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REVIEW OF MEDICINAL USES, PHYTOCHEMISTRY, AND PHARMACOLOGICAL PROPERTIES OF DRIMIA ELATA

Drimia elata is an important and well-known medicinal plant in tropical Africa. This study critically reviewed the medicinal applications, phytochemistry, and pharmacological activities of D. elata. Literature on medicinal applications, phytochemical, and pharmacological activities of D. elata was collected from multiple internet sources including Elsevier, Google Scholar, SciFinder, Web of Science, PubMed, BMC, ScienceDirect, and Scopus. Complementary information was gathered from pre-electronic sources such as books, book chapters, theses, scientific reports, and journal articles obtained from the university library. This study showed that D. elata is used for treating several medical conditions, particularly general ailments, blood and cardiovascular system, reproductive system and sexual health, urinary system, infections and infestations, digestive system, respiratory system, and muscular-skeletal system disorders. Phytochemical compounds identified from the species include bufadienolides, alkaloids, aromatic acids, flavonoids, phlobatannins, saponins, steroids, tannins, and terpenoids. Ethnopharmacological research revealed that D. elata extracts have acetylcholinesterase enzyme inhibitory, antibacterial, antifungal, antimycobaceterial, anticancer, anti-inflammatory, antioxidant, hemagglutinating, and cytotoxicity activities. D. elata should be subjected to extensive in vivo experiments and also future studies should focus on how potential toxic components of the species can be managed when it is used as herbal medicine.


MEDICINAL USES OF D. ELATA
The medicinal applications recorded from literature were classified into ten medical categories following the Economic Botany Data Collection Standard [32] with some changes proposed by Macía et al. [33] and Gruca et al. [34]. This review showed that D. elata is used for treating several medicinal conditions, particularly general ailments, blood and cardiovascular system, reproductive system and sexual health, urinary system, infections and infestations, digestive system, respiratory system, and muscular-skeletal system disorders (Fig. 2). D. elata is used as herbal medicine against three out of five diseases categorized by the World Health Organization (WHO) as the top five killer diseases in sub-Saharan Africa in 2012. These diseases include human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), lower respiratory tract infections, and diarrheal diseases [35]. Most medicinal uses are linked to the bulb and leaf or the entire plant in ritual or magical uses, and the species is also used mixed with other plant species (Table 1). Research by Gurib-Fakim [36] and Maroyi [37,38] revealed that traditional medicines are often prepared by combining several different plant species to effect synergistic properties or to initiate an interaction with a relevant molecular target.

PHYTOCHEMICAL CONSTITUENTS OF D. ELATA
D. elata is characterized by cardiac glycosides, particularly bufadienolides. All the bufadienolides that have been isolated from D. elata are collated in Table 2. Kellerman et al. [59,60] argued that bufadienolide containing plants are toxic to livestock with an estimated 33% of plant-related mortality in cattle in South Africa attributed to this compound. Van et al. [61] argued that there is a danger of accidental poisoning or that people may be harmed if bulbs of D. elata are used indiscriminately as rubbing the bulb scales or leaves on bare skin produces a stinging and irritating effect and a skin rash is produced. However, bufadienolides are known to have a wide range of biological activities including anti-tumor, antiproliferative, and cytotoxic activities [62][63][64][65][66][67][68].
Okem et al. [71] argued that D. elata bulbs obtained from the herbal medicine informal markets in Pietermaritzburg, KwaZulu-Natal Province in South Africa contained high levels of heavy metals, with aluminum, cadmium, manganese, and chromium being above the WHO recommended safety levels ( Table 3). Quantities of mineral elements and phytochemical compounds isolated from D. elata are listed in Table 3.

Acetylcholinesterase enzyme inhibitory activities
Ndhlala et al. [2] investigated the acetylcholinesterase enzyme inhibitory activities of aqueous bulb extracts of D. elata using the enzyme isolated from electric eels with galanthamine as the positive control. The extract showed moderate AChE inhibitory activity of 50.0% with half maximal inhibitory concentration (IC 50 ) value of 487.4±8.0 µg/mL [2]. The ability of D. elata bulb extracts to inhibit acetylcholinesterase shows potential therapeutic potential of the species in the management of memory loss and neurodegenerative disorders.

Antibacterial activities
Luyt et al. [72] evaluated antibacterial activities of aqueous, ethyl acetate, and ethanol bulb and leaf extracts of D. elata against Bacillus    [72]. Ncube et al. [76] evaluated antibacterial activities of aqueous, dichloromethane, ethanol, and petroleum ether extracts of bulb and leaves of D. elata between spring, summer, autumn, and winter seasons against Bacillus subtilis, S. aureus, E. coli, and K. pneumoniae using the microdilution bioassay with neomycin (μg/ml) as the positive control. The extracts were active in all seasons except for winter when the leaves are not available showing minimum inhibitory concentration (MIC) values ranging from 0.8 mg/ml to >12.5 mg/ml [76]. Ndhlala et al. [2] evaluated the antibacterial activities of aqueous, petroleum ether, dichloromethane, and ethanol bulb extracts of D. elata against Bacillus subtilis, E. coli, K. pneumoniae, and S. aureus using the microdilution bioassay with neomycin as the positive control. The extracts showed activities with MIC values ranging from 0.8 to >12.5mg/mL [2]. Baskaran et al. [77] evaluated the antibacterial activities of ethanol bulb, leaf, shoots, and plantlet extracts of in vitro and ex vitro regenerated D. elata in comparison to naturallygrown plants against S. aureus, Enterococcus faecalis, E. coli, and P. aeruginosa using the microdilution method with neomycin (100 µl) as the positive control. All extracts exhibited activities with MIC values ranging from 0.2 mg/ml to 12.5 mg/ml [77]. Okem et al. [71] evaluated antibacterial activities of ethanol stem bulb extracts of D. elata against E. coli and S. aureus using microdilution assay with neomycin (2 µg/ml) as the positive control. The extracts exhibited activities with MIC values ranging from 6.3 mg/mL to 12.5 mg/mL [71]. Okem et al. [78] evaluated the effects of cadmium and aluminum accumulation on antibacterial activities of ethanol stem bulb extracts of D. elata against E. coli and S. aureus using microdilution assay with neomycin (2 µg/ml) as the positive control. The control extracts exhibited MIC values of 0.4 mg/ml and 0.8 mg/ml against S. aureus and E. coli, respectively, while antibacterial activities decreased in extracts exposed to increasing heavy metal stress with MIC values ranging from 0.8 mg/ml to 12.5 mg/ml [78]. Madisha [50] evaluated the antibacterial activities of ethanol, methanol, hydroethanol, and dichloromethane bulb extracts of D. elata against Bacillus cereus, E. faecalis, E. coli, Neisseria gonorrhoeae, Proteus vulgaris, P. aeruginosa, Shigella flexneri, S. aureus, Staphylococcus epidermidis, and Vibrio parahaemolyticus using agar well dilution method and streak plate disc diffusion assays. The extracts revealed varying degrees of activities with the zone of inhibition values ranging from 8.0 mm to 19.0 mm and MIC values ranging from 0.1 mg/mL to 12.5 mg/mL [50]. Madisha [50] also evaluated the antibacterial activities of ethanol and hydroethanol bulb extracts of D. elata mixed with roots of Elephantorrhiza elephantina and leaves of Aloe marlothii and Maurea angolensis against B. cereus, E. faecalis, E. coli, N. gonorrhea, P. vulgaris, P. aeruginosa, S. flexneri, S. aureus, S. epidermidis, and V. parahaemolyticus using agar well dilution method and streak plate disk diffusion assays. The extracts exhibited activities against tested pathogens with MIC values ranging from 0.4 mg/mL to 1.6 mg/mL [50]. Matotoka [43]. The documented antibacterial activities exhibited by extracts of D. elata corroborate the traditional application of the species as herbal medicine against bacterial infections causing diarrhea [43], gonorrhea [19,52,53], sexually transmitted infections [55], and sores [51].

Antifungal activities
Ncube et al. [76] evaluated antifungal activities of aqueous, dichloromethane, ethanol, and petroleum ether extracts of bulb and leaf extracts of D. elata between spring, summer, autumn, and winter seasons against Candida albicans using the microdilution bioassay with amphotericin B (μg/ml) as the positive control. The extracts were active in all seasons except for winter when the leaves are not available showing MIC and MFC values ranging from 0.4 mg/ml to >12.5 mg/ml [76]. Ndhlala et al. [2] investigated the antifungal activity of aqueous, petroleum ether, dichloromethane, and ethanol bulb extracts of D. elata against C. albicans using the microdilution assay with amphotericin B as the positive control. The extracts exhibited activities with MIC and MFC values ranging from 3.1 to 6.3 mg/mL and 6.3 mg/mL to 12.5 mg/mL [2].

Antimycobacterial activities
Madisha [50] evaluated the antimycobaceterial activities of ethanol, methanol, hydroethanol, and dichloromethane bulb extracts of D. elata against Mycobacterium tuberculosis, Mycobacterium smegmatis, Mycobacterium peregrinum, and Mycobacterium haemophilus using agar well dilution method and streak plate disc diffusion assays. The extracts revealed varying degrees of activities with the zone of inhibition values ranging from 9.0 mm to 21.0 mm and MIC values ranging from 0.1 mg/mL to 12.5 mg/mL [50]. Madisha [50] also evaluated the antimycobacterial activities of ethanol and hydroethanol bulb extracts of D. elata mixed with roots of Elephantor rhizaelephantina and leaves of A. marlothii and M. angolensis against M. tuberculosis, M. smegmatis, M. peregrinum, and M. haemophilus using agar well dilution method and streak plate disc diffusion assays. The extracts exhibited activities against tested pathogens with MIC values ranging from 0.1 mg/mL to 1.6 mg/mL [50]. These findings show the potential of D. elata in the treatment and management of respiratory problems such as blocked nose [48], chest pains [46][47][48], colds [43,44,47], cough [48], and runny nose [50].

Antioxidant activities
Matotoka and Masoko [70] evaluated antioxidant activities of acetone and hexane extracts of D. elata bulb using 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay. The hexane extracts exhibited antioxidant activities [70]. Matotoka and Masoko [43] evaluated antioxidant activities of an herbal mixture of D. elata bulb together with leaves of M. angustifolia, S. viminale and Vahlia capensis, Kirkia wilmsii (leaves, roots, and twigs), and Hypoxis hemerocallidea (corm) using the DPPH free radical scavenging assay and ferric reducing power with L-ascorbic acid as the positive control. The free radical scavenging activity showed that the herbal concoction exhibited moderate antioxidant activities. The ferric reducing power measuring the reduction of Fe3+ to Fe2+ revealed that the herbal concoction exhibited good reducing activity compared to L-ascorbic acid, the positive control [43]. The documented antioxidant activities of the bulb extracts of D. elata are probably due to flavonoids, gallotannins, phenolics, saponins, and tannins which have been isolated from the species [43,71,76].

Hemagglutinating activities
Gaidamashvili and Van Staden [84] evaluated hemagglutinating activities of aqueous bulb extracts of D. elata toward fresh and glutaraldehyde-treated rabbit erythrocytes using the hemagglutination and hapten inhibition assays. The extracts yielded hemagglutinating activity which was detected in the crude protein extracts at the minimal concentrations of 19.9 mg/ml. The was inhibited by 200 mM lactose along with major inhibition by D(+) trehalose, >DL arabinose, and D fructose [84]. The documented information on hemagglutinating activities and the identification of proteins from D. elata may be useful for future characterization of the species extracts in developing pharmaceutical products.

Cytotoxicity activities
Matotoka and Masoko [43] evaluated cytotoxicity activities of an herbal mixture of D. elata bulb together with leaves of M. angustifolia, S. viminale and Vahlia capensis, Kirkia wilmsii (leaves, roots, and twigs), and Hypoxis hemerocallidea (corm) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide calorimetric assay with actinomycin D as the negative control. The cytotoxic concentration (CC 50 ) values of all the concoctions were above the highest concentration used (1000 μg/mL) and Actinomycin D; the negative control exhibited CC 50 value of 0.6 μg/mL [43]. The documented cytotoxicity activities exhibited by D. elata extracts may be attributed to bufadienolides as these compounds are known to have cytotoxicity activities [64,65].

CONCLUSION
Based on information about D. elata that has been documented in this review, there appear to be research gaps on ethnopharmacological evaluation and clinical research on the species. No in vivo evaluations nor an assessment of target-organ toxicity have been carried out using the extracts from the species. Since D. elata is widely used in combination with other plant species in various herbal concoctions, there is a need for extensive research to evaluate synergistic effects of the different extracts and also to evaluate their ability to enhance the efficiency of the additive mixtures. Future research should also focus on aerial parts of the species to ensure full utilization of the possible medicinal potential of the species. Literature studies show that the major phytochemical compounds isolated from D. elata so far are mainly bufadienolides but very little attempt has been made to correlate the activities of these compounds with the ethnomedicinal uses of the species. Therefore, detailed phytochemical studies of D. elata and its pharmacological properties, especially the mechanism of action of its bioactive constituents to illustrate the correlation between its ethnomedicinal uses and pharmacological activities should be the focus of future research studies. Extensive in vivo experiments are required to validate the existing pharmacological activities. Since D. elata contain potentially toxic compounds, future studies should research on how potential toxic components of the species can be managed.

AUTHOR'S CONTRIBUTIONS
The author declares that this work was done by the author named in this article.

CONFLICTS OF INTEREST
The author declares that there are no conflicts of interest regarding the publication of this paper.