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This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology
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For many years now the world’s scientific literature has been perfused with articles on the therapeutic potential of natural products, the vast majority of which have herbal origins, as in the case of free radical-induced diseases. What is often overlooked is the effort of researchers who take into consideration the preclinical and clinical evaluation of these herbal products, in order to demonstrate the therapeutic efficacy and safety. The first critical issue to be addressed in the early stages of the preclinical studies is related to pharmacokinetics, which is sometimes not very favorable, of some of these products, which limits the bioavailability after oral intake. In this regard, it is worthy underlining how it is often unethical to propose the therapeutic efficacy of a compound on the basis of preclinical results obtained with far higher concentrations to those which, hopefully, could be achieved in organs and tissues of subjects taking these products by mouth. The most widely used approach to overcome the problem related to the low bioavailability involves the complexation of the active ingredients of herbal products with non-toxic carriers that facilitate the absorption and distribution. Even the induction or inhibition of drug metabolizing enzymes by herbal products, and the consequent variations of plasma concentrations of co-administered drugs, are phenomena to be carefully evaluated as they can give rise to side-effects. This risk is even greater when considering that people lack the perception of the risk arising from an over use of herbal products that, by their very nature, are considered risk-free.
For many years the use of natural products derived from herbs (thereafter “herbal products”), has been proposed as adjuvant therapy in diseases in which free radicals play a key role on the pathogenesis, e.g., neurodegenerative diseases, cancer, diabetes mellitus, and cardiovascular diseases (
As herbal products taken with food or contained in supplements are different from “prescription drugs” derived from plants (e.g., atropine, digitalis, morphine), they are often referred to as dietary supplements. In light of this, for the purpose of this paper, the terms “herbal products” and “dietary supplement” will be considered equivalent.
Because of their chemical structure, several herbal products possess a low solubility and stability in water solution or are quickly deteriorated in body fluids whose pH is neutral. (–)-Epigallocatechin gallate (EGCG,
Summary about the complexation-induced modifications on the main pharmacokinetic parameters of some active ingredients of herbal products.
Compound/formulation | AUC | Reference | |||
---|---|---|---|---|---|
ECGC | ~116 nM⋅ha | ~34.3 nMa | 1.5 ha | 3.4 ha | |
Chitosan-NP-ECGC | ~179 nM⋅ha | ~37.8 nMa | 1.5 ha | ||
Curcumin (CUR) | ~312 ng/ml⋅hb | ~245 nMb | 0.5 hb | ~1.0 hb | |
Curcumin-PLGA | ~3224 ng/ml⋅hc | ~710 nMc | 2.0 hc | ||
Curcumin-TMC | ~12760 ng/ml⋅hd | ~3.3 μMd | 2.0 hd | ~12 hd | |
Curcumin-SLN | ~42000 ng/ml⋅he | ~38 μMe | 0.5 he | ||
Quercetin (QCT) | ~56 μg/ml⋅hf | ~6 μg/mlf | 5 hf | 6 hf | |
Quercetin-SLN | ~324 μg/ml⋅hf | ~12 μg/mlf | 8 hf | 18 hf |
One aspect still to be evaluated when using lipid carriers or polysaccharides is the ability that they are able to “guide” the compound towards the target organs where the accumulation must occur and this is all the more complex as the organs are protected by specific anatomical structures. An example may be the central nervous system as the brain and spinal cord are protected by the blood–brain barrier (BBB), which reduces the penetration of many substances. In this case, the use of certain formulations has proven particularly effective. As demonstrated by
A further issue to be considered when deciding to evaluate a preparation of nanoparticles, particularly when administered for prolonged periods, is the possible toxicity of the carriers with which the active ingredients are complexed. The use of nanoparticles produced using indigestible oils (e.g., mineral oils) rather than digestible ones (e.g., corn oil) should be avoided because those produced using the indigestible oils may have a considerable growth in size due to the aggregation in the passage from the mouth to the stomach and to the intestine and this may cause a degree of toxicity for those who take it (
The influence of the processes of absorption and distribution in determining the bioavailability and blood and tissue concentrations of a dietary supplement, points out, if proof were needed, the importance of the concentrations achieved compared to the doses administered, a factor that not always guarantees the shift of the results from preclinical studies to man. In this regard, the case of the CUR is exemplary. Due to its low lipophilicity and low bioavailability (for an extensive review on the pharmacokinetics of CUR, see
The possibility that dietary supplements interact with drug metabolizing enzymes is no longer a matter of debate. Among these enzymes there are isoforms of cytochrome P450 (CYP) and UDP-glucuronosyltransferases (UGT) and sulfotransferases (SULT). The several isoforms of CYP account for phase I metabolism, whereas both UGT and SULT are responsible for phase II reactions. In most cases, both phase I and phase II enzymes increase the hydrophilicity of drugs promoting their elimination, while only a small number of drugs, so-called pro-drugs, needs activation, usually mediated by CYP, to give rise to a pharmacological action (
Numerous studies have been conducted to evaluate the effects of dietary supplements on drug metabolizing enzymes, although not always the results were consistent. There are several reasons that do not always ensure univocity of evidence, including the different experimental systems used (e.g., the use of cell lines vs. laboratory animals vs. clinical studies), the doses administered and the resulting blood/tissue concentrations reached, above all, the use of individual components of the multicomponent herbal products versus extracts. A typical example is the EGCG that in studies of human hepatocytes or immortalized cell lines induced the CYP1A1 isoform, while in S.
In recent years, numerous studies have shown dietary supplements are able to regulate many intracellular pathways involved in the mechanisms of cytoprotection/cytotoxicity. Several papers are available in literature showing inhibitory interactions between herbal products and clearly cytotoxic signaling systems [e.g., the inducible isoforms of nitric oxide synthase (iNOS) or cyclooxygenase (COX-2), NADPH oxidase] and stimulatory interactions on cytoprotective signaling systems [e.g., superoxide dismutases, catalase, heme oxygenase-1 (HO-1), etc.]. However, one aspect is not always rightly pointed out and on which more and more attention should be focused in the future, is the assessment of some of these cellular systems with borderline effects, that are cytoprotective or cytotoxic on the basis of the type of cell or tissue and their redox state. For example, NADPH oxidase is a membrane enzyme that, in the presence of NADPH, is able to transfer electrons to molecular oxygen generating free radicals, such as superoxide anion, which, in some compartments, is further converted to hydrogen peroxide (for an extensive review see
On the basis of the above views, the induction or inhibition of drug metabolizing enzymes by herbal products and the relative changes of hemoconcentrations of any co-administered drugs, are important factors that contribute to the onset of side effects. As previously explained, the literature data related to changes of the enzyme activity of CYP, UGT, or SULT isoforms, are not always univocal, indeed, they are sometimes also contradictory and this has so far not allowed to state any definite theories about the necessity or convenience, to avoid associations between herbal products and certain medications. The main problems in this regard have arisen since the majority of the evidence to support derived from preclinical studies carried out on cell lines or laboratory animals without evidence of a direct effect on humans. For example,
Another exception must be made for the grapefruit juice for which there is clinical evidence of dangerous drug interactions. Indeed, grapefruit is rich in furanocoumarins, also well absorbed following grapefruit intake (
The above considerations highlight the difficulties faced by researchers when deciding on the possibility or not to start studying the herbal-derived products as adjuvants to conventional therapies for many diseases in which free radicals play a prevalent pathogenic role. Some problems, such as those related to the absorption and distribution of herbal products can be overcome with the help of medicinal chemistry that allows to enhance better absorbed formulations when administered orally, and to reach high concentrations of active ingredient in target organs and tissues. Unfortunately, to date there are no sufficient clinical studies demonstrating the efficacy and safety of these new formulations; in this respect, greater interaction is advocated among researchers who are committed to the preparation and preclinical evaluation of these formulations, often belonging to non-profit institutions, with the pharmaceutical industry, which would have the financial resources to design and implement clinical trials.
The problems stemming from the modulation by herbal products of drug metabolizing enzymes are difficult to manage. What makes it even more difficult is to avoid side-effects arising from the simultaneous intake of medications, dietary or as a supplement, with herbal products and the almost total lack of risk perception by patients. Who would ever think that eating a grapefruit for breakfast or drinking 2–3 glasses of grapefruit juice a day (in particular in warm periods of the year) can pose a serious health risk in case of simultaneous intake of progestogens, statins, or nifedipine? An even more unacceptable risk when considering that the most affected could be vulnerable populations, such as, possibly, the elderly affected by heart disease. A serious approach to solving this problem would provide accurate information on potential risks arising from a prolonged use of herbal products, always recommending medical supervision and shelving the idea that everything is “natural” is “healthy” and “devoid of risks.”
The Associate Editor Silvana Gaetani declares that, despite having collaborated with the author Cesare Mancuso, the review process was handled objectively and no conflict of interest exists. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This worked was supported by Fondi Ateneo.