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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5976_Библиотеки_им_академика_М_И_Перельмана
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TABLE 3.6 Examples of metallic nanoparticles for the delivery of plant bioactives.
Bioactive DDS
Therapeutic
applications Outcomes References
Doxorubicin Gold NPs Cancer Cardiotoxicity reduction [266]
Resveratrol-coated
gold NPs
Not mentioned [267]
Gold-coated iron
oxide NPs
Cancer Magnetic targeting [268]
Gold nanorods Cancer theranostics Simultaneous drug delivery and imaging [269]
Gold nanospheres Photothermal
combined
chemotherapy
Synergistic effect [270]
Silver NPs Cancer Enhanced loading capacity [271]
Iron oxide NPs Magnetic targeting and sustained drug release [272]
Paclitaxel Cancer theranostics Simultaneous drug delivery and imaging [273]
Titanium dioxide
NPs
Cancer Targeted and sustained drug delivery [261]
Camptothecin Mesoporous silica-
encapsulated iron
oxide NPs
Cancer theranostics Simultaneous drug delivery and imaging [274]
Resveratrol Silver NPs Bacterial infections Enhanced antibacterial activity [275]
Gold NPs Diabetic
retinopathy
Thinning of diabetic retinae [276]
Cancer Enhanced antitumoral activity [277]
Bacterial infections Enhanced antibacterial activity [275]
Cancer Enhanced antitumoral activity [278]
Daunorubicin Silver NPs Enhanced loading capacity [271]
Curcumin Bacterial infections Enhanced antibacterial activity [279]
Gold NPs Cancer and
antioxidant
Increased bioavailability [279,280]
Rutin Silver NPs Thrombosis Increased antithrombotic activity, reduction of
hemorrhagic risk of free rutin and increased
bioavailability
[281]
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improve stability, and biocompatibility [288,289]. For instance, coating gold NPs with poly-
mers, such as PEG and hyaluronic acid, creates a platform for drug conjugation, allowing the
NPs to more efficiently carry drugs, and/or for surface functionalization [255,256,289e291].
5.4 Hybrid nanoparticles
Considering the advantages and limitations of each nanosystem/NP, research efforts have
been focused on the development of hybrid nanoplatforms that combine, at least, two distinct
materials. This approach intends to overcome some drawbacks of single components and
optimize the properties of the delivery system [292].
The design of hybrid NPs conjugating two materials of organic origin has been accom-
plished for delivery of plant derivatives. For example, an optimized nanocarrier took advan-
tage of liposomes and mPEG-PLGA NPs for the delivery of panax notoginsenoside, the main
constituent of the extract from the traditional Chinese herb Panax notoginseng. In rat models of
global cerebral ischemia/reperfusion and acute myocardial ischemia, the oral administration
of these hybrid NPs protected panax notoginsenoside from degradation and improved its
bioavailability, leading to reduced brain edema and infarct volume [293]. Furthermore, to
overcome some limitations associated with LNPs, namely limited physical stability, re-
searchers have developed hybrid core-shell lipid-protein NPs, where the external part is
composed of zein, a natural hydrophobic protein. Considering their a pplication for pulmo-
nary administration, an inhalable dry powder was produced [294]. These hybrid NPs were
coated with biotin and all-trans retinoic acid (ATRA) for dual-targeting. Moreover, this sys-
tem was coloaded with ATRA and genistein, an isoflavo ne frequently found in soy and fava
beans and that acts as tyrosine kinase inhibitor. In vitro, the NPs were efficiently internalized
by A549 lung cancer cells, exerting cytotoxic effects. In a urethane-induced lung cancer mice
model, the inhalation of the NPs greatly inhibited cancer progression, providing an effective
tool for localized lung drug delivery [294]. Another nanoplatform, designated as virosomes,
TABLE 3.6 Examples of metallic nanoparticles for the delivery of plant bioactives.dcont’d
Bioactive DDS
Therapeutic
applications Outcomes References
Apigenin Gold NPs Cancer Enhanced antitumoral and antiangiogenic
effects
[282]
Quercetin Silver NPs Improved safety profile, increased proliferation
suppression and apoptosis
[283]
Iron oxide NPs Inhibition of cell proliferation by increasing
ROS
Amphotericin
B
Silver NPs Fungal infections Enhanced antifungal activity [284]
DDS, drug delivery system; NPs, nanoparticles; ROS, reactive oxygen species.
5. Nanotechnology as key strategy to deliver bioactives 59
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has been explored for carrier of plant actives. Virosomes are composed of membrane lipids
and viral glycoproteins, reconstituting the original viral envelope, devoid of nucleic acids.
These virallike particles retain their fusogenic ability, being useful as delivery tools for biolog-
ically active molecules, namely drugs and genetic material [295]. Researchers have developed
influenza A/H1N1 virosomes loading nanocurcumin, consisting in NPs of curcumin with
improved aqueous solubility and with a size range of 65e75 nm. In vitro results demon-
strated an effective controlled drug release, high cytotoxic activity toward breast cancer cells,
and no significant cytotoxic effect on normal mesenchymal stem cells, highlighting virosomes
as promising delivery systems for natural-based compounds [296].
NPs combining organic and inorganic materials have also been investigated. For instance,
tungsten oxide (W
18
O
49
) NPs (WO NPs) are being explored as photothermal agents. Consid-
ering this, researchers have developed hybrid chitosan-WO NPs loading doxor ubicin to
achieve a combination treatment of photothermal therapy and chemotherapy. Using mice
induced with hepatoma cell line H22, these hybrid NPs accumulated at the tumor site, mini-
mizing toxicity and enh ancing antitumor activity [297]. Using magnetic Fe
3
O
4
-chitosan
hybrid NPs, the plant extract of Ocimum tenuiflorum was evaluated in zebrafish. The devel-
oped NPs led to a time- and concentration-dependent toxicity in the in vivo model, being
necessary to carefully assess this parameter before further applications [298].
Also, focusing on cancer theranostics, investigation has been conducted aiming to design
and evaluate a multifunctional hybrid nanoplatform of albumin-quantum dots. These NPs
combined the fluorescence-based imaging with the codelivery of two therapeutic agents:
pemetrexed, a chemotherapeutic drug, and resveratrol, a natural antioxidant. In human
MCF-7 and MDA-MB-231 breast adenocarcinoma cells, the NPs enhanced cytotoxicity and
cellular uptake. In mice bearing Ehrlich ascites tumors, their intravenous administration
remarkably reduced the tumor volume in vivo, providing encouraging data for the applica-
tion of this appro ach for breast cancer therapy and imaging [299].
6. Screening models for formulation development
Bioactive compound discovery and formulation development process of new candidates
involves several steps, namely discovery, preclinical research, clinical trials, approval by reg-
ulatory agencies, and post-market monitoring [300]. In silico, in vitro, in vivo, and ex vivo
research, using appropriate cell culture and animal models (Fig. 3.3), provide valuable in-
sights on the potential mechanisms of action, as well as on the therapeutic potential and
safety profile.
6.1 In silico assays
In silico approaches, i.e., computational modeling, have emerged as a tool for rational drug
design and for prediction and measurement of biopharmaceutical data [301,302]. Computa-
tional tools result from an interdisciplinary approach, where mathematical and computa-
tional methods provide useful information regarding tested compounds [302e304]. In
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silico analysis reduces the need for expensive and time-consuming experimental assays,
allowing the screening and selection of lead candidates from more than several millions of
compounds. Add itionally, in silico predictive models are also useful for the elucidation of
structureeactivity relationship problems and prediction of the pharmacokinetic and pharma-
codynamic profiles of compounds [302,304,305].
Several examples of in silico studies are described in the literature. Integrated in silico and
in vitro analyses to screen libraries of natural-based products are often used [306]. For
example, researchers have screened, in vitro and in silico, a series of compounds isolated
from the root back of Ulmus davidiana as inhibitors of the enzyme-soluble epoxide hydrolase,
which is involved in renal injury and decreased blood pressure in animal models. One com-
pound was identified as a lead candidate for the development of new cardiovascular disease
treatments [307]. In a work focusing on the parasitic disease human African trypanosomiasis,
molecular docking studies were performed in a total of 386 compounds derived from 19 spe-
cies of Nigerian medicinal plants. Depending on the compounds’ structure, different protein
targets were identified and validated, providing a framework for further applications against
trypanosomal disease [308]. Aiming to treat breast cancer, researchers have studied, in silico
and in vitro, Aloe vera leaf extract. The molecular docking study suggested that bioactive com-
pounds present in the leaf extract had a greater binding affinity toward estrogen alpha recep-
tor, compared to tamoxifen. Further, the cytotoxic activity of the extract against breast cancer
FIGURE 3.3 Schematic representation of in silico, in vitro, in vivo, and ex vivo models for drug discovery and
development.
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cell line (MCF-7) was much higher compared to noncancerous cells (NIH-3T3), also display-
ing free radical scavenging activity [309].
Puerarin, the major bioactive and the most abundant secondary metabolite from the root of
Pueraria lobata, was investigated as a therapeutic agent against Alzheimer disease. An initial
screening using in silico methods (i.e., molecular docking) was performed to dete rmine po-
tential therapeutic targets, pathological pathways, and interactions between puerarin and
Alzheimer diseasee related proteins. The in silico data were confirmed in an amyloid
b-peptideeinduced rat model of the disease [310].
Maize zeins have been proposed as a source of peptides with diverse bioactivities. Re-
searchers have analyzed and characterized three novel peptides derived from the 19 kDa
a-zein, developing a structural model in silico, to simulate struc tural changes and peptide-
solvent interactions, and determining their bioactive profile in vitro, including cytotoxicity
and antioxidant and cell penetration activities [311]. Moreover, other bioactive peptides
were investigated in the invasive marine sea grass Halophila stipulacea, a very abundant spe-
cies in the Mediterranean Sea. Applying in silico tools for the proteolytic fragmentation of the
rubisc/o protein from this sea grass, the authors showed different bioactive peptides with
different activities, including antioxidant, hypolipidamic, and inhibition of angiotensin-
converting enzyme [312].
6.2 In vitro and ex vivo assays
In vitro cell culture systems are important to study biological, physiological, and patholog-
ical cellular processes [313], and several in vitro methods are available to evaluate the prop-
erties of natural products, including antioxidant, cytotoxic, and immunomodulatory
activities. Furthermore, in vitro models that simulate the gastrointestinal tract, namely oral
cavity, stomach, and small intestine, have been established. Unfortunately, there is a lack
of standardization among different studies and proper validation is required. Nevertheless,
valuable information regarding plant derivatives has been obtained using in vitro digestion
models [314].
The most commonly used cell culture method is the adherent 2D model [315,316]. This is a
simple and low-cost system that is useful for a variety of biological tests. However, 2D cell
cultures do not entirely mimic the in vivo tissue architecture and diversity of cell-cell and
cell-extracellular matrix interactions, limiting the natural cellular responses [315,316]. To
overcome these drawbacks, 3D cell culture models have been established, being more com-
plex and more closely representing several functions of in vivo tissues [301,317]. Both 2D
and 3D models are often used in combination to evaluate the properties of natural products.
For instance, the cytotoxicity and chemosensitizing effects of glycoalkaloidic extract were
investigated using bladder cancer cells, both commercialized and patient-derived. Cells
from the patient were highly resistant to cisplatin and 3D spheroids increased the IC
50
values,
compared to 2D models. Also, the combination of the natural extract with cisplatin demon-
strated a synergistic effect in both 2D and 3D cell culture systems [318]. Also, the anticancer
potential of extracts from Sutherlandia frutescens and Xysmalobium undulatum were assessed
against colorectal cells, both in 2D cell culture and 3D spheroids. The results showed cyto-
toxic effects compared to paclitaxel, decreasing cell growth and viability, as well as glucose
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consumption [319]. Another example was a study where the immunomodulatory effects of
celastrol enriched extract, from Tripterygium wilfordii, were evaluated. The results obtained
in both 2D and 3D human models of psoriasis showed that the extract inhibited Th17/
Th22 pathway, major inflammation parameters, and psoriasis-associated biomarkers [320].
Finally, ex vivo assays, in which biological sample s obtained from in vivo models are
analyzed, are also important to validate both the therapeutic potential of natural-based can-
didates and their safety [301]. For instance, researchers have performed the phorbol myristate
acetate (PMA)-whole blood assay to assess the antioxidant activities of polyphenol-rich fruit
and vegetable juices. This assay provided relevant data fo r predicting the in vivo antioxidant
activity of phenolic compounds, namely the inhibition of superoxide anion production, a
radical produced by univalent reduction of oxygen [321]. In addition, the antihypertensive
activity of Otostegia integrifolia leaf extract was analyzed in an ex vivo assay using rat aortic
strips. The results demonstrated a reversible and time- and concentration-dependent vasode-
pressor effect of the extract [322]. In another study, the authors investigated the neuroprotec-
tive potential of ursolic acid, commonly found in fruits, spi ces, and herbs, in oxidative brain
injury. The studies performed in isolated rat brains showed the neuroprotective effects of
ursolic acid, mitigating oxidative stress, improving purinergic and cholinergic functions,
and suppressing proteolytic activity [323].
6.3 In vivo studies
Despite the efforts for the validati on of alternative methods to reduce the use of animal
models, in vitro assays have major limitations for the nonclinical evaluation of several param-
eters. For this reason, the use of laboratory animals is still a major component in the process of
drug development [301]. Different purposes justify the use of animal models, namely, to
investigate different routes of administration, to determine dose regimens and appropriate
formulations, to assess potential safety risks, to discover and valid ate novel therapeutic tar-
gets, to evaluate the therapeutic efficacy, and to study the pharmacokinetic and pharmacody-
namic profiles [324,325]. The usefulness of animal models is reinforced by studies of chronic
inflammatory diseases, in which the effective doses of plant actives were translated into
human-relevant equivalents, in comparison to currently used drugs [326 ]. Importantly,
in vivo models are crucial for a proper evaluation of the therapeutic potential of plant actives
since, even though these demonstrate promising benefits in vitro, when transposing to the
in vivo setting, different results may be obtained [327]. Indeed, a major factor that influences
in vivo activity of plant derivatives is their pharmacokinetics and bioavailability. Therefore
appropriate animal models must be established to evaluate these parameters and, in the
case of orally administered compounds, special consideration should be given to the gastro-
intestinal barrier [327].
The two most common animal species used as models are mice and rats. In a research
work, both species were used to investigate the pharmacokinetics and anti-inflammatory ac-
tivity of anatabine, an alkaloid. After inhalation or intraperitoneal administration, anatabine
treatment inhibited acute inflammatory disease in both models and alleviated the symptoms
of c hronic inflammation in mice. Also, the administration of anatabine via inhalation was
validated as a suitable route for this type of preclinical studies. Despite the promising and
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valuable results, since the pharmacokinetic profile of rodents differs from humans, the trans-
lation of the observed anti-inflammatory activity to patients may still represent a challenge
[328].
Other species are also used for in vivo evaluation of plant actives, including pigs. This an-
imal species presents many similarities with humans in terms of anatomy, physiology, ab-
sorption of nutrients, and gastrointestinal immune system [329]. In a porcine model of
hypercholesterolemia and chronic myocardial ischemia, resveratrol was evaluated as cardio-
protective and proangiogenic agent. Oral administration of resveratrol improved myocardial
and coronary vascular functions, and upregulated markers of angiogenesis [330]. Despite
their usefulness, there are some limitations to the use of pigs as models, including the
need for highly specialized animal facilities, high costs, and low reproductive rate [329].
For instance, in given example, the authors mentioned the relatively low number of animals
per group (n ¼ 7), and that the obtained results should be carefully interpreted [330].
Guinea pigs are also used as preclinical models for therapeutic evaluation of plant-derived
compounds. The phenolic component hydroxychavicol, abundant in the plant Piper betle L.,
was investigated as a topical antifungal agent in a guinea pig model of cutaneous fungal
infection. The obtained data demonstrated an effective antifungal activity of hydroxychavicol
[331].
The zebrafish, Danio rerio, is also often used for in vivo screening of plant actives, as
already described in previous sections [184,186,298]. Frequently, this animal model provides
important information regarding embryo toxicity and regenerative properties of tested mol-
ecules. For instance, aqueous extracts from Piper sarmentos um showed a concentration-
dependent reduction on embryo viability and abnormal morphology. Howeve r, a superior
and faster regenerative activity was obtained for higher extract concentrations [332].
Finally, the evaluation of the safety and efficacy of plant-derived compounds is also impor-
tant, since main objective for the development of novel drug products is to, ideally, provide
increased efficacy and reduced toxicity. Preliminary assays on the efficacy and safety of tested
compounds are performed in cultured cells, providing information about cytotoxicity,
affecting cellular pathways, binding to plasmatic proteins (e.g., albumin) and capacity to
cross membranes [333]. Moreover, in vitro hemolysis assays should be performed to ensure
the safety of formulations for parenteral administration [334].
In vivo, besides monitorization of animal behavior and weight, morbidity and survival
rates, hematological and biochemical parameters, as well as tissue index, are frequently eval-
uated in preclinical models. In addition to mammal models and as mentioned previously,
zebrafish is also often used for assessment of the rapeutic effect and toxicity
[184,186,298,332]. In terms of hematological analysis, several factors are accounted for,
including red blood cells, white blood cells and platelets count. These tests allow identifying
certain conditions, such as dehydration [29], decline or augment of immunity, and platelet
aggregation [335]. Changes in serum levels of alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) allow the detection or prediction of hepatotoxicity [336]. Renal
toxicity is detected by increased blood levels of creatinine, urea, and uric acid, which may
be related with imp aired function of glomeruli and tubular damage [337]. Tissue index values
provide information about organ development. An increase in this parameter suggests organ
hypertrophy, congestion or edema, while reduced values indicate organ atrophy and degen-
erative changes [338,339]. Importantly, histopathological examination is also conducted,
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involving macroscopic and microscopic analysis in tissues to identify potential alterations
(e.g., inflammation and necrosis). Hematoxylin and eosin staining is the most commonly
employed, being widely used to detect changes in tissues [340].
Occasionally, an accurate efficacy and safety assessment is hindered by controversial re-
sults obtained from different studies. For example, in the case of Morus nigra extract, on
the one hand, researchers showed that its oral administration (100 mg/kg twice daily, for
42 days) significantly increased serum levels of ALT and AST in both healthy and diabetic
mice [341]. Moreover, acute toxicity was evaluated in mice at doses of 2000 mg/kg and
5000 g/kg, administered intraperitoneally and orally, respectively. No mortality and no alter-
ations in hematological and biochemical parameters were reported [342]. On the other hand,
in rats, the oral administration of the extract at a single dose (2000 mg/kg) or repeated doses
(500, 750, or 1000 mg/kg, for 28 days) did not induce significant real or liver toxicity [343].
Therefore, and as mentioned in previous sections, special attention should be given when
selecting the preclinical model, dosage, therapeutic regimen, and administration route in or-
der to obtain accurate information about the safety and efficacy of plant derivatives.
7. Regulatory framework of isolated compounds from plants, extracts, or
plant-derived products
Food supplements and drugs are regulated in part by their intended use, which is deter-
mined by claims and labeling information. When deciding the category in which the appli-
cant request a product to fall, manufacturers should be aware of the safety requirements,
the several labeling requirements, and the appropriate notification procedures for ingredients
in their products. Table 3.7 describes the main regulatory categories and depicts this diversity
of products in terms of nomenclature.
Each category requires different data submitted before its commercialization. Example, for
the food supplements, Directive 2002/46/EC describes some rules that protect consumers
against potential health risks of such products and ensure that they do not contain any
misleading information. With respect to the safety of food supplements, this directive lays
down a harmonized list of vitamins and minerals in Annex I and Annex II, which contains
a list of permitted sources (vitamin and mineral substances) from which those vitamins
and minerals may be manufactured.
In this context, there is no global and harmonized regulatory framework or, in some coun-
tries, the progress in product regulation is not occurring at an equal pace to product global-
ization and diversification [344]. It is known that many countries have established guidelines
and regulations regarding health-related claims. The existing regulations vary considerably
between them. In this subject, the WHO plays a significant role in harmonizing regulation
at an international level. Considering the context of Europe, a simplified registration proced-
ure for traditional herbal medicinal products was introduced in 2004 through Directive 2004/
24/EC which amends Di rective 2001/83/EC. This regulation aims to protect public health
and make safe the commercialization of herbal medicinal products within the EU [345].
Talking about the approval process, in general pharmaceutical companies seeking to brin g
this type of products to the market in EU Member States should strictly follow the national
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procedures overseen by national competent authorities. To approve a herbal medicinal prod-
uct in Europe, there are three main regulatory pathways: traditional use registration, well-
established use marketing authorization, and stand-alone or mixed applications.
In case of the traditional use registration (Article 16a (1) of Directive 2001/83/EC), it is
stated that no clinical test and trials on safety are required as long as sufficient safety data
and plausible efficacy are demonstrated. This marketing authorization involves bibliographic
data and these products must have been used for at least 30 years (at least 15 years within
EU). Additionally, these products are intended to be used without supervision of a medical
practitioner and they should not be administered by injection.
On the other hand, the well-established use (Article 10a of the same directive) requires sci-
entific literature establishing that the active substances of the medicinal products have been in
well-established medicinal use within the EU for at least 10 years, with recognized efficacy
and an acceptable level of safety. This process generally involves assessment of mostly biblio-
graphic safety and efficacy data.
Finally, the stand-alone or mixed application (Article 8(3) of the same directive) refers that
safety and efficacy data should come from the company’s own development or a combination
of own studies and bibliographic data.
To sum-up, in any situation, a full-quality dossier is required as well as other fundamental
principles that are applicable to all medicinal products. Good Manufacturing Practice, Phar-
macovigilance and requirements on packaging and labeling are some crucial principles.
TABLE 3.7 Regulatory categories available for natural-based products.
Regulatory Category
Functional food Foods with added biologically active substances (e.g., vitamins, fatty acids or dietary fibers,
phytochemicals, probiotics, and foods containing minerals).
Dietary supplement Any substance intended to supplement the diet and contains, either alone or in
combination, a medicinal product, a vitamin, a mineral, or an amino acid.
Herbal substance Whole, fragmented, or cut plants, plant parts, algae, fungi, lichen in an unprocessed form
(they can be dried or fresh).
Herbal preparation Substances subjected to some specific treatments (expression, extraction, concentration,
distillation, fractionation, purification, or fermentation).
Herbal medicinal product Any medicinal product, exclusively containing as active ingredients one or more
substances or one or more medicinal product preparation.
Additional categories Products classified differently to those listed above included: traditional medicines,
cosmetics, and homeopathic medicines.
Over-the-counter
medicine (OTC)
Medicines purchased without a prescription.
Prescription medicine Medicines purchased with a prescription.
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The regulation of this type of medicinal products is also complicated because it varies in
terms of both how the plant is used and where it is used. As example, Curcuma longa L.
can be used as a culinary ingredient but also as a functional food or over-the-counter
(OTC) medicines.
Although legislation and regulation vary considerably, i.e., there are some products being
sold without any restriction or regulation in some countries, probably sold as a food or die-
tary supplement, while in others, they are classified as a medicine, with therapeutic claims
and indications.
It is an unquestionable issue that significantly different perspectives exist, from country to
country.
In case of medicines comprising a drug substance from plant, the regulatory framework is
more restricted [346] and similar to any synthetic-based drug. The full research, development,
and approval process for a new drug product is a long process, independent of the origin of
the drug substance. It can take from 12 to 15 years and the rate of success is generally very
low; only one in 1000 of the compounds that enter laboratory testing pursue to human
testing. Additionally, only a small percentage of those reach the market.
The process of drug approval is also controlled by a governme ntal regulatory agency. The
agency reviews each process closely using an independent team of asses sors who evaluate
safety, efficacy, and labeling of the proposed product. After approval, the agency follow-
up continues to make sure that these new medicines continue to be safe and effective
(post-marketing monitoring). If the drug substance is totally new, the pharmaceutical com-
pany submits an investigational new drug application data and it must include several key
points. First, manufacturing information to demonstrate the pharmaceutical company can
properly manufacture the drug. This information should include data related to the compo-
sition, stability, controls used for manufacturing the drug substance and the drug product.
Secondly, data gathered during the animal studies but also data from human clinical trials
(phase 1e3). Finally, the pharmaceutical company’s proposed label for the drug in drug
approval has been made. The number of new drug substances is higher every year. As
example, each year, the FDA reviews about 1500 investigational new drug applications
[347]. On average, it takes hundreds of millions of dollars to get a new medicine approved
and only about 10% of potential drugs make it through the rigorous process and are
approved.
Despite these challenges, researchers remain hard at work to develop new, safe, and effec-
tive natural-based medicines. The ideal scenario of harmonized regulations is also a major
challenge. Currently, the EU legal framework represents, perhaps, the most advanced system
to be accepted by all member states within a region for herbal medicinal products.
It is obvious that it is urgent to have a complete process of harmonization and herein the
communication and science are key drivers toward its continued global development.
8. Conclusions and future perspectives
Natural products are a promising pool for the discovery of new lead molecules with high
structural diversity and many bioactivities. These products can be directly used as starting
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