Sunday, 22 April 2018

Is there a role for herbal medicine in the treatment and management of periodontal disease?

Journal of Herbal Medicine Available online 10 March 2018 In Press, Corrected ProofWhat are Corrected Proof articles? Journal of Herbal Medicine Author links open overlay panelJulijaMilovanova-PalmerBarbaraPendry Medicines Research Group, School of Health, Sport and Bioscience, University of East London, Water Lane, Stratford, London E15 4LZ, UK Received 9 June 2017, Revised 28 January 2018, Accepted 25 February 2018, Available online 10 March 2018. Get rights and content Abstract Periodontal disease is an inflammatory condition of the tissues of the periodontium that affects up to 90% of the world’s population. Emerging antibiotic and antimicrobial resistance in oral biofilms has sparked off an increased interest in the potential of medicinal plants to treat periodontal pathologies. The last decade has seen a surge in numbers of in vitro and in vivo studies on herbs traditionally used for their anti-bacterial properties in ethno-pharmacological applications. This review paper assesses the current status and role of medicinal plants in the treatment and management of periodontal disease. Keywords Periodontal disease Periodontitis Gingivitis Herbal medicine Phytotherapy Antibiotic Antimicrobial Review Anti-inflammatory Herbal mouthwashes Mouthwashes Medicinal plants Oral health Herbal extracts Clinical research in vivo in vitro Treatment Alternative medicine Oral gel 1. Introduction Periodontal disease is widely recognised as a public health issue (Petersen and Ogawa, 2012). It is a leading cause of tooth loss (FDI World Dental Federation, 2014) and thus can seriously compromise quality of life (Batchelor, 2014; Sravani et al., 2015). Periodontal disease has high prevalence. The milder form (gingivitis) affects up to 90% of the world’s population (Philstrom et al., 2005), whereas the severe form of the disease (chronic periodontitis) affects up to 20% of the world’s population (FDI World Dental Federation, 2014). From the information of the National Health Service of the United Kingdom, about 50% of the UK population suffers from some form of periodontal disease (National Health Service, 2015). 1.1. Pathogenesis of periodontal disease Periodontal disease is a chronic inflammatory pathology that gradually destroys the structures of the periodontium: gingiva, alveolar bone, cementum and periodontal ligament (Jain et al., 2008). Periodontal disease can manifest as gingivitis, reversible inflammation of the gums, or chronic periodontitis, inflammation of the subgingival areas with irreversible damage to the periodontium and formation of distinctive periodontal pockets (Nguyen et al., 2015; Highfield, 2009). The major cause of periodontal disease is the proliferation of pathogenic oral biofilms, which are robust layers of mucilage adhering to solid surfaces and containing communities of bacteria and other micro-organisms, resulting in dental plaque formation (Palombo, 2011). Different bacteria occur in supragingival (cariogenic) and subgingival (periodontopathogenic) dental plaques. Supragingival plaque is host to facultative anaerobic bacteria such as Streptoccocus spp. and Actinomyces spp., whereas subgingival plaque is host to Gram-negative anaerobic bacteria such as Porphyromonas gingivalis, Actinobacillus, Prevotella intermedia, Fusobacterium nucleatum, Aggregatibacter actinomycetemcomitans, Capnocytophaga spp. and Veillonella spp. (Lazar et al., 2016). Chronic periodontitis is associated with proliferation of subgingival Gram-negative oral biofilms (Kouidhi et al., 2015; Srinath and Lakshmi, 2014; Palombo, 2011; Batista et al., 2014). It thus can be deduced that gingivitis is associated with facultative anaerobic bacteria. The progress of periodontal disease includes cyclical phases of exacerbation, remission and latency and is closely associated with the host immune-inflammatory response (Lazar et al., 2016, Yarnell et al., 2009, p.286; Cochran, 2008; Preshaw, 2000). Bacteria in subgingival dental plaques cause excessive proliferation of pro-inflammatory mediators (cytokines, prostanoids and enzymes) which intensify the destruction of periodontium (Preshaw, 2000). 1.2. Risk factors There are factors that may increase the risk of development of periodontal disease. These include hormonal changes due to pregnancy and puberty (Highfield, 2009; Hoffman, 2003, p. 268), systemic diseases such as diabetes mellitus (Highfield, 2009; Izuora et al., 2015), certain medications (Highfield, 2009), and such common behavioral risk factors as smoking, alcohol, poor diet, physical inactivity, and obesity (Genco and Genco, 2014). Furthermore, periodontal disease has been associated with systemic pathologies including cardiovascular pathologies, (Aarabi et al., 2015; Nguyen et al., 2015), stroke (Genco and Genco, 2014), oral cancer (Javed and Warnakulasuriya, 2015), and rheumatoid arthritis (Kaur et al., 2014). 1.3. Problems with current periodontal disease management Surgical intervention to reduce periodontal pockets is expensive. For example, in the U.S. surgery costs US$4000–5000 and is not covered by health insurance. (Lazar et al., 2016). The standard non-surgical treatment for periodontal disease is mechanical plaque removal (professional scaling, root planing and tooth brushing) alongside strict plaque control using antibacterial mouthwashes (e.g. chlorhexidine, which is considered the gold standard) and/or local and systemic application of antibiotics (tetracycline and metronidazole, the latter acting primarily on anaerobic bacteria) (Batista et al., 2014; Kouidhi et al., 2015; Karim et al., 2014, Jain et al., 2008) as well as systemic use of subantimicrobial dose doxycycline as a new adjunct host-modulatory therapy option (Preshaw, 2000; Shinwari et al., 2014). Non-surgical treatments have significant drawbacks. Mechanical plaque removal cannot reach all the areas where bacteria hide and can lead to re-colonization with pathogens (Batista et al., 2014). Chlorhexidine, when used for longer than 15 days, exhibits several adverse effects in staining the teeth and tongue, increasing oral sensitivity and provoking allergic reactions (Balappanavar et al., 2013; Batista et al., 2014). Long term use of chlorhexidine was also found to increase accumulation of dental calculus (Schwach-Abdellaoui et al., 2000). A major issue with current periodontal disease management is the risk of development of antibiotic and antimicrobial resistance. Recent research suggests that long-term use of chlorhexidine products has a link to the development of multidrug resistance in dental plaque bacteria. Moreover, chlorhexidine appears to have the same mode of action in causing bacteria to develop anti-microbial resistance as four major groups of antibiotics ampicillin, kanamycin, gentamicin and tetracycline (Saleem et al., 2016). This puts under long term threat the therapeutic value of the major pharmaceutical anti-plaque agent for gingivitis and periodontal disease. 1.4. Herbal medicine as an alternative solution for management of periodontal disease A combination of antibiotic resistance risk and the drawbacks of existing treatment modalities create a need for alternative treatments that are safe and effective (Batista et al., 2014; Karim et al., 2014; Srinath and Lakshmi, 2014; Palombo, 2011; Projan and Youngman, 2002). In the last decade, there has been much in vitro and in vivo research into the efficacy of medicinal plants with known anti-inflammatory and antibacterial qualities to treat periodontal disease. This paper reviews the evidence in order to determine whether herbal medicine has a role in the treatment and management of periodontal disease. 2. Method 2.1. Herbal texts A selection of contemporary western herbal texts was screened in order to identify traditionally used herbs for treatment and management of periodontal disease. The following search words were used: “gingivitis”, “periodontal disease” and “gum disease”. To be included, the texts had to be written by professional herbalists, pertain to Western Herbalism, have information on treatment of periodontal disease in its content, be easily accessible to professionals and public alike and date not earlier 1995. There were 18 texts that met the inclusion criteria which are listed here in date order: (Alexander and Staub-Bruce, 2014; Pizzorno and Murray, 2013; Braun and Cohen, 2010; McIntyre, 2010; Fisher, 2009; Yarnell et al., 2009; Wood, 2008; Wood, 2009; Chevallier, 2007; Hoffman, 2003; Mills and Bone, 2003; Barnes et al., 2002; Barker, 2001; Weiss, 2001; Blumenthal et al., 2000; Mindell, 2000; Tyler, 1999; Bartram, 1998; Robbins, 1995). 2.2. Literature review A systematic literature search was performed using four online databases: Science Direct, PubMed, Scopus and ResearchGate from October 2015 to May 2017. Wiley Online and Web of Science generated no additional research literature of interest to this study during preliminary assessment, so these sources were not included. Search terms applied were “periodontal disease OR gingivitis OR gum disease OR oral biofilm OR periodontal bacteria”, and “herbal medicine OR phytotherapy OR herbs OR medicinal plants”. The full text of each paper was obtained. Initially, an electronic search for in vitro papers generated 423 articles in total, and n = 37 articles met all inclusion criteria, which were for in vitro studies on herbs showing activity against periodontal bacteria, published in English in peer-reviewed journals from 2007 onwards. An electronic search for randomised controlled trials initially generated 954 articles, and n = 26 articles met all inclusion criteria, which were for clinical studies testing whole herb extracts on humans, published in English in peer-reviewed journals from 2007 onwards. Studies on animal cells or animals, studies on single herbal constituent extracts and articles on commercial products containing herbal extracts were excluded. It was beyond the scope of this review to cover the use of essential oils in the treatment of periodontal disease. 3. Results 3.1. Herbal texts 3.1.1. Medicinal plants for treatment of gingivitis and periodontitis In total, 64 medicinal plants were identified in the western herbal texts by 18 authors. Only 14 medicinal plants were mentioned by at least 3 different authors (Table 1). Commiphora molmol (n = 12) was the most popular choice in the herbal texts. Thus, Wood (2008) and Hoffman (2003) considered Commiphora molmol to be a specific remedy for periodontal disease. Salvia officinalis (n = 11) was the second most popular choice, followed by Calendula officinalis and Matricaria recutita (n = 7). The other popular herbs appeared in the following sequence: Echinacea purpurea (n = 6), Hydrastis canadensis, Quercus spp. and Vaccinium myrtilis (n = 5); Camellia sinensis (n = 4); Achillea millefolium, Azadirachta indica, Centella asiatica, Mentha piperita, Myrica spp., Plantago spp., Symphytum spp. and Thymus vulgaris (n = 3). Table 1. Herb Species Indicated For Treatment & Management Of Periodontal Disease In At Least 3 Different Contemporary Herbal Texts. Herb species Alexander and Straub-Bruce (2014) Pizzorno and Murray (2013) Braun and Cohen (2010) McIntyre (2010) Yarnell et al. (2009) Fisher, 2009 Wood (2008) and Wood (2009) Chevallier (2007) Hoffman (2003) Mills and Bone (2003) Barnes et al. (2002) Barker (2001) Weiss (2001) Blumenthal et al. (2000) Mindell (2000) Tyler (1999) Bartram (1998) Robbins (1995) Count Achillea millefolium ○ ○ ○ 3 Azadirachta indica ○ ○ ○ 3 Calendula officinalis ○ ○ ○ ○ ○ ○ ○ 7 Camellia sinensis ○ ○ ○ ○ 4 Centella asiatica ○ ○ ○ 3 Commiphora molmol ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 12 Echinacea purpurea ○ ○ ○ ○ ○ ○ 6 Hydrastis canadensis ○ ○ ○ ○ ○ 5 Matricaria recutita ○ ○ ○ ○ ○ ○ ○ 7 Mentha piperita ○ ○ ○ 3 Myrica spp. ○ ○ ○ 3 Plantago major ○ ○ ○ 3 Quercus spp. ○ ○ ○ ○ ○ 5 Salvia officinalis ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 11 Sanguinaria canadensis ○ ○ ○ ○ ○ 5 Symphytum spp. ○ ○ ○ 3 Thymus vulgaris ○ ○ ○ 3 Vaccinium myrtilis ○ ○ ○ ○ ○ 5 Species Count 12 4 3 8 10 10 3 3 2 3 2 3 3 1 5 6 10 3 18 It is difficult to ascertain whether this list is exhaustive since many authors gave marginal attention to periodontal disease, gum disease or gingivitis. 3.2. Literature review 3.2.1. Significance of medicinal plant research in vitro against oral periodontal bacteria Herbal extracts demonstrated inhibitory effects on supragingival and subgingival bacteria in 37 in vitro studies published since 2007 (see Table 2). These studies tested whole plant extracts of 52 different species. The highest numbers of in vitro studies were carried out on Psidium guajava (n = 4), followed by Camellia sinensis (n = 2), Murraya koenigi (n = 2), Punica granatum (n = 2) and Salvadora persica (n = 2). The total number of in vitro studies in recent years has increased. Table 2 displays the results in order of lead author’s name. Out of 37 studies, 23 investigated inhibition of Streptococcus mutans and 23 investigated inhibition of Porphyromonas gingivalis. Table 2. Summary Of In Vitro Studies. Source plant References Supragingival micro-organisms tested Subgingival micro-organisms tested Mangifera indica (mango), Anacardium occidentale (cashew) Anand et al. (2015) Streptococcus mutans Coffea arabica, Coffea canephora Antonio et al. (2011) Streptococcus mutans Camellia sinensis (green tea) Araghizadeh et al. (2013) Streptococcus mutans (20 strains) Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia (20 strains each) Artemisia herba-alba (white wormwood), Opuntia focus-indica (Indian fig), Camellia sinensis (green tea), Phlomis crinita (Jerusalem sage) Arbia et al. (2017) Porphyromonas gingivalis, Prevotella intermedia Copaifera reticulata (copaiba) Bardaji et al. (2016a,b) Streptococcus mutans, S. salivarius, S. mitis Fusobacterium nucleatum, Prevotella nigrescens, Porphyromonas gingivalis Quercus infectoria (gall oak) Basri et al. (2012) Streptococcus mutans, S. salivarius Porphyromonas gingivalis, Fusobacterium nucleatum Acacia nilotica (gum arabic tree), Murraya koenigi (curry tree), Psidium guajava (guava) Chandrashekar et al. (2016) Streptococcus mutans, S. sanguis, S. salivarius Porphyromonas gingivalis, Fusobacterium nucleatum Cymbopogon citrates (lemongrass), Plectrathus amboinicus (Mexican mint), Conyza bonariensis (hairy fleabane) Da Silva et al. (2012) Streptococcus mutans, S. salivarius, S. oralis Punica granatum (pomegranate), Glycyrrhiza glabra (liquorice), Equisetum arvense (horsetail), Stryphnodendron barbatimam De Oliveira et al. (2013) Streptococcus spp. Porphyromonas gingivalis, Aggregatibacter actinomycetemcoitans, Prevotella intermedia Salvadora persica (toothbrush tree) Jelvehgaran Esfahani et al. (2014) Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans Aloe vera (aloe) Fani and Kohanteb (2012) Streptococcus mutans Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Bacteroides fragilis Psidium cattleianum (cherry guava), Myracrodruon urundeuva (timber tree) Gaetti-Jardim et al. (2011) Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum Glycyrrhiza uralensis (Chinese liquorice) Villinski et al. (2014) Streptococcus mutans, S. sobrinus Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum Psacalium decompositum (Indian plantain) Garcia-Palencia et al. (2016) Streptococcus mutans Porphyromonas gingivalis, Prevotella intermedia Geum urbanum (wood avens) Granica et al. (2016) Morus alba (mulberry) Gunjal et al. (2015) Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forsythia Citrus sinensis (orange) Hussain et al. (2015) Prevotella intermedia, Porphyromonas gingivalis, Aggregatibacter actinomyctemcomitans Moringa oleifera (drumstick tree), Murraya koenigii (curry tree), Psidium guajava (guava), Eclipta prostata (false daisy), Phyllanthus fraternus (gulf leaf-flower) John et al. (2013) Streptococcus mutans, S. salivarius, S. mitior, S. sanguinis, S. mitis, S. milleri Pistacia lentiscus (mastic gum) Karygianni et al. (2014) Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum Terminalia chebula (myrobalan) Lee et al. (2017) Streptococcus mutans Aggregatibacter actinomycetemcomitans Ocimum sanctum (tulsi) Mallikarjun et al. (2016) Porphyromonas gingivalis, Prevotella intermedia, Aggregatibacter actinomycetemcomitans Citrus reticulata (orange) Mankar et al. (2016) Porphyromonas gingivalis, Prevotella intermedia, Aggregatibacter actinomycetemcomitans Azadirachta indicum (neem), Mimusops elengi (bakul), Tinospora cardifolia (giloy), Ocimum sanctum (tulsi) Mistry et al. (2014) Streptococcus mutans Verbascum thapsus (mullein) Moghaddam et al. (2015) Streptococcus mutans, S. sanguinis, S. salivarius Vitis vinifera (grape vine) Muñoz-González et al. (2014) Streptococcus mutans, S. oralis, Actinomyces oris Fusobacterium nucleatum Zingiber officinale (ginger) Park et al. (2008) Porphyromonas gingivalis, Porphyromonas endodontalis, Prevotella intermedia Phytolacca americana (american pokeweed) Patra et al. (2014) Streptococcus mutans Porphyromonas gingivalis, Escherichia coli Robinia pseudoacacia (black locust) Patra et al. (2015) Streptococcus mutans Porphyromonas gingivalis Azadirachta indicum (neem), Piper betel (betel) Salam et al. (2014) Streptococcus mutans Enterococcus faecalis Myristica fragrans (nutmeg) Shafiei et al. (2012) Streptococcus mutans, S. mitis, S. salivarius Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Fusobacterium nucleatum Salvadora persica (toothbrush tree) Sofrata et al. (2007) Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Haemophilus influenza Copaifera langsdorffii (Salam tree) Souza et al. (2011) Porphyromonas gingivalis Hypericum perforatum (St. John's wort) Süntar et al. (2015) Streptococcus mutans, S. sobrinus Enterococcus faecalis, Lactobacillus plantarum Punica granatum (pomegranate), Psidium guajava (guava) and Schinus terbinthifolius (Brazilian pepper-tree) Vieira et al. (2014) Streptococcus mutans Magnolia officinalis (magnolia) Walker et al. (2016) Streptococcus spp. Porphyromonas gingivalis Psidium guajava (guava),Mangifera spp.(mango), Mentha spp. (mint) Wan Nordini Hasnor et al. (2013) Streptococcus sanguinis, S. mitis Vaccinium macrocarpon(cranberry) Yamanaka et al. (2007) Streptococcus spp. 3.2.2. Significance of medicinal plants in clinical research: randomised controlled clinical trials There were 26 randomised clinical trials since 2007 which fulfilled eligibility criteria. These clinical trials are summarized in Appendix A (available in Supplementary data only), including detailed information on herbal extracts assessed, trial aim, type of preparation, trial duration, number of participants, inclusion/exclusion criteria, dosage and results. Due to space limitations in the current review paper, only summary findings of the clinical trials are offered in the body of the text. The findings of the clinical trials are divided into categories based on the delivery mechanism of the herbal extracts: subgingival delivery, herbal mouthwashes, trans-mucosal delivery, chewing gum, oral gel. For more detail on each trial, please refer to the Appendix A (available in the Supplementary data only). 3.2.3. Subgingival delivery of herbal extracts in chronic periodontitis There were 3 clinical trials (see Appendix A) which evaluated efficacy of medicinal plants in subgingival delivery mode for patients with chronic periodontitis. Subgingival irrigation with Azadirachta indica (neem) extract significantly (P < 0.05) reduced gingivitis, bleeding, and periodontal disease over a 30-day period in a group of 15 chronic periodontal disease sufferers (Bedi et al., 2011). In another short-term study, Bhat et al. (2011) demonstrated that Aloe vera gel injected into periodontal pockets significantly (P < 0.05) reduced periodontal pocket depth, gingivitis and bleeding. Rassameemasmaung et al. (2008) found that when Garcinia mangostana gel was introduced to the subgingival space, the periodontal pocket depths were reduced but not to a significant level (P < 0.05). Gingival inflammation and bleeding were reduced significantly (P < 0.05) after 3 months. 3.3. Herbal mouthwashes 3.3.1. Comparison of herbal mouthwashes to chlorhexidine The effectiveness of herbal mouthwashes was compared to chlorhexidine, considered to be the gold standard commercial mouthwash, in 16 randomised clinical trials (see Appendix A, available in Supplementary data only). Of these, 15 studies showed no significant difference in effectiveness (P < 0.05) between chlorhexidine and the following herbal mouthwashes (in concentrations ranging from 0.2% to 0.12%): 0.5% Camellia sinensis and 2% Azadirachta indica (Balappanavar et al., 2013); Azadirachta indica (Sharma et al., 2014); Punica granatum and Matricaria recutita (Batista et al., 2014); Aloe vera 100% gel mouthwash (Chandrahas et al., 2012), Aloe vera mouthwash (Karim et al., 2014; Gupta et al., 2014; Vangipuram et al., 2016); Ocimum sanctum (Gupta et al., 2014); a polyherbal mouthwash of Zingiber officinale, Rosmarinus officinalis and 5% Calendula officinalis (Mahyari et al., 2016); a polyherbal mouthwash containing Salix alba, Malva sylvestris and Althaea officinalis alongside scaling and root planing (Radvar et al., 2016); Cinnamomum verum (Gupta and Jain, 2015); Terminalia chebula (Gupta et al., 2015); Curcuma longa (Waghmare et al., 2011); a polyherbal mouthwash of Salvadora persica and Camellia sinensis (Abdulbaqi et al., 2016), a polyherbal mouthwash triphala of Emblica officinalis, Terminalia chebula and Terminalia bellirica (Naiktari et al., 2014). No side effects were observed from herbal mouthwashes. In contrast, one study found that Aloe vera mouthwash was significantly less effective in reducing plaque than chlorhexidine (Yeturu et al., 2016). 3.3.2. Comparison of herbal mouthwashes to placebo Jenabian et al. (2012) tested 5 ml of 5% Camellia sinensis mouthwash against a placebo in schoolchildren with gingivitis. Both groups carried out flossing and tooth brushing three times a day. Gingivitis reduction was highly effective with the mouthwash (P < 0.001), but there was no statistically significant difference from gingivitis reduction outcomes of the placebo group (P > 0.05). Aspalli et al. (2014) found that, following scaling, a polyherbal mouthwash containing Salvadora persica, Terminallia bellerica, Piper bitel, Gandhapura taila, Ela, Peppermint satva and Yavani satva significantly reduced gingivitis, plaque and bleeding (P < 0.05). 3.4. Trans-mucosal herbal patch A study on a transmucosal herbal patch containing extracts of Centella asiatica, Echinacea purpurea and Sambucus nigra on gingivitis patients showed high effectiveness (P = 0.009) compared to a placebo controlled group, and no side effects (Grbic et al., 2011). 3.5. Herbal chewing gum A chewing gum randomised clinical trial conducted by Amoian et al. (2010) tested Salvadora persica extract in a chewing gum administered 4 times daily for at least 1 h following tooth brushing to 72 high school students with gingivitis. There was a significant reduction in gingivitis (P < 0.001) and bleeding (P < 0.005), but no significant reduction in plaque (P < 0.579). 3.6. Oral gel Farjana et al. (2014) evaluated efficacy of Curcuma longa gel for gingivitis treatment with significant reduction of bleeding on probing (P < 0.579). 4. Discussion Periodontal disease is a highly complex pathology that stems from the actions of pathogenic bacteria and the host immune-inflammatory response (Lazar et al., 2016). The standard periodontal treatment protocol focuses on the eradication of pathogenic biofilms through mechanical and antimicrobial means including systemic antibiotics and antimicrobial mouthwashes. However, periodontopathogenic bacteria have been developing resistance to antibiotics and most recently also to antibacterial mouthwashes such as chlorhexidine, the gold standard in periodontology (Saleem et al., 2016). It is just a matter of time for these standard treatment modalities to become ineffective. Future treatment strategies will need to provide several modes of anti-bacterial action at once, alongside down-modulation of the host inflammation response (Lazar et al., 2016). Lazar refers to the benefits of the synergistic action of herbal medicines in finding new treatment modalities for periodontal disease. Synergy is the core concept of herbal medicine in which complex interactions take place between combinations of phytochemical constituents generating a synergistic effect where the whole effect is greater than the sum of the part effects (Heinrich et al., 2012). For example, the flavonoid quercetin is an active constituent of Calendula officinalis that exhibits strong antioxidant activity. A whole plant extract of Calendula officinalis showed stronger inhibition of pro-inflammatory MMP-2 enzymes and gingival fibroblast-mediated collagen degradation than quercetin alone (Saini et al., 2012). Petrovic et al. (2015) considers “the biggest problem” in validating herbal treatments for periodontal disease is the lack of understanding of mechanisms of action of multiple compounds working in synergy. However, lack of understanding of the synergistic model does not indicate its lack of effectiveness. Further benefits of herbal medicine are the low research cost, low consumer cost and few or no side effects (Lazar et al., 2016; Batista et al., 2014; Pizzorno and Murray 2013, p. 257). 4.1. Difference in treatment protocols – holistic treatment protocol Until recently, the standard treatment protocol for periodontal disease was confined to a single-pointed focus on eradication of pathogenic biofilms by mechanical or antimicrobial means. Host inflammatory mediators are now believed to be the main cause of disease progression (Lazar et al., 2016). Host modulation therapy, a relatively new concept in periodontics, has now been offered as an adjunct therapy with the only licenced systemic medication in the form of a sub-antimicrobial dose of doxycycline (Shinwari et al., 2014). In comparison, herbal medicine’s treatment protocol is holistic at its core, and would include a choice of herbs with vulnerary (wound healing), anti-inflammatory, anti-bacterial, anti-haemorrhagic, membrane and collagen integrity improving, analgesic and immunomodulatory actions (Table 3). Table 3. Comparison of Theraputic Goals Set for Treatment of Periodontal Disease in Herbal and Scientific Approaches. Therapeutic goals for periodontal disease in herbal approach Therapeutic goals for periodontal disease in scientific approach Promote wound healing (vulnerary) Inhibit growth of oral pathogens (anti-bacterial) Improve membrane and collagen integrity Reduce development of dental plaque Decrease inflammation in the mouth (anti-inflammatory) Reduce adhesion of microbial pathogens to the tooth surface Improve immune status (immunomodulatory) Down-regulate host-immune inflammatory response (new adjunct therapy) Reduce bleeding of gums (anti-haemorrhagic) Reduce pain (analgesic) Inhibit growth of oral pathogens (anti-bacterial) Compiled from sources: Hoffman (2003), Palombo (2011), Yarnell et al. (2009), Pizzorno and Murray (2013), Shinwari et al. (2014), 4.2. Pros and cons of the evidence Successful use of herbal medicine to treat chronic periodontal disease or gingivitis was evident in 85% of the 26 clinical trials that met the inclusion criteria. Gingivitis treatment was successful in 16 trials (62%) using herbal extracts from Aloe vera (n = 4), Azadirachta indica (n = 2), Camellia sinensis (n = 3), Centella asiatica (n = 2), Curcuma longa, Echinacea purpurea, Garcinia mangostana, Matricaria recutita, Salvadora persica (n = 3), Calendula officinalis, Rosmarinus officinalis, Sambucus nigra, Terminalia chebula, Ocimum sanctum and Zingiber officinale delivered through varying therapeutic modalities. Chronic periodontitis treatment was successful in 6 trials (23%) using herbal extracts from Althaea officinalis, Azadirachta indica, Malva sylvestris, Matricaria recutita, Punica granatum, triphala (Emblica officinalis, Terminalia chebula and Terminalia bellirica), Salix alba and gels containing Aloe vera and Garcinia mangostana extracts (see Appendix A). Many studies (n = 16, 62%) compared the efficacy of herbal extracts to chlorhexidine mouthwash. Of these, 15 studies showed herbal extracts to be equally effective to chlorhexidine in reducing disease indicators. These 15 studies examined extracts from 12 plants, including Aloe vera, Althaea officinalis, Azadirachta indica, Calendula officinalis, Camellia sinensis, Malva sylvestris, Matricaria recutita, Ocimum sanctum, Punica granatum, Rosmarinus officinalis, Salix alba and Zingiber officinale. In contrast to chlorhexidine, however, herbal extracts showed no side effects. Several studies (n = 4) compared herbal extracts to a placebo, together with mechanical debridement, but without including a chlorhexidine control group. Statistically significant reductions in gingivitis disease indicators were achieved for Centella asiatica, Echinacea purpurea, Sambucus nigra, Camellia sinensis and Salvadora persica via delivery systems such as a trans-mucosal herbal patch (Grbic et al., 2011) and chewing gum (Amoian et al., 2010). Chronic periodontitis was treated by subgingival delivery of Azadirachta indica, Aloe vera, Centella asitatica, Punicum granatum and Garcinia mangostana as herbal extracts, gels and biodegradable strips (Bedi et al., 2011; Bhat et al., 2011). There was significant reduction of periodontal pocket depth, gingivitis and bleeding following the mechanical debridement therapy of scaling and root planing. Some clinical studies showed a mixture of positive and negative results. Salvadora persica extracts significantly reduced gingivitis and bleeding but had no significant effect on plaque (Amoian et al., 2010). Aloe vera extracts reduced plaque and gingivitis but not by as much as chlorhexidine (Yeturu et al., 2016). Whilst Asadirachta indica extract showed equal efficacy to chlorhexidine in reducing plaque, it was not as good at reducing gingivitis, though still a significant improvement compared to controls (Sharma et al., 2014). One study found that Curcuma longa extract significantly reduced total bacterial numbers and gingivitis but was not as good as chlorhexidine at reducing plaque (Waghmare et al., 2011). Another study found that Curcuma longa extract significantly reduced plaque and gingivitis, and though chlorhexidine performed slightly better in this test, the difference was not significant (Gupta and Jain, 2015). 4.3. Limitations of the current evidence Despite a fairly convincing number of clinical trials (n = 26) presented in the current review, the design of the studies has the following limitations: (a) most studies n = 16 (62%) were small in size, conducted on ≤100 participants, whilst there were only a few larger studies n = 9 (35%), conducted on ≥100 participants, and only n = 3 on ≥200 particpants (11%); (b) the dose of herbal extracts administered was not specified in n = 17 (65%), whilst none of the studies established the minimum effective dose level; (c) n = 8 (31%) studies out of 26 did not indicate P-value creating ambiguity in the statistical significance of the research. Webb (2012, p.129) cited a systematic study by Mother et al. (1998) that found that “low quality trials were associated with a 39% increase in estimated treatment benefit compared to better conducted trials”. The inclusion criteria presented some limitations, e.g. English language research publications only meant that some potentially valuable evidence was not assessed. Most clinical trials for periodontal disease were based in India (n = 16, 62%), where herbal medicine is supported and promoted at a Governmental level. These tended to research medicinal plants pertinent to Ayurvedic Materia Medica that are not usually used in western herbal practice. Other countries where clinical trials were conducted were Iran (n = 4),Brazil (n = 1), Malaysia (n = 1), Thailand (n = 1), Sweden/Saudi Arabia (n = 1) and USA (n = 1). This could be the reason why there were no clinical trials conducted on the two most popular herbs listed in the western herbal texts, Commiphora molmol and Salvia officinalis. 4.4. Other factors On a different note, it is also important to remember that the overall success of periodontal treatment depends, not only on medical intervention, but also on the absence of negative behavioural factors in treated individuals (Sravani et al., 2015) such as incorrect tooth brushing, smoking and poor diet. Somu et al. (2012) referred to research that many adults fail to brush teeth properly (Nogueira-Filho et al., 2000). Genco and Genco (2014) discussed smoking cessation interventions that successfully reduced periodontal disease. Kondo et al. (2014) confirmed that a high-fibre, low-fat diet improved periodontal disease markers. 4.5. Recommendations After evaluating the literature, this review proposes three recommendations to improve the quality of medicinal plant research for periodontal disease treatment: a) Clinical trials should be conducted with larger, more statistically-reliable populations; (b) Recommended therapeutic dosage and minimum dosage should be identified; (c) P-values showing statistical significance of all studies should be presented. These steps would greatly improve the quality of the clinical trials and boost their statistical significance and reliability. This would then increase the value of using the Cochrane GRADE system to assess the quality of evidence for the outcome that herbal treatments are effective for treating periodontal disease. Most of the plants identified in the randomised controlled clinical trials were tested only once on rather small population numbers which reduced the statistical reliability of such studies and undermines the attractiveness of medicinal plants on a larger scale. Since several trials tested the same herbal species, there may be some opportunities for increasing population size through meta-analysis, combining several studies into one. However, the variability of the trial conditions may reduce the value of this route of investigation. The two most popular herbs for treatment of periodontal disease in herbal texts and pharmacopoeias, Commiphora molmol and Salvia officinalis, were not tested in randomised clinical trials. These medicinal plants should be important candidates for future clinical trials. 5. Conclusion Herbal medicine has great potential to treat periodontal disease, especially in the context of emerging global antimicrobial resistance to conventional drugs. Whole plant herbal extracts are less susceptible to antibiotic resistance due to complex pharmacological profiles and synergistic action. The herbal protocol is holistic in its nature and would allow several medicinal plants with antibacterial, anti-inflammatory and immunomodulatory actions to be combined. Herbal medicine appears most effective in treating gingivitis using herbal mouthwashes and managing chronic periodontitis via subgingival delivery of herbal gels, alongside scaling and root planing. There is ample evidence in vitro that many whole plant extracts are effective against periodontopathogenic bacteria, with the most popularly-studied plants being Psidium guava, Camellia sinensis, Punica granatum, Murraya koenigi and Salvadora persica. However in vivo, 88% of clinical trials show significantly positive reduction in gingivitis and chronic periodontitis, and 82% demonstrated significant reductions in plaque, gingivitis and bleeding levels. The most popular plants for in vivo studies are Aloe vera, Azadirachta indica and Camellia sinensis. Herbal medicines have the key benefit of being safe and showing no side effects, unlike commercial mouthwashes. In order for this positive evidence of efficacy to be translated into herbal medicine use by mainstream clinicians, clinical trial quality must be improved to increase confidence. This should be done through increased population sample sizes, more standardised calculation methodology for statistical significance and specifying the dosage of herbal extracts being tested. Future research should focus on the most successful plant candidates in order to increase the statistical significance of earlier findings. These should include medicinal plants with proven traditional evidence as listed in western herbal texts, such as Commiphora molmol, Salvia officinalis, Calendula officinalis and Matricaria recutita. These should also include herbs with the highest numbers of successful trials, including Aloe vera, Camellia sinensis, Centella asiatica and Punica granatum. Appendix A. Detailed summary of 26 clinical trials References Country Herbs Tested Type of Preparation Study Topic Type of Study Trial Size Participant Inclusion Criteria Study Duration Dosage Results/P-value Abdulbaqi et al. (2016) Malaysia Salvadora persica (toothbrush tree), Camellia sinensis (green tea) aqueous herbal extracts as mouthwashes Evaluation of Salvadora persica and gree tea effect on plaque Double-blind randomised controlled crossover clinical trial n = 14; polyherbal; 0.12% chlorhexidine; placebo 25–40 year olds in good health and more than 20 teeth 24 h 0.25 mg/ml green tea and 7.82 mg/ml S persica aqueous extracts Polyherbal significantly better than chlorhexidine 1.317 ± 0.344 (P < 0.0167) Amoian et al. (2010) Iran Salvadora persica (toothbrush tree) chewing gum with extract of Salvadora persica Evaluation of effectiveness of Salvadora persica in gingivitis Double blind randomised clinical trial n = 72 female high school students aged 15–18 years old, with plaque-induced moderate gingivitis 14 days chew gum three times a day after brushing teeth for at least 1 h showed significant results in reduction of gingival index (P < 0.001), bleeding index (P < 0.005), but no significant results in reducing plaque index (P < 0.579). Aspalli et al. (2014) India Salvadora persica (toothbrush tree), Terminallia bellerica (bibhitaka), Piper bitel (nagavalli), Gandhapura taila, Ela, Peppermint satva, Yavani satva polyherbal mouthwash Evaluation of the effectiveness of a polyherbal mouthwash compared to scaling procedure only Randomised clinical trial n = 100: n = 50 polyherbal mouthwash plus scaling; n = 50 scaling only Generally healthy, with minimum 20 teeth, diagnosed with mild to moderate gingivitis 21 days 15 ml for 30 s twice daily greater reduction in plaque index scores, gingival index scores, and gingival bleeding scores in G2 (P < 0.05) Balappanavar et al. (2013) India Camellia sinensis (green tea) & Azadirachta indica (neem) mouthwash with single herb extract Evaluation of the effectiveness of a mouthwash with green tea and neem extrats against chlorhexidine 0.2% Randomised controlled clinical trial n = 30: n = 10 2% neem extract; n = 10 green tea extract; n = 10 0.2% chlorhexidine 18–25 years old, generally healthy, diagnosed with mild to moderate gingivitis, minimum of 20 teeth, no antibiotics in the last 6 months 21 days 700 ml 2% neem extract; 0.5% green tea extract; 500 ml 0.2% chlorexidine 0.5% tea showed better effectiveness (P < 0.05) followed by 2% neem and then 0.2% chlorhexidine mouthwash. Batista et al. (2014) Brazil Punica granatum (pomegranate) & Matricaria recutita (chamomile) mouthwash with single herb extract Evaluation of chamomile and pomegranate mouthwashes Randomised controlled clinical trial n = 55 divided randomly into 3 groups: n = 19 chamomile extract; n = 18 pomegranate extract; n = 18 0.12% chlorhexidine mouthwash Over 18 years old, patients with periodontal disease, but no periodontal treatment or antibiotics for at least 3 months 9 months not available Pomegranate and chamomile mouthwash were as effective as chlorhexidine 0.12% (P < 0.001) Bedi et al. (2011) India Azadirachta indica (neem) herbal extract Evaluation of neem extract for subgingival irrigation Randomised controlled clinical trial n = 20: n = 10 subgingival irrigation with neem extract plus scaling and root planing; n = 10 scaling and root planing 30–55 years old, chronic generalised periodontitis with probing pocket depth of 5 mm 30 days not available Neem extract showed significant (P < 0.05) improvement on gingival index, clinical attachment level, reduction of pocket depth and aspartate transaminase levels – thus better results than using mechanical debridement alone Bhat et al. (2011) India Aloe vera gel evaluation of the efficacy of injecting Aloe vera into periodontal pocket Randomised controlled clinical trial n = 15 20–35 years old, generally healthy with moderate periodontitis, no antibiotics or periodontal treatment in past 6 months, probing depth of 5 mm plus bleeding on probing 3 months not available Significant decrease (P < 0.05) in pocket depth and relative decrease in gingival and plaque indexes at 1 month and 3 months Chandrahas et al. (2012) India Aloe vera mouthwash evaluation of Aloe vera mouthwash on plaque reduction comparing to 0.2% chlorhexidine Randomised controlled double blind clinical study n = 120 persons; both sexes; aged 18–25 years randomly divided into 3 groups: G1 −100% Aloe vera; G2-placebo/distilled water; G3 − 0.2% chlorhexidine gingivitis or mild periodontitis, generally healthy, at least 1 maxillary quadrant full with premolars and molars, no pocket depth greater than 3 mm, no recent antibiotic use, no history of systemic diseases 14 days induction phase, 22 days intervention phase 10 ml twice daily for a minute Significant (P < 0.05) reduction in plaque index and gingivial index and effect comparable to chlorhexidine Farjana et al. (2014) India Curcuma longa (turmeric) Curcumin extract oral gel Evaluation of curcumin on bleeding index, bleeding on probing Pilot clinical study n = 10 severe gingivitis 21 days applied herbal gel twice a day for 3 weeks after brushing and leave gel in mouth for at least 10 min before rinsing Curcumin gel reduced bleeding on probing (P < 0.001) Grbic et al. (2011) USA Centella asiatica (gotu cola); Echinacea purpurea; Sambucus nigra (elderberry) transmucosal herbal patch evaluation of the efficacy of using transmucosal herbal patch with polyherbal extracts in treatment of gingivitis Randomised double blind controlled trial n = 53: herbal transmucosal patch and placebo patch 18 to 65 years old, at least 3 posterior teeth in both maxillary quadrants, no hormonal treatment, no antibiotics, no anti-inflammatory therapy, no systemic conditions 15 days not available Gingival index was significantly (P < 0.009) decreased in persons using the herbal patch; an effective and safe agent for reducing topical gingival inflammation Gupta and Jain (2015) India Cinnamomum verum (cinnamon) herbal extract Evaluation of cinnamon extract on plaque and gingival health Triple blind randomised controlled clinical trial n = 105: n = 35 cinnamon; n = 35 chlorhexidine; n = 35 distilled water 4 weeks not available Chlorhexidine reduced PI and GI more than cinnamon, but this was not statistically significant Gupta et al. (2015) India Terminalia chebula (chebulic myrobalan) herbal extract mouthwash Evaluation of Terminalia chebula on plaque and gingival inflammation Double-blind randomised control trial n = 90: n = 30 terminalia chebula mouthwash; n = 30 0.2% chlorhexidine; n = 30 distilled water undergraduate students 30 days not available Terminalia is as effective as chlorhexidine (P < 0.05) at BI and PI reduction at 15 and 30 days vs placebo Gupta et al. (2014) India Ocimum sanctum (holy basil) mouthwash Evaluation of the effectiveness of a mouthwash with holy basil extrats against chlorhexidine 0.12% Randomised triple blind controlled clinical trial n = 108: n = 36 holy basil 4% mouthwash; n = 36 0.12% chlorhexidine mouthwash; n = 36 placebo mouthwash generally healthy individuals, mild to moderate gingivitis, no antibiotic or anti-inflammatory therapy history for past 3 months, no systemic diseases 30 days 10 ml twice a day of Ocimum sanctum for 30 days Ocimum santcum mouthwash prevented plaque as well as 0.12% clorehexidine (P < 0.059) Gupta et al. (2014) India Aloe vera mouthwash Evaluation of Aloe vera mouthwash for dental plaque reduction Randomised double blind controlled clinical trial n = 300: n = 100 Aloe vera mouthwash; n = 100 chlorhexidine mouthwash; n = 100 saline/placebo generally healthy wth gingivitis, no antibiotic therapy for past 2 weeks 4 days 10 ml twice a day Aloe vera 100% juice used as a mouthwash Aloe vera mouthwash (100% juice) was as effective as chlorhexidine Jenabian et al. (2012) Iran Camellia sinensis (green tea) mouthwash Evaluation of green tea extract mouthwash in treatment of gingivitis Randomised single-blind controlled clinical trial 50 high school students aged 14–16 years old were randomly divided into 2 groups: G1 n = 25 green tea 5% mouthwash; G2 n = 25 saline/placebo generally healthy, but with gingivitis 6 weeks 5 ml Camellia sinensis extract twice a day A herbal mouthwash with Camellia sinensis showed reduction in gingival index and inflammation Karim et al. (2014) India Aloe vera mouthwash Evaluation of Aloe vera mouthwash for reduction of dental plaque and gingival index Randomisex tripple-blind control clinical trial 345 persons were randomply divided into 3 groups: G1 = Aloe vera mouthwash (n = 115); G2 = chlorhexidine (n = 115); G3 = placebo/distilled water (n = 115) generally healthy with signs of gingivitis included, but exluded if had dental treatment, antibiotic or anti-inflammatory therapy in the last 3 month, if have systemic diseases and if smoke. 30 days 10 ml twice a day for 1 min and not to rinse with water afterwards Aloe vera mouthwash showed equally effective results to that of chlorhexidine mouthwash in reducing gingivial, bleeding and plaque indixes Mahyari et al. (2016) Iran Zingiber officinalis (ginger); Rosmarinus officinalis (rosemary); Calendula officinalis (marigold) polyherbal mouthwash Evaluation of the effectiveness of a polyherbal mouthwash with ginger, rosemary and marigold (5%) extracts Randomised double blind controlled trial 60 persons aged 18–65 were randomly divided into 3 groups: G1 n = 20 polyherbal mouthwash; G2 n = 20 chlorhexidine mouthwash; G3 n = 20 placebo generally healthy with gingivitis, but not on antibiotic or anti-inflammatory therapy for the past 14 days, not pregnant and with no Sjogren's syndrome 14 days twice a day Polyherbal mouthwash was found to be as effective as chlorhexidine but with no side effects Naiktari et al. (2014) India Triphala Amalaki (Phyllanthus emblica, aka Emblica officinalis), Haritaki (Terminalia chebula) and Bahera (Terminalia bellirica) herbal mouthwash Evaluation of Phyllanthus emblica, Terminalis chebula and Terminalis bellirica Double-blind randomized multi-centre clinical trial n = 120: n = 40 triphala; n = 40 0.2% chlorhexidine; n = 40 distilled water hospitalised patients with periodontal disease 15 days mouthwash 1 min twice daily for 2 weeks No significant difference between triphala and chlorhexidine (P < 0.05). But both PI and GI had a significant reduction compared with distilled water. Radvar et al. (2016) Iran Salix alba, Malva sylvestrais and Althaea officinalis polyherbal mouthwash Evaluation of Salix alba, Malva sylvestrais and Althaea officinalis on periodontitis and gingivitis Randomised clinical trial n = 30 periodontitis study, after 6 weeks of scaling and root planing: n = 10 herbal mouthwash; n = 10 chlorhexidine; n = 10 placebo mouthwash; gingivitis study n = 34: same groups as periodontitis study chronic periodontitis patients with pocketing and attachment loss in all quadrants, all over 45 years old; gingivitis patients with signs of gum inflammation but no attachment loss or bone recession periodontitis study: 4 weeks. gingivitis study: 2 weeks 100% ethanol extracts of 5 parts A. officinalis: 1.25 parts S. alba: 1 part M. sylvestris, dried and diluted 5% weight/volume to 0.31% g in 2 ml H2O herbal mouthwash and root planing reduced periodontitis indices more than root planing alone, but this reduction was not statistically significant. For gingivitis patients, herbal mouthwash significantly reduced BOP and GI, by same level as chlorhexidine. There was tooth and tongue staining with chlorhexidine Rassameemasmaung et al. (2008) Thailand Garcinia mangostana (purple mangosteen) gel Evaluation of the effectiveness of purple mangosteen gel applied topically Randomised double blind pilot study n = 31; n = 16 herbal gel plus scaling and root planing; n = 15 only scaling and root planing otherwise healthy, at least 2 periodontal pockets of 7–9 mm, but 5–6 mm for rest, no antibiotics in 3 months, no periodontal treatment in 6 months 3 months not available Test group had greater reduction in periodontal pocket depth, gingival and bleeding indices, but both groups had good results (P < 0.05) after 3 months of treatment Sharma et al. (2014) India Azadirachta indica (neem), Mangifera indica (mango) Indigenously-prepared neem and mango chewing stick mouthwashes Evaluation of neem and mango on plaque and gingival indices Triple-blind randomised controlled trial n = 105: n = 35 neem; n = 35 mango; n = 35 0.2% chlorhexidine school children aged 12–15 4 months not available Neem possesses equivalent efficacy to chlorhexidine in reducing plaque, whilst chlorhexidine has superior antigingivitis properties Sofrata et al. (2011) Sweden, Saudi Arabia Salvadora persica chewing stick Evaluation of S persica on plaque and gingivitis, subgingival microbiota and GI Double-blind randomised clinical trial n = 68: n = 30 S persica; n = 28 = control over 18 years age, at least 24 teeth, no systemic disease, antibiotics, in last 6 months, no pregnancy 3 weeks not applicable active S persica actively reduced plaque (P = 0.007) Vangipuram et al. (2016) India Aloe vera Aloe vera mouthwash Evaluation of Aloe vera on plaque and gingival indices Randomised controlled trial n-390: n = 130 Aloe vera; n = 130 chlorhexidine; n = 130 placebo dental students 30 days not available No significant difference between Aloe vera and chlorhexidine (P < 0.05) Waghmare et al. (2011) India Curcuma longa (turmeric) herbal mouthwash Evaluation of turmeric in preventing plaque formation and gingivitis unknown n = 100: n = 50 chlorhexidine; n = 50 for herbal mouthwash 25–35 year olds, with fair to poor gingival index scores and plaque index >1 21 days not available chlorhexidine reduces PI better than turmeric mouthwash (P < 0.05), but these had same results for GI and total microbial count Walker et al. (2016) Austria Magnolia officinalis L. bark extract in fortified chewing gum Evaluation of Magnolia officinalis chewing gum in reducing inflammatory response in oral epithelial cells Four-armed parallel designed human intervention trial, with double-blind study for chewing gum intervention n = 40: n = 10 Magnolia bark chewing gum; n = 10 normal chewing gum; n = 10 Colgate toothpaste with 0.3% triclosan; n = 10 control healthy volunteers 14 days chewing two “dragees” of Magnolia bark gum for at least 10 min five times per day Magnolia gum more effective than normal chewing gum at reducing lipopolysaccharide-induced inflammation and oral stress of epithelial cells by 73.4% Yeturu et al. (2016) India Aloe vera unspecified Evaluation of Aloe vera on plaque and gingivitis Single blind randomized single-centre parallel group controlled trial n = 90: n = 30 Aloe vera; n = 30 chlorhexidine; n = 30 chlorine dioxide outpatients from periodontal department under fixed orthodontic treatment 15 days not available Aloe vera reduced PI scores by 20.38% (±16.74) in 14 days, but this was significantly less than (P < 0.05) for chlorhexidine (31.59% (±16.58) or chlorine dioxide; and for GI score at 9.88% reduction (±8.77) significantly less than for chlorhexidine at 16.3% (±9.98) Appendix B. Supplementary data The following is Supplementary data to this article: Download spreadsheet (19KB) Help with xlsx files References Aarabi et al., 2015 G. Aarabi, J. Eberhard, D.R. Reissmann, G. Heydecke, U. Seedorf Interaction between periodontal disease and atherosclerotic vascular disease – fact or fiction? 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