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Choosing natural drugs is not without risk

Germans like natural solutions and show a marked preference for medicines made from St. John’s wort, valerian, devil’s claw or Marian Thistle. However, when taking herbal medicines people are well advised to be cautious: "herbal" does not automatically mean safe, warns Thomas Simmet, pharmacologist from the University Hospital of Ulm.

“The greatest risk are the patients themselves,” said Simmet, medical specialist in the Institute of Pharmacology of Natural Products and Clinical Pharmacology at Ulm University Hospital. He urgently warns people about the huge risk of purchasing phytopharmaceuticals on the Internet and he also highlights the danger of purchasing a counterfeit preparation. He explains that Asian phytopharmaceuticals, for example, contain high quantities of chemically synthesised compounds. An investigation into herbal asthma drugs has shown that these drugs contain huge amounts of cortisone. Simmet points out that purchasers have no guarantee at all that such drug preparations have undergone thorough control.

When gentle medicine has massive interactions

St. John’s wort (the photo shows a blossom) is taken by many people for depression. © JPW Peters/pixelio.de

If patients take herbal medicines in conjunction with other medication there is a major risk that the substances could interact with each other. "The pharmacological sector still knows little about such interactions," said Simmet with an air of regret, citing St. John's wort as an example, a product that is frequently used to treat mild depression; around 40 St. John's wort preparations are marketed in Germany.

Patients who have undergone organ transplantation frequently develop depression and like to use St. John's wort as a remedy. However, the problem with St. John's wort is that the plant substance accelerates the metabolism of immunosuppressive drugs given to these patients in order to prevent the rejection of the transplanted organs. In the worst case, the transplanted organ is rejected.

Interactions – a serious problem

Prof. Dr. Thomas Simmet calls on patients to act more responsibly © University Hospital Ulm

Relatively little is known about such interactions and St. John's wort is known to massively interact with other compounds. "Gentle medicine" might have severe consequences: hormonal contraceptives or HIV drugs that no longer function properly. "This is a problem that we have to take seriously, and even more so since only limited research has been carried out on such interactions," said Simmet explaining that the safety of medications is impeded by the fact that many patients purchase the drugs without consulting a doctor. And since the majority of phytopharmaceuticals that are taken to treat mild health disturbances are not paid for by the health insurance funds, there is no control whatsoever.

In many cases pharmacists, if they are asked for advice at all, do not know whether and which other drugs their clients are taking and are therefore unable to warn people about potential interactions. Simmet explains that many Scandinavian GPs do not know how many and which kind of drugs their patients are taking because either the patients do not remember (age) or do not want to disclose such information (drugs taken to treat depression). It is unknown whether the same is true for GPs in Germany, but it seems rather likely. Data are, however, not available.

Huge grey market without any control

The danger of consuming herbal medicines is in indirect consequence of their legal status. Drugs of plant origin are not only found in the regulated area of approved and registered drugs, but to an increasing extent on the grey market where no controls exist.

Herbal medicines have huge economic power. The European market volume (mainly Germany and France) of phytopharmaceuticals amounts to 3.5 billion euros (IMS International, Bundesverband der Arzneimittelhersteller (Association of Pharmaceutical Producers)); German phytopharmaceutical manufacturers are the market leaders in Europe (BPI, Pharmadaten 2010).

Different classification of herbal medicines

Isolated plant substances such as atropine are not classified as phytopharmaceuticals © Jens Goetzke/pixelio.de

Phytopharmaceuticals can be produced from the leaves, flowers, roots, bark, shells or any other part of a plant. These raw materials used for pharmaceutical purposes are referred to as medicinal drugs. In Germany, herbal medicines consist of several different substances. They also include extracts that are sometimes made of several hundreds of individual substances.

Individual substances such as atropine (a substance derived from belladonna), which are isolated from plant extracts, are not classified as phytopharmaceuticals. The same is also true for individual substances such as cardiac glycosides (digitoxin) or morphine. Food additives, weight reducers, food, homoeopathic drugs and anthroposophic drugs are not classified as phytopharmaceuticals either.

The majority of herbal medicines are sold over the counter

According to the German Medicines Act (AMT) herbal medicines underlie the same approval procedures as synthetic drugs; these preparations are strictly controlled as to purity and levels of active constituents; they must also be harmless (which is a very elastic word). Traditional herbal medicinal products can be registered using a simplified procedure (Directive 2004/24/EC of the European Parliament and of the Council of 31 March 2004) provided that there is sufficient evidence of the medicinal use of the product throughout a period of at least 30 years, including at least 15 years in the European Community. The majority of these medicines can be sold over the counter without a prescription (OTC medicinal products).

Simmet finds it difficult to imagine the reasons why people are so keen to use phytopharmaceuticals in Germany. Nevertheless, he is aware that Germany is home to a highly developed phytopharmacological and phytopharmaceutical industry that has its origins in abbey medicine. Patients and consumers tend to use herbal medicines particularly in the treatment of mild disorders.

50 per cent of all doctors prescribe phytopharmaceuticals

Gentle plant-based medicine is very popular © Karin Jung / pixelio.de

Almost fifty per cent of all general practitioners in Germany prescribe phytopharmaceuticals. Simmet believes that patients see natural drugs as a gentler type of medicine, with fewer side effects than chemically synthesised drugs. However he is well aware that this is not the case with all natural drugs as he knows of medications with allegedly few side effects that were found to cause severe adverse reactions (liver failure) and were withdrawn from the market, for example "Kava kava", a root extract from the South Seas known to have a sedating effect.

The safety of drugs is compromised mainly through the drugs' interactions with other drugs and by over-the-counter-sale, which removes them from doctors' control and means that they do not have the quality guarantee of drugs sold in pharmacies. Therefore, little is known about potential adverse drug reactions. Simmet knows that the manufacturers are usually informed at a very late stage about adverse drug reactions; in addition, Simmet believes that little research is available on the effectiveness of phytopharmaceuticals, which he sees as another major problem.

Multisubstance mixtures – inaccessible to evidence-based medicine

In the strictest sense, herbal multisubstance mixtures cannot be subject to evidence-based medicine. Proof of the drugs’ efficacy is only available for a handful herbal medicines. It is circular process: only if proof of evidence of a drug’s efficacy has been given and a drug has been cleared for a certain indication, is the development of this drug then backed by industrial and economic interests. However, industry must be interested in the process from the word go in order to provide financial investment for the investigation of interactions. It is not easy to patent the actual phytopharmaceuticals, patents can only be filed for special extracts or manufacturing methods.

Criticism related to the effect of herbal medicines

Gingko biloba is believed to have an anti-dementia effect © Grace Winter / pixelio.de

In Germany four herbal medicines are available on prescription: St. John's wort, which is by far the most common antidepressant used in Germany, Ginkgo biloba (for the treatment of dementia), Psyllium seed husks (for the relief of constipation, etc.) and Marian Thistle (improves the quality of life of tumour patients). However, the majority of scientific publications cast doubt on the effect of Marian Thistle and Gingko biloba extracts (about Gingko biloba, JAMA 2008; 300: 2253-2262, Cochrane Database Syst Rev. 2009 Jan 21;(1):CD003120).

Medical doctors do not believe that St. John's wort has a clear antidepressant effect. The treatment recommendations for depression published by the Drug Commission of the German Medical Associations believe that there are not enough data available to prove the efficacy of St. John's wort. Although a statistically confirmed effect has been shown for mild and moderate depression, doctors are nevertheless unsure whether this effect is of relevant clinical extent. The following concession by doctors shows how difficult it is to evaluate mixtures consisting of several substances: Hypericin, which is one of the principal active constituents of St. John's wort, was previously believed to have an antidepressant effect. Nowadays, an antidepressant effect is ascribed to hyperforin, which is another principal active ingredient of St. John's wort.

The pharmacologist from Ulm does not completely reject the use of herbal medicines for the treatment of mild depression; it is of key importance, he believes, that people buy drugs in pharmacies and tell the pharmacist or their doctor which other medications they are taking. However, Simmet cannot hide the fact that he is generally very sceptical about the use of herbal medicines: "How effective these medicines are is another question altogether." The effectiveness of herbal medicines needs to be analysed in clinical studies, and Simmet is sure that virtually nobody is willing to pay for such costly studies.

Thomas Simmet, Director of the Institute of Pharmacology of Natural Products and
Clinical Pharmacology, is basically focused on two priorities: the treatment of chronic inflammation and the treatment of cancers, in particular therapy-resistant tumours of the brain, pancreas or prostate.

Pharmacology involving natural compounds has a great future

Simmet is convinced that pharmacology involving natural compounds has a great future, despite the fact that it is rather neglected in research. There are many things that could be investigated and only a small number of natural compounds with a pharmaceutical effect are known. The composition of herbal substances is a lot more complex than the composition of traditional chemically synthesised substances; only a small fraction of these substances can be produced using combinatorial chemistry. It is far easier to isolate “trivial substances such as cardiac glycosides” from natural drugs than to synthesise them chemically.

Once the composition is known, lead compounds can be identified for the further development of certain mechanisms of action. Researchers at Simmet’s institute use computer-based methods to calculate how structures isolated from natural drugs interact with certain target molecules. Using their own techniques, the researchers can subsequently test the model calculations in real situations. Simmet believes that this is an approach that enables the discovery of natural active ingredients or the semi-synthetic optimisation of these drugs.

Natural substance mixtures cannot be used for “hard pharmacotherapies”, which need treatment with individual substances, particularly in the case of tumours. “It is not that natural compounds lack value, quite the contrary is true”: A major proportion (up to 75 per cent) of substances used for the treatment of tumours is derived from natural substances.

Industry is becoming interested in natural substance to treat psoriasis

Simmet’s work involves basic as well as preclinical research. For the analysis of pure substances, university researchers need the support of industry, which has the money to pay for such extremely costly and time-consuming analyses.

Research involving transgenic animals led Simmet and his team to discover a natural substance that inhibits the development of arteriosclerosis in animals. In addition, the researchers know the molecular mechanism of this inhibition and the target molecule. In cooperation with the Department of Dermatology at the University Hospital in Ulm, Simmet carried out a study on psoriasis using a mouse model. The study found that the mice could be cured with active compounds developed by the researchers. Simmet finds that these convincing data should be explored further, in particular since human psoriasis is also associated with arthritis. The pharmaceutical industry is of the same opinion and is very interested in this natural compound.

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