|Year : 2017 | Volume
| Issue : 1 | Page : 17-22
N-acetylcysteine as a candidate therapeutic for recurrent aphthous and aphthous-like ulcers
Saleem Abdulrab1, Esam Halboub2, Imad Barngkgei3, Nezar Al-Hebshi4
1 Department of Restorative Dental Sciences, Alfarabi Colleges, Riyadh, Saudi Arabia
2 Department of Maxillofacial Surgery and Diagnostic Sciences, College of Dentistry, Jazan University, Jazan, Saudi Arabia
3 Department of Oral Medicine, Faculty of Dentistry, Damascus University, Damascus; Department of Oral Medicine, Faculty of Dentistry, Syrian Private University, Damascus, Syria
4 Kornberg School of Dentistry, Temple University, Philadelphia, Pennsylvania, USA
|Date of Web Publication||14-Mar-2017|
Department of Restorative Dental Sciences, Al Farabi colleges, Riyadh
Source of Support: None, Conflict of Interest: None
Introduction: Recurrent aphthous stomatitis (RAS) is a painful ulcerative oral disease with a general population prevalence exceeding 20%. The etiology of RAS remains largely unknown, however, nutritional deficiency, autoimmunity, psychological stress, and, recently, oxidative stress have been implicated. The pain associated with RAS may be very severe and disabling, hence, treatment is centered on the control of pain and acceleration of healing. N-acetylcysteine (NAC) is a potent antioxidant with anti-inflammatory, immune-modulatory, and antimicrobial properties. It is available as a safe dietary supplement, and has been successfully used as adjuvant/treatment of inflammatory conditions including ulcerative lesions. The Hypothesis: Using NAC as a candidate for treatment and/or prevention of RAS and aphthous-like ulcers is hypothesized here. We propose to use NAC systemically or topically in the form of powder, paste, adhesive tablets, or mouthwash to treat active RAS or for prophylaxis in cases with frequent attacks. Evaluation of the Hypothesis: The current hypothesis should be tested on animal models of RAS. However, because NAC is currently approved and used for other indications, the hypothesis can also be directly evaluated in well-designed, randomized clinical trials.
Keywords: Antioxidant, aphthous ulcer, N-acetylcysteine, oxidative stress, recurrent aphthous stomatitis
|How to cite this article:|
Abdulrab S, Halboub E, Barngkgei I, Al-Hebshi N. N-acetylcysteine as a candidate therapeutic for recurrent aphthous and aphthous-like ulcers. Dent Hypotheses 2017;8:17-22
|How to cite this URL:|
Abdulrab S, Halboub E, Barngkgei I, Al-Hebshi N. N-acetylcysteine as a candidate therapeutic for recurrent aphthous and aphthous-like ulcers. Dent Hypotheses [serial online] 2017 [cited 2017 Dec 11];8:17-22. Available from: http://www.dentalhypotheses.com/text.asp?2017/8/1/17/202028
| Introduction|| |
Recurrent aphthous stomatitis (RAS), also called recurrent aphthous ulcers or Canker sore, is the most common oral mucosal disease characterized by recurring painful ulcers of the nonkeratinized lining mucosa, that are oval or round usually with a gray-white pseudomembranous center surrounded by erythematous halo reflecting an intense inflammation. Based on the size and number of the ulcers, RAS is categorized as minor, major, and herpetiform. Because the episodes are short in duration, the point prevalence of RAS is low ranging from 0.9% to 2.7%. However, the annual and lifelong prevalence rates have been reported to be as high as 20% and 40%, respectively., Certain subpopulations are at higher risk of developing RAS including high socioeconomic strata, females, nonsmokers, and young adults.
The pain associated with RAS can be so severe that it interferes with talking, eating, swallowing, and oral health practices and significantly lowers the patient’s quality of life.,, Many treatment modalities of RAS have been studied revealing inconsistent results; these have been comprehensively reviewed elsewhere., In principle, a curative therapy is lacking and treatment is centered on the control of pain and acceleration of healing.
Despite the extensive research done on RAS, the etiology and pathogenesis of the disease remains poorly understood. A number of factors have been implicated in the etiology of RAS including malnutrition,, psychological stress,, viral infection, oral microbial dysbiosis,,,, trauma, immune dysfunction, genetic predisposition,,,,,, and allergy. Recently, there has been growing evidence to support a strong role for oxidative stress in the etiology of RAS; this is reflected in significant upregulation of oxidant and/or downregulation of antioxidant markers in serum,,,,, and/or locally in saliva., In brief, oxidative stress is characterized by an increased level of reactive oxygen species (ROS) that disrupts the intarcellular reduction–oxidation (redox) balance. While the production of ROS is an essential part of normal cellular metabolism, when increased, it creates a state of oxidative stress that may impair metabolism, causes oxidative damage, and eventually results in cell death and tissue destruction. In fact, oxidative stress is implicated in the pathogenesis of many inflammatory diseases such as atherosclerosis, diabetes mellitus, rheumatoid arthritis, and chronic periodontitis. Therefore, maintaining/restoring the redox balance is a potentially useful approach for the management of these diseases.
N-acetylcysteine (NAC) is an FDA-approved dietary supplement. It is converted in the human body by deacetylation into the amino acid cysteine. The latter is in turn metabolized by the action of two enzymes, glutamate cysteine ligase (GCL) and glutathione synthetase (GS), into glutathione, a key antioxidant. It is rapidly absorbed following an oral dose with a plasma half-life of 2.5 hours. No NAC is detectable 10–12 hours after administration. The oral bioavailability of the intact NAC molecule was estimated to be approximately 10%. Renal clearance constitutes approximately 30% of total body clearance of NAC, with only 3% excreted in feces after oral administration. The almost complete absorption leaves a large amount of NAC for in-vivo metabolism, cellular uptake, deacetylation to cysteine, and synthesis of glutathione or other sulphur compounds.
NAC has several pharmacological actions with potential therapeutic applications. For example, it has potent anti-inflammatory and immunomodulatory properties,,,,, and possesses antimicrobial and antibiofilm activities.,,,, In addition, it is well-known for its strong antioxidative effects; i.e., regulation of the glutamatergic system, which is the basic mechanism behind its therapeutic effects. In clinical situations where glutathione deficiency and/or oxidative stress are involved, treatment with NAC has proven to be effective. For example, it is a life-saving drug for acetaminophen poisoning. NAC has also been shown to scavenge oxygen free radicals that mediate cell necrosis after myocardial infarction and angioplasty. In addition to its use as an antioxidant, NAC has been used for pulmonary diseases as a mucolytic agent, in the management of addictive behaviors, psychiatric illnesses such as schizophrenia, and infectious diseases such as human immunodeficiency viris (HIV) and hepatitis C, and as a bioprotectant against toxicities, chronic kidney, and heart diseases, as well as some cancers.,, NAC also acts as a methyl donor in the conversion of homocysteine (a risk factor for cardiovascular disorders) to methionine, and has been shown to possess vasodilatory properties.
NAC is available as a dietary supplement as well as a medication that is administrated orally or intravenously, or is inhaled as a mist. It is a safe drug; mild gastrointestinal symptoms are the most common side effects. There are, however, rare reports of renal stone formation during NAC treatment. When used as a mucolytic agent, it has also been reported to cause local irritation. Side effects are more noticeable at high doses (>3 g/day) and when administered intravenously.
| The Hypothesis|| |
In view of the role of the oxidative stress, inflammation, immune dysregulation, microbial, and nutritional factors in the etiopathogenesis of RAS, we hereby postulate NAC as a strong candidate therapeutic for the treatment and/or prophylaxis of RAS and aphthous-like ulcers. Our hypothesis is primarily based on NAC being a potent antioxidative but also on its anti-inflammatory, immunomodulatory, antimicrobial, and nutritional properties, as elaborated below.
In RAS patients, there is a decrease in the total antioxidant status (TAS) against an increase in the total oxidative status (TOS) and oxidative status index (OSI) in RAS patients.,,, Specifically, the antioxidant enzymessuperoxide dismutase,, glutathione peroxidase,,, arylesterase, and catalase, are depleted, whereas there is a buildup of reactive oxygen species (ROS), namely malondialdehyde,, and oxidized glutathione. This high oxidative stress results in cellular damage and a vicious cycle of inflammation, which in the case of RAS is translated into ulceration. In this context, a potent antioxidant, such as glutathione, can be used to reverse the oxidative stress and inflammation in RAS and subsequently reduce the pain and promote healing. However, glutathione, although available as dietary supplement, is destroyed by intestinal enzymes and has limited bioavailability; instead, NAC is well absorbed from the intestine and is a precursor of cysteine, the main factor limiting the synthesis of reduced glutathione. In addition, NAC works as a direct reactive oxygen species scavenger. The antioxidant effects of NAC have in fact been demonstrated in several previous studies, and are dose-dependent.
Upregulation of inflammatory mediators and dysregulation of the immune system have been reported to be involved in RAS. High levels of cytokines including IL-2, IL-10, IL-12, IL-13, IL-17, and IL-18, and INF-gamma,,, have been demonstrated in RAS patients. An increase in CD56+ cells, autoimmunity potential, and chemokine receptors such as CCR5 and CXCR3 have also been reported. Interestingly, NAC has been shown to reverse the dysregulation in many of these cytokines,,,,,,,,,,, probably through inhibition of proinflammatory transcription factors such as activator protein-1 and NF-KB., Therefore, the anti-inflammatory and immunomodulatory properties of NAC represent another basis for using it for managing RAS.
The possible role of oral microbiota in the etiopathogenesis of RAS is emerging although investigators believe it plays a secondary role to other factors. A recent study using next generation sequencing (NGS) of the 16S rRNA gene demonstrated that species belonging to Porphyromonadaceae and Veillonellaceae predominated in ulcerated sites whereas Streptococcaceae spp. predominated in the mucosa of healthy controls. Other studies also claimed a role for the changes in the oral microbial community, bacteria, and/or viruses in the pathogenesis of RAS.,,, NAC can potentially play a role in the management of RAS at this level as well given its antimicrobial activities. NAC, for example, has been found to be more effective on both Streptococcus mutans and Enterococcus faecalis than sodium hypochlorite and chlorhexidine, and thus has been suggested as an endodontic irrigant.,, It has also been shown to decrease biofilm formation, inhibit bacterial adherence, reduce the production of extracellular polysaccharide matrix, and the cell viability of various Gram-negative and Gram-positive bacteria., The antibacterial effect of NAC is mediated by its thiol group that breaks disulfide bonds and thus results in the irreversible damage of bacterial proteins that are essential for bacterial growth., How NAC influences the structure and function of the oral microbiome is an area that needs to be investigated further using NGS technologies.
The severe forms of RAS have been found to be associated with malnutrition,,, and correction of such malnutrition have been shown to result in dramatic clinical improvement. The most commonly implicated nutrients are vitamin B12, foliate, and iron., However, these deficiencies seem to contribute to RAS again by evoking a state of oxidative stress. For example, vitamin B12 deficiency has been found to cause a profound reduction of plasma glutathione and total antioxidant capacity (TAC). Intriguingly, treatment with glutathione precursor (e.g., NAC) has been shown to reverse the oxidative stress induced by this deficiency. In addition, supplementation with NAC has been demonstrated to increase available glutathione by up to 510% in a malnourished population. In mice with protein malnutrition, NAC supplementation results in accelerated wound healing and restored early inflammatory responses.
The use of NAC for the treatment and/or prevention of RAS is thus proposed based on its antioxidant, anti-inflammatory, immune-modulatory, nutritional, and antimicrobial properties.
| Evaluation of the Hypothesis|| |
Drug discovery usually passes through the following stages set by the US Food and Drug Administration (FAD): discovery and development; preclinical research (in-vitro and experimental animals); clinical research (four phases of clinical trials); and review and post-market safety monitoring. NAC is already FDA approved – although for non-RAS indications – and has broad margins of safety.,, Therefore, the current hypothesis can be evaluated in animal models as well as in humans.
An animal model of oral ulceration has been described and used to test the therapeutic effects of many drugs.,,, The ulcers are chemically-induced using disks impregnated with acetic acid. This model can be employed to demonstrate both the therapeutic and prophylactic properties of NAC. Topical application of NAC, in the form of powder or adhesive paste, on the induced ulcer can be compared with other drugs in common use, such as amlexanox and triamcinolone, whereas systemic whereas systemic administration can be compared with systemic corticosteroids such as prednisolone or with systemic colchicine. Experimental outcomes should comprise the severity of ulceration and time required to develop the ulcers (prophylactic effects) and ulcer healing time and levels of inflammatory markers (therapeutic effects). These experiments will help identify the right form, route of administration, and dosage of NAC.
In humans, the therapeutic potential of NAC can be evaluated in well-designed, parallel-arm randomized clinical trials (RCTs). Guided by results from the animal studies, the right dose of NAC can be administered topically (powder, paste, adhesive tablets, chewing tablets, lozenges, or mouthwash) or systemically to treat active RAS, and compared with topical or systemic steroids, as described for the animal studies above. The main outcomes to be measured can include pain intensity, healing time, and levels of inflammatory markers. The prophylactic potential can on the other hand be assessed in crossover RCTs. A group of patients with frequent attacks of RAS can be followed for a period of time to establish recurrence rate; NAC will then be given systemically and the group will be followed up to reassess recurrence rate and compare it with the baseline rate.
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Conflict of interest
There are no conflicts of interest.
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