: Mothana RA, Grünert R, Lindequist U, Bednarski PJ

The present work evaluated the anticancer activity of methanol extracts from 24 plants used in Yemeni traditional medicine. To evaluate the in vitro cytotoxic potency of the investigated extracts, an established microtiter plate assay based on cellular staining with crystal violet was used with 5 human cancer cell lines: two lung cancer (A-427 and LCLC-103H), two urinary bladder carcinoma (5637 and RT-112) and one breast cancer (MCF-7) line. The methanolic extracts of Dendrosicyos socotrana, Withanina aduensis, Withania riebeckii, Dracena cinnabari and Buxus hildebrandtii exhibited the highest toxicity on all tumor cell lines with IC50 values ranging between 0.29 and 5.54 microg/ml. The extracts of Jatropha unicostata and Punica protopunica showed a moderate potency on the most tumor cell lines.

Case report: acute unintentional carbachol intoxication.

Site Editor — Wed, 30 May 2007 01:29:44 -0700

Case report: acute unintentional carbachol intoxication.: Crit Care. 2006;10(3):R84 Authors: Schulz M, Graefe T, Stuby K, Andresen H, Kupfermann N, Schmoldt A

INTRODUCTION: Intoxications with carbachol, a muscarinic cholinergic receptor agonist are rare. We report an interesting case investigating a (near) fatal poisoning. METHODS : The son of an 84-year-old male discovered a newspaper report stating clinical success with plant extracts in Alzheimer's disease. The mode of action was said to be comparable to that of the synthetic compound 'carbamylcholin'; that is, carbachol. He bought 25 g of carbachol as pure substance in a pharmacy, and the father was administered 400 to 500 mg. Carbachol concentrations in serum and urine on day 1 and 2 of hospital admission were analysed by HPLC-mass spectrometry. RESULTS: Minutes after oral administration, the patient developed nausea, sweating and hypotension, and finally collapsed. Bradycardia, cholinergic symptoms and asystole occurred. Initial cardiopulmonary resuscitation and immediate treatment with adrenaline (epinephrine), atropine and furosemide was successful. On hospital admission, blood pressure of the intubated, bradyarrhythmic patient was 100/65 mmHg. Further signs were hyperhidrosis, hypersalivation, bronchorrhoea, and severe miosis; the electrocardiographic finding was atrio-ventricular dissociation. High doses of atropine (up to 50 mg per 24 hours), adrenaline and dopamine were necessary. The patient was extubated 1 week later. However, increased dyspnoea and bronchospasm necessitated reintubation. Respiratory insufficiency was further worsened by Proteus mirabilis infection and severe bronchoconstriction. One week later, the patient was again extubated and 3 days later was transferred to a peripheral ward. On the next day he died, probably as a result of heart failure. Serum samples from the first and second days contained 3.6 and 1.9 mg/l carbachol, respectively. The corresponding urine concentrations amounted to 374 and 554 mg/l. CONCLUSION: This case started with a media report in a popular newspaper, initiated by published, peer-reviewed research on herbals, and involved human failure in a case history, medical examination and clinical treatment. For the first time, an analytical method for the determination of carbachol in plasma and urine has been developed. The analysed carbachol concentration exceeded the supposed serum level resulting from a therapeutic dose by a factor of 130 to 260. Especially in old patients, intensivists should consider intoxications (with cholinergics) as a cause of acute cardiovascular failure.

Veratrum poisoning.

Site Editor — Fri, 11 May 2007 15:23:59 -0700

Veratrum poisoning.: Toxicol Rev. 2006;25(2):73-8 Authors: Schep LJ, Schmierer DM, Fountain JS

Several species of the Veratrum genus are associated with toxicity in humans and animals. The principal toxins are steroid alkaloids; some have a modified steroid template, whereas others differ in their esterified acid moieties. These alkaloids act by increasing the permeability of the sodium channels of nerve cells, causing them to fire continuously. Increased stimulation, associated with the vagal nerve results in a reflex that causes the triad of responses known as the Bezold-Jarisch reflex: hypotension, bradycardia and apnoea. Clinically, various Veratrum extracts were marketed for clinical use as antihypertensive drugs, but because of their narrow therapeutic index were withdrawn from the market. Following the ingestion of Veratrum alkaloids, expected signs and symptoms include vomiting and abdominal pain, followed by cardiovascular effects such as bradycardia, hypotension and cardiac conduction abnormalities and death. Similar symptoms arise in other mammalian species ingesting these alkaloids; teratogenic effects may occur to the fetuses of animals that have grazed on Veratrum californicum. Treatment consists of supportive care, with an emphasis on haemodynamic stability with fluid replacement, atropine and vasopressors. The onset of symptoms occurs between 30 minutes and 4 hours, and the duration of the illness can range from 1 to 10 days; however, with prompt supportive care, patients typically make a full recovery within 24 hours.

The early toxicology of physostigmine: a tale of beans, great men and egos.

Site Editor — Fri, 11 May 2007 15:22:10 -0700

The early toxicology of physostigmine: a tale of beans, great men and egos.: Toxicol Rev. 2006;25(2):99-138 Authors: Proudfoot A

Mid-19th century European visitors to Old Calabar, an eastern province of Nigeria, could not avoid becoming aware of native belief in the power of the seeds of a local plant to determine whether individuals were innocent or guilty of some serious misdemeanour. The seeds were those of a previously unknown legume and soon referred to as the ordeal bean of Old Calabar. Their administration was known locally as 'chop nut'. Missionaries who arrived in Calabar in 1846 estimated that chop nut caused some 120 deaths annually and documented the course of poisoning. The latter information and samples of the beans rapidly found their way to Scotland, the home of the missionaries' parent church, explaining why the early toxicology of physostigmine, quantitatively the most important of three active alkaloids in the beans, has such strong Scottish, predominantly Edinburgh, associations. However, it was 1855 before the first of many medical scientists, Robert Christison, a toxicologist of repute, investigated the effects of the beans to the extent of eating part of one himself and documenting the moderate, if not severe, consequences. A further 6 years were to pass before Balfour's comprehensive botanical description of the bean plant appeared. It was he who named it Physostigma venenosum. It was not so long until the next event, one that sparked more intensive and international interest in the beans. In 1863 a young Edinburgh ophthalmologist, Argyll Robertson, published a paper announcing the arrival of the first agent that constricted the pupil of the eye. The drug was an extract of Calabar beans and Argyll Robertson openly admitted that he had been alerted to its unusual property by his physician friend, Thomas Fraser. A minor flood of contributions on the ophthalmic uses of bean extracts followed in the medical press in the next few months; those on their systemic toxicity were fewer. Fraser's MD thesis, submitted to the University of Edinburgh in 1862 and clearly pre-dating Argyll Robertson's involvement with the beans, became generally available a few weeks after the appearance of Argyll Robertson's paper and was the first to address in detail the features of systemic administration of extracts of the beans. A major problem facing all early researchers of the beans was that of deciding how best to extract their active principle, a task made all the more difficult because bioassays were the only means of determining if the toxin was being tracked. The stability of extracts was an inevitable issue and the active principle finally became known as physostigma or physostigmine, after the botanical name of the parent plant. The features of physostigmine toxicity were soon exhaustively documented, both in animals and humans. How they were mediated was another matter altogether. Fraser maintained that muscular paralysis, the cardinal feature, was the result of depression of the spinal cord and was generally, but far from unanimously, supported. Of those who had reservations, Harley was the most prominent. He concluded that paralysis was secondary to effects on the motor nerve endings and, in so doing, came nearest to present-day knowledge at a time when acetylcholine, cholinesterases and cholinesterase inhibitors were not even imagined. Differences of opinion on the mode of action of the beans were to be expected and it is hardly surprising that they were not resolved. No standard formulation of physostigmine was available so the potency of those used would have varied from one investigator to another, the range of animals experimented upon was large while the number used by any researcher was commonly in single figures, more readily available cold-blooded creatures seemed less sensitive to physostigmine toxicity than warm-blooded ones and only Fraser determinedly pursued an answer; in general, the others made one foray into bean research then turned their attentions elsewhere. The same problems would beset other aspects of bean research. While Fraser did not get as close to the mode of action of physostigmine as Harley, he reigns supreme when it comes to antagonism between physostigmine and atropine. By this time, the 1870s had dawned and although the concept of antagonism between therapeutic agents was not new, it had little, if any, reliable scientific foundation. This was about to change; antagonism was becoming exciting and rational. Fraser's firm belief that physostigmine and atropine were mutually antagonistic at a physiological level was contrary to the conventional wisdom of his contemporaries. This alone would earn him a place in history but his contribution goes much, much further. Unlike any other at the time, he investigated it with scientific rigour, experimenting on only one species, ensuring as best he could the animals were the same weight, adjusting the doses of drugs he gave them for bodyweight, determining the minimum lethal dose of each drug before assessing their antagonistic effects, adopting a single, incontrovertible endpoint for efficacy and carrying out sufficient numbers of experiments to appear convincing in a later era where the statistical power of studies is all-important. To crown it all, he presented his results graphically. Fraser never claimed to have discovered the antagonism between physostigmine and atropine. Bartholow in 1873 did, based on work done in 1869. But his data hardly justify it. If anyone can reasonably claim this particular scientific crown it is an ophthalmologist, Niemetschek, working in Prague in 1864. His colleague in the same discipline, Kleinwächter, was faced with treating a young man with atropine intoxication. Knowing of the contrary actions of the two drugs on the pupil, Niemetschek suggested that Calabar bean extract might be useful. Kleinwächter had the courage to take the advice and his patient improved dramatically. Clearly, this evidence is nothing more than anecdotal, but the ophthalmologists were correct and, to the present day, physostigmine has had an intermittent role in the management of anticholinergic poisoning. The converse, giving atropine to treat poisoning with cholinesterase inhibitors, of which physostigmine was the first, has endured more consistently and remains standard practice today. It is salutary to realise that the doses and dosage frequency of atropine together with the endpoints that define they are adequate were formulated by Fraser and others a century and a half ago.

[...] cichorium root extract on the morphofunctional state of liver in rats with carbon tetrachloride induced hepatitis model

Site Editor — Wed, 21 Feb 2007 17:56:39 -0800

[The effect of cichorium root extract on the morphofunctional state of liver in rats with carbon tetrachloride induced hepatitis model]: Eksp Klin Farmakol. 2006 Nov-Dec;69(6):34-6 Authors: Krylova SG, Efimova LA, Vymiatina ZK, Zueva EP

It is established that cichorium root extract therapy leads to normalization of some morphofunctional liver features (decreases glycogen content and cell of necrosis and increases the number of cells with pronounced protein synthesis activity) in rats with CCl4-induced hepatitis.

Novel selective cytotoxicity of wild sarsaparilla rhizome extract.

Site Editor — Thu, 01 Feb 2007 16:52:25 -0800

Novel selective cytotoxicity of wild sarsaparilla rhizome extract.: J Pharm Pharmacol. 2006 Oct;58(10):1399-403 Authors: Huang YG, Li QZ, Ivanochko G, Wang R

Among six fractions, including total extract and fractions of hexane, ethyl acetate, butanol, water and boiling water extracted and separated from wild sarsaparilla rhizome, the hexane fraction (HRW) was the most effective in eliminating four different human cancer cell lines with cellular viability less than 6.8%. HRW exhibited the highest potency against human leukaemia cells with an IC50 (concentration that inhibited the growth rate of cells by 50%) of 3.3 +/- 0.3 microg mL(-1), which was 17.6-fold smaller than that against normal human umbilical vein endothelial cells (IC50, 58.0 +/- 1.5 microg mL(-1)). For its rich natural resources, simple extraction procedure and high yield (3.2%), HRW has the potential to be developed as a selective anti-cancer nutraceutical or pharmaceutical natural health product with low side effects and high economical return.

Rubrisandrins A and B, lignans and related anti-HIV compounds from Schisandra rubriflora.

Site Editor — Thu, 01 Feb 2007 16:51:38 -0800

Rubrisandrins A and B, lignans and related anti-HIV compounds from Schisandra rubriflora.: J Nat Prod. 2006 Dec;69(12):1697-701 Authors: Chen M, Kilgore N, Lee KH, Chen DF

Bioactivity-directed fractionation of an ethanolic extract of the fruits of Schisandra rubriflora led to the isolation and identification of dibenzocyclooctadiene lignans including the new lignans rubrisandrins A (1a + 1b) and B (2) and the known lignans gomisin J (3), (+/-)-gomisin M1 (4), (+)-gomisin M2 (5), schisanhenol (6), deoxyschisandrin, schisantherin B, schisandrin, tigloylgomisin P, gomisin O, angeloylgomisin P, and epigomisin O. Their structure and stereochemistry were determined by spectroscopic methods, including 2D-NMR techniques. Compounds 1 and 3-6 were active as anti-HIV agents. (+/-)-Gomisin M1 (4) exhibited the most potent anti-HIV activity, with EC50 and therapeutic index (TI) values of <0.65 microM and >68, respectively.

Antidotes for acute cardenolide (cardiac glycoside) poisoning.

Site Editor — Sat, 20 Jan 2007 16:33:32 -0800

Antidotes for acute cardenolide (cardiac glycoside) poisoning.: Cochrane Database Syst Rev. 2006;(4):CD005490 Authors: Roberts DM, Buckley NA

BACKGROUND: Cardenolides are naturally occurring plant toxins which act primarily on the heart. While poisoning with the digitalis cardenolides (digoxin and digitoxin) are reported worldwide, cardiotoxicity from other cardenolides such as the yellow oleander are also a major problem, with tens of thousands of cases of poisoning each year in South Asia. Because cardenolides from these plants are structurally similar, acute poisonings are managed using similar treatments. The benefit of these treatments is of interest, particularly in the context of cost since most poisonings occur in developing countries where resources are very limited. OBJECTIVES: To determine the efficacy of antidotes for the treatment of acute cardenolide poisoning, in particular atropine, isoprenaline (isoproterenol), multiple-dose activated charcoal (MDAC), fructose-1,6-diphosphate, sodium bicarbonate, magnesium, phenytoin and anti-digoxin Fab antitoxin. SEARCH STRATEGY: We searched MEDLINE, EMBASE, the Controlled Trials Register of the Cochrane Collaboration, Current Awareness in Clinical Toxicology, Info Trac, www.google.com.au, and Science Citation Index of studies identified by the previous searches. We manually searched the bibliographies of identified articles and personally contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials where antidotes were administered to patients with acute symptomatic cardenolide poisoning were identified. DATA COLLECTION AND ANALYSIS: We independently extracted data on study design, including the method of randomisation, participant characteristics, type of intervention and outcomes from each study. We independently assessed methodological quality of the included studies. A pooled analysis was not appropriate. MAIN RESULTS: Two randomised controlled trials were identified, both were conducted in patients with yellow oleander poisoning. One trial investigated the effect of MDAC on mortality, the relative risk (RR) was 0.31 (95% confidence interval (CI) 0.12 to 0.83) indicating a beneficial effect. The second study found a beneficial effect of anti-digoxin Fab antitoxin on the presence of cardiac dysrhythmias at two hours post-administration; the RR was 0.60 (95% CI 0.44 to 0.81). Other benefits were also noted in both studies and serious adverse effects were minimal. Studies assessing the effect of antidotes on other cardenolides were not identified. One ongoing study investigating the activated charcoal for acute yellow oleander self-poisoning was also identified. AUTHORS' CONCLUSIONS: There is some evidence to suggest that MDAC and anti-digoxin Fab antitoxin may be effective treatments for yellow oleander poisoning. However, the efficacy and indications of these interventions for the treatment of acute digitalis poisoning is uncertain due to the lack of good quality controlled clinical trials. Given pharmacokinetic differences between individual cardenolides, the effect of antidotes administered to patients with yellow oleander poisoning cannot be readily translated to those of other cardenolides. Unfortunately cost limits the use of antidotes such as anti-digoxin Fab antitoxin in developing countries where cardenolide poisonings are frequent. More research is required using relatively cheap antidotes which may also be effective.

Evidence-based systematic review of saw palmetto by the Natural Standard Research Collaboration.

Site Editor — Fri, 19 Jan 2007 18:42:13 -0800

Evidence-based systematic review of saw palmetto by the Natural Standard Research Collaboration.: J Soc Integr Oncol. 2006;4(4):170-86 Authors: Ulbricht C, Basch E, Bent S, Boon H, Corrado M, Foppa I, Hashmi S, Hammerness P, Kingsbury E, Smith M, Szapary P, Vora M, Weissner W

Here presented is an evidence-based systematic review including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.

Proliferative activity of Echinacea angustifolia root extracts on cancer cells: interference with doxorubicin cytotoxicity.

Site Editor — Sat, 06 Jan 2007 00:22:54 -0800

Proliferative activity of Echinacea angustifolia root extracts on cancer cells: interference with doxorubicin cytotoxicity.: Chem Biodivers. 2006 Jun; 3(6): 695-703 Authors: Huntimer ED, Halaweish FT, Chase CC

Doxorubicin is an anticancer drug that causes apoptosis in cells, but cardiotoxicity limits the cumulative dose that can remain in the blood. Echinacea extracts have been prescribed to supplement cancer chemotherapy. In a recent study, it was reported that Echinacea purpurea extracts protected noncancerous cells from apoptosis. Our study aimed to determine interference with doxorubicin chemotherapy, and if fractions and compounds from Echinacea angustifolia roots protected the cells. Cervical and breast cancer cells were treated with the Echinacea samples and doxorubicin. At 0.05 and 0.5 microM doxorubicin concentration, cynarine increased HeLa cell growth by 48-125% and 29-101%, respectively (p<0.01). At 0.05 microM doxorubicin concentration, chicoric acid increased cell growth by 23-100% (p<0.01). When MCF-7 cells were treated with Echinacea and doxorubicin, the ethyl acetate fraction increased cell growth by 20-25%, and chicoric acid increased cell growth by 10-15%. Cynarine showed proliferative activity on HeLa cells, but showed antiproliferative activity on MCF-7 cells. Results indicate that phenolic compounds are responsible for proliferative activity. Studies with individual compounds show that chicoric acid and cynarine interfered with cells treated with 0.5 microM doxorubicin. The results of this study show that Echinacea herbal medicines affect cell proliferation despite cancer treatment, and that herbal medicines require further study with respect to anticancer drugs.

Ginseng extract exhibits antimutagenic activity against induced mutagenesis in various strains of Salmonella typhimurium.

Site Editor — Thu, 04 Jan 2007 17:56:17 -0800

Ginseng extract exhibits antimutagenic activity against induced mutagenesis in various strains of Salmonella typhimurium.: Indian J Exp Biol. 2006 Oct;44(10):838-41 Authors: Geetha T, Saini A, Kaur IP

Ginseng has been reported to exhibit antioxidant and antimutagenic activity. The present study was undertaken with a view to confirm whether the antioxidant activity of Ginseng is responsible for its antimutagenic action. The concentrated root extract of Panax ginseng (Ginseng extract I) and its lyophilized powder (Ginseng extract II) obtained from two different manufacturing houses, were tested against mutagenesis using the well-standardized Ames microsomal test system. The extracts exhibited antimutagenic effect against hydrogen peroxide induced mutagenesis in TA100 strain, and against mutagenesis produced by 4-nitroquinoline-N-oxide in both TA98 and TA100 strains of Salmonella typhimurium. Both the extracts failed to show any antimutagenic potential against tert-butyl hydroperoxide (an oxidative mutagen) in TA102 strain, a strain highly sensitive to active oxygen species. The extracts also indicated a weak antioxidant activity in a series of in vitro test systems viz., 1,1-diphenyl picryl hydrazyl (DPPH) assay, hydrogen peroxide scavenging and superoxide anion scavenging. The results indicate that the protective effects shown by ginseng extract(s) against 4-nitroquinoline-n-oxide and hydrogen peroxide induced mutagenesis in TA98 and TA100 could mainly be due to its property to initiate and promote DNA repair rather than free radical scavenging action.

Protective effect of ethanolic and water extracts of sea buckthorn (Hippophae rhamnoides L.) against the toxic effects of mustar

Site Editor — Thu, 04 Jan 2007 17:54:52 -0800

Protective effect of ethanolic and water extracts of sea buckthorn (Hippophae rhamnoides L.) against the toxic effects of mustard gas.: Indian J Exp Biol. 2006 Oct;44(10):821-31 Authors: Vijayaraghavan R, Gautam A, Kumar O, Pant SC, Sharma M, Singh S, Kumar HT, Singh AK, Nivsarkar M, Kaushik MP, Sawhney RC, Chaurasia OP, Prasad GB

Ethanolic extract of H. rhamnoides L. leaf (HL-EOH), water and ethanolic extract of H. rhamnoides fruit (HF-W and HF-EOH), and H. rhamnoides flavone from fruit (HR-flavone) were evaluated against percutaneously administered sulphur mustard (SM), a chemical warfare agent. The animals administered with SM (9.7, 19.3 and 38.7 mg/kg) died at various days depending upon the dose and there was a significant reduction in the body weight. The H. rhamnoides extracts (1 g/kg; 3 doses; po) significantly protected the lethality, with a protective index of 2.4, 1.7, 1.7 and 2.2 for HL-EOH, HF-W, HF-EOH and HR-flavone respectively. Reduced glutathione (GSH) and oxidized glutalthione (GSSG) levels were reduced, and malondialdehyde (MDA) was elevated after percutaneous administration of SM. Oral administration of HL-EOH and HR-flavone significantly protected the body weight loss. Recovery in the levels of GSH, GSSG and MDA were also observed following oral administration of HL-EOH and HR-flavone. All the extracts were non-toxic and the LD50 was more than 5 g/kg. The present study shows that percutaneous administration of SM induces oxidative stress and ethanolic extract of leaf of H. rhamnoides and H. rhamnoides flavone from fruit can significantly protect it.

[Acute hepatitis due to kava-kava and St John's Wort: an immune-mediated mechanism?]

Site Editor — Wed, 04 Oct 2006 19:03:18 -0700

[Acute hepatitis due to kava-kava and St John's Wort: an immune-mediated mechanism?]: Dtsch Med Wochenschr. 2006 Aug 25;131(34-35):1880-1; author reply 1882-3 Authors: Teschke R

Gomisin A alters substrate interaction and reverses P-glycoprotein-mediated multidrug resistance in HepG2-DR cells.

Site Editor — Wed, 04 Oct 2006 18:18:47 -0700

Gomisin A alters substrate interaction and reverses P-glycoprotein-mediated multidrug resistance in HepG2-DR cells.: Biochem Pharmacol. 2006 Aug 2; Wan CK, Zhu GY, Shen XL, Chattopadhyay A, Dey S, Fong WF

Through an extensive herbal drug screening program, we found that gomisin A, a dibenzocyclooctadiene compound isolated from Schisandra chinensis, reversed multidrug resistance (MDR) in Pgp-overexpressing HepG2-DR cells. Gomisin A was relatively non-toxic but without altering Pgp expression, it restored the cytotoxic actions of anticancer drugs such as vinblastine and doxorubicin that are Pgp substrates but may act by different mechanisms. Several lines of evidence suggest that gomisin A alters Pgp-substrate interaction but itself is neither a Pgp substrate nor competitive inhibitor. (1) First unlike Pgp substrates gomisin A inhibited the basal Pgp-associated ATPase (Pgp-ATPase) activity. (2) The cytotoxicity of gomisin A was not affected by Pgp competitive inhibitors such as verapamil. (3) Gomisin A acted as an uncompetitive inhibitor for Pgp-ATPase activity stimulated by the transport substrates verapamil and progesterone. (4) On the inhibition of rhodamine-123 efflux the effects of gomisin A and the competitive inhibitor verapamil were additive, so were the effects of gomisin A and the ATPase inhibitor vanadate. (5) Binding of transport substrates with Pgp would result in a Pgp conformational change favoring UIC-2 antibody reactivity but gomisin A impeded UIC-2 binding. (6) Photocrosslinking of Pgp with its transport substrate [(125)I]iodoarylazidoprazosin was inhibited by gomisin A in a concentration-dependent manner. Taking together our results suggest that gomisin A may bind to Pgp simultaneously with substrates and alters Pgp-substrate interaction.

Effect of benzophenones from Hypericum annulatum on carbon tetrachloride-induced toxicity in freshly isolated rat hepatocytes.

Site Editor — Wed, 04 Oct 2006 17:01:28 -0700

Effect of benzophenones from Hypericum annulatum on carbon tetrachloride-induced toxicity in freshly isolated rat hepatocytes.: Effect of benzophenones from Hypericum annulatum on carbon tetrachloride-induced toxicity in freshly isolated rat hepatocytes. Redox Rep. 2006;11(1):3-8 Authors: Mitcheva M, Kondeva M, Vitcheva V, Nedialkov P, Kitanov G

Five benzophenones and a xanthone, isolated from Hypericum annulatum Moris, were investigated for their protective effect against carbon tetrachloride toxicity in isolated rat hepatocytes. The benzophenones and the xanthone gentisein were administered alone (100 microM) and in combination with CCl4 (86 microM). CCl4 undergoes dehalogenation in the liver endoplasmic reticulum. This process leads to trichlormethyl radical (*CCl3) formation, initiation of lipid peroxidation, and measurable toxic effects on the hepatocytes. The levels of thiobarbituric acid reactive substances (TBARS) were assayed as an index of lipid peroxidation (LPO). Lactate dehydrogenase (LDH) leakage, cell viability and reduced glutathione (GSH) depletion were used as signs of cytotoxicity. CCl4 significantly decreased hepatocyte viability, GSH level and increased TBARS level and LDH leakage as compared to the control. Our data indicate that 2,3',5',6-tetrahydroxy-4-methoxybenzophenone, 2-O-alpha-L-arabinofuranosyl-3',5',6-trihydroxy-4-methoxybenzophenone and 2-O-alpha-L-3'-acetylarabinofuranosyl-3',5',6-trihydroxy-4-methoxybenzophenone showed weaker toxic effects compared to CCl4 and in combination showed statistically significant protection against the toxic agent.

Herbal hepatotoxicity.

Site Editor — Fri, 09 Jun 2006 07:21:34 -0700

Herbal hepatotoxicity.: J Hepatol. 2005 Nov;43(5):901-10 Authors: Stickel F, Patsenker E, Schuppan D

Acute renal failure induced by a Brazilian variety of propolis.

Site Editor — Fri, 09 Jun 2006 07:15:57 -0700

Acute renal failure induced by a Brazilian variety of propolis.: Am J Kidney Dis. 2005 Dec;46(6):e125-9 Authors: Li YJ, Lin JL, Yang CW, Yu CC

Propolis is a resinous substance collected by honeybees and used in hive construction and maintenance. Cumulative evidence suggests that propolis may have anti-inflammatory, antibiotic, antioxidant, antihepatotoxic, and antitumor properties. In addition to topical applications, products containing propolis have been used increasingly as dietary supplements. Although reports of allergic reactions are not uncommon, propolis is reputed to be relatively nontoxic. Its systemic toxicity is rarely reported and hence may be underestimated. This is the first report of propolis-induced acute renal failure. A 59-year-old man required hemodialysis for acute renal failure. The patient had cholangiocarcinoma and had ingested propolis for 2 weeks before presentation. Renal function improved after propolis withdrawal, deteriorated again after reexposure, and then returned to a normal level after the second propolis withdrawal. This case indicates that propolis can induce acute renal failure and emphasizes the need for vigilance and care when propolis is used as a medicine or dietary supplement.

Inhibition of sulfotransferases by xenobiotics.

Site Editor — Fri, 09 Jun 2006 07:15:00 -0700

Inhibition of sulfotransferases by xenobiotics.: Curr Drug Metab. 2006 Jan;7(1):83-104 Authors: Wang LQ, James MO

The sulfotransferase (SULT) family comprises important phase II conjugation enzymes for the detoxification of xenobiotics and modulation of the activity of physiologically important endobiotics such as thyroid hormones, steroids, and neurotransmitters. SULT enzymes catalyze the transfer of a sulfuryl group, donated by 3'-phosphoadenosine-5'-phosphosulfate (PAPS), to an acceptor substrate that may be a hydroxy group or an amine group in a process originally called sulfation, but more correctly referred to as sulfonation or sulfurylation. SULT activity may be inhibited when humans are exposed to certain xenobiotics including drugs (mefenamic acid, salicylic acid, clomiphene, danazol etc.), dietary chemicals (catechins, food colorants, flavonoids and phytoestrogens etc.), and environmental chemicals (hydroxylated polychlorinated biphenyls, hydroxylated polyhalogenated aromatic hydrocarbons, pentachlorophenol, triclosan and bisphenol A, etc.). Inhibition of individual SULT isoforms may cause adverse effects on human health. For example, hydroxylated polychlorinated biphenyls have been shown to interfere with the transport of thyroid hormones, inhibit estradiol sulfonation, and inhibit thyroid hormone sulfonation, thereby potentially disrupting the thyroid hormone system. Formation of sulfate conjugates of toxic xenobiotics usually decreases their toxicity, so inhibition of this pathway may lead to prolonged exposure to the compounds. Conversely, some sulfate conjugates are chemically reactive, inhibition of their formation may protect from toxicity. This manuscript will review the literature concerning the inhibition of SULTs by xenobiotics including isoform-selective effects, inhibition kinetics and health effects resulting from the inhibition.