4. Therapeutic Uses of Artemisia Species Based on Clinical Trials

Encouraged by long traditional use of many Artemisia species for treatment of various ailments, research into their pharmacological effects has been carried out and seem to support the traditional applications [5,12,15,16,17]. In this regard, Artemisia species and their biologically active compounds have already been introduced as antimalarial, antioxidant, cytotoxic, antispasmodic, anthelmintic, antinociceptive, neuroprotective, anti-inflammatory, and antimicrobial agents, among others [16,44]. It is noteworthy that although Artemisia species have been intensively studied in vitro as cytotoxic agents, there are no reports on their clinical evaluation for cancer therapy in humans [4]. However, one report by Saeed et al. showed that supplementing pet food with an A. annua formulation (Luparte^®) clearly improved survival prognosis in veterinary treatment of small tumors [158].

Nevertheless, clinical evaluations of Artemisia species for a range of other diseases have been carried out [4]. The effect of A. annua in traditional medicine in China for treating fever, inflammation and malaria [9] have been evaluated in clinical trials for stiffness and functional limitation associated with osteoarthritis of the hip and knee, pain management, experimental heterophyid infection and treatment of malaria [159,160,161].

Artemisia dracunculus has been used for glycemic control, insulin sensitivity, and insulin secretion [162] and likewise, A. princeps was evaluated for the same effects in subjects with impaired fasting glucose and mild-type 2 diabetes [163] and A. absinthium in the control of diabetes type 2 [164].

Ointments and liniments of A. absinthium can be effective in the treatment of knee osteoarthritis [165]. Based on the suppressor activity of A. absinthium compounds on tumor necrosis factor alpha (TNF-α) and other interleukins [166], Krebs et al. [167] established the curative effect of this Artemisia species in patients with Crohn’s disease. There was improvement in symptoms after treatment with dried powder of the plant together with a conventional therapy, and a cardamonin present in the plant was considered responsible for the anti-inflammatory activity.

In addition to being widely used clinically to treat itching in icteric and dialytic patients, owing to its anti-histaminic and anti-allergenic effects, A. vulgaris (mugwort) lotion has also provided good results in patients with post-burn hypertrophic scars [168].

Recently, the preventive effect on hepatitis B cirrhosis of A. capillaris decoction combined with the entecavir has been evaluate by a randomized, double-blind and placebo controlled clinical trial (Chinese Clinical Trial Registry: ChiCTR1900021521), to assess its efficacy and safety [169].

Artemisia annua and A. vulgaris are the species of the genus that produce the highest levels of allergens in their pollen, being one of the main causes of seasonal allergic rhinitis (“hayfever”). Lou et al. [170] carried out a phase III clinical trial (ClinicalTrials.gov identifier: NCT03990272) from March 2017 (approximately 4 months before the local natural Artemisia pollen season) to October 2017, involving patients from 13 centres across Northern China. The aim was to test the efficacy and safety of sublingual immunotherapy (SLI) with drops of A. annua for allergic rhinitis related to this plant. Results indicated that A. annua was a safe and significantly effective therapy. However, longer term follow-up is required, particularly to determine the mechanism of action.

Based in previous study where Xiao et al. [25] demonstrated using in vivo models, the ability of A. ordosica Krasch. extracts to control the allergic inflammatory response in rhinitis, clinical trials using nasal spray preparations of A. abrotanum containing its essential oils and flavonols have been performed with good results [171].

Munyangi et al. [172] published a randomized controlled clinical trial reporting far superior cure rates of A. afra and A. annua infusions than with artemisinin combination therapy (artesunate—amodiaquine), in the treatment of malaria. Contrastingly, a recent review by Toit and van der Kooy [15] concluded that tea infusions do not have in vitro activity, and in fact contain no artemisinin. Another randomized large-scale double-blind controlled trial on A. annua and A. afra tea vs. praziquantel for the treatment of schistosomiasis was documented by Munyangi et al. [173]. Controversially, Gillibert found scientific and ethical issues such as the article on schistosomiasis referring to the same ethics committee registration number as the malaria article [174].

Sensitive skin was initially believed to be an unusual reaction occurring in only a small subset of individuals. However, during recent decades, it has been shown to affect half the population of the world [175]. Accordingly, extensive in vitro, preclinical, and clinical research with artemisinin and its derivatives has been undertaken, notably into their anti-inflammatory, immunomodulatory and antioxidant properties [176]. Yu et al. [177] tested the effectiveness of cosmetics containing A. annua extract in repairing sensitive skin. In this study, the xylene-induced ear swelling and human clinical efficacy tests were used, and the authors found that applications containing A. annua extract can inhibit inflammation, repair the skin barrier, improve damaged skin, and reduce redness and other sensitive skin symptoms. Aside from this, its leaves are eaten in salads in some Asian countries and in the United States, and several companies currently sell ground leaves and their extracts as dietary supplements [178].

5. Some Sesquiterpene Lactones Constituents of Artemisia Species with High Clinical Relevance

The pharmaceutical industry has always been interested in the secondary metabolites produced by plants, for the treatment of diseases, in cosmetics, dyes, fragrances and flavorings [179]. The Artemisia species are well known by its content of sesquiterpene lactones [40,41,43,50]. These family of compounds have been studied and reveal high therapeutic potential [180,181]. Here are presented some of the most studied and promise sesquiterpene lactones constituents of edible Artemisia species (does not intent to be an exhaustive list) which, due to its medicinal properties discussed above, could contributes to the benefits effects of the Artemisia species. Sesquiterpene lactones such as arglabin parthenolide, cynaropicrin, helenalin, costunolide and thapsigargin identified in species of the genus Artemisia [40,41,50,180] and other genera, exhibit high pharmacological potential, including in in vivo studies and clinical trials, as demonstrated and discussed very recently [181]. So, they will not be considered in this work. The most recent and relevant experimental evidence of other sesquiterpene lactones medical potential will be highlighted discussed below. In this selection, was considerate mainly the in vivo and clinical studies, once they are the last steps of new drugs development and their results are the most significant to drug development.

The chemical structures of the selected sesquiterpene lactones discussed below are indicated in the Figure 1.

Figure 1. Chemical structures of some sesquiterpene lactones constituents of edible Artemisia sp. and derivatives with pharmacological relevance.

Concerning the Artemisia constituents, clinical and in vivo studies involving artemisinin and its derivatives show them as efficient antimalarial and anticancer agents. Additionally, the additive or synergistic interactions of artemisinin and derivatives in combination with a wide array of clinically established drugs to combat different cancer are highlighted. The high therapeutic potential is evident in the WHO proposal to investigate artemisinin and derivatives as well as A. annua to the treatment of Covid-19 infection. In addition to artemisinin and its derivatives, other sesquiterpene lactones isolated from different species of Artemisia, such as santonin, achillin and tehranolide, have been the target of further studies with a view to the development of new derivatives and their application as medicines. These compounds exhibit very interesting activities, in in vivo models, such as immunosuppressant and anti-inflammatory and potent antinociceptive effect. Achillin acts as a meiotic inhibitor and smooth muscle cell relaxant, properties very relevant to improve human embryonic development in-vitro fertilization procedures and to treat asthma and chronic obstructive pulmonary disease, respectively.