Abdelaziz Ghanemi

Shorter and sturdier bridges between traditional Chinese medicines and modern pharmacology.

Dear Editor, Chinese ancient philosophy describes divers concepts such as Qi (spirit or energy) and the five natural elements (fire, earth, water, wood and metal) that along with the Yin and yang principle (Xu et al., 2011, 2013; Zeng et al., 2013) represent the fundamental bases of Traditional Chinese medicines (TCM) theories that consider the unbalances in the body as the pathological state and thus, rebalancing the body as remedy. From a therapeutic viewpoint, TCM have always benefitted from natural products, including plants, animals and minerals. TCM are based on different principles such as the Doctrine of Signatures, that thrived particularly during the Middle Ages, and it supposes a relation between the plant‘s shape, structure, biological behavior and the symptoms of the disease for which this plant could represent a remedy (Richardson-Boedler, 1999). Based on simple empiric observations (Ho, 1993), but also on religious or philosophical beliefs in some cases, the selection of useful natural drugs is a process that has taken centuries and has required cumulative efforts of many generations to find out the most efficient therapeutic approaches for each health problem. Yet, TCM have succeeded in treating many diseases, however have also failed to treat others and have even been toxic in other cases. Chinese scientists, as well as international researchers, working on TCM and more generally on natural products, have been continuously trying to map the “Pharmacological Puzzle” of TCM (Liu et al., 2013a; Song et al., 2013; Li and Zhang, 2013), especially with the standards and requirements of modern pharmacology and the divers national, regional and international regulations that put conditions for any product or molecule before it can be designed as “Drug” or “Medicine” within both a legal and therapeutic context. The main obstacle that TCM progress faces is that many products are still a part of the ethnopharmacology and have not switched yet into the modern pharmacology. The main research field that might solve this issue remains the pharmacognosy since it is the science that mainly combines a scientific precise description of the phytochemical constituents and their pharmacodynamic activity. Importantly, for a product or a molecule to be considered as “Drug” or “Medicine” biological, chemical, pharmacological and toxicological profiles need to be established, which requires the implication of divers research fields, such as biochemistry, molecular biology, cytology and molecular pharmacology, that constitute together the bridge we are in need of to move from TCM as “Ehnopharmacology” to modern therapy with a full Pharmacological profile. Indeed, the data we have now are very encouraging (Li and Zhang, 2013; Boubertakh et al., 2013; Liu et al., 2013b; Wang et al., 2013a) and the future of TCM appears highly promising. TCM constitute a gargantuan therapeutic dictionary, within which each word needs a “modern pharmacological definition” to be recognized as a “modern therapy”. The basic processes consist on selecting TCM known for their ethnopharmacological use, and after a phytochemical study, selected compounds would go through in vitro then in vivo pharmacological and toxicological investigations. The final step would be clinical studies (Pengfei et al., 2013; Liu et al., 2014) to confirm the final pharmaco-toxicological profile of the TCM and their active ingredients. Importantly, the modern pharmacology has identified the G protein coupled receptor as an extremely important target (Emery, 2013; Ghanemi, 2015; Ghanemi et al., 2013) especially within the nervous system on one hand (Millar et al., 2012; Ghanemi, 2014b).On the other hand, the chemostructural similarities that exist between some phytochemical compounds and the endogenous neurotransmitters have encouraged more investigations toward the discovery of TCM derivatives and extracts to treat many diseases, such as neurological disorders (Wang et al., 2013) including schizophrenia and Parkinson’s diseases, which have divers neurotransmitters implicated within the underlying patho-mechanisms (Weickert et al., 2013; Ghanemi, 2013). The use of developed cellular and animal models (Ghanemi, 2014a; Reddy and McWeeney, 2006; Chen et al., 2013) for disease studies is still highly required for further elucidation of TCM therapeutic effects. These bridges linking TCM to modern pharmacology have beneficial impacts on other fields such as cosmetology. Indeed, the example of skin whitening products would clarify this approach, and here we mention the efficient volcanic mud, which is effective in skin whitening. Furthermore, it has been also found out that Nigella glandulifera Freyn et Sint seeds contain ingredients that have melanogenesis inhibition activity (Nguyen et al., 2007). These two natural products are both black, and they both have a skin whitening effect, and this may, probably according to the Doctrine of Signatures, encourage focusing more on black drugs when looking for skin whitening effect, as this would save time during primary investigations. Yet, it remains important to follow the modern recognized methods and techniques to study the pharmacodynamics, toxicology, clinic and other aspects of the TCM. For instance, after identification of this activity in N. glandulifera seeds, and the isolation of the active ingredient, that is dioctyl phthalate, it has been classified as an endocrine disrupter and its use was prohibited (Sekiguchi et al., 2006; Tickner et al., 2001). This example may apply for any natural product showing any potential to be active against any disease before further necessary scientific investigations, and this would help to expedite the progress of drug discovery toward a modern pharmacological use of the TCM.

Is mapping borders between pharmacology and toxicology a necessity

The existent common features between pharmacology and toxicology and the shared basic concepts, in addition the similarities between the principles of the two fields made them both be considered as one scientific subject by many authors. However, the descriptions of toxicology and pharmacology as two distinct areas have strong arguments as well. Therefore, the question of the existence of borders between pharmacology and toxicology and their nature represent continuous debates especially after the emergence of new advances and novel concepts in both areas such as those related to the G protein coupled receptor (Ghanemi, 2013b,c) and the factors that can influence this receptor (Ghanemi et al., 2013) along with the new descriptive approaches of drug-target interactions. Moreover, the development of traditional Chinese Medicine-based therapeutic approaches and theories (Boubertakh et al., 2013; Jiang, 2005; Yan et al., 2012; Yao et al., 2013) provides new natural products for modern pharmacology (Ghanemi and Boubertakh, 2014), all these elements have further strengthened those debates. Pharmacology represents a science that mainly deals with therapeutic approaches using natural and synthetic compounds that are not always without any toxicological properties. In fact in some cases the toxic effect represents the basis of the therapeutic effect such as in some cytotoxic compounds used as anticancer drugs (Goodarzi et al., 2013). Furthermore, certain side effects of drugs are example of molecules with both therapeutic and toxic impacts especially within the central nervous system (Bet et al., 2013; de Kinderen et al., 2014) that represents a network within which the divers neurotransmitters and the drugs that interact with the neural transmission influence each other (Ghanemi, 2013a). On the other hand to describe a molecule as toxic or therapeutic, it may first depend on some parameters. Indeed, a compound may be therapeutic in a certain dosage but toxic in other dosages, or may be toxic for a species while it treats another species. Importantly, examples about interactions between chemical elements and live cells (Ghanemi, 2014) will open more doors regarding the overlaps between pharmacology and toxicology. The results we come out with are that the concepts of pharmacology or toxicology remain relative and drawing limits cannot always be reliable except if we define references according to which we want to map those borders such as dosage or species within a precise context including the patho-physiological conditions, drug interactions and the physicochemical properties of the compounds.

How important is pharmacognosy for doctors and dentists

Pharmacognosy is a biological science with therapeutic aspects that is an important part of the teaching content for pharmacists, but this knowledge is not always taught to other medical health professionals, such as doctors and dentists. Doctors and dentists mainly have knowledge about modern pharmacology and prescribe conventional drugs within the contexts of pharmacology and toxicology (Saeidnia and Abdollahi, 2013; Ghanemi, 2014c). However, because doctors and dentists must manage the health status of their patients and prescribe drugs, they should consider factors that could influence the effects of prescription drugs, including natural compounds and the active ingredients these compounds may contain. By natural compounds, we refer to products used as traditional, herbal, or natural therapies, as well as diet products. In fact, the active ingredients of natural compounds may influence the physiological and pathological status of patients and may interact with therapies when they are taken together. Furthermore, a variety of drugs have been developed from natural products, indicating that compounds derived from natural products can have strong biological and pharmacological activities (Patwardhan, 2005). Indeed, different pharmacological properties have been linked to natural compounds and have been proposed as potential candidates for the development of therapeutic agents (Ghanemi and Boubertakh, 2014; Ghanemi, 2013, 2014b,d; Boubertakh et al., 2013). Therefore, as clinicians who prescribe medicines, doctors and dentists should be aware of these factors to select the best therapeutic approaches. In addition, they must guide their patients to avoid, or at least minimize, the interactions between natural compounds and prescribed drugs. Natural compounds may influence drug effects not only by interacting with a drug but also by modifying a drug’s targets, such as membrane receptors (Ghanemi et al., 2013). In addition, even in patients who are not prescribed therapy, doctors and dentists should explain the risks related to the use of natural products by clarifying that natural products are not guaranteed to be safe and that foods and beverages can have pharmacological or toxicological effects. Thus, patients who consume natural compounds should pay attention to factors such as the timing, quantity, and frequency that they take these products with respect to prescribed drugs and with respect to their physiological or pathological status. As a related point, natural compounds can also influence the results of biomedical analyses on which prescriptions may be based because the chemicals in natural compounds may interact with cells or with laboratory reagents and lead to false results (Ghanemi 2014a,e). In conclusion, the study of the pharmacological and toxicological properties of natural compounds is no less important for doctors (Simaan, 2009) and dentists than it is for pharmacists. More attention should be paid to topics regarding natural compounds within the faculty of medicine.

How to define a pharmacological or a toxic food

Elements of our daily lives including food and beverage are more and more likely to include compounds that have pharmacological or toxic effects on the body which can be either an advantage or a disadvantage based on several factors. The active compounds that might be within the food and beverage we are taking on daily basis may be of two main origins, naturally included or artificially added. Rarely, other compounds can exist without being neither natural nor artificially added, such as those due to pollutions. Such elements are defined in reference to both pharmacology and toxicologyrelated concepts. Natural active compounds are mainly those described by pharmacognosy such as flavonoids, alkaloids, terpenoids among which some have shown different usages in pharmacology, therapy and chemistry. Persons -willing or notto take active compounds within their daily food find themselves consuming them on a regular basis within their fruits, vegetables for example. These elements can be very helpful and have been described by some others as natural medicine which is preventive rather than curative. Indeed, an individual who selects on scientific basis both the quality and the quantity of his diets may protect himself from diseases and reduce the risk of others. One of the best examples for that is the antioxidants. Comparatively, the active elements found within food may be toxic even when taken at a small dosage for some elements or if taken in a high dosage for other less toxic elements. Importantly, some active compounds contained within food may interact with some prescribed therapeutic treatments which represent a serious issue that we need to educate both clinicians and patients about its aspects and consequences. The second type of active compounds is represented by those artificially added for diverse purposes such as therapeutic effects (antibiotics), athletic usage (energetic beverage) or diet effects (food for diabetics or high blood pressure patients). In fact, we may mix drugs with food to hide the taste or for specific patients in pediatrics or psychiatry for example where it is, in some case, difficult to deal with patients. Another case in which we can find added active elements in food is when those elements are added to ameliorate the food quality or to treat the animal or the plant from which the food is produced. Indeed, pesticides, insecticides and antibiotics, which are commonly used in a diversity of crops and animals, constitute a threat to the human health. Contaminants are less common but also require attention and elements resulting from pollution can be found within the food. Some plants used as crops have the ability to accumulate some elements within their tissues and later be consumed by humans. The dangers or benefits that active elements, contained within food, do not only depend on the nature of the products but also on the concentration, the chemical combination (either with elements within the same food or as a result of the interaction with other foods or drugs), in addition to the individuals taking that food in term of type of diet, pathophysiological status, climate and healthcare. Further studies are required toward elucidating the full profile of the food active compounds; such investigations are strongly related to the extractions, purifications and analysis methods (for examples see).

Toward overcoming the challenges facing biomedical analyses

Regardless of the different diagnosis methods than can exist, medical diagnosis is a practice based on diverse approaches that aim to find out the causes of a pathology or the underlying reasons of an unhealthy status. A robust diagnosis needs to lie on a variety of approaches that combine elements including questionnaire, imagery and analysis. The biomedical analyses may be the most commonly used approaches in the medical diagnosis, especially for the molecular diagnosis, due to the variety of parameters they cover and the different abnormalities they can reveal. Biomedical analyses have challenges to overcome, yet standards to respect. Indeed, it is important to select the appropriate biological sample, the time of sampling and the condition under which it is sampled in terms of period, patients’ diet, patient’s age and the drugs the patients are taking. For instance, to test blood sugar or blood lipids the patients should fast several hours before the blood is drawn, in addition, when interpreting the results the clinician should take into consideration the fact that a patient is taking some drugs like insulin, anti-cholesterol drugs, other medicines or even some types of food or natural products that interact with the metabolic process which may influence the level of some biological molecules such as glucose, triglycerides and cholesterol. Furthermore, based on what we are looking for or what we are suspecting, choosing the type of sample and the region to sample represents an important issue. In fact, some false diagnoses can be due to a wrong sampling choice such as searching for a specific antibody in the blood of an immune-deficient patient who will have a limited amount of antibodies instead of searching for other disease markers. This may happen when the pathological status of the patient is not well reported. Another example of a sampling choice in terms of time and region is diagnosing infections where different options may exist including antibody detection, bacterial or inflammatory marker detections and depending on the infection phases and the patients we may base our diagnosis on one or more of those parameters. The laboratory steps of the medical analysis also represent an important issue. Indeed, the equipment quality and the appropriate use of it, in addition to the selection of the analytical methods along with the use of suitable reagents at the optimum conditions especially those able to react with the live cells are important. These factors can influence the results based on which a doctor will prescribe a drug, adjust the dosage of treatment, ask for further analysis or recommend a diet for the patient. Thus, the experimental steps of the laboratory should be given more importance and the laboratory personnel need to receive appropriate training. Furthermore, the patients need to be educated regarding the precautions related to the biomedical analysis and need to respect the diet recommended by doctors or clinicians, be punctual for the sampling and report any details that may influence the results such as the disease familial history and an eventual treatment that the patient is taking. These concepts can also be recommended for similar biological approaches used in scientific research in areas such as pharmacology, genetics and immunology to reach new advances toward new drug development for medical usage. However, in diverse cases the biomedical analysis is not enough for a precise diagnosis and further complementary tests and explorations such as imageries, physiological tests and exploratory surgery are required to map the pathological status of patients. In all cases, the collaboration of all the individuals concerned, starting form clinicians, laboratory assistants, pharmacists and the family members of the patients; is the minimum requirement to optimize the results and the efficiency of the biomedical analysis toward an accurate diagnosis.

How to map the bridges between zoology and pharmacology

Acknowledgment The evolution of the modern sciences had lead to divers amifications and to the emergence of new fields from the nown classical sciences (Vermeulen et al., 2013). Yet, such lassical sciences and the new emerging fields are still closely elated due to the interactions they have with each other’s nd the features they share which make mapping the links etween them an important issue to both achieve more dvances and eventually redefine the existing borders. Modern esearch areas such as biological sciences and medicine are mportant multidisciplinary fields for which both zoology nd pharmacology play important roles in the advancement, escription and applications of the new findings within novel ontexts. Herein, common features and strong links can be escribed between zoology and pharmacology. Zoology, as a provider for data related to animal properties nd species characteristic details, has been important for pharacology not only for drug animal experiments (De Wasch t al., 2002) but also for cells (Jonsson et al., 2012; Braam nd Mummery, 2010) and animal models (Spertzel and the ublic Health Service Animal Models, 1989; Laurijssens t al., 2013) for different pathways tests and pharmacological tudies. Indeed, generally the first stage of active compounds potential future drugs) studies is mainly to evaluate the effects f the compounds on cell cultures (Ghanemi, 2014b), which re mainly derived from animals especially in primary cultures, r in vivo cell culture inside animal bodies such as rats. urthermore, before we can move to the clinical trials, animal xperiments are carried out to find out more elements about he side effects, the toxicology (Ghanemi, 2014c) and define ome parameters such as pharmacokinetic values. Moreover, nimal behaviour and memory studies are extremely important ainly for the study of some specific classes of drugs such as sychotropic medicines and drugs used in the treatment of eurodegenerative diseases, in addition, it allows us to undertand more about the psychiatric or psychological side effects ome drugs (not only the psychotropic) may have. Imporantly, new finding, based on cell cultures and animal esearches, have revealed important data about the G protein Ab Pre eer review under responsibility of The Egyptian German Society for oology.

For dentists and doctors: The neglected concepts about the factors influencing the effects of drugs

The study or the evaluation of the effects of not only an active compound, mainly drugs but also a toxic compound (Ghanemi, 2014a, Ghanemi, 2014b, Ghanemi, 2014c, Ghanemi, 2014d), always takes into consideration well-known influencing factors such as the drug concentration, drug–drug interactions (Ritter, 2009, Hamoud et al., 2014, Tischer and Fontana, 2014, Yeh et al., 2014) or the type of excipient or solvent used during the drug administration. However, some factors can significantly influence the activity a drug or a compound can have on cells (Ghanemi, 2014a, Ghanemi, 2014b, Ghanemi, 2014c, Ghanemi, 2014d), tissues or organisms. Drug interactions with food (Lin et al., 2008, Wang and Sweet, 2012) and some natural products may significantly influence the efficacy of a drug. Indeed, since food or natural products used either as nutriments or as herbal preparations such as tea may contain active compounds including flavonoids, alkaloids and others, this could have the same consequence as the drug–drug interactions between the drug and the active compounds contained within the food and the natural compounds that may inhibit for example intestinal metabolism and transport (Won et al., 2012). Such concepts are extremely important mainly in therapeutics especially that it is largely believed that “natural products” are safe and without any possible negative impact on health, which is not always correct. In fact, modern pharmacology has pointed out divers active compounds derived from natural products such as Traditional Chinese Medicines (Boubertakh et al., 2013, Ghanemi and Boubertakh, 2014) that are potential candidates for drug development showing strong biological activity and thus the potential interaction they may have with drugs if taken simultaneously. Chemical environment that may result from the ingested food is also an important influencing factor. Indeed, elements such as the stomach pH and the type of molecules taken or administrated simultaneously with the drug might influence the pharmacokinetics mainly by modifying the drug ionic status and by creating competitiveness between the drug and the other molecules used as transporters during the absorption into the circulation or into the site of drug action. Within this context the chemical environment may also modify some properties of drug receptors such as the reported data about the factor the G protein coupled receptor (Ghanemi et al., 2013) that represents probably the most important therapeutic target in the modern pharmacology (Ghanemi, 2013a, Ghanemi, 2013b, Ghanemi, 2014a, Ghanemi, 2014b, Ghanemi, 2014c, Ghanemi, 2014d) which shows how “chemistry” can change drugs the drug receptor or cells properties (Ghanemi, 2014a, Ghanemi, 2014b, Ghanemi, 2014c, Ghanemi, 2014d) and thus, modifies drug activity. Physical conditions such as temperature may have an impact as well. For instance, temperature may influence the chemistry of the drug or the molecules of the compounds with which the drug interacts. Furthermore, the temperature may lead to a modification to some pharmacokinetic-related parameters such as vasoconstrictions which influence both drug absorption and drug elimination. Drug metabolism parameters (Cheikh Rouhou et al., 2013, Yang et al., 2013, Cheikh Rouhou and Haddad, 2014), in addition to the physiological or the pathological status of the cells, the tissue or the patients represent other elements that should be considered as well. Indeed, a slow or an active metabolism (due to genetic factors (Zanger and Schwab, 2013) or alcohol abuse for example) will influence drug elimination and, importantly, the metabolism will be more obvious when the drug is used to treat metabolic diseases. Physiological or pathological situations might exert influence at different levels including both pharmacodynamics and pharmacokinetics. For example a pregnant woman will produce steroid hormones that may have the same blood transporters as steroids drugs, an athlete would have a better drug metabolism than a sedentary patient and a diabetic patient would respond less to antihyperlipidemic agents compared to non-diabetic patients if they are given to both patients in the same dosage. These factors should be considered by both clinicians while prescribing therapies and researchers working on experimental pharmacology to develop pharmacology toward optimized laboratory conditions and more efficient clinical applications.

International drugs markets database to improve global drugs accessibility

One aim of organizations such as the United Nations is to provide economically depressed regions with high-quality drug products at an accessible coast. Within this context, collaborations between diverse organizations and governments are required at all levels. To provide diverse organizations in charge of medication distribution with a panoramic view of the market, theWorld Health Organization (WHO) in collaboration with the manufacturers, providers, governments and other stakeholders could establish an international database that includes the prices, availability and the delivery delay of the medications. This database would include all drugs and medical products available and that have been controlled to assure the quality, safety and eventually affordability. This will create a competitiveness between suppliers and lead to price reduction that does not impact quality, as a quality control system would be established, and products would not be displayed before they pass through that system and are controlled in international laboratories supervised or managed by the WHO and related organizations. In parallel with those international databases, an economics/financialdepartment could be established to both prevent the monopoly and allow countries and organizations willing to assist (for example by financial donations to purchase drugs for poor countries, refugees) to optimize the effort. Within this context, nations can be encouraged to reduce taxes to further improve accessibility.