INTRODUCTION
Oral mucositis is among the serious complications that are secondary to cancer therapy.1 Approximately 20%-40% of patients who underwent conventional chemotherapy, 80% of patients undergoing high dose chemotherapy due to hematopoietic stem cell transplantation, and nearly all patients receiving radiotherapy due to head and neck cancer may present oral mucositis.2,3,4 Mucositis is described as the inflammation of the mucosa, which results from mucotoxic cancer therapy either via chemotherapy or radiation. It is known as erythema and/or ulceration of mucosa, which may be induced by trauma or secondary infections.1,5 Mucositis not only affects the quality of life of patients with cancer but also imposes remarkable financial costs. More than 75% of patients receiving head and neck radiotherapy usually experience severe pain and burning sensation in their mouths, leading to the difficulty in chewing and swallowing and ultimately causing several problems in their dieting.6 Additionally, oral diseases are expensive to treat and sometimes inaccessible.7
According to the World Health Organization (WHO), most people in developing countries tend to use medicinal plant resources due to their accessibility, effectiveness, and fewer complications. Iran is an ancient Asian country with a great history of medicine thousands of years ago.8 Ancient Iranian medicine based on humoral theory was a global medical paradigm during the medieval times.9 Despite the replacement of traditional Persian medicine with modern medicine in academia from the 19th century, ethnomedicine with its potent traditional history is still very common among Iranian people.8,10 For instance, a study demonstrated that 62.5% of the urban population in Isfahan utilize at least one of the traditional and complementary medicine methods.11 People in different parts of Iran use medicinal plants for the management of diseases based on their ethnic culture and ethno-knowledge. For instance, a study on the ethnobotany of Khabr and Rouchon region in Kerman province, Iran showed that the native people utilize 50 medicinal plant species for the alleviation of different disorders, especially gastrointestinal problems.12 It is reported that more than 77 medicinal plant species are used by the elderly in Sirjan city, Iran, of which the plants with therapeutic effects on the respiratory tract have been more considered.13 Traditional healers, named “Attar”, who work in traditional herbal shops, named “Attari”, are the most common consultants and practitioners of ethnomedicine services in Iran.8,10 Attars are individuals who prescribe and sell medicinal herbs and natural drugs, whose (most of them) information on herbal medicine is inculcated from older generations (verbally), personal experiences, and traditional medicine cultures. These resources can potentially form the basis for the use of medicinal herbs in new drug discovery after scientific research. Recording the ethno-knowledge and techniques of these traditional healers can help prevent the loss of such non-written information due to death.14,15
Several studies on ethnopharmacological knowledge of Iranians population have been published;8,14 however, to the best of our knowledge, no report in this regard has been found in Zahedan. In contrast, there is a need to explore and preserve ethno-knowledge by documenting the herbs and natural products that have been traditionally applied in folkloric medicine. In this regard, this ethnobotanical study was designed to collect natural products and herbs that are practically used for the treatment of oral mucositis in Zahedan, Southeast Iran and to evaluate them by applying current medical concept and recent scientific studies. We also aimed to highlight weaknesses in current knowledge and suggest future studies.
MATERIALS AND METHODS
Study area
Zahedan is the capital city of Sistan and Baluchestan (SB) province, the widest province of Iran, located in the Southeastern region of the country. It has a common international border (187,502 km2) with Afghanistan and Pakistan at the East and Southeast region, respectively, and also a common maritime boundary in the Northern coast of Oman Sea. Kerman and Hormozgan provinces are located in the West and South, respectively. Khorasan province is located at the North of SB (Figure 1).
SB province consists of two distinct regions that are naturally different from each other and have a varied herbal flora: 1- Baluchestan is located in the Southern part of the province with diverse climates tied to the Oman Sea. 2- The Northern part of the Province is named Sistan, which is characterized by the Hirmand River, and Hamun, which is a large freshwater lake.16
Shahr-e sukhteh is an archaeological site “[Burnt city (BC)” from the third millennium BC and is located 154 kilometers far from Zahedan, with a considerable evidence on the advanced ancient medicine, which can be regarded as an honored record of this area of Iran.17,18
The climatic diversity resulting in unique vegetation areas and trade relations with Afghanistan, Pakistan, and India (through the sea), the ancient history of medicine, and great traditional physicians, such as Hakim Azam Khan (Nazim Jahan) in the 19th century19,20 have made this region rich and noteworthy in traditional medicine and ethnomedicine.
Zahedan, similar to many other capitals, has its attractions compared with other cities in the province. As a result, several immigrants from other cities of the province have gathered in this city. Traditional medicine is a common among people living in Zahedan and it takes the advantages of both native and nonnative herbs for treating diseases. This city (31250 km2 area) is located between latitude 29°29’46.68”N and longitude 60°51’46.44”E. It mostly enjoys a warm and dry weather throughout the year. It has hot days and very low-temperature nights in summer. The average annual rainfall is 120 mm. It has an altitude of 1385 m and is comprised of ~672,589 people.
Ethnopharmacological investigation and data collection
The protocol of this research has been approved by the Ethics Committee of Kerman University of Medical Sciences (code: IR.KMU.REC.1399.023). This study was conducted from September to October 2018. Face to face interview with traditional healers was conducted and structured questionnaires were filled. First, personal information of traditional healers (attar), including age, sex, education, and source of their information, was taken. The traditional healers were asked to explain which traditional remedies can help patients with “oral mucosa inflammation (relatively characterized by erythema and pain of mucosa) with/without ulcer”. All needed information, including local name, part(s) used, preparation, and administration methods of the remedies, were collected.
Identification
A sample of all reported traditional drugs was collected from their habitat and transferred to the Department of Pharmacognosy, Faculty of Pharmacy, Kerman University of Medical Sciences and a voucher code was assigned for each sample as mentioned in the result section.
The information is systematically shown in Table 1.
Data analysis and literature review survey
The next step was to investigate studies on the intended plants, especially those associated with mucositis and the relative pharmacological properties published in Scopus and Pubmed databases (Table 2). The scientific name of plants and the following keywords were used for the literature search:
1- Mucositis
2- Antibacterial, antimicrobial
3- Antifungal
4- Wound, ulcer wound healing, ulcer protection
5- Inflammation, antiinflammatory
6- Pain, analgesia, antinociceptive, antinociceptive, analgesic
In this research, no specific statistical method was used (except for the cases expressed as percentage).
RESULTS
Information from herbal practitioners
Of the 36 traditional herbal stores, 29 attars volunteered to be interviewed for the study. All healers were male, with the age range of 23-68 years, and 55% of them were younger than 40 years of age. Approximately 48% of the participants had a below diploma degree, 24% had a high school diploma, and 28% had an academic education. 62% of the healers reported that they have obtained information via older generations, 20% obtained theirs by reading traditional medicine and herbal remedies books, 38% had their own experiences, and 17% obtained theirs via the internet (some of the interviewees had more than one source of information).
Information about traditional remedies
A total of 18 medicaments were introduced for the management of oral mucositis (Table 1), of which 15 samples had herbal origin and three samples had synthesis or mineral origin. Alcea digitata Alef (11 attars), Cotoneaster discolor Pojark (10 attars), Johare ghermez, which has mineral origin (10 attars), and Rhazya stricta Decne (9 attars) were the most recommended species (Figure 2). Approximately 83% of the drugs were native to Iran and the others were transferred from India or Afghanistan to Iran. Three medicaments were used both topically and orally, 12 medicaments were used topically, and four medicaments were used orally. The preparation methods were mostly decoction, dissolving in water, extraction, distillation, maceration, oil and hydrocolloid produced in water (loab), and powder.
Information obtained via the literature search in various databases reveal the effect of only two herbs, including Matricaria chamomilla L. and Alcea digitata Alef, on mucositis. These two studies respectively demonstrated that these herbs are effective against mucositis. Different studies on the other 11 herbs indicated some related pharmacological activities for the management of mucositis, such as anti-inflammatory, antibacterial, antifungal, and wound healing effects. No study was found to prove the effect of Cotoneaster discolor Pojark and Bambusa arundinacea Willd on mucositis, as well as their relative pharmacological effects (Table 2).
DISCUSSION
Oral mucositis has been described as erythema or/and ulcer of the oral cavity mucosa. The proposed pathobiology of mucositis is a complex pathway that involves five phases. Inflammation is among the most important and effective factors in the process of mucositis and it causes the thinning of the epithelial layer and it inclines the development of ulcers. Through progression of the damage from the epithelium into the submucosa, ulceration and oral bacterial colonization can occur. Due to this superimposed infection, the condition may get worse. The lesions of oral mucositis are typically very painful, thus analgesic agents, especially opioids are required. Healing phase is the last phase of mucositis. This phase begins with signaling from extracellular matrix of submucosa and eventuates to migration, proliferation, and differentiation epithelial cells at the border of the mucosal ulcers.70,71 Accordingly, reducing inflammation as an initiator factor plays an important role in the control of mucositis. Additionally, antibacterial and antifungal agents are effective in mucositis treatment, since they prevent or treat secondary infections. Pain control can also lead to a sense of well-being in patients and enhance their quality of life. Speeding up the wound healing process by shortening the duration of mucositis can decline mucositis complications.
This study provided the first ethnopharmacological survey, focusing on oral mucositis. The traditional healers applied various preparation methods for different remedies. Maceration is among the common specific methods for plant extraction, where heat is not normally used. Some of the examples cited in the sources or deduced from traditional stores of medicinal plants only mentioned the extract method, but failed to provide details of the extraction method. Thus, extraction is a generic term and it involves decoction, infusion, and maceration, among other methods. In distillate method, the plant is heated in water so that the essential oil of the plant enters the water in a few amounts and gives a weak odor to the water.72 In maceration method, as mentioned above, extraction is done without the use of heat.73 For oil isolation, hydro-distillation method is done using Clevenger apparatus,74 while for powder preparation, the plant is milled and passed through a sieve with definite mesh. Hydrocolloid is extracted by floating the plant in water and, after a definite time, the extract is filtered and dried.75
The literature review demonstrates that, among the 15 recommended herbs, the effectiveness of Matricaria chamomilla L. and Alcea digitata Alef have been directly evaluated. In a pilot study, the effectiveness of a combination of Alcea digitata Alef and Malva sylvestris L. was evaluated for prevention of head and neck radiotherapy-induced oral mucositis. A total of 23 patients were divided into intervention and placebo groups that received the drug for 7 weeks. The WHO scale was used for evaluation of severity of oral mucositis symptoms weekly. The results indicated that patients in the placebo group experienced more severe mucositis from the second week, which was significantly different from the herbal drug-treated group (p<0.0001).21 A randomized-controlled phase II clinical trial has been conducted on the effectiveness of liquid extract of Chamomilla recutita at the dosages of 0.5%, 1%, or 2% in prevention and treatment of oral mucositis in patients undergoing hematopoietic stem cell transplantation. Patients who received the standard care plus mouthwash of C. recutita at 1% dosage showed less incidence, intensity, and duration of oral mucositis when compared with the control group.43
The search throughout scientific databases revealed that several remedies used by traditional healers in Zahedan for mucositis treatment have approved pharmacological properties. In this study, we aimed to categorize the mechanism of actions according to recent scientific studies as follows:
Plants with antiinflammatory activities (Alhagi maurorum Medik.,23 Caryophyllus aromaticus L.,26 Cichorium intybus L.,30 Descurainia sophia (L.) Webb ex Prantl,35 Linum usitatissimum L.,38 Matricaria chamomilla L.,#*#ref44 Myrtus communis L.,48 Plantago ovata Forssk.,54 Punica granatum L.,58 Rhazya stricta Decne.,63 and Rhus coriaria L.66); plants with wound healing properties (Alhagi maurorum Medik.,24 Cichorium intybus L.,32 Linum usitatissimum L.,41 Matricaria chamomilla L.,46 Myrtus communis L.,50 Plantago ovata Forssk.,56 and Punica granatum L.60); plants with antimicrobial/antifungal effects (Alcea digitata Alef.,22 Alhagi maurorum Medik.,25 Caryophyllus aromaticus L.,28,29 Cichorium intybus L.,34 Fumaria parviflora Lam.,37 Linum usitatissimum L.,42 Matricaria chamomilla L.,47 Myrtus communis L.,52 Plantago ovata Forssk.,57 Punica granatum L.,61,62 Rhazya stricta Decne.,64,65 and Rhus coriaria L.68); and plants with antinociceptive properties (Alhagi maurorum Medik.,23 Caryophyllus aromaticus L.,27 Cichorium intybus L.,31 Fumaria parviflora Lam.,36 Linum usitatissimum L.,40 Matricaria chamomilla L.,45 Myrtus communis L.,49 Plantago ovata Forssk.,55 Punica granatum L.,59 Rhazya stricta Decne.,63 and Rhus coriaria L.).67
Utilization of traditional medicine among Iranian people has a wide range of 10-75%, depending on diversity of populations.76,77,78,79 Considering that the application of traditional medicine in patients with cancer is associated with potential advantages and possible risks, the necessity for further studies on herbal remedies has become more pertinent. For instance, although the antineoplastic properties of many herbs have been approved, the safety of some other herbs is uncertain. Administration of aqueous extracts of Dioscorea opposita and Cistanche deserticola in both estrogen receptor negative (SKBR3 and MDA-MB-231) and estrogen receptor positive (MDA-MB-361 and MCF-7) breast cancer cells can lead to stimulation of cell viability. However, patients with breast cancer in some parts of the world use these two herbs to relieve the adverse effects of cancer treatment.80 Therefore, designing accurate scientific studies on herbal medicines to provide evidence to advice or forbid the mentioned remedies are indispensable.
CONCLUSION
Among the 18 medicaments used as ethnomedicine to alleviate mucositis in Zahedan, three of them had synthesis or mineral origin. Only two herbs were evaluated for their direct efficacy against mucositis, while the others have not yet been tested. Scientific studies have approved the related pharmacological effects of 11 medicaments. Accordingly, they can be regarded as appropriate candidates for future studies on the determination of their probable influences on mucositis, followed by the discovery of new pharmacologic agents. However, the fact that the application of traditional medicine may be associated with potential risks instigates more scientific investigations.
Conflicts of interest: No conflict of interest was declared by the authors. The authors alone are responsible for the content and writing of the paper.