- Email: [email protected]
Herbal medicines in health care—Benefits and risks
148
Abstracts / Toxicology 240 (2007) 129–153
missed as adverse effects often mimic other diseases or the association not made especially when patients have not disclosed their use of herbal medicine to their doctor. In the last 10 years there have been reports on hepatotoxicity and renal toxicity of some commonly used herbs, such as Piper methysticum and Aristolochia species. With increased globalisation, traditional herbal medicines are constantly being introduced into new communities sometimes in inappropriate ways. And as over-the-counter products are developed changing methods of use may also result in unexpected side effects as the pharmacological properties of a herbal tea is likely to be very different to that of a selective concentrated extract. The potential for toxicity of some medicinal herbs is recognised in system such as Traditional Chinese medicine or Ayurvedic medicine. These systems use different processing methods to change the properties of herbs, such as boiling in water or vinegar to increase or decrease specific activities. Some herbal combinations are specifically used to reduce potential toxicity, for example in Chinese medicine liquorice is combined with aconite. Using such herbs out of context may therefore result in unexpected health effects. Adverse effects of herbal medicines can also be caused by inappropriate use, interactions or delays in seeking medical treatment. There are regular quality concerns with some products and substitution of ingredients or adulteration with pharmaceuticals has been reported. Once the EU Directive on Traditional Herbal Medicinal Products comes into force in 2011 all over-the-counter herbal medicinal products will have to conform to standards of quality and safety. Regulation of herbal practitioners is also under development. Attitudes to herbal medicines are often polarised and they are either viewed as toxic and ineffective or totally safe and effective. Neither view is totally correct and a balanced perspective is needed. Theoretical safety or toxicity may be misleading and critical investigation of suspected adverse effects, within the context of actual use can be more revealing. With improved regulation, pharmacovigilance can identify toxicity and safety issues but this needs to be supported by appropriate research to ensure the safe and effective use of those herbal medicines which can contribute positively to health care systems. doi:10.1016/j.tox.2007.06.032
Herbal medicines in health care—Benefits and risks Michael Heinrich HoC, Centre for Pharmacognosy and Phytotherapy, The School of Pharmacy, University of London, 29-39 Brunswick Sq., London WC1N 1AX, UK E-mail address: [email protected]. Herbal Medicines, which have always been a popular heath care choice in the UK, have in recent years become under increased scrutiny regarding the products’ quality and safety. Overall it is certainly fair to say that most herbal medicines or products derived from it have an excellent safety record. Many current herbal medicinal products are already assessed and monitored appropriately; others exist that are not of an acceptable quality, giving the products in general a bad name. Examples of poor quality medicines include products which contain in addition to the herbal product heavy metals or other pharmaceuticals like glucocorticoids or sildenafil. Clearly one needs to be concerned about the potential impact on public health of such poor quality products in an unregulated market. Quality and safety are intrinsically linked. However, ensuring the quality of herbal medicinal products (HMPs) presents a number of unique challenges compared with conventional pharmaceutical formulations. At there simplest HMPs will contain one herbal substance or herbal preparation but this in turn will consist of a complex mixture of phytochemical constituents. The legal framework for HMPs is changing fast from such an unregulated market to one which is based on quality and safety monitoring for all HMPs. The European Union recently established a simplified registration procedure for traditional herbal medicinal products for human use (Directive 2004/24/EC), which requires all products to be registered. For example, echinacea preparations are one of the best selling herbal medicinal products (HMPs) with a well established therapeutic use in the prophylaxis of upper respiratory tract infections. Their consumption is increasing, but information about their ability to inhibit cytochrome P450 enzymes (CYP) is fragmentary. The picture is further complicated by a lack of phytochemical characterisation of previously tested preparations. To assess whether CYP inhibition might be a general feature of Echinacea preparations, 10 commercially available liquid preparations were screened using CYP3A4. All tested preparations inhibited CYP3A4, but inhibitory potencies (expressed as median inhibitory concentra-
URL: http://www.pharmacy.ac.uk/pharmacognosy.html.
Abstracts / Toxicology 240 (2007) 129–153
tions, IC50 ) varied by a factor of 150. This indicates that detailed information about the extraction and formulation of any herbal medical product is needed. Because alkylamides are thought to be responsible for the immunomodulatory activities of Echinacea, the concentrations of 2E,4E,8Z,10E/Z-tetranoic acid isobutylamide (1) and total alkylamide content were determined in all preparations and the latter was found to be associated with their CYP3A4 inhibitory potency. The chemically pure alkylamides dodeca2E,4E,8Z,10E/Z-tetranoic acid isobutylamide (1) and dodeca-2E,4E-dieonoic acid isobutylamide (2) showed inhibitory activity on CYP2C19, 2D6 and 3A4. However, unlike the Echinaforce® extract, the alkylamides did not induce CYP1A2 inhibition. Thus, other, as yet unidentified constituents also contribute to the overall weak inhibitory effects seen with Echinacea preparations in vitro. Overall these data indicate that while many HMPs are certainly safe, we need detailed investigations of fully chemically extracts using methods for evaluating the safety of these products in model systems approved by the regulatory agencies. doi:10.1016/j.tox.2007.06.033 Novel plant based pharmaceuticals and functional foods Antonia Orsi Phytopharm plc, Corpus Christi House, 9 West Street, Godmanchester PE29 2HY, United Kingdom E-mail address: [email protected]. Phytopharm is a pharmaceutical development and functional food company whose products are generated from medicinal plant extracts. The Company’s strategy is to develop these products through ‘proof of principle’ clinical testing, and then secure partners for late stage development, sales and marketing. Our pharmaceutical product, CoganeTM is a patented, orally active, neurotrophic factor inducer that reverses the decrease of neuronal growth factors and restores the learning and memory ability in Alzheimer’s disease models and reverses dopaminergic neuronal damage in Parkinson’s disease models. In a 3 month, Phase II clinical study in mild-moderate Alzheimer’s patients, a strong trend to halting disease progression was observed in CoganeTM treated moderate Alzheimer’s patients. Our pharmaceutical product, MyoganeTM is a patented, orally active, neurotrophic factor inducer and is in phase I clinical trials for Motor Neurone
149
Disease (ALS). When administered orally to transgenic pre-clinical models of ALS, MyoganeTM delays the loss of muscle strength and extends survival time. Our patented functional food, Hoodia gordonii extract, is in clinical trials for incorporation into weight loss products and is licensed globally to Unilever. Phytopharm also has a marketed functional food, PhytopicaTM , a three plant extract, licensed globally to Schering-Plough. Phytopharm’s process of developing pharmaceuticals and functional foods from medicinal plant extracts will be presented. doi:10.1016/j.tox.2007.06.034 Paracetamol toxicity: A 40 year odyssey Donald S. Davies Imperial College London, United Kingdom E-mail address: [email protected]. Paracetamol was synthesised in 1878 and the first clinical use was reported in 1893 but it was not until it was identified as the active metabolite of phenacetin and acetanilide (Brodie and Axelrod, 1948; Smith and Williams, 1948) that it was marketed as a drug. At therapeutic doses paracetamol was found to be an effective and safer alternative to phenacetin and aspirin and it became a leading non-prescription drug. This widescale availability lead to its use in self-poisoning and the first reports of serious liver damage following overdoses appeared in 1966 (Prescott, 1996). In the early 1970s an elegant series of studies in Bernard Brodie’s laboratory at the NIH established that the liver toxicity of paracetamol was mediated by a chemically reactive metabolite which depleted protective glutathione (reviewed in Mitchell et al., 1973) and lead to the use of N-acetylcysteine as a safe and effective antidote (Prescott et al., 1977). At this time it was assumed that covalent binding of the reactive metabolite, identified as N-acetyl-p-benzoquinoneimine (NABQUI), to critical cellular targets was the cause of toxicity. However, studies by us and others in the 1980s suggested that reversible oxidation of critical thiols rather than covalent binding was responsible for paracetamol toxicity (Tee et al., 1986) providing an explanation for the effectiveness of late treatment with N-acetylcysteine. In recent years targets for oxidative attack by NABQUI have been identified (see Park et al., 2006) possibly bringing to a conclusion the studies of parac-
Abstracts / Toxicology 240 (2007) 129–153
missed as adverse effects often mimic other diseases or the association not made especially when patients have not disclosed their use of herbal medicine to their doctor. In the last 10 years there have been reports on hepatotoxicity and renal toxicity of some commonly used herbs, such as Piper methysticum and Aristolochia species. With increased globalisation, traditional herbal medicines are constantly being introduced into new communities sometimes in inappropriate ways. And as over-the-counter products are developed changing methods of use may also result in unexpected side effects as the pharmacological properties of a herbal tea is likely to be very different to that of a selective concentrated extract. The potential for toxicity of some medicinal herbs is recognised in system such as Traditional Chinese medicine or Ayurvedic medicine. These systems use different processing methods to change the properties of herbs, such as boiling in water or vinegar to increase or decrease specific activities. Some herbal combinations are specifically used to reduce potential toxicity, for example in Chinese medicine liquorice is combined with aconite. Using such herbs out of context may therefore result in unexpected health effects. Adverse effects of herbal medicines can also be caused by inappropriate use, interactions or delays in seeking medical treatment. There are regular quality concerns with some products and substitution of ingredients or adulteration with pharmaceuticals has been reported. Once the EU Directive on Traditional Herbal Medicinal Products comes into force in 2011 all over-the-counter herbal medicinal products will have to conform to standards of quality and safety. Regulation of herbal practitioners is also under development. Attitudes to herbal medicines are often polarised and they are either viewed as toxic and ineffective or totally safe and effective. Neither view is totally correct and a balanced perspective is needed. Theoretical safety or toxicity may be misleading and critical investigation of suspected adverse effects, within the context of actual use can be more revealing. With improved regulation, pharmacovigilance can identify toxicity and safety issues but this needs to be supported by appropriate research to ensure the safe and effective use of those herbal medicines which can contribute positively to health care systems. doi:10.1016/j.tox.2007.06.032
Herbal medicines in health care—Benefits and risks Michael Heinrich HoC, Centre for Pharmacognosy and Phytotherapy, The School of Pharmacy, University of London, 29-39 Brunswick Sq., London WC1N 1AX, UK E-mail address: [email protected]. Herbal Medicines, which have always been a popular heath care choice in the UK, have in recent years become under increased scrutiny regarding the products’ quality and safety. Overall it is certainly fair to say that most herbal medicines or products derived from it have an excellent safety record. Many current herbal medicinal products are already assessed and monitored appropriately; others exist that are not of an acceptable quality, giving the products in general a bad name. Examples of poor quality medicines include products which contain in addition to the herbal product heavy metals or other pharmaceuticals like glucocorticoids or sildenafil. Clearly one needs to be concerned about the potential impact on public health of such poor quality products in an unregulated market. Quality and safety are intrinsically linked. However, ensuring the quality of herbal medicinal products (HMPs) presents a number of unique challenges compared with conventional pharmaceutical formulations. At there simplest HMPs will contain one herbal substance or herbal preparation but this in turn will consist of a complex mixture of phytochemical constituents. The legal framework for HMPs is changing fast from such an unregulated market to one which is based on quality and safety monitoring for all HMPs. The European Union recently established a simplified registration procedure for traditional herbal medicinal products for human use (Directive 2004/24/EC), which requires all products to be registered. For example, echinacea preparations are one of the best selling herbal medicinal products (HMPs) with a well established therapeutic use in the prophylaxis of upper respiratory tract infections. Their consumption is increasing, but information about their ability to inhibit cytochrome P450 enzymes (CYP) is fragmentary. The picture is further complicated by a lack of phytochemical characterisation of previously tested preparations. To assess whether CYP inhibition might be a general feature of Echinacea preparations, 10 commercially available liquid preparations were screened using CYP3A4. All tested preparations inhibited CYP3A4, but inhibitory potencies (expressed as median inhibitory concentra-
URL: http://www.pharmacy.ac.uk/pharmacognosy.html.
Abstracts / Toxicology 240 (2007) 129–153
tions, IC50 ) varied by a factor of 150. This indicates that detailed information about the extraction and formulation of any herbal medical product is needed. Because alkylamides are thought to be responsible for the immunomodulatory activities of Echinacea, the concentrations of 2E,4E,8Z,10E/Z-tetranoic acid isobutylamide (1) and total alkylamide content were determined in all preparations and the latter was found to be associated with their CYP3A4 inhibitory potency. The chemically pure alkylamides dodeca2E,4E,8Z,10E/Z-tetranoic acid isobutylamide (1) and dodeca-2E,4E-dieonoic acid isobutylamide (2) showed inhibitory activity on CYP2C19, 2D6 and 3A4. However, unlike the Echinaforce® extract, the alkylamides did not induce CYP1A2 inhibition. Thus, other, as yet unidentified constituents also contribute to the overall weak inhibitory effects seen with Echinacea preparations in vitro. Overall these data indicate that while many HMPs are certainly safe, we need detailed investigations of fully chemically extracts using methods for evaluating the safety of these products in model systems approved by the regulatory agencies. doi:10.1016/j.tox.2007.06.033 Novel plant based pharmaceuticals and functional foods Antonia Orsi Phytopharm plc, Corpus Christi House, 9 West Street, Godmanchester PE29 2HY, United Kingdom E-mail address: [email protected]. Phytopharm is a pharmaceutical development and functional food company whose products are generated from medicinal plant extracts. The Company’s strategy is to develop these products through ‘proof of principle’ clinical testing, and then secure partners for late stage development, sales and marketing. Our pharmaceutical product, CoganeTM is a patented, orally active, neurotrophic factor inducer that reverses the decrease of neuronal growth factors and restores the learning and memory ability in Alzheimer’s disease models and reverses dopaminergic neuronal damage in Parkinson’s disease models. In a 3 month, Phase II clinical study in mild-moderate Alzheimer’s patients, a strong trend to halting disease progression was observed in CoganeTM treated moderate Alzheimer’s patients. Our pharmaceutical product, MyoganeTM is a patented, orally active, neurotrophic factor inducer and is in phase I clinical trials for Motor Neurone
149
Disease (ALS). When administered orally to transgenic pre-clinical models of ALS, MyoganeTM delays the loss of muscle strength and extends survival time. Our patented functional food, Hoodia gordonii extract, is in clinical trials for incorporation into weight loss products and is licensed globally to Unilever. Phytopharm also has a marketed functional food, PhytopicaTM , a three plant extract, licensed globally to Schering-Plough. Phytopharm’s process of developing pharmaceuticals and functional foods from medicinal plant extracts will be presented. doi:10.1016/j.tox.2007.06.034 Paracetamol toxicity: A 40 year odyssey Donald S. Davies Imperial College London, United Kingdom E-mail address: [email protected]. Paracetamol was synthesised in 1878 and the first clinical use was reported in 1893 but it was not until it was identified as the active metabolite of phenacetin and acetanilide (Brodie and Axelrod, 1948; Smith and Williams, 1948) that it was marketed as a drug. At therapeutic doses paracetamol was found to be an effective and safer alternative to phenacetin and aspirin and it became a leading non-prescription drug. This widescale availability lead to its use in self-poisoning and the first reports of serious liver damage following overdoses appeared in 1966 (Prescott, 1996). In the early 1970s an elegant series of studies in Bernard Brodie’s laboratory at the NIH established that the liver toxicity of paracetamol was mediated by a chemically reactive metabolite which depleted protective glutathione (reviewed in Mitchell et al., 1973) and lead to the use of N-acetylcysteine as a safe and effective antidote (Prescott et al., 1977). At this time it was assumed that covalent binding of the reactive metabolite, identified as N-acetyl-p-benzoquinoneimine (NABQUI), to critical cellular targets was the cause of toxicity. However, studies by us and others in the 1980s suggested that reversible oxidation of critical thiols rather than covalent binding was responsible for paracetamol toxicity (Tee et al., 1986) providing an explanation for the effectiveness of late treatment with N-acetylcysteine. In recent years targets for oxidative attack by NABQUI have been identified (see Park et al., 2006) possibly bringing to a conclusion the studies of parac-