Medicinal Plants with Anti-Trichomonas vaginalis Activity in Iran: A Systematic Review.

Background
Trichomoniasis, due to Trichomonas vaginalis, is one of the most common sexually transmitted parasitic diseases in the world such as Iran. This systematic review aimed to explore the studies evaluating the medicinal herbs with anti-T. vaginalis activity which used in Iran.


Methods
Articles published in 4 Persian and 4 English databases were obtained between 2000 and 2015 including Google Scholar, PubMed, Science Direct, Scopus, Magiran, Barakatkns (formerly IranMedex), Elm net, and SID (Scientific Information Database). Studies out of Iran, studies on animal models and articles on other parasite species than T. vaginalis were excluded from this review.


Results
Twenty-one articles including in vitro experiments, met our eligibility criteria. Thoroughly, 26 types of plants were examined against T. vaginalis. Medicinal herbs such as Artemisia, Zataria multiflora, and Lavandula angustifolia are remarkably effective on T. vaginalis. As such, use of other parts of these plants in different concentrations and timelines is recommended for future in vivo studies.


Conclusion
The present systematic review provides comprehensive and useful information about Iranian medicinal plants with anti-T. vaginalis activity, which would be examined in the future experimental and clinical trials and herbal combination therapy.


Introduction
richomonas vaginalis(T. vaginalis) is a flagellated protozoan parasite that attaches to vaginal epithelial cells leading to the occurrence of trichomoniasis. Trichomoniasis is one of the most common sexually transmitted parasitic diseases in the world such as Iran (1). The overall prevalence rate of trichomoniasis in Iran was estimated to be 8% (2). This infection is likely to remain asymptomatic in 10%-50% of the cases. In women, trichomoniasis may lead to different conditions, including vaginitis, dysuria, dyspareunia, premature delivery, premature rupture of membranes, low birth weight, spontaneous abortion, ectopic pregnancy, postpartum endometritis, salpingitis, cervical erosion, chronic cervicitis, cervical cancer, (3,4) and infertility (5). Although trichomoniasis is associated with no significant clinical symptoms in men, it has been reported to cause urethritis (6).
The risk of T. vaginalis increases with the removal of the secretory protease of white blood cells, which protects the vaginal mucosa membrane cells against the human immunodeficiency virus (HIV). Furthermore, some researchers believe T. vaginalis to be a co-factor for the transmission of HIV and other sexually transmitted infections (7,8). Metronidazole is considered the most useful medication in the treatment of trichomoniasis (9). Metronidazole has numerous side effects and in some cases, it has low efficacy in the treatment of infections caused by different bacterial strains. In other words, antibiotic resistance against this medication has increased. Among the main side effects of metronidazole are nausea and vomiting, bad taste in the mouth, gastrointestinal disorders, skin rashes, urticaria, angioedema, dizziness, peripheral neuropathy, and transient neutropenia. There is disagreement among medical specialists regarding the use of this antibiotic during pregnancy, while the use of metronidazole is forbidden during the first trimester of pregnancy (9). Moreover, carcinogenic and mutagenic effects of metronidazole have been reported in animal models (10)(11)(12). WHO has recommended the use of medicinal herbs and natural food compounds for the treatment of various diseases in order to reduce the side effects of chemical drugs (13). Different studies have evaluated the efficacy of medicinal herbs in the treatment of trichomaniasis. In this systematic review, we explored the studies assessing the utilities of medicinal plants with anti-T. vaginalis activity in Iran. Evaluation of the studies on the effects of different medicinal herbs on trichomaniasis could provide an overview of the proper treatment of this infection in Iran. The results of this review help researchers find the proper compounds for trichomaniasis treatment with no and or fewer complications.
This study aimed to investigate the effects of anti-T. vaginalis medicinal plants in Iran.

Searching plan
This systematic review was conducted through searching in 8 databases such as Google Scholar, PubMed, Science Direct, Scopus, Magiran, Barakatkns (formerly IranMedex), Elm net, and SID (Scientific Information Database) throughout 2000-2015 ( Fig.1). We chose all the articles published in Persian and English languages evaluating anti-T. vaginalis medicinal plants using the following keywords: Trichomonas vaginalis, trichomoniasis, herb, medicinal plant, herbal medicine, anti-T. vaginalis and Iran both separately and combined.

Quality assessment and article selection
All the articles identified in the aforementioned databases were evaluated by two authors independently. After the review of the titles, abstracts, and full texts of the articles, T unrelated studies were excluded from the review. Remaining articles were investigated using quality assessment checklists.
Inclusion criteria of this study were the articles evaluating the in-vitro effects of medicinal herbs on T. vaginalis in Iran between 2000 and 2015. Exclusion criteria were the studies conducted outside the determined deadline, articles on other parasite species than T. vaginalis, and invivo studies performed on animal models.

Data extraction
Essential data including the scientific name of plants, type of herbal extracts, used parts of the plants, extract concentrations, and killing or growth-inhibitory effects were obtained from the selected articles and recorded in prepared forms.

Results
Overall, 254 articles published from 2000 to 2015 (16 years) in Iran were identified in the literature search. Considering the inclusion and exclusion criteria of the study and after the review of the titles, abstracts, and full texts of these articles, 21 articles were selected for this systematic review. Overall, 26 types of plants had assessed among the selected articles (Table 1).
Myrtus communis and Zataria multiflora medicinal plants were reported to have the most anti-T. vaginalis activity. Among the studied medicinal herbs, Z. multiflora and Lavandula angustifolia were observed to apply the most significant inhibitory effects against T. vaginalis.
Only a limited number of medicinal plants, such as Stachys lavandulifolia and Eucalyptus camaldulensis, were found to have minimal inhibitory effects against T. vaginalis, and no significant difference was reported between the effects of these plants and control groups.

Discussion
Quite a lot of evidence based studies have supported the use of herbs in complementary and preventive medicine to facilitate treat of various sickness or disorders. Considering the adverse effects of chemical drugs, increasing antibiotic resistance, and lack of access to many of these medicines, use of medicinal plants could be beneficial in the treatment of infectious diseases.
Many synthetic drugs have a natural origin, such as emetine (34), quinine (anti-malarial drug), and Artemisinin (35), as such, parasites of the Plasmodium spp. have reported to have no resistance to these agents. In this systematic review, we systematically reviewed the effects of medicinal plants used against T. vaginalis in Iran.
Plants of the genus Artemisia exhibit antimicrobial activities in different laboratory animals, while the possible toxic effects of these plants should be evaluated in different cultured cells. In the absence of such toxic effects and efficacy of these medicinal plants in vivo, combinations of these herbs have been used as an appropriate alternative for antitrichomonial therapy.
Various anti-parasitic and antifungal properties have been attributed to artemisinin, extracted from Artemisia annua plant as an important medicinal herb. In this regard, studies were performed to assess the effects of the essence and methanol extract of Artemisia aucheri (A. aucheri) on T. vaginalis. A. aucheri is one of the most important medicinal plants used against T. vaginalis, and the essence of this herb had more significant effects compared to the alcoholic extract (14,15).
Based on the results of the aforementioned studies, the most effective dose of the herbal extract of A. aucheri was 0.1 mg/mL (14,15).
In another study, the antifungal activity of the herbal extracts obtained from the aerial parts of different species of genus Artemisia against Candida albicans, Aspergillus flavus, A. niger, Trichophyton rubrum, and Epidermophyton floccosum were investigated, all of which could be pathogenic to human (47).
The in vitro anti-parasitic effects of Artemisinin on Neospora caninum were evaluated and it could inhibit the growth of N. caninum tachyzoites (48). In this regard, Shuhua et al. also investigated the protective and therapeutic effects of Artemether on animal models infected with Schistosoma mansoni. The parasitic infection did not spread in the laboratory animals treated with Artemether during the first month. In addition, the infection decreased by 72%-82% compared to the control group, while treatment replication reduced the infection by 97.2%-100% (49).
Previous studies have reported different antimicrobial and therapeutic properties for potherbs such as thyme, Z. multiflora and myrtle, M. communis. For instance, the anti-T. vaginalis properties of the oil and alcoholic extracts of different Artemisia spp. were examined, and the most effective inhibitory dose was determined at 0.1 mg/mL. As such, these extracts could be used as capable anti-T. vaginalis agents for in vivo studies in the future (14,15).
In this regard, the study was performed to investigate the anti-T. vaginalis activity of lavender, Lavandula angustifolia. The anti-parasitic effects of the concentrations of 0.1, 0.01, and 0.001 mg/mL of this plant were examined after 3, 4, 5, 6, 12, 24, 48, and 72 h. Concentration of 0.1 of the lavender extract killed all T. vaginalis trophozoites after 90 min (8). Lavender plant has been shown to have sedative and antimicrobial properties. The effects of lavender extract on bacteria such as Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and Pseudomonas aeruginosa were evaluated. Minimal inhibitory concentration for S. pneumoniae, S. pyogenes, S. aureus, and P. aeruginosa was 0.097, 0.097, 6.25, and 3.125 µg/mL, respectively (51).
In a study, the inhibitory effects of lavender against A. fumigatus were evaluated and this plant exerted protective effects against A. fumigatus and could be used as a natural antifungal agent (52).
The genus Allium spp. of the Liliaceae family has more than 600 species, the most important of which are nourishing plants such as garlic (A. sativum ) and onion (A. cepa ) (34). Several investigations have been performed on different properties of these species (35,(53)(54)(55)(56). A. sativum has been widely used as a therapeutic plant in the traditional and modern medicine due to its anti-microbial, anti-viral, anti-fungal, and anti-parasitic properties. Furthermore, the results proposed by Moazeni et al. were indicative of the presence of extraordinary anti-protoscolex agents in garlic in vitro (57). The findings of Behnia et al. were indicative of the anti-parasitic effects of garlic against Entamoeba histolytica denoting no significant difference between the effects of garlic plant and metronidazole in this regard (58). Two species of genus Allium, including A. sativum and A. hirtifolium, were reported to have adequate anti-T. vaginalis activity (16). With respect to the in vitro and in vivo effects of garlic extract on flagellated Giardia lamblia, this herbal extract had the most significant inhibitory effect against G. lamblia at the dose of 80 mg/mL, which resulted in the complete recovery of mice within three days (59).
In addition, the in vitro effects of the liquid extracts of three herbal species of the genus Allium (garlic, onion, and shallot) assessed against Giardia spp. cysts. Mean of the inhibitory dose of garlic was 107.534.1 mg/ mL with the rate of 43.2%. In onion, mean of the inhibitory dose was 102.839.88 mg/ mL with the rate of 40.8%, while these rates were determined at 84.664.80 mg/mL and 33.6% in shallot, respectively (60,61).
Eucalyptus, Echinophora platyloba, is a plant traditionally used in herbal medicine for various conditions. In this regard, Kazemian et al. According to the findings of the present review, Mentha longifolia is one of the most effective medicinal plants against T. vaginalis (31). Moreover, Eucalyptus camaldulensis, exhibit significant inhibitory effects against T. vaginalis and it could be used as safer and effective alternatives of chemical agents in the treatment of this infection in future (21,23,25,26).

Conclusion
Considering the adverse effects of many current chemical drugs, increasing drug resistance, and lack of access and high costs of the available drugs, it is recommended apply for natural sources and cost-effective medicines in the treatment of parasitic infections (62) such as T. vaginalis infection. To date, several natural compounds have been shown to be effectual in the treatment of trichomoniasis. Unfortunately, limited research has been conducted as to investigate the exact effects of all these medicinal plants, and the use of natural anti-T. vaginalis agents are not approved by the Food and Drug Administration (FDA).
Various plants including Artemisia spp. members of the Allium family, potherbs (Z. multiflora, M. communis), and lavender could exert significant inhibitory effects against T. vaginalis and are considered relatively safer and efficient alternatives for treatment of T. vaginalis infections rather than metronidazole. The present systematic review provides comprehensive and useful information about Iranian medicinal plants with anti-T. vaginalis activity, which would be examined in the future experimental and clinical trials and herbal combination therapy.