Evaluation of clinical trials of the plants, which have ethnobotanical uses for skin disorders in Turkey: a review

Ethnobotanical studies investigating a large number of traditional herbs and uses have an important role in the discovery of new drugs. Nowadays, some of these traditional herbs are researched directly in the clinical trials. In this study, it is aimed to evaluate the 19 plant species that have been identified in the clinical trials among 300 plant species belonging to 79 families with traditional use for skin problems in Turkey. Natural sources are very important to treat diseases for thousands of years. The ethnopharmacological research of natural products ranges from the collection of biogenic samples such as plants to preclinical and clinical studies with the aim of developing drug templates or new drugs. In the ethnopharmacological approach, it is aimed to reach the result based on the traditional and modern knowledge about natural resources. The biggest advantage of this approach is synthesizing new and old information. After the plant or natural compound is determined, other processes work similarly with conventional drugs. Ethnobotanical papers, thesis and projects in Istanbul University Faculty of Pharmacy Department of Pharmaceutical Botany and databases (PubMed and Google Scholar) have been sought and results were synthesized. Most of the clinical uses of herbs have been seen similar to their traditional uses. On the other hand, there are some plants on which their clinical uses differ from the traditional uses such as Borago officinalis, Calendula officinalis or Euphorbia peplus. When the frequency of traditional uses of herbs are compared, Plantago species, Plantago major and Plantago lanceolata are the most used taxa in Turkey, secondly, Hypericum perforatum comes. However, Plantago species are not of much interest in clinical trials. It is seen that most of the plants in the clinical research are tried for wound healing occuring due to different origins such as cancer, surgery and injury. Side effects were observed only during the application of Allium cepa, Cydonia oblonga and H. perforatum. When clinical trials are evaluated in terms of efficacy and overall results, significant differences and effective results are seen in treatment groups given herbs in comparison with placebo or control groups.


Introduction
Numerous investigations depend on ethnopharmacological approaches have been carried out about medicinal plants and their bioactive compounds via using various different concepts and methods. These multidisciplinary researches concerned with the observation, description and experimental investigations are ranging from anthropology to various fields such as pharmaceutical botany, pharmacognosy, pharmacology, natural product chemistry, toxicology, pharmaceutics, clinical research, and molecular biology [1].
As an interesting example, it is also listed in our article, the species of Euphorbia peplus L (garden spurge or petty spurge) which is traditionally used for a number of skin problems like warts could be a novel anticancer agent for skin cancers in future [2].
The skin is the largest sensory and contact organ in the human body. It is composed of two layers: the epidermis and the dermis. The skin serves not only to protect the body from the external environment but also to prevent loss of water from the body. The outermost layer of the skin, the stratum corneum, acts as the primary permeability barrier [3].
There are many types of skin conditions that have a tremendous impact on human health and quality of life, including acne, psoriasis, dermatitis, chronic wounds, and infections. The majority of these skin diseases could be treated topically as shown in Table 1, thereby avoiding the potential for systemic side effects [4,5].
In addition to the above mentioned first-line therapies, there has been a resurgence of the use of ethnobotanical remedies in recent years. Herbal therapies have been tried for the treatment of skin conditions for centuries in the world. Many plants and their extracts have been used traditionally for the management and treatment of various skin disorders. The aim of this paper is to compare the traditional uses of Turkey's wild plants which are used by local people for the treatment of skin disorders with their clinical trials.

Methods
The study consists of two stages, screening of ethnobotanical studies and determination of plants tried in clinical studies for skin problems. In the evaluation, firstly their suitability for traditional use was reviewed in detail. Then, clinical studies were evaluated according to the criteria of Patient population, Design, and Intervention, Outcomes, Efficacy and Safety/ Tolerability.
We assessed the significance of the results of clinical trials with p-value (p < 0.05 values are significant) and the healing percentage (complete healing is significant). The study includes randomized, non-randomized, double-blinded, single-blinded, non-blinded, and placebo-controlled clinical studies. However, nonrandomized and non-blinded studies can give us limited results. Atopic dermatitis Atopic dermatitis is the most common type of eczema. It typically begins in childhood and it is a severe, chronic, and pruritic inflammatory skin disease.
All documents have been sought on Pubmed and Google Scholar, thesis and projects in IU Faculty of Pharmacy Department of Pharmaceutical Botany.

Results and discussion
A total of 300 medicinal plants belonging to 79 families have been compiled from the research areas in Turkey as shown in Table 2. The family Asteraceae, in the first rank, is the largest family which includes the most species in the world and Turkey. Although the family Lamiaceae, in the second, is not the second largest family in Turkey, it has very important medicinal and aromatic plants in the Mediterranean phytogeographic area.
Considering the species, it could be to evaluate Plantago species, P. major and P. lanceolata, which are first in the most used taxa ranking, as the same plant. Because these species are used with a similar name and in a similar way without distinguishing. Then, H. perforatum comes as one of the most used species for skin problems in Turkey.
In the following table, 19 plant species on which their clinical studies are arranged alphabetically. The botanical names are followed by the family names, a Turkish name, traditional uses, and differentiations between clinical and traditional uses of 19 plants as shown in Table 3. In the last part, these clinical studies are summarized as shown in Table 4.
Especially, when we compare the healing efficacy of herbs or their mixtures considering complete healing response, p values, and methods, these could be more effective than others for their special clinical uses of skin disorders: Ankaferd Blood Stopper (Vitis vinifera, Urtica dioica, Glycyrrhiza glabra, Alpinia officinarum, Thymus vulgaris), Calendula officinalis and H. perforatum. Additionally, we have known that these herbs have been used by Turkish traditional medicine for many years. Unfortunately, all herbs we searched have very limited clinical trials and therefore it is hard to compare and understand their efficacy and side effects for longterm clinical uses [35,36]. Hence, we propose to increase the number of clinical trials because of these reasons.
The clinical trials of the plants listed in Table 4 are different from each other, that's why the evaluation of these studies was done within some rules. The most important of these rules is the evidence hierarchy, when the data contradict each other. Therefore, the results of the meta-analysis are strongest evidence, when there is any contradiction. However, in some cases, the results of the retrospective studies could be also very important, even though they represent weak evidence [62]. Metaanalysis and randomized controlled trials are at the top of the evidence pyramid, while the case reports and expert opinions are at the bottom of the evidence pyramid. The best evidence is quality, while considering these studies. The quality of evidence increases as it goes from bottom to top [63]. Randomization provides epidemiologically the highest quality data. When randomization is not appropriate for various reasons, researchers may be required to rely on non-randomized studies. In randomized studies, performing blind study is to prevent taking sides. In the single-blind studies, only researchers or patients are not aware of the drug, while both patients and researchers do not know which drug is given to which group in the double-blind studies. These studies are among the valuable studies in the evidence pyramid.
As the technique and technology in the field of medicine advance, research on the use of herbs in diseases may differ over the centuries. For example, Sambucus ebulus L. has been used for different ailments including: joint pains, cold, wounds, and infections. Nevertheless, recent evidence has revealed its potential for making attempts at treating cancer and metabolic disorders [64]. This review aimed to provide a comprehensive information of herbs regarding their traditional uses and modern findings which may contribute to the development of novel natural-based therapeutic agents.

Conclusions
Most of the uses of herbs studied in the clinical trials appear to be similar to their traditional uses. Many products prepared from these plants are sold in the market.                          No side-effects were noted during the [60] herbs. Because, skin wounds, either acute or chronic, might affect the quality of patients' life significantly. Especially, chronic wounds might be progressive and resistant to treatments. These wounds become chronic because of a number of underlying conditions such as diabetes, vascular disease, and neuropathy [65][66][67]. Herbs studied clinically for general wound healing are: Alkanna tinctoria, Allium cepa, H. perforatum, Achillea millefolium/H. perforatum and H. perforatum/Calendula arvensis. Some studies have been also made in specific areas, these are: for episiotomy or caesarean section wounds with Lavandula stoechas, Achillea millefolium/ H. perforatum and H. perforatum/Calendula arvensis combinations; for undergoing transradial catheterization and tonsillectomy with Vitis vinifera/Urtica dioica/Glycyrrhiza glabra/Alpinia officinarum/Thymus vulgaris; for skin ulcer caused by punch biopsy with Cydonia oblonga.
Oncology is another important area where clinical studies with herbs have been carried out frequently. Although there is not much direct use of herbs in cancer treatment, they have been generally tried for the side effects of cancer treatment. However, an example of a clinical study can be given as follows, even if it is not used for this purpose in Turkey: Euphorbia peplus was tried directly for basal cell carcinoma, intraepidermal carcinoma or squamous cell carcinoma in Phase I/II clinical study [2]. Some herbs, such as the use of No side-effects were noted during the study [61]