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Rapid Responses: Rapid Responses published:
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Hepatotoxicity of medicinal plants
- F Firenzuoli, L Gori, P Maione (25 January 2001)
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Are Standardised Extracts Truly Herbal Medicine?
- Peter Whitton (7 March 2001)
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kava and gamma-glutamyltransferaseincrease: hepatic enzymatic induction or liver function alteration
- Barguil (21 March 2001)
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Kava and Benzodiazepines-worsening withdrawal
- Aidan Cartledge, Joan Rutherford (31 August 2001)
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False assumption
- Ron Law (21 November 2003)
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F Firenzuoli, Director Department of Phytotherapy, L Gori, P Maione
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Dear Editor, We think that one of the main problems of toxicology in phytotherapy is actually not only limited to pharmacovigilance, which obviously is of paramount importance, but also to the merchandising and consumption of many hepatotoxic plants (Symphytum officinale, Crotalaria retusa, Tussilago farfara, Petasites officinale, Larrea tridentata ...). Some months ago we decided to see if Germander (Teucrium chamaedrys), an hepatotoxic plant used as digestive and for slimming, was available on the WWW. We were very surprised to find out that there were at least 13 web pages where Germander was easily available. So we decided to survey in 4 sanitary districts of our region (Tuscany, Italy), if Germander , a plant officially declared a venom since 1996, was sold by chemist's and health food stores too. We surveyed 63 drugstores (41 pharmacies and 22 health food stores) asking to buy Germander. Only in 4 cases (6,3%) was Germander recognized as toxic, while in 59 cases (93.7%) it was not identified as a toxic plant, in this group 6 shoppers (9.4%) answered it was not available on the market for unknown reasons; 14 (22.2%) did not know what it was ; 13 (20.7%) had Germander immediately available or asked to wait just for a few days to get an extract; 26 (41.3%) accepted the request, but did not find it on the market and gave no explanation. Neo-clerodane diterpenes, which are associated with Germander's hepatotoxicity, are also in many other plants (Teucrium scorodonia, Teucrium marum, Scutellaria altissima, Ajuga reptans, Ajuga chamaepytis, Salvia splendens ...) and in Propolis too. We think merchandising toxic plants for human consumption is actually a major problem of clinical phytotherapy. |
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Peter Whitton, Product Quality and Development Manager Phytomedical Group Ltd
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A study in comparative extraction techniques from Piper methysticum Preamble The purpose of this document is to establish the fact that a standardized extract from a medicinal herb is significantly different from the traditional extracts on which the historical evidence for safety and efficacy are based. This assumption has lead to numerous papers appearing in the scientific press, which cite previously unknown side effects and complications of “traditional” herbal remedies. Method Five grames of cut piper methysticum root were extracted from in different solvents and the results compared to the commercial 1:4 Piper methysticum tincture by HPLC with diode array detection. The solvents used were:
The extraction was carried out by reflux percolation for one hour for each sample. The resulting liquids then had their specific gravity and percentage solids determined by the techniques described in the British Pharmacopoeia 1999. The total kavalactones were measured by HPLC using an acetonitrile/ water solvent gradient. As kavalactone extracts are traditionally produced using a pure acetone extraction it was assumed for the purposes of this paper that the acetone extract contained only kavalactones (this will be confirmed at a later date by solid phase micro extraction and gas chromatography with mass spectrometry detection). This means that for the purposes of this study the kavalactones can be identified and quantified from the acetone extract. All of the other extraction techniques can then be compared to this and the amounts of compounds other than kavalactones can then be quantified. It is the intention to identify the non-kavalactone constituents Results SAMPLE WEIGHT PER ML % SOLIDS TOTAL KAVALACTONE ABSORBANCE/% SOLIDS WATER 1:20 EXTRACTION 0.9972 0.49% 21583.75 44048.47 25% ETHANOL 0.86% 197601.1 229768.72 96% ETHANOL 0.7823 0.10% 158015.6 1580156 ACETONE 0.7822 0.26% 382178.1 1469915.78 Taking the absorbance/% solids for the acetone extract as showing the unit absorbance for pure kavalactones then it can be seen that the ethanol extract contains 0.1 units kavalactones, the 25% ethanol extract contains 0.13 units kavalactones and the water extract contains 0.0146 units kavalactones. This shows that the amont of the % solids due to kavalactones in each sample is
The hepato-toxicity is probably due to the kawain component of the kava lactones which could well have a similar effect to paracetamol due to the exposed benzene ring in the structure with the double bonded oxygen molecule. This could easily be seen to interact with the vitamin K dependant clotting factor manufacturing mechanisms in the liver which would explain the patients clinical laboratory results on the liver enzymes and coagulation factors. It should be stressed that the proposals to provide traditional use liscences for herbal medicines should only apply to those medicinee ths which are traditional in themselves and not a standardised extract of a particular drug which is in a totally different form than the traditional extract. The traditional method of producing a standardised extract for this herb is anacetone extraction which is then dried onto a polysaccharide base. It can be seen from these results that these are two totally different products and it is nomore relavent to use data collected on one for efficaccy and safety on another than it would be with any other class of drug. It would be well advised to consider whether the regulation of herbalists and herbal medicine should become a priority and whether the education of the medical profession should be amended to include this aspect of treatment as patients will always be attracted to alternative or complementary practices. This statement does not assume that physicians are nessarssarily the best people to administer the various branches of complementary medicine but should be more open to branches with the fact they should seek out and converse with those practicing in those areas to ensure the highest standards of training and professionalism are enforced. |
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Barguil , director Pathology Laboratory, New-caledonia hospital
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EDITOR--Escher has reported a case of fulminant hepatic failure with kava extract used as a herbal remedy for anxiety (1). She has pointed out Mathews’ observation that heavy consumption of kava has been associated with increased concentrations of gamma-glutamyltransferase, suggesting potential hepatotoxicity (2). In New-Caledonia, the beverage kava was introduced from vanuatu around 20 years ago. For 10 years, more and more “kava bars” have opened for economical reasons. In contrast to other Pacific islands and like Australia, New-Caledonia does not possess any kava cultural reference or kava history. Nowadays we observe people who can drink 10 times the amount and even more than what it is currently drunk in countries where kava is a traditional beverage. We wanted to know what biological problems occurred with heavy new-caledonian kava drinkers taking no alcohol and no medication. 19 men and 2 women, heavy kava drinkers (mean: 4.55 units/day, 5.9 days/week: 8g total kavalactones/week, since more than 5 years) were studied with their agreement. Urine and blood tests were performed for kavalactone screening, biochemistry, haematology and coagulation. The only significative abnormality we noticed was a slight increase in gamma-glutamyltransferase (GGT) (6 men and 1 women), mean GGT value: 81.5 U/l (normal < 43) p=0.08. Ultrasonography, blood tests for hepatitis A, B, C and serum protein electrophoresis were then performed and gave normal results. 3 volunteers reduced their kava consumption for 1 month and GGT decreased to normal values. This isolated GGT increase following chronic heavy kava consumption with no clinical sign other than an ichtyosis (47% of heavy drinkers in our study) previously described by Ruze (3) and no other biological disturbance suggests that it could be due to an enzymatic induction as it can be seen with phenobarbital users, for instance. However, there are acute accidents with kava, leading to subfulminant or fulminant hepatitis or allergic oedema. These accidents occur, in our observation, in new users of kava drink or in those taking medication or light kava drinkers, suggesting an immunoallergic mechanism. Yann BARGUIL Anne MANDEAU Laboratoire, Centre Hospitalier de Nouvelle-Calédonie, BP J5 98849 Nouméa Cédex, New-Caledonia Benard GENELLE Tristan DERYCKE, Service d’Hépatogastroentérologie, Centre Hospitalier de Nouvelle- calédonie. Catherine MERZEAU Claudie MOUQUET-LEEMAN Sylvie BARNY Daniel DUHET Pierre CABALION Institut de Recherche et de Développement, Centre de Nouméa. 1 Escher M, Desmeules J. Hepatitis associated with kava, a herbal remedy for anxiety. BMJ 2001;322: 139.(20january) 2 Mathews JD, Riley MD, Fejo L, Munoz E, Milns N, Gardner ID, et al. Effects of the heavy usage of kava on physical health: summary of a pilot survey in an Aboriginal community. Med J Aust 1988; 148: 548-55 3 Ruze P. Kava-induced dermopathy: a niacin deficiency? The Lancet 1990; 335: 1442-45 |
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Aidan Cartledge, Senior House Officer In Psychiatry, Consultant Psychiatrist Farnham Road Hospital, Tolworth Hospital, Joan Rutherford
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EDITOR—We were very interested to read the report from Escher et al (1) on a patient who presented with jaundice, and required liver transplantation following the ingestion of Kava as a self prescribed treatment for anxiety. The case was reported to the Swiss Pharmacovigilance Center. We are curious to know how many such interactions have been reported to the Committee on Safety of Medicines in the UK since a letter was circulated last year from Professor Breckenridge, CSM Chairman, warning of interactions between St John’s Wort (Hypericum perforatum) preparations and prescribed medicines (2). Following the guidelines in the March 2000 letter, we used the Yellow Card Scheme to report an interaction between Kava and benzodiazepines. Our patient was a 52 year old probation officer who presented in an acute confusional state, experiencing second person auditory hallucinations, visual hallucinations of people and spiders and feeling in a dream-like state. Due to longstanding insomnia she had been prescribed various benzodiazepines by her GP, most recently flunitrazepam 2 mg nocte. She had never experienced withdrawal symptoms from benzodiazepines. On hearing from a work colleague of Kava’s relaxing properties, she took the remedy for three weeks in addition to flunitrazepam, before discontinuing Kava. Within 36 hours she became confused. On admission to an acute psychiatric ward, she was agitated, irritable, disorientated and wearing her dress inside out. Blood pressure was 130/80. (She was a known hypertensive). FBC, U&E and liver function tests were normal. An MSU showed no infection. She was treated with Diazepam 5 mg bd and Droperidol 10 mg bd; symptoms completely resolved within 48 hours and medication was withdrawn. She returned to work within one week and has remained well at follow up. An EEG, possible only after the acute episode, was normal. A CT scan revealed a small old infarct in the heads of both caudate nuclei, and moderate to severe small vessel disease reported as being compatible with hypertensive changes. Published studies do tend to focus on herbal interactions in psychiatric patients (3,4). Given that herbal remedies are advertised as safe medication, we are pleased that other medical specialities are encouraged to enquire about patient use of over-the-counter health products. Aidan Cartledge, Senior House Officer In Psychiatry, Farnham Road Hospital, Farnham Road, Guildford. Joan Rutherford, Consultant Psychiatrist, Tolworth Hospital, Red Lion Road, Surbiton, Surrey. KT6 7QU (address for correspondence) (1) Escher. M, Desmeules, J, Giostra,E, and Mentha, G.. Hepatitis associated with Kava, a herbal remedy for anxiety. BMJ 2001; 322:139.(20th January). (2) Breckenridge, A. Important interactions between St John’s Wort (Hypericum perforatum) preparations and prescribed medicines, 29th February 2000. (3) Almeida J.C.,and Grimsley, E W. Coma from the Health Food Store, interaction between Kava Kava and Alprazolam. Annals of Internal Medicine 1996, vol 125 pages 940 - 941. (4) Wong,A.H.C, Smith, M and Boon, H.S. Herbal remedies in Psychiatric practice. Arch Gen Psychiatry 1998, 55, 1033-1042. Editorial comment
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Ron Law, Critical analyst Home
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This article states, "Heavy consumption of kava has been associated with increased concentrations of -glutamyltransferase, suggesting potential hepatotoxicity." Mathews study found no such relationship. Competing interests: None declared |
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