J Jebdp 2020 101470

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A scoping review on arginine in caries prevention
Mohammed Nadeem Bijle, BDS, MDS, Manikandan Ekambaram, BDS, MDS, PhD,
Cynthia Kar Yung Yiu, BDS, MDS, PhD
PII: S1532-3382(20)30118-4
DOI: https://doi.org/10.1016/j.jebdp.2020.101470
Reference: YMED 101470
To appear in: The Journal of Evidence-Based Dental Practice
Received Date: 12 December 2019

Revised Date: 4 May 2020
Accepted Date: 20 June 2020
Please cite this article as: Bijle MN, Ekambaram M, Yung Yiu CK, A scoping review on arginine in
caries prevention, The Journal of Evidence-Based Dental Practice (2020), doi: https://doi.org/10.1016/
j.jebdp.2020.101470.
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1 Title Page
2 Title of the manuscript: A scoping review on arginine in caries prevention
3 Running Title: Arginine in caries prevention.
4 Authors: Mohammed Nadeem Bijle1 (Bijle MN), Manikandan Ekambaram2 (Ekambaram M), Cynthia
5 Kar Yung Yiu3 (Yiu CKY)
6 Qualifications
1
7 BDS, MDS
2, 3
8 BDS, MDS, PhD
9 Affiliations
1
10 PhD Candidate, Pediatric Dentistry and Orthodontics, Faculty of Dentistry, The University of Hong
11 Kong. Email: mnbijle@connect.hku.hk
2
12 Senior Lecturer, Paediatric Dentistry, Faculty of Dentistry, University of Otago, Dunedin, New Zealand.
13 Email: mani.ekambaram@otago.ac.nz
3
14 Clinical Professor, Pediatric Dentistry and Orthodontics, Faculty of Dentistry, The University of Hong
15 Kong. Email: ckyyiu@hkucc.hku.hk
16
17 Corresponding author, address and contact details: Professor Cynthia Yiu, Division of Pediatric
18 Dentistry and Orthodontics, Faculty of Dentistry, The University of Hong Kong, 34 Hospital Road, Sai
19 Ying Pun, Hong Kong SAR, China. Email: ckyyiu@hkucc.hku.hk
20
21 Competing Interests: None
22 Conflicts of Interests: None
23 Declaration of Interests: None
24 Source of Funding: Declared
25
26 Total No. of Figures: 2
27
28 Total No. of Tables: 5
29
30 Supplemental File: 1 (2 Tables including PRISMA-ScR checklist)
31
32
33
34
1
1 Abstract Page
2 A scoping review on arginine in caries prevention
3 Abstract
4 Background: Emerging science on arginine/arginine formulations has driven the need to examine the
5 research in the field.
6 Objectives: The scoping study objectives were - 1) to identify the extent, range, and type of evidence on
7 the role of arginine/arginine formulations in caries prevention; and 2) to explore the future scope of
8 research on arginine-containing caries-preventive agents.
9 Methods: A systematic search was performed using PubMed, Scopus, and Web of Science. In vitro
10 studies, clinical trials, narrative reviews, systematic reviews and/or meta-analysis, and umbrella
11 reviews/meta-evaluation examining arginine/arginine formulations for caries prevention were included.
12 Data charting process involved extracting variables followed by evidence synthesis. Arginine variants
13 investigated up to date were discussed to explore future scope of research.
14 Results: Thirty-nine articles were included for review from 105 identified citations comprising of in vitro
15 studies, clinical trials, and reviews. Majority of articles studied 1.5% arginine-fluoride toothpaste. Most
16 studies were from Asia followed by North America; with fewest studies in Europe and South America.
17 Arginine/arginine formulations demonstrated a superior caries-preventive effect compared to their
18 matched controls (including fluorides); however, the evidence is with high risk of bias. Until now, three
19 arginine variants have been investigated with L-arginine monohydrochloride as the least explored variant.
20 Conclusions: The evidence on the caries-preventive effect of arginine/arginine formulations has a high
21 risk of bias. High-quality clinical trials are needed to assess the caries-preventive potential of arginine in
22 commercial formulations. The role of L-arginine monohydrochloride in caries prevention can further be
23 explored by incorporating in self- and professionally applied caries preventive agents.
24
25 Keywords: arginine, caries, prevention, review.
26
27
2
1 A scoping review on arginine in caries prevention
2 1. Introduction
3 Prevention of dental caries remains a major challenge to high-risk patients as untreated carious lesions is
4 the most prevalent oral condition worldwide.1 Although fluoride is the known standard of care for caries
5 prevention, its effect on oral biofilms is limited.2 Several ecological-based caries-preventive approaches3
6 have been developed to supplement the actions of fluorides.4 The role of anti-microbial agents to control
7 infections and dental caries is well known.3 However, the use of anti-microbials like chlorhexidine might
8 alter the composition of the oral microflora by indiscriminate bacterial destruction and allow other
9 bacteria that are resistant to anti-microbials to flourish.
10
11 Lately, research evidence suggests the use of certain microorganisms (in an appropriate therapeutic form
12 and dosage) identified as probiotics to promote oral health.5 Nonetheless, the intake of probiotics only
13 leads to a temporary colonization of the oral environment.6,7 Conversely, an ecological-based caries-
14 preventive approach utilizing prebiotics has a beneficial effect on optimizing the metabolism of certain
15 oral bacteria with healthy by-product outputs.8 Prebiotics are “non-digestible food ingredients that
16 beneficially affects the host by selectively stimulating the growth of health promoting-bacteria”.9 The
17 prebiotic means of using arginine in caries management has become an area of research interest recently.
18 Several studies have regarded the arginine-based prebiotic measures as an effective anti-caries approach
19 when compared to fluorides alone.10,11
20
21 Arginine is a semi-essential amino acid available as salivary substrates owing to dietary protein
22 metabolism.12–15 Arginine is metabolized by the arginolytic bacteria, Streptococcus sanguinis,
23 Streptococcus parasanguinis and Streptococcus gordonii via the Arginine Deiminase System (ADS) to
24 ornithine, citrulline, ammonia, CO2, and ATP, which modulates the cariogenic biofilms via alkali
25 production.16,17 Arginine promotes the enamel fluoride uptake into demineralized enamel lesions by
26 enhanced fluoride absorption18–20, synergistically inhibits S. mutans (cariogenic bacteria) and enriches S.
3
1 sanguinis (alkalogenic bacteria) with fluorides.21 Unlike urea, arginine supplementation substantiates the
2 arginolytic potential of ADS-positive bacteria to increase alkali production.22
4 The caries-preventive effect of arginine/arginine formulations has been evaluated in several in vitro
5 studies and randomized clinical trials23,24, which were further assessed in systematic reviews, meta-
6 analysis and extended umbrella reviews.25–27 There are some experimental arginine products which are
7 still in their pre-clinical stages of investigations.28 There is a wide range of evidence available on the
8 caries-preventive effects of different arginine formulations. The emerging science on arginine and
9 arginine formulations has driven the need to examine and update the extent of research in the field. A
10 scoping review rapidly maps literature in a systematic method to address the broader range of studies,
11 where many studies of different designs can be included for review without emphasizing the need for
12 quality assessment.29 Such review further provides channels for appraising or generating evidence. Thus,
13 the objectives of this scoping review were – 1) to identify the extent, range and type of evidence on the
14 role of arginine/arginine formulations in caries prevention; and 2) to explore future scope of research on
15 arginine-containing caries-preventive agents.
16
17 2. Methods
18 The present study is performed as per PRISMA Extension for Scoping reviews (PRISMA-ScR) and a
19 seminal paper on scoping review methodology.29,30 Further guidance on the methodology and reporting
20 was sought from a Joanna Briggs Institute paper.31
21
22 2.1 Protocol & registration
23 A priori study protocol was drafted using PRISMA-ScR guidelines that included the proposed review
24 objectives, eligibility criteria, preliminary search strategy, data charting and synthesizing methods. The
25 final draft of the protocol was approved by all reviewers and then registered on Open Science Framework
26 for access with link – https://osf.io/9qvpn/.

4
1
2 2.2 Data Sources & Resources Selection
3 2.2.1 Eligibility criteria
4 For inclusion in the review, articles (irrespective of the study designs) examining the effect of arginine or
5 arginine formulations on caries prevention were eligible. Peer-reviewed papers, written in English, and
6 following the strategy – Population-(any)-concept-(arginine)-context-(caries prevention) as base-map
7 were deemed eligible. The study protocol did not demand any specific primary/secondary outcome
8 measure for review. The inclusion criteria for the review were as follows:
10 Inclusion Criteria: In vitro studies, clinical trials (including in situ studies), systematic reviews
11 with/without meta-analysis, umbrella reviews/meta-evaluation, and narrative reviews.
12
13 Exclusion Criteria: Studies with no keywords for specific components, observational studies identifying
14 the potential of arginine as a caries risk assessment method, non-specific keywords-based reviews,
15 commentaries, opinions, and articles in language other than English. Articles on potential uses of
16 arginine-based formulations as desensitizing agents or any other applications (apart from caries
17 prevention) were not included in the review process.
18
19 2.2.2 Information sources
20 To identify articles for inclusion in the review; PubMed, Scopus, and Web of Science databases were
21 searched with a refined targeted strategy developed after multiple iterations until 31 March 2019. The
22 database search was supplemented with an additional resources search – google search (using keywords
23 for specific interventions – toothpaste/paste, mouth rinse, varnish, and confection), reference search of the
24 selected articles, print journals not indexed in databases, and experience/internal expert opinion (CKY).
25
26 2.2.3. Search strategy
5
1 The basic map generalizing strategy was Intervention (concept)–CROSS–Outcome (context) that was
2 further supplemented with a Boolean operator - “AND”. The refined search strategy was keyword
3 dependent connected with operators – (arginine) AND (caries) AND (prevention). The final detailed
4 search strategy for PubMed is available in Table S1.
5 Combining primarily devised eligibility criteria, information sources and search strategy, two independent
6 reviewers (MNB and ME) screened potentially relevant articles for inclusion and performed data charting
7 process followed by synthesis. Any disagreements were resolved with mutual consensus and/or discussed
8 with an expert in the field (CKY).
10 2.3 Data charting and synthesis
11 A pre-piloted data charting form approved by all the reviewers at the protocol drafting stage determined
12 the variables to extract (https://osf.io/9qvpn/). Data were charted for all included articles where the
13 variables were - author (year), location, participants & study duration (if applicable), intervention,
14 commercial product (if any), control/comparator, and derived conclusions as applicable to respective
15 study designs. The process was further matched and results were summarized as per consensus between
16 all the reviewers. The data synthesis process specifically meant for commercial interventions included
17 abstracting the data per intervention to draw summarized conclusions. As an additional step, up to date
18 investigated arginine variants were discussed to explore future scope for research.
19
20 Results
21 3.1 Evidence sources selection
22 A detailed overview of evidence sources selection is presented in Figure 1 following PRISMA flow for
23 study selection and PRISMA-ScR checklist (Table S2). A composite of 105 citations were identified
24 from information resources, of which 30 were duplicates. Seventy-five titles and abstracts were screened
25 to match eligibility for study inclusion. When in doubt, full-text of the articles was retrieved to confirm
6
1 study characteristics for inclusion in the review process. After excluding 36 articles, 39 were finally
2 eligible and included for review per agreement of all reviewers as percent proportion of 1.
4 3.2 Evidence characteristics
5 The characteristics of evidence included in the review are presented in Tables 1, 2, 3 and 4. Ten in vitro
6 studies18,28,32–39 (Table 1), 18 clinical trials10,11,23,24,40–53 (Table 2), 4 systematic reviews and/or meta-
7 analysis25,27,54,55 (Table 4), 1 umbrella review/meta-evaluation26 (Table 4), and 6 narrative reviews56–61
8 (Table 3) examined the caries-preventive effect of L-arginine33,36,38,39, L-arginine monohydrochloride34
9 (L-Arg.HCl), arginine sugarless confection25,41,55, arginine bicarbonate mouth rinse50,52, arginine non-
10 fluoridated toothpaste40, 1.5% arginine-fluoride/fluoride-free toothpaste10,23–27,37,43–46,48,49,53,54,56–60, 1.5%
11 arginine-zinc-fluoride toothpaste61, 8% arginine-fluoride toothpaste11,32,35,42,51, L-Arg.HCl in NaF
12 toothpaste18, L-arginine adhesive28, and arginine varnish47.
13
14 Majority of the articles10,23–27,37,43,45,46,48,49,53,54,56–60 (19) studied 1.5% arginine-fluoride toothpaste; whereas
15 only a single study each investigated L-Arg.HCl34, L-Arg.HCl in NaF toothpaste18, L-arginine adhesive28,
16 arginine non-fluoride toothpaste40, arginine varnish47, and 1.5% arginine-zinc-fluoride toothpaste61. Most
17 studies (20) were from Asia – (Japan36, China10,23–25,32,35,42,48,50–53, Hong Kong SAR18,26, Thailand43,45,49,
18 India60, and Israel47), followed by North America28,33,34,37,38,44,56–59,61 (11); whereas Europe (4) -
19 (Netherlands11,32, Germany54, and Sweden27), and South America (4) – (Brazil46,48 and Venezuela40,41) had
20 the fewest studies.
21
22 3.3 Interventions
23 3.3.1 In vitro studies
24 a) L-arginine
25 The caries preventive effect of L-arginine was evaluated in four in vitro studies33,36,38,39. The conclusions
26 of the two studies38,39 were, L-arginine was effective in maintaining the healthy oral biofilms by
27 improving pH homeostasis through remodeling of the oral microbial community; of which one study39
7
1 highlighted that L-arginine reduced biofilm biomass and water-insoluble exopolymeric substances (EPS)
2 production in biofilm matrix. Researchers33 concluded that L-arginine affected the substrate adhesion
3 properties of S. mutans; whereas other researchers36 concluded that the intervention destabilized mature
4 oral biofilms. The results of these in vitro studies show that L-arginine is potentially capable of reversing
5 the biofilm shift from dysbiosis to non-pathological state by modulating the microbial community (Table
6 1).
8 b) L-arginine monohydrochloride
9 In one study34 the effect of pH neutralized L-Arg.HCl on multi-species biofilm in an open biofilm model
10 was investigated. It was concluded that L-Arg.HCl moderated multi-species oral biofilm development by
11 destabilizing biofilm in a concentration-dependent manner and enhanced the antimicrobial activity of
12 cetylpyridinium chloride. The study further recommended incorporation of the variant in oral health care
13 products for enhanced biofilm control (Table 1).
14
15 c) Arginine-fluoride toothpaste
16 i. 1.5% Arginine-fluoride toothpaste
17 Colgate Maximum Cavity Protection PLUS Sugar Acid Neutralizer™ toothpaste contains 1.5% arginine,
18 insoluble calcium base and 1450-ppm NaMFP. The proposed mechanism of action was that the addition
19 of arginine to fluoride toothpaste would target dental plaque biofilm by utilizing ADS to prevent the
20 initiation of caries process.62 An in vitro study37 evaluating the formulation (bannered as Elmex caries
21 professional) suggested that the fluoride uptake potential of 1.5% arginine-fluoride toothpaste was
22 significantly lower than the combined 1500 ppm NaF and 1000 ppm NaMFP toothpaste (Table 1).
23
24 ii. 8% Arginine-fluoride toothpaste
25 The 8% arginine-fluoride dentifrice (Colgate Sensitive Pro-Relief™ Toothpaste) comprising of 8%
26 arginine bicarbonate, calcium carbonate and 1450 ppm NaMFP was introduced as a relieving agent for
27 dentin hypersensitivity. Few studies have evaluated its anti-caries efficacy11,32,35,42,51. In an in vitro study35
8
1 evaluating the remineralization effect of different toothpastes containing bioactive elements using micro-
2 hardness assessment, polarized light and confocal laser scanning microscopy showed that 8% arginine-
3 fluoride toothpaste had better remineralization potential than casein phosphopeptide-amorphous calcium
4 phosphate. Similarly, another in vitro study32 concluded that the remineralization potential of the arginine
5 toothpaste was significantly greater than casein phosphopeptide-amorphous calcium phosphate mousse
6 and 1400 ppm NaF solution (Table 1).
8 iii. L-arginine monohydrochloride in NaF toothpaste
9 An in vitro study18 examined the remineralization effect of 2%, 4%, and 8% L-Arg.HCl in a 1100-ppm
10 NaF toothpaste using a 10-day pH cycling model. The 2% L-Arg.HCl in 1100-ppm NaF commercially
11 available toothpaste has been shown to modify its properties possibly due to its interaction with fluoride
12 for effective caries preventive benefit. The authors of the study concluded that the incorporation of 2% L-
13 Arg.HCl in NaF toothpaste might provide a synergistic anti-caries effect given the proven prebiotic
14 benefits of arginine and the demonstrated remineralization effect with micro-CT and increased fluoride
15 uptake. The formulation is not yet commercially available (Table 1).
16
17 d) L-arginine adhesive
18 Arginine (5%, 7%, and 10%) has been incorporated in a two-step etch-and-rinse adhesive for secondary
19 caries prevention, which is deficient in current adhesives. The primer and adhesive comprised of
20 methacrylate and di-methacrylate monomers, ethanol, photo-initiators with L-arginine in a weight
21 concentration of 5%, 7%, and 10%. The authors of the study reported that the incorporation of 7% L-
22 arginine in adhesives did not alter its existing mechanical properties but exhibited profound antibacterial
23 effects; however, the formulation is not yet commercially available (Table 1).28
24
25 3.3.2 Clinical trials and reviews
26 a) Arginine sugarless confection
9
1 CaviStat® (Ortek Therapeutics, Inc., Roslyn, NY, USA) - an arginine bicarbonate-calcium carbonate
2 complex added to a sugarless mint confection was introduced as BasicMints® to the market. Primarily,
3 arginine in the CaviStat® was intended to counter the cariogenic pH fall and calcium to increase the
4 saturation at the tooth surface with respect to the tooth mineral with the bicarbonate/carbonate favoring
5 neutralization. A double-blind randomized controlled clinical trial performed on 195 Venezuelan children
6 aged 10.5 – 11 years demonstrated that children who used BasicMints® (4 mints a day) had 52.4% fewer
7 non-cavitated caries lesions in the first permanent molars; with fewer carious lesions in primary molars
8 and some early erupting premolars as compared to the children who received a sugarless mint control at
9 12-month follow-up.41 Although, the study was comprehensively performed, a longer follow-up period
10 would provide better insights. In addition, the use of BasicMints® 4 times/day might limit the expected
11 compliance of the patients (Table 2).
12
13 b) Arginine bicarbonate mouthrinse
14 An in vivo study was performed to analyze the pH neutralising effect (using pH telemetry) of arginine
15 bicarbonate (0.5%, 1%, and 2%) mouth rinse during a sucrose challenge.50 It was observed that arginine
16 bicarbonate mouth rinse was able to sustainably maintain the plaque pH above 5.7. The study highlights
17 the ability of the mouthrinse to neutralize pH was due to the base formation of arginine rather than
18 bicarbonate. However, the bicarbonate component may facilitate the effect of arginine, since it provides a
19 favorable environment for arginine metabolism by oral arginolytic bacteria. The authors of the study
20 suggest that the arginine bicarbonate (0.5 – 2%) mouthrinse can be a potential caries-preventive agent,
21 especially for high-risk patients following carbohydrate consumption. The supplementation can lead to
22 modification of microflora, promoting more resistant microenvironment for acidogenic and aciduric
23 bacteria. However, the results of this study50 need to be interpreted with caution, since the number of
24 participated subjects were only 6; whereby concerns on external validity arises.
25 Another in situ double-blind randomized cross-over study52 on 14 adults (age: 42-77 years) evaluated the
26 caries-preventive potential of 2% arginine bicarbonate mouth rinse against 1% urea and/or 0.05% NaF
27 solution using quantitative light-induced fluorescence. The study concluded that arginine rinsing provided
10
1 limited remineralization benefit over a period of 4 weeks. Hence, the results of both clinical trials on the
2 use of arginine bicarbonate mouth rinse are conflicting and warrants further studies with appropriate
3 sample size to provide better insights. Until now, arginine bicarbonate rinse is not yet commercially
4 available (Table 2).
6 c) Arginine non-fluoridated toothpaste
7 CaviStat® -containing dentifrice was proposed to have a three-fold working principle on the basis of their
8 active components. Primarily, arginine in the dentifrice would counter the pH fall due to acid production
9 in the caries process. Secondly, the calcium within the complex will increase the saturation at the tooth
10 surface with respect to the tooth mineral. Lastly, the bicarbonate and carbonate components would favor
11 neutralization of acid produced and maintain the pH for base formation with arginine. Therefore,
12 combining all the effects of the CaviStat® toothpaste, use of the toothpaste results in an increased
13 alkalogenic microflora, thereby preventing carious lesion formation. A clinical trial was undertaken to
14 compare the caries-preventive effect of CaviStat® (arginine bicarbonate-calcium carbonate complex)-
15 containing toothpaste to a 1100 ppm fluoride toothpaste on carious lesion development in 10 to 11-year-
16 old Venezuelan children with a two-year follow-up using DMFS scores.40 The authors concluded that the
17 test toothpaste had a significant inhibitory effect on the development and progression of the carious
18 lesions as compared to the control. The trial follow-up period was long enough to conclude the possible
19 effect as ascertained in the study (Table 2).
20
21 d) Arginine-fluoride toothpaste
22 a. 1.5% Arginine-fluoride/fluoride-free toothpaste
23 One clinical trial conducted with 1.5% arginine fluoride-free toothpaste44 showed a shift in bacterial
24 composition to a healthier community similar to caries-free individuals (Table 2).44
25
26 Several clinical trials (Table 2)10,23,24,43–46,48,49,53 and systematic reviews (Table 4)25,27,54 identified superior
27 caries-preventive efficacy of arginine-fluoride dentifrices as compared to matched control fluoride
11
1 dentifrices. However, the level of evidence was downgraded because of the risks of bias and potential
2 publication bias.25,27 All narrative reviews (Table 3)56–60 concluded that the 1.5% arginine-fluoride
3 dentifrices have a clear potential to significantly enhance the caries-preventive potential of toothpaste
4 with F alone; however, a reviewer57 emphasized that final recommendations for arginine should be made
5 after results have been confirmed in high-quality, long-term and potentially less biased randomized
6 clinical trials.
8 Two clinical trials48,53 evaluated the effect of 1.5% arginine-fluoride toothpaste on root caries suggested
9 that the formulation provided a greater anti-caries benefit than fluoride toothpaste on primary root carious
10 lesions. A 6-month clinical trial48 conducted on 253 subjects in Brazil evaluated the effect of 1.5%
11 arginine-fluoride toothpaste on the management of primary root carious lesions as compared to 1450 ppm
12 NaMFP. The lesions were evaluated based on plaque index (the amount of plaque covering the lesion),
13 lesion dimensions (height, width, and distance from gingival margin) and lesion hardness. The researchers
14 showed that there was a statistically significant improvement in primary root carious lesions of
15 individuals using 1.5% arginine-fluoride toothpaste (70.5%) as compared to the control group (58.1%).
16 Another clinical trial53 conducted on 412 adults aged 50-70 years in China for 6 months suggested that the
17 formulation provides a greater anti-caries benefit than fluoride toothpaste on primary root carious lesions.
18
19 The remaining primary studies10,23,24,43–46,49 were on coronal caries. One in situ parallel single-blinded
20 split-mouth study46 as opposed to other primary studies concluded that arginine-fluoride dentifrices had
21 similar anti-caries effect as regular fluoride dentifrices (Table 2). Therefore, it appears that majority of
22 the studies demonstrated a superior caries-preventive effect of 1.5% arginine-fluoride toothpaste;
23 however, the evidence appraised had concerns of potential risk of bias.
24
25
26 b. 1.5% Arginine-zinc-fluoride toothpaste
12
1 A narrative review61 (Table 3) exploring the newly introduced 1.5% arginine-zinc-fluoride (1450-ppm
2 NaF) toothpaste highlighted its potential benefits on oral health, due to arginine-fluoride synergism
3 resulting in better caries prevention. The product is now marketed as Colgate Total Whole Mouth Health,
4 Dual Zinc plus arginine-fluoride toothpaste promoting the advantageous effects of zinc (0.96% zinc oxide
5 and zinc citrate) in boosting the immune system. The authors of the review paper introduced several
6 studies63–66 on the comprehensive Whole Mouth Health technology showing an effect in reducing oral
7 bacterial concentrations, dental plaque, and intra-oral halitosis.
10 c. 8% Arginine-fluoride toothpaste
11 An eight-week pilot clinical trial11 on 9 healthy individuals using meta-genomic sequencing concluded
12 that the use of arginine dentifrice affected sucrose metabolism, leading to a health-promoting microbiome
13 shift. Another in situ study51 on 12 adults over 6 weeks in Chengdu, China showed that the arginine-
14 containing toothpaste significantly reduced lactic acid production and biofilm biomass by around 50%
15 compared to 1450 ppm NaF toothpaste. A clinical trial42 conducted in Chengdu, China evaluated 42
16 individuals over 4 weeks concluded that the dentifrice maintained healthy oral microbial equilibrium
17 compared to 1450 ppm NaF toothpaste. However, concerns have been raised on the use of higher
18 concentrations of arginine for promoting the overgrowth of oral anaerobes Porphyromonas gingivalis
19 within the alkalized plaque (Table 2).21
20
21 e) Arginine varnish
22 A customized arginine-based sustained-release varnish was prepared by embedding 3% arginine in
23 adjusted ethyl cellulose polymer matrix, which produced a self-degradable thin film on teeth. An 8-week
24 pilot placebo-controlled clinical trial comparing the effectiveness of arginine varnish to matched placebo
25 in 34 mentally disabled patients (age: 18-45 years in Jerusalem) revealed significant reductions in S.
26 mutans count in the experimental group.47 The varnish was applied daily/8 weeks on buccal and lingual
27 surfaces of all teeth, and bacterial samples from selected teeth were collected at week 1 and week 5. The
13
1 study researchers suggested that the use of arginine varnish might serve as an important adjunct for oral
2 hygiene measures in high-risk patients (Table 1).
4 3.4. Evidence Synthesis
5 Evidence with relative number of study designs was synthesized for interventions with commercial
6 formulations as highlighted in Table 5. For 1.5% arginine-fluoride toothpaste10,23–27,37,43,45,46,48,49,53,54,56–60
7 the synthesis revealed that the toothpaste has a superior caries-preventive effect when compared to their
8 matched controls (including fluorides), but the evidence is with high risk of bias. The evidence
9 synthesized for 8% arginine-fluoride dentifrice11,35,39,42,51 identified that the formulation provides a
10 superior caries-preventive effect with a potential to maintain healthy oral microbiome; however, the
11 recent evidence11,42,51 needs further appraisal for conclusive recommendations. The 1.5% arginine-zinc-
12 fluoride toothpaste61 and arginine non-fluoridated toothpaste40 were deemed to have insufficient evidence
13 (due to limited information) for synthesized conclusion. On the contrary, arginine sugarless
14 confections25,55 were identified as superior to the control for caries prevention but the evidence is with
15 high risk of bias.
16
17 3.5. Arginine variants and scope for research
18 Arginine-fluoride has demonstrated an evident synergism for caries prevention. So far, L-
19 arginine10,28(Figure 2a), L-Arg.HCl20,21(Figure 2b), and arginine bicarbonate32(Figure 2c) are the
20 variants investigated. Until now, there are only 2 in vitro studies on L-Arg.HCl marking the variant as the
21 least investigated.18,34 whereby a study18 incorporated the variant in a NaF toothpaste to examine the
22 remineralization potential of the combined arginine and fluoride toothpaste. The potential of L-Arg.HCl
23 remains unexplored in fluoridated self-care products like mouth rinse and professionally deliverable
24 fluoride-containing varnish. Thus, incorporating L-Arg.HCl in such self- and professionally deliverable
25 fluoride containing agents will further explore the caries preventive potential of the variant.
26
27 4. Discussion
14
1 Our review findings of 39 included articles indicated that although majority of the primary studies on
2 arginine and arginine formulations demonstrate its superior caries-preventive effect when compared to the
3 matched controls; the evidence evaluated through systematic reviews for commercial arginine products
4 highlights a concern about the high risk of bias. Furthermore, there is a need to generate evidence from
5 countries in Europe and South America as these continents had the least reported studies on anti-caries
6 effect of arginine.
8 The majority of articles (19) included in the review studied 1.5% arginine-fluoride toothpaste as opposed
9 to other formulations/variants that were discussed in the remaining 20 primary articles. This could be due
10 to the commercial availability of 1.5% arginine-fluoride toothpaste that was primarily launched as a
11 caries- preventive agent. Also, the 1.5% arginine-fluoride toothpaste has been recommended by all56,58–60
12 but one57 narrative review as opposed to the systematic reviews25,27, which lay a caution on the potential
13 risk of bias that shows conflicting results, whereby the results of more vigorous evidence assessed by
14 systematic reviews prevail. The commercial dentifrices currently available for caries prevention are
15 limited to 1.5% arginine-fluoride toothpaste, 8% arginine-fluoride toothpaste, and 1.5% arginine-zinc-
16 fluoride toothpaste as the commercial availability of CaviStat® dentifrices and BasicMints® has now
17 ceased.
18
19 The 1.5% arginine-zinc-fluoride toothpaste has recently been introduced in the market; thus, no
20 synthesized conclusions could be derived on the toothpaste as more robust evidence assessment is needed
21 from the clinical trials discussed by the review included in the present study.61 Similarly, evidence
22 assessment is needed to provide recommendations on the caries-preventive effect of 8% arginine-fluoride
23 toothpaste due to very recent published studies11,42,51, which so far have not been included in existing
24 systematic reviews.25,27
25
15
1 L-arginine bicarbonate mouth rinse is shown to have a pH neutralizing effect50; however, another study
2 concludes that the mouth rinse might provide limited (if any) remineralization effect.52 The conflicting
3 results of the two reported studies directs the need to generate further evidence on the caries-preventive
4 effect of L-arginine bicarbonate mouth rinse. Until now, L-arginine bicarbonate mouth rinse is not
5 available as a commercial product. Foremost, the development of L-arginine bicarbonate mouth rinse is of
6 primary importance following which its caries-preventive effect can be evaluated. The development of the
7 product can be based on the premise that the arginine variant has shown the caries-preventive potential
8 with 8% arginine-fluoride toothpaste which contains arginine bicarbonate.
10 Attempts have been made in the past to investigate the effects of professional application of arginine-
11 based caries-preventive agent47; however, the same is not yet commercialized. A more inclusive ground
12 appears for professionally-delivered arginine combined with fluoride means of caries prevention, enabling
13 long-lasting control for the disease, which eventually enhances the evident effect of fluoride therapy. The
14 incorporation of arginine (irrespective of the variant) in fluoride varnish seems to be a possibility for
15 long-standing professional delivery of arginine as a caries-preventive agent since varnish is known to
16 prolong contact with the tooth. However, such professional or targeted delivery of arginine-fluoride
17 therapy with sustained effect for caries control needs additional steps for standardization and
18 implementation of the technology in the real clinical environment.
19
20 L-arginine monohydrochloride – the least investigated arginine has been examined by 2 studies; one in its
21 salt form34 and the other incorporated in a NaF toothpaste18. The possibility of the HCl component
22 affecting the pH of the formulation might be the main reason for it being the least investigated variant.
23 However, it has recently been shown that the incorporation of 2% L-Arg.HCl in NaF toothpaste
24 demonstrated a superior remineralization effect when compared to the control, thereby refuting the
25 adverse effect of HCl. Since both L-arginine33,36,38,39 and L-Arg.HCl 34 have been shown to modulate oral
16
1 biofilms by improving pH homeostasis; thus, L-Arg.HCl can also be added to self-/professionally
2 deliverable fluoride-containing product for its anti-caries effect.
4 In future, long-term high-quality randomized clinical trials are needed to further confirm the evidence on
5 the caries-preventive effect of the commercially available arginine-containing formulations including
6 those newly introduced in the market. The caries-preventive potential of L-Arg.HCl needs evaluation by
7 incorporating the variant in various self- and professionally-deliverable fluoride containing products.
9 This scoping review clearly represents an illustration of how results of primary studies and narrative
10 reviews can be contrasting to systematic reviews, which include rigorous evidence synthesis. Also, the
11 present review emphasizes the need of undertaking further systematic reviews based on new evidence that
12 has not been included in previous systematic reviews. Furthermore, the present review highlights all
13 potential reasons for conducting the scoping review as per the seminal paper29 i.e. – the review 1)
14 examined the extent, range, and nature of research activity; 2) determined the necessity of undertaking
15 full systematic review; 3) summarized and disseminated available research findings; and 4) identified
16 research gaps on the caries-preventive potential of arginine.
17
18 Although comprehensive, the present review has some limitations. Only articles in English language were
19 included due to the consensual ability of contributors to comprehend the language in common. In
20 addition, the relative weaker evidence from the included in vitro studies as compared to clinical trials
21 impacts the synthesized evidence, thereby generating additional drawbacks. Further, an inherent
22 limitation of the scoping review is non-appraisal of the quality of evidence of the primary research.
23 However, the present review leads us with further platform to critically appraise the evidence quality
24 using a more robust model and generate evidence where needed.
25
26 5. Conclusion
17
1 Within the limitations of the present review, it can be concluded that –
2 1. The evidence on the caries-preventive effect of arginine/arginine formulations is with high risk of
3 bias. Hence, conclusive recommendations on the caries-preventive potential of arginine is
4 unlikely.
5 2. High-quality clinical trials are needed to assess the caries-preventive potential of arginine in
6 commercial formulations.
7 3. The role of L-arginine monohydrochloride in caries prevention can be further explored by
8 incorporating the variant in self- and professionally applied caries preventive agents.
10 Acknowledgements
11 This review article was supported by General Research Fund 17118519. The funders have no role in this
12 study.
13
14 Conflict of interest: The authors declare no conflict of interest.
15
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22
1
2
3
4
5 Legends
6
7 Figures
8 Figure 1: Study search and selection
9 Figure 2: Structure of (a) arginine; (b) L-arginine; (c) L – arginine monohydrochloride; and (d) arginine
10 bicarbonate
11
12 Tables
13 Table 1: In vitro studies on anti-caries effect of arginine formulations
14 Table 2: Clinical trials assessing the anti-caries effect of arginine formulations
15 Table 3: Narrative reviews on arginine formulations
16 Table 4: Systematic reviews and/or meta-analysis, and umbrella reviews/meta-evaluation examining
17 evidence on the anti-caries effect of arginine formulation
18 Table 5: Evidence synthesis of arginine commercial formulations
19
20 Supplemental File
21 Table S1: Final detailed search strategy for PubMed (excluding preliminary sequence).
22 Table S2: PRISMA-ScR Checklist
23
Figures
Figure 1: Study search and selection
24
Figure 2: Structure of (a) L-arginine; (b) L – arginine monohydrochloride; and (c) arginine bicarbonate
25
Tables
Table 1: In vitro studies on anti-caries effect of arginine formulations
Commercial
SN Author (Year) Country/City Intervention Control/Alternative interventions Conclusion
Product
L-arginine
L-arginine affects the substrate
1 Sharma et al. (2014) Los Angeles, USA L-arginine - Glycine adhesion properties of S.
mutans
Acidic L-arginine destabilizes
2 Tada et al. (2016) Kagawa, Japan L-arginine - Saline or Citrate
mature oral biofilms
Arginine improved pH
3 Agnello et al. (2017) California, USA L-arginine - No treatment or sucrose homeostasis by modulating
microbial community
Arginine reduces biofilm
biomass impacting water
Amsterdam,
4 Huang et al. (2017) L-arginine - No treatment insoluble EPS thereby keeping
Netherlands
oral biofilms heathy through
homeostasis
L-arginine monohydrochloride
L-arginine monohydrochloride
moderates multi-species oral
pH neutralized L-
biofilm development by
5 Kolderman et al. (2015) Michigan, USA arginine - Cetylpyridinium chloride
destabilizing biofilm in a
monohydrochloride
concentration-dependent
manner
1.5% Arginine-fluoride toothpaste
The fluoride uptake potential
of arginine-fluoride toothpaste
1.5% Arginine- Elmex caries 1100 - 2500 ppm fluoride dentifrices
6 Moore et al. (2017) Ohio, USA was significantly lower than
fluoride toothpaste professional or placebo
1500 ppm NaF + 1000 ppm
NaMFP toothpaste
8% Arginine-fluoride toothpaste
26
Colgate
Sensitive Pro- 1100 ppm fluoride toothpaste, Caesin The remineralization potential
8% Arginine- Relief™ Phosphopeptide-Amorphous Calcium of arginine-fluoride toothpaste
7 Huang et al. (2013) ChongQing, China
fluoride toothpaste Toothpaste, Phosphate (tooth mousse) and 1400 was significantly greater than
Colgate- ppm NaF solution the control toothpaste
Palmolive
Arginine toothpaste presents
Colgate
an advantage in enhancing
Sensitive Pro-
Caesin Phosphopeptide-Amorphous remineralization and inhibiting
Jiangsu, People 8% Arginine- Relief™
8 Wang et al. (2016) Calcium Phosphate; Calcium sodium demineralization for incipient
Republic of China fluoride toothpaste Toothpaste,
phosphosilicate; and no treatment carious lesions as compared to
Colgate-
casein phosphopeptide-
Palmolive
amorphous calcium phosphate
L-arginine monohydrochloride in NaF toothpaste
2% arginine in NaF toothpaste
might provide a synergistic
anti-caries effect given the
2%, 4%, 8% L-
Hong Kong, Hong proven prebiotic benefits
9 Bijle et al. (2018) arginine in NaF - 1100 ppm commercial NaF toothpaste
Kong SAR of arginine in caries prevention
toothpaste
and the demonstrated
remineralization effect in the
study
L-arginine adhesive
7% L-arginine did not affect
the physical/mechanical
properties of adhesives and
5%, 7%, and 10% released arginine at rate and
10 Geraldi et al. (2017) Gainesville, USA - No arginine adhesive
L-arginine adhesive concentration that exhibited
antibacterial effects thereby
providing better anti-caries
control
27
Table 2: Clinical trials assessing the anti-caries effect of arginine formulations
Author Participants Commercial Control/Alternative

SN Study Type Country/City Intervention Conclusion
(Year) & Duration Product interventions
Arginine sugarless confection
Arginine
sugarless
Mint confections
Double-blind confection BasicMints®
Sucre in 195 children; containing arginine are
Acevedo et randomized (arginine confection,
1 Miranda State, Age: 10.5 - 11 Sugarless mint control able to inhibit both caries
al. (2008) controlled bicarbonate- Ortek
Venezuela years; 1 year onset and caries
clinical trial calcium Therapeutics
progression
carbonate
complex)
Arginine bicarbonate mouthwash
Regular use of arginine
Arginine
bicarbonate mouth rinse
Peking, People 6 adults; Age: bicarbonate
Wang et after carbohydrate
2 Clinical trial Republic of 56 - 72 years; mouth rinse - Sodium Bicarbonate
al. (2012) consumption can be an
China 6 weeks (0.5%, 1%,
effective approach to
and 2%)
counter caries
In situ,
14 adults;
double-blind, Arginine rinsing
Yu et al. Age: 42-77 2% arginine 1% urea or 0.05% NaF
3 randomized, Beijing, China - provides limited
(2017) years; 18 bicarbonate solution
cross-over remineralization benefit
weeks
study
Arginine non-fluoridated toothpaste
Arginine containing
CaviStat® dentifrice was more
Sucre in 726 children; Arginine non-
Acevedo et Controlled Dentifrices, Fluoride-containing effective than fluoride
4 Miranda State, Age: 10 - 11 fluoridated
al. (2005) clinical trial Ortek dentifrice toothpaste in inhibiting
Venezuela years; 2 years toothpaste
Therapeutics caries initiation and
progression
1.5% Arginine-fluoride/fluoride-free toothpaste
28
Colgate
Maximum Arginine-fluoride
Cavity toothpaste was
253 adults; 1.5% Protection significantly efficacious
Randomized
Souza et Sao Paulo, Age: 36.5 - Arginine- PLUS Sugar in arresting and
5 controlled Fluoride dentifrice
al. (2013) Brazil 54.9 years; 6 fluoride Acid reversing active root
clinical trial
months toothpaste Neutralizer™ carious lesions compared
Toothpaste , to fluoride (alone)
Colgate- dentifrice
Palmolive
1.5% Colgate
Double-blind Arginine- Maximum Arginine toothpaste
randomized fluoride Cavity provides significantly
three- toothpaste Protection greater protection against
Kraivapha 6000 children;
treatment Bangkok, with either di- PLUS Sugar caries lesion cavitation
6 n et al. 6-12 years; 2 Fluoride dentifrice
controlled Thailand calcium Acid in a low to moderate
(2013) years
parallel- phosphate or Neutralizer™ caries risk population
group calcium Toothpaste , compared to fluoride
clinical trial carbonate Colgate- dentifrice
base Palmolive
1.5% Colgate
Arginine- Maximum
fluoride Cavity
Arginine-fluoride
Randomized, 446 children; toothpaste Protection
Yin et Chengdu, toothpaste provides
double-blind Age: 10 - 12 with either PLUS Sugar
7 al.[a] People Republic Fluoride dentifrice significantly greater anti-
controlled years; 6 dicalcium Acid
(2013)24 of China caries benefit than the
clinical trial months phosphate or Neutralizer™
control
calcium Toothpaste ,
carbonate Colgate-
base Palmolive
Colgate
Maximum Arginine-fluoride
Cavity dentifrice provides
Randomized, 438 children; 1.5% Protection NaF toothpaste in superior efficacy in
Yin et al. Chengdu,
double-blind Age: 9 - 13 Arginine- PLUS Sugar silica base and arresting or reversing
8 [b] People Republic
controlled years; 6 fluoride Acid dentifrice without buccal caries lesions
(2013)23 of China
clinical trial months toothpaste Neutralizer™ arginine/fluoride compared to
Toothpaste , conventional fluoride
Colgate- dentifrice
Palmolive
29
Colgate
Maximum
Arginine-fluoride
Cavity
toothpaste provided
Randomized, 331 children; 1.5% Protection
Srisilapana significant superior
double-blind Chiang Mai, Age: 7-14 Arginine- PLUS Sugar
9 n et al. Fluoride dentifrice efficacy in arresting and
controlled Thailand years; 6 fluoride Acid
(2013) reversing active coronal
clinical trial months toothpaste Neutralizer™
caries than matched
Toothpaste ,
control dentifrice
Colgate-
Palmolive
Colgate
Maximum
Cavity Arginine-fluoride
Randomized, 412 adults; 1.5% Protection dentifrice provided
Chengdu,
Hu et al. double-blind Age: 50-70 Arginine- PLUS Sugar greater anti-caries
10 People Republic Fluoride dentifrice
(2013) controlled years; 6 fluoride Acid benefit than the
of China
clinical trial months toothpaste Neutralizer™ fluoridated toothpaste on
Toothpaste , primary root caries
Colgate-
Palmolive
Arginine toothpaste
Single blind 45 adults; 1.5%
Nasciment treated individuals
randomized Age:18-34 Arginine-
11 o et al. Florida, USA - Fluoride dentifrice showed a bacterial shift
controlled years; 6 fluoride-free
(2014) similar to caries free
clinical trial weeks toothpaste
individuals
Colgate
Maximum
Randomized, Cavity
The study concludes a
examiner- 1.5% Protection
3706 children; positive anti-caries effect
Petersen et blind parallel Songkhla, Arginine- PLUS Sugar
12 Age: 4-6 Fluoride dentifrice of arginine-fluoride
al. (2015) group Thailand fluoride Acid
years; 2 years toothpaste as compared
controlled toothpaste Neutralizer™
to the control
clinical trial Toothpaste ,
Colgate-
Palmolive
30
Colgate
Maximum
Arginine-fluoride
Randomized, Cavity
toothpaste provides
double blind, 1.5% Protection
5669 children; superior protection
Li et al. unsupervised Arginine- PLUS Sugar
13 Sichuan, China Age: 8-10 Fluoride dentifrice against caries lesion
(2015) , parallel- fluoride Acid
years; 2 years cavitation compared to
group toothpaste Neutralizer™
1450 ppm NaF
clinical trial Toothpaste ,
toothpaste
Colgate-
Palmolive
Colgate
Maximum
In situ, Cavity
Arginine-fluoride
parallel, 15 adults; 1.5% Protection
dentifrices have similar
Sanchez et single- Porto Alegre, Age: 22-32 Arginine- PLUS Sugar
14 Fluoride dentifrice anti-caries effect to
al. (2018) blinded, Brazil years; 3 fluoride Acid
regular fluoride
split-mouth months toothpaste Neutralizer™
dentifrices
study Toothpaste ,
Colgate-
Palmolive
In situ,
double-
Colgate
blinded, Arginine containing
12 adults; Sensitive Pro-
single- Chengdu, 8% Arginine- toothpaste significantly
Xue et al. Age: 20-25 Relief™
15 center, People Republic fluoride Fluoride dentifrice reduces lactic acid
(2017) years; 6 Toothpaste,
randomized of China toothpaste production and biofilm
weeks Colgate-
controlled biomass
Palmolive
crossover
study
Arginine can be regarded
Colgate as a genuine prebiotic as
Sensitive Pro- it leads to a healthy shift
Koopman 9 healthy 8% Arginine-
Amsterdam, Relief™ of oral microbiome,
16 et al. Clinical trial volunteers; 8 fluoride Fluoride dentifrice
Netherlands Toothpaste, affects arginolytic
(2017) weeks toothpaste
Colgate- capacity and also
Palmolive reduces sucrose
metabolic activity
31
Colgate
Sensitive Pro- Arginine-fluoride
Chengdu, 42 8% Arginine-
Zheng et Relief™ dentifrice maintains
17 Clinical trial People Republic individuals; 4 fluoride Fluoride dentifrice
al. (2017) Toothpaste, healthy oral microbial
of China weeks toothpaste
Colgate- equilibrium
Palmolive
Arginine varnish
The daily application of
34 mentally arginine varnish over 8
retarded Custom-made weeks revealed
Shapira et Jerusalem,
18 Clinical trial patients; Age: 3% arginine - Chlorhexidine varnish significant reductions in
al. 1994) Israel
18 - 45 years; varnish S. mutans count and non-
8 weeks significant increase in S.
sanguis counts
32
Table 3: Narrative reviews on arginine formulations
SN Author (Year) Country/City Intervention Commercial Product Conclusion
Colgate Maximum
Cavity Protection PLUS Arginine-fluoride toothpaste
1.5% Arginine-
Sharma et al. Bangalore, Sugar Acid enhances arresting and
1 fluoride
(2015) India Neutralizer™ reversing buccal, coronal and
toothpaste
Toothpaste , Colgate- root caries.
Palmolive
Colgate Maximum
Cavity Protection PLUS The study identified some
1.5% Arginine-
Fontana et al. Michigan, Sugar Acid evidence for the prebiotic use
2 fluoride
(2016) USA Neutralizer™ of arginine to potentially
toothpaste
Toothpaste , Colgate- boost the action of fluorides
Palmolive
Colgate Maximum Arginine-fluoride dentifrice
Cavity Protection PLUS helps maintain the natural
1.5% Arginine-
Cummins et al. Sugar Acid oral flora that is compatible
3 Florida, USA fluoride
(2016) Neutralizer™ with health and thereby
toothpaste
Toothpaste , Colgate- significantly reducing the risk
Palmolive of dental caries
L-arginine, Colgate Maximum
1.5% arginine- Cavity Protection PLUS Arginine delivery regularly to
Nascimento et fluoride Sugar Acid supra-gingival biofilms can
4 Florida, USA
al. (2018) toothpaste, and Neutralizer™ be an effective therapy for
ADS positive Toothpaste , Colgate- caries intervention
probiotic strains Palmolive
Clinical trials have shown
Colgate Maximum clear potential of arginine to
Cavity Protection PLUS boost performance of
Gonzalez- 1.5% Arginine-
Michigan, Sugar Acid fluoride, however, final
5 Cabezas et al. fluoride
USA Neutralizer™ recommendations are to be
(2018) toothpaste
Toothpaste , Colgate- made after conducting high-
Palmolive quality and potentially less
biased clinical trials
Colgate Total Whole The new advanced toothpaste
1.5% Arginine- Mouth Health - Dual containing dual zinc plus
Cummins et al.
6 Florida, USA Zinc-Fluoride zinc plus arginine- arginine and fluoride will be
(2019)
toothpaste fluoride Dentifrice, helpful to achieve better
Colgate-Palmolive caries prevention
33
Table 4: Systematic reviews and/or meta-analysis, and umbrella reviews/meta-evaluation examining evidence on the anti-caries effect of
arginine formulations
Control/Alternative
SN Author (Year) Study Type Country/City Intervention Commercial Product Conclusion
interventions
Colgate Maximum Daily use of arginine-
Cavity Protection fluoride toothpaste was
Systematic 1.5% Arginine-
Wierichs et al. PLUS Sugar Acid Fluoride containing shown effective than
1 review & meta- Aachen, Germany fluoride
(2015) Neutralizer™ toothpaste standard toothpaste but
analysis toothpaste
Toothpaste , Colgate- the evidence level was
Palmolive graded as low
BasicMints®
Arginine-fluoride
confection, Ortek
Arginine dentifrices provides a
Therapeutics & Colgate
Systematic confection and Control confection superior effect compared
Maximum Cavity
2 Li et al. (2015) review & meta- Nanjing, China 1.5% Arginine- and/or fluoride to fluoride alone
Protection PLUS Sugar
analysis fluoride toothpaste toothpaste with a
Acid Neutralizer™
toothpaste concern on potential
Toothpaste , Colgate-
publication bias
Palmolive
Although studies with
moderate risk of bias
demonstrated greater
anti-caries potential with
Colgate Maximum
arginine-fluoride
Cavity Protection
Systematic 1.5% Arginine- dentifrices than fluoride
Astvaldosdottir PLUS Sugar Acid Fluoride containing
3 review & meta- Stockholm, Sweden fluoride toothpaste but due to the
et al. (2016) Neutralizer™ toothpaste
analysis toothpaste potential risk of bias it
Toothpaste , Colgate-
was concluded that there
Palmolive
was insufficient evidence
to support the inclusion
of arginine in fluoride
toothpaste
Arginine-containing
mint confection were
BasicMints®
Wang et al. Systematic Arginine found to reduce caries
4 Nanjing, China confection, Ortek Control confection
(2017) review confection development in primary
Therapeutics
teeth but the evidence
was at high risk of bias
34
Arginine-fluoride
Umbrella Colgate Maximum
toothpaste seems to be a
review/meta- Cavity Protection
1.5% Arginine- promising agent but
Bijle et al. evaluation of Hong Kong, Hong PLUS Sugar Acid
5 fluoride Fluoride toothpaste more well designed
(2018) systematic Kong SAR Neutralizer™
toothpaste clinical trials can provide
reviews and Toothpaste , Colgate-
better insights in the
meta-analysis Palmolive
future
35
Table 5: Evidence synthesis of arginine commercial formulations
SN Interventions with commercial products Studies Study Types Synthesized Conclusion

In vitro study (1);
Clinical trials (9);
Narrative reviews 1.5% Arginine-fluoride
1.5% Arginine-fluoride toothpaste (Colgate In vitro study - 37; Clinical trials - 10,23,24,43,45,46,48,49,53 (5); and Systematic toothpaste have a superior caries
Maximum Cavity Protection PLUS Sugar Systematic reviews with/without meta-analysis and reviews preventive effect compared to
1
Acid Neutralizer™ Toothpaste , Colgate- umbrella reviews/meta-evaluation - 25–27,54; Narrative with/without meta- their matched controls (including
Palmolive/Elmex Caries Professional) reviews - 56–58,60,61. analysis and fluorides) but the evidence is with
umbrella high risk of bias
reviews/meta-
evaluation (4)
provides a superior caries
8% Arginine-fluoride toothpaste (Colgate preventive effect with a potential
In vitro studies (2);
2 Sensitive Pro-Relief™ Toothpaste, In vitro studies - 32,35; Clinical trials - 11,42,51. to maintain healthy oral
Clinical trials (3)
Colgate-Palmolive) microbiome; however the
evidence needs further appraisal
for conclusive recommendations
1.5% Arginine-Zinc-Fluoride toothpaste

Insufficient evidence for
3 (Colgate Total Whole Mouth Health - Dual One narrative review61 Narrative review (1)
synthesized conclusion
zinc plus arginine-fluoride Dentifrice)
Arginine non-fluoridated toothpaste

Insufficient evidence for
4 (CaviStat® Dentifrices, Ortek One clinical trial40 Clinical trial (1)
synthesized conclusion
Therapeutics)
Clinical trial (1); Arginine sugarless confection are

Arginine sugarless confection
Clinical trial - 41; Systematic reviews with/without Systematic reviews superior to control confections for
5 (BasicMints® confection, Ortek
meta-analysis - 25,55 with/without meta- caries prevention but the evidence
Therapeutics)
analysis (2) is with high risk of bias
36
Acknowledgements
This review article was supported by the Research Grants Council of Hong Kong
(#17118519). The authors declare no potential conflicts of interest with respect to the
authorship and/or publication of this article.

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A scoping review on arginine in caries prevention

To appear in: The Journal of Evidence-Based Dental Practice

Received Date: 12 December 2019

© 2020 Published by Elsevier Inc.

2 Title of the manuscript: A scoping review on arginine in caries prevention

3 Running Title: Arginine in caries prevention.

2 A scoping review on arginine in caries prevention

5 research in the field.

8 research on arginine-containing caries-preventive agents.

11 reviews/meta-evaluation examining arginine/arginine formulations for caries prevention were included.

13 investigated up to date were discussed to explore future scope of research.

17 Arginine/arginine formulations demonstrated a superior caries-preventive effect compared to their

23 explored by incorporating in self- and professionally applied caries preventive agents.

25 Keywords: arginine, caries, prevention, review.

9 bacteria that are resistant to anti-microbials to flourish.

13 leads to a temporary colonization of the oral environment.6,7 Conversely, an ecological-based caries-

19 when compared to fluorides alone.10,11

22 metabolism.12–15 Arginine is metabolized by the arginolytic bacteria, Streptococcus sanguinis,

2 arginolytic potential of ADS-positive bacteria to increase alkali production.22

15 arginine-containing caries-preventive agents.

20 was sought from a Joanna Briggs Institute paper.31

22 2.1 Protocol & registration

26 for access with link – https://osf.io/9qvpn/.

2 2.2 Data Sources & Resources Selection

3 2.2.1 Eligibility criteria

6 following the strategy – Population-(any)-concept-(arginine)-context-(caries prevention) as base-map

11 with/without meta-analysis, umbrella reviews/meta-evaluation, and narrative reviews.

17 prevention) were not included in the review process.

19 2.2.2 Information sources

26 2.2.3. Search strategy

4 search strategy for PubMed is available in Table S1.

8 with an expert in the field (CKY).

10 2.3 Data charting and synthesis

21 3.1 Evidence sources selection

4 3.2 Evidence characteristics

8 (Table 3) examined the caries-preventive effect of L-arginine33,36,38,39, L-arginine monohydrochloride34

10 fluoridated toothpaste40, 1.5% arginine-fluoride/fluoride-free toothpaste10,23–27,37,43–46,48,49,53,54,56–60, 1.5%

11 arginine-zinc-fluoride toothpaste61, 8% arginine-fluoride toothpaste11,32,35,42,51, L-Arg.HCl in NaF

12 toothpaste18, L-arginine adhesive28, and arginine varnish47.

14 Majority of the articles10,23–27,37,43,45,46,48,49,53,54,56–60 (19) studied 1.5% arginine-fluoride toothpaste; whereas

20 the fewest studies.

23 3.3.1 In vitro studies

11 destabilizing biofilm in a concentration-dependent manner and enhanced the antimicrobial activity of

13 products for enhanced biofilm control (Table 1).

16 i. 1.5% Arginine-fluoride toothpaste

24 ii. 8% Arginine-fluoride toothpaste

25 The 8% arginine-fluoride dentifrice (Colgate Sensitive Pro-Relief™ Toothpaste) comprising of 8%

6 and 1400 ppm NaF solution (Table 1).

8 iii. L-arginine monohydrochloride in NaF toothpaste

15 uptake. The formulation is not yet commercially available (Table 1).

20 methacrylate and di-methacrylate monomers, ethanol, photo-initiators with L-arginine in a weight

25 3.3.2 Clinical trials and reviews

26 a) Arginine sugarless confection

11 compliance of the patients (Table 2).

13 b) Arginine bicarbonate mouthrinse

24 participated subjects were only 6; whereby concerns on external validity arises.

4 available (Table 2).

6 c) Arginine non-fluoridated toothpaste

14 compare the caries-preventive effect of CaviStat® (arginine bicarbonate-calcium carbonate complex)-

19 effect as ascertained in the study (Table 2).

22 a. 1.5% Arginine-fluoride/fluoride-free toothpaste

24 composition to a healthier community similar to caries-free individuals (Table 2).44