At the end of this Millennium it is worth for taking into account the possibilities, requirements facing the present day pharmaceutical sciences. Without any exaggeration it can be stated that a revolution has occurred in the last decades in the world. In the light of these changes the perspectives of natural, predominantly plant products in pharmacy will be analysed from international and Hungarian point of view. It may be useful to see how the international changes are reflected in Hungary, a country which is one representative of the Middle and South-eastern European countries. In the focus of this brief analysis I would like to provide some illustration only hoped that some of my conclusions may have relevance for the other Balkan countries too. I would like to refer to some world tendencies that can be seen well from the review articles published by such journals like Phytochemistry, Natural Products Chemistry, Planta Medica, etc. (Gordon, Cragg et al. 1997; Cordell 1995; Farnsworth and Bingel 1977) and some books published recent years on this topics (De Smet, Keller et al. 1992; 1993).

Before going into details, it would be worth looking back to a historical point that may be connected with the term 'medical plant'. The term was originally denoted exclusively to the group of plants that could be used in a rather direct way in curing illnesses. A revolutionary change was made by the 'Quinta essentia' theory of Paracelsus in the 16th century. However, its revolutionary effect on the pharmacy could be felt only since the beginning of the 19^th century. Since then more and more plant active ingredients have become known and the isolated compounds have become active ingredients of medicines. The isolation of chemicals and their structure elucidation made it possible, like in the very important field of steroids, to convert one biologically less or non effective compound into active ones. This brought about the need of enlarging the 'term' medicinal plants to comprise the group of raw materials too. So, plants, never used as medicinal plants in the past, now serving as industrial raw materials can practically be integrated into both the term. Recent years, the biotechnological possibilities, the possibilities of gene manipulations have also widened the utilisation of plants for medical purposes and as consequence also the category medicinal plant. As any plant can provide healing ingredients either by processing or in a direct way and it does not seem to be exaggeration, if any plants at least potentially as medicinal plant is regarded in the plant kingdom. Behind the international acceptance of the urgent need for preservation of the biodiversity of our biosphere this recognition should also be present (Rio de Janeiro conference 1992).

Consequently medicinal plants are the traditional medicinal and aromatic plants, raw materials of medicines that can be used in a direct or indirect way for health care. In the case of raw materials, it is possible to produce the pure effective compounds of medicines either via isolation or synthetic, or semi-synthetic production. These products can not be the constituents of herbal remedies, according to the EEC definition (Table 2.) As far as the research activities are concerned we would like to deal with both group of products, or more exactly with some trends that can be taken into consideration, if research activities are concerned. First we discuss some considerations that can be regarded as 'preparative' aspects. Methods by what the new active compounds are obtained and the 'analytical' aspect which is dominant in the evaluation of herbal remedies and their composition.

It should also be emphasised that medicinal plant research (Pharmacognosy) is a compound science of minimum three main disciplines: (Pharmaco)botany, (Phyto)chemistry and Phytotherapy (or other applied sciences). Development on any partial discipline of the three may significantly influence the others and of course the evaluation of medicinal plants. It is beyond our present possibilities to discuss these fields in details. I would like to refer to some aspects other than chemical ones.

2-3 million species live on the earth, 250.000-500.000 of these are the higher plants. According to Bates (Bates 1985) they can be grouped in three pools: The number of the most extensively used species is 100. They are mainly food plants. The other pool contains about 1000 species belong to the second group those foods, aromatic species etc. species of moderate exploitation and third pool has some 50.000 species with sporadic exploitation. From among them 20.000-40.000 species may be medicinal plant. 12-13 species supply main foods to more than half of the mankind (Máthé Sen. 1971). If we regard these figures and also such facts like the number of endangered species in certain regions reaches the 10% of the local flora, like in the USA (Farnsworth, Bingel 1977) and, if we regard that, for instance in Hungary, till 1977 117 species had disappeared, and some 420 species were endangered (Csapody 1982), it is obvious that the plant kingdom is under exploited and its biodiversity is dramatically decreasing.

As far as our knowledge about the chemical constituents of plant kingdom concerned only estimations are available. We have chemical information only about 5-15% of the known plant species. Farnsworth and Bingel justified the importance of natural products in health care in the everlasting debate with synthetic product supporters when they pointed out that in the USA 25.2% of all prescriptions in 1973 contained higher plants, 13.3% microbes, 2.7% animal products. (Farnsworth and Bingel 1977). Since then their opinion has been confirmed by newer findings.

We looked after how many species (excluding the legumes) from the 2,161 species of the Hungarian Flora (Simon 1992) can be found at all in Hegnauer's 10 volume large chemotaxonomic work (Hegnauer 1966-1989). Table 1. shows the results. It turned out that only some 50% of species information at all are available.

Medicinal and Aromatic Plant Abstracts (MAPA), published in India were regarded, it turned 155 genera out from among the 555 genera, the species of which are represented in Hungary have not been mentioned by Medline at all and an additional 160 genera were referred to only sporadically. Cannabis, Digitalis, Vinca, Brassica, Vicia, Pisum Glycyrrhiza, Solanum, Allium, Triticum, Salvia, Hordenum, Datura, Avena were the decreasing order of citations in the period 1966-1998. If we regard in the MAPA the representation between years 1995-1998 on species level the most frequently cited species belonged to the traditional medicinal plants like Acorus calamus, Artemisia annua, Taxus baccata, Salvia officinalis, Hypericum perforatum, Urtica dioica, Datura strammonium, Mentha sp., Solanum sp. It is interesting that 50% of the most frequently cited 'Medline genera' are common food species containing ones, like wheat, rye etc.

It has turned out that from the survey above that only some 50% of the species of the Hungarian flora has been investigated here or somewhere in the world and in a lot of cases only sporadic data are available. Summarising the data it become obvious that the information on our flora is not enough, if we want say something about its chemical diversity, about their medical usefulness.

Recent years has seen the evaluation of species for new compounds like the diterpenoids of the toxic Euphorbia species (Hohmann, Vasas, et al. 1997; 1998; 1999; Hohmann, Evanics, et al. 1999; Hohmann, Günther, at al. 1999), the less available organs of common species like the roots of Salvia (for diterpenoids) (Yang, Blunden, et al. 1996; Nagy, Yang, et al.1997; Nagy, Dobos, et al. 1998; Nagy, Günther, et al. 1999), the non characteristic, minor ingredients of well known medicinal plants and their relatives like the essential oils of the species of Section Salvia (Máthé, Nagy et al. 1997; Genova, Dobos et al. 1998), the plants endangered, rare, disappearing or endemic in Hungary or other regions (Nagy, Günther et al. 1999; Máthé, Nagy et al. 1997), from the viewpoint of isolation less available (high solubility in water, chemically labile compounds like iridoids, or macromolecules, oligosacharides, glycosides, etc. (Máthé 1997), new technical approaches, like supercritical fluid extraction (Simándi, Kéry, et al. 1996) or the new, more sensitive analytical instrumentation, like GC -MS spectroscopy in the reinvestigation of known species for providing e.g. new breeds (Varga, Hajdú et al.1998) the screening for active ingredients like ecdysteroids (Girault, Báthor et al. 1996; Báthori, Girault et al.1997; 1999), or new activity (Hohmann, Zupkó et al. 1999), and also biochemical, stereochemical considerations like the formation strictosidine a precursor of the indol alkaloids (Patthy-Lukáts, Károlyházy et al. 1997; Patthy-Lukáts, Kocsis et al. 1999), mentioning only just a few aspects that orient the research activities of pharmacognosts and phytochemists in Hungary. The specialists are available for the interdisciplinary, many-sided approaches but the co-ordination and the financial (e.g. industrial) background and the capacities in the particular fields are not in all cases enough. (Here should be mentioned that only some examples from the last 5-10 years illustrate the Hungarian medicinal plant research trends. About the cultivation, breeding experiments can be read in other chapters of this volume (see Bernáth's and Németh's reviews).

The quick development in the separation technique and in the structure elucidation of molecules, due to mainly the computerisation either in the molecule modelling or instrumentation, is going on in our days too. Another important aspect, beyond our possibilities to discuss here, is the new biotechnological approaches like utilisation of the multi-enzyme systems in synthesis. (Scott 1994).

The most frequently used highly productive techniques are as follows: TLC, GC-(MS), LC-(MS), HPLC, DCCC, RLCC, CPC, OPTLC, CE, etc. and their different versions, combinations. Nyiredy elaborated the so-called "prism" model for the optimisation of choosing the developing solvent systems (Nyiredy, Erdelmeyer et al. 1985), he did much for the utilisation of chromatographic evaluation for natural products (Nyiredy 1998) and launched in 1988 the 'Journal of Planar Chromatography', Tyihák elaborated the OPLC (Overpressure Layer Chromatography, now, Optimal Performance Layer Chromatography) technique which provides more sophisticated and faster separation exploiting all the advantages of TLC and LC. This technique was in separation of ascorbigen (Kátay, Szőke et al. 1998) and other biologically interesting compounds highly effective. (Botz, Nyiredy et al. 1990).

Besides the commonly applied TLC, HPLC separation DCCC is used e.g. in the ecdysteroid researches (Báthori and Máthé 1996; Báthori et al. 1997; Girault, Báthori et al. 1999), OPLC (Tyihák, Mincsovics 1979), TLC/Densitometry in the rosmarinic, caffeic acids, ursolic and oleanolic acid, (Janicsák and Máthé 1997), GC-MS e.g. essential oils of Salvia sp. (Máthé, Nagy et al. 1997; Genova, Dobos et al. 1998). Supercritical fluid extraction is also used as and isolation techniques (Simándi, Kéry et al. 1996), Kalász and Báthori use displacement chromatography in the ecdysteroid research (Kalász, Báthori et al. 1995).

The modernisation in the structure elucidation of new compounds means that less and less samples are required for a quicker and much more reliable analyses than we needed in the past. Nowadays, some mg of pure samples of secondary metabolites of mid-sized molecules make a complete structure elucidation possible. The availability of the 'high-tech' instrumentation has got closer to the bench phytochemists. The most frequently used techniques in structure elucidation are IR, UV, ¹H, ¹³C, ¹⁵N NMR: 1D, 2D, (¹H-¹H, ¹H-¹³C COSY, NOESY, HETCOR, HMQC, HSQC, HMBC, COLOC, HOESY, (Correl 1995; Claridge 1999), ¹H-¹⁵N GHMBC, SMIDG, etc. (Martinan and Hadden 2000; Braun, Kalinowski at al. 1998; (Correl 1995)), MS, MS-MS, CD, X-ray crystallography, etc. (Correl 1995).

In our laboratory many of the mentioned techniques are applied. 1D, 2D NMR techniques, like ¹H-, ¹³C-NMR, ¹H-¹H, ¹H-¹³C COSY, NOESY, HMBC, HMQC, ROESY for example for the investigation of Euphorbia diterpenes, (Hohmann, Evanics et al. 1999; Hohmann, Vasas, et al. 1999), for ecdysteroids (Girault, Báthori et al. 1996), DNOE, COLOC, NOESY for sesquiterpene esters of Euonymus sp. (Hohmann, Nagy et al. 1992), and for Euphorbia diterpenoids X-ray crystallography (Hohmann, Günther at al. 1999) etc. just to mention a few, proved to be especially effective. It should be mentioned that the spectrum of the Hungarian medicinal plant, phytochemical researches are much broader; the cited references are only representatives of the literature.

In recent years, besides the traditional cell-based in vitro assays (antibacterial, antifungal, antiviral, cytotoxic assays) numerous new methods were elaborated on the basis of understanding the biological occurrences on receptors, enzymes, genetic switches, cell systems, etc. Applying this knowledge, thousands of samples of small quantity can be assayed within a very short time. (Cordell 1995; Shu 1998). These discoveries have caused revolutionary changes in the rapidity, expenses, reliability and capacity of screening with the consequence of the elaboration of new strategies for not only biological but whole pharmaceutical researches. Out of the assays the pharmaceutical companies apply, in Hungary antiinflammatory, antimicrobial, antioxidant, insect moulting, etc. effects are studied in connection with pharmacognosts' researches. The antioxidant effect is screened e.g. in Lamiaceae and other species, parallel with chemical analyses. (Hohmann, Zupko et al.1999). The other aspects of Lamiaceae researches has ben pulished recently (Máthé 1997).

Due to the high efficiency of biological tests new compounds from plants and fungi has become good candidates against severe diseases like from Calophyllum lanigerum (+)-canaloide A as an anti-HIV, from Croton lechleri SP-303 (proanthocyanidins) against herpes, and other DNA and RNA viruses, from Artemisia annua artemisinin an antimalarial compound, from the well-known effective ingredients of Claviceps purpurea cabergoline, tergulide against Parkinson's disease (and also the artificial product from Papver somniferum, apomorphine too), and in the treatment of schizophrenia, from Huperzia serrata huperzine, from Galanthus nivalis galanthamine, and from Physostigma venenosum, physostigmine against against Alzheimer's disease AD, from Catharanthus, beside vinblastin and vincristin antitumor agents, vinconate effects the cerebral circulation, from Coleus forskohlii forskolin influences the blood pressure and is good in cardiac insufficiency, from Tripterygium wilfordii triptolide is against rheumatoid arthritis, autoimmune diseases, ginkgolides from Ginkgo biloba, among others, platelet-activating factor receptor antagonist, in Schisandra chinensis gomisin A (lignan) in Sylibum marianum silybin are human hepatoprotectants (Shu 1998).

Taxus brevifolia, T. baccata and, in all, 10 Taxus taxa with their low but highly effective taxol content initiated intensive research activities (isolation, semi-synthetic, synthetic, biotechnological and even processing and chemotaxonomic researches) which have resulted, among others, some 250 taxans (or taxoids) since 1992, to then the already known 100 taxoids (Baloglu, Kingston 1999). The Taxus story is a real good example of the multidisciplinary, highly effective research programmes as the slowly growing trees contain highly the active anticarcinogenic taxol only in 0.0159-0.0217% of the clippings (EtSohly, Croom et al. 1994), which would not be obtained in sufficient quantities for clinical practices from the natural yew populations. Considering four possibilities (total syntheses, biosynthesis, chemotaxonomic possibilities, semi-synthetic approaches) the partial synthesis from 10-deacetylbaccatin III could solve the problem (Cordell 1995).

In recent years new and some formerly well-known but not interesting compounds have proved to be of anticancer effect like Betula papyrifer betulin, Salvia sp. (Lamiaceae) oleanolic acid, Helenium atumnale (Compositae) helenalin, Baileya multiradiata (Compositae) multigilin, Combretum caffrum (Combretaceae) combrestatin A-4, bretastatin A-4, Pancratium littoralis pancratistatin, Phyllanthus acuminatus (Euphorbiaceae) phyllanthostatin-1, beside from the marine organisms and animal product at the NCI (National Cancer Institute) and CCNSC (Cancer Chemotherapy National Service Center) (Pettit 1996) or active against new diseases like HIV (Kashiada, Wang et al. 1998.; Yang, Zhao et al. 1999).

Our discussion of the 'traditional medicinal plants and their products' should be started with the definitions provided by the EEC in 1989. Table 2. gives the definition of herbal remedies and their ingredients (De Smet 1993). From chemical aspects one should face with similar problems when herbs, herbal drugs are evaluated. They differentiate from each other in the degree of their complexity. Each are of active, known or unknown beneficial ingredients and supposedly neutral, less defined, ballast components and may have at least potentially, harmful, toxic not required ingredients, too. Their proportions may vary due to many factors: to the variation of plants, to processing, storage conditions, etc. Consequently, they should be taken into account, if we want fulfil the present-day requirements of safety, effectiveness, standard quality. The GMP (Good Manufacturing Processes) are in the focus of the quality requirements. The products should be standardised for marker compound(s). Their presence in a determined quantity is a quality requirement and theoretically refers to the other ingredients too. The problem however is that there is no guarantee of the parallel changes of all the beneficial components in a mixture.

The vegetable drugs itself depends upon the raw materials, namely upon the plant itself: its chemotaxonomic (genetic diversity) and ecological effects (effects of abiotic: edaphic, climatic and biotic; predominantly human activities via the influencing the environmental conditions). The organ composition of drugs, at what stage of development they were harvested, how they were processed, stored, etc. may also influence the chemical ingredients, the activity, the quality of the drug. All these questions should be taken into account by predominantly chemical analysis of the product. To get better knowledge about the herbal remedies more and more markers, the chemical profiles, fingerprint spectra (TLC, HPLC, GC chromatograms) of compounds present in the product are advisable to consider. Even in this case the different profile may have different effects due to the various less, or not known active ingredients and their co-effect of sometimes unknown mechanism, and with less reliably dosing. This may be a reason why the medical doctors often neglect the utilisation of herbal remedies. Just to minimise these uncertainties, Tyler recommends the introduction of the term 'phytoequivalenc' which could be determined in brief after the clinical evaluation of a preparation, followed by chemical profiling. By this way the effect should be ordered to a chemical profile (Tylor 1999).

 For Quality assurance of medicinal products therefor the followings are recommended by the Committee for Proprietary Medicinal Products (CPMP): description of the qualitative and quantitative particulars of the constituents, description of the method of preparation, control of starting materials, control tests carried out at intermediate stage of manufacturing process, and finished products, stability tests.

Nowadays risk factors may be: predominantly contaminants, like a./ certain plant metabolites (e.g. adulterants), b./ pesticides, (first of all the chlorinated ones are dangerous because of the longer half life in human body), fumigation agents, c./ micro-organisms (aerobe bacteria Ł10³-10⁵/g, yeasts and moulds Ł10²-10⁴/g, enterobacteria and Gram-negative Ł10² -10³/g, Salmonella, Escherichia coli, etc. should be negative) and their toxins: endotoxins, mycotoxins (e.g. Aspergillus sp. and their products, like the highly toxic aflatoxin B₁), unwanted biotransfomations may provide dangerous products. d./ Toxic metals, elements, like Pb, Cd, Hg, As, etc. due mainly to the motorization and industrial activities accumulate in human body so that in the developed countries they may reach very high proportion of the tolerable daily amounts of the FAO/WHO limits (e.g. in USA Pb 19%, Cd 55%, Hg 12%, As 50% etc.) (De Smet 1992) In Hungary, too, detailed studies mapped the heavy metal contamination, for example, the accumulation in soil, plants alongside the roads. Many aspects of heavy metal accumulation in the food chain were also studied and discussed (Kádár 1995). e./ Radioactivity should also be controlled, first of all after the Chernobyl disaster (April 26, 1986) and the WHO monographs (Anonymous 1999) recommend the residual control of ⁹⁰Sr, ¹³¹I, ¹³⁴Cs, ¹³⁷Cs, ²³⁹Pu.

As far as the risk factors concerned our knowledge is rather limited in the medicinal plant field. Targeted researches started only some years ago so it is understandable that in many cases the regulations and limits valid on foods had to be adopted on medicinal plants. It should also be mentioned that in the light of newer researches some active ingredients of plants may prove harmful, toxic, like pyrrolizidine alkaloids, estragole, some allergic sesquiterpenes, b-asarone in Acous calamus, thujone in Artemisaia absintium and in the essential oil of Salvia officinalis, etc. The assurance of safe application of herbal preparations has become the number one priory of phytotherapy which is reflected in ESCOP, WHO, another monographs (Anonymous 1990-1992; Anonymous 1999). It is also obvious that continuous researches are needed for clarifying a lot of unanswered question in the 'risk factors' field.

On the basis of the above mentioned it can be clearly seen that the natural products among them their sources the (medicinal) plants have continuously great importance in the health care of mankind. It is clearly seen that the natural resources among them plants are not known adequately. Their chemical investigation should be intensified. Even the plants that had already been studied can provide new biologically active ingredients because of the chemotaxonomic differences, new unknown chemical constituents, newly discovered biological effects, because of the possibilities of chemical and/or biological processing of plants and its ingredients for getting favourable activity.

In our region too, like in the other, developed countries, the biological activity of plants should be one of the main guiding principle for screening and other type of investigations. The enzyme, cell, receptor, etc. tests should be used more intensively as well as the knowledge of local people on plants. Our knowledge on the plants of the Balkan flora and their chemical ingredients is still rather limited which means that urgent screening activities, like it has started in other part of the world would be necessary in co-operation, the principles of which has been internationally accepted (Baker, Borris et al. 1995)

If we regard the present day trends in medicinal plant research the best picture can be obtain, if we analyse 870 presentations of the last joint congress of the world's four leading medicinal plant organisations; the American Society of Pharmacognosy, Association Francaise pour l'Enseignement et la Recherche en Pharmacognosie, Gesellschaft für Arzneipflanzen-forschung, Phytochemical Society of Europe, held in Amsterdam in 1999. Without surveying in details the abstracts it become obvious at first sight that the traditional subjects, traditional medicinal plants and their products were the prevailing themes. Important, however, to emphasise that effectiveness of the plant's compounds has received outstanding importance.

If we regard the plants as research targets, the rare, endemic, less available plants, less available plant parts, tissue cultures, results of genetic modifications seem to be dominant From chemical viewpoint the hardly available compounds; due to sensitivity, solubility, minor components, substances with complicated structures, oligo- macro-molecules etc. will provide new natural products together with the biotechnological, and computer modelling approaches. Those compounds bearing strong biological effectiveness e.g. against serious illnesses, like HIV, cancer, malaria etc. will be screened for by the quickly developing bioassays. This seems to be the most effective process that can govern the whole interdisciplinary research activity. It will be served by the databases collecting information from any mentioned fields and also from traditional, ethnobotanical, ethnomedical sources.

In our region, too, the study of environmental pollutants and their accumulation in plants is of outstanding importance from the point of view of safe application of medicinal plants and their products.

This work has been aided by the Hungarian National Research Fund (OTKA T 020213).

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