|Year : 2016 | Volume
| Issue : 5 | Page : 57-60
A regulatory review for products containing glutathione
Nur Hidayah Abd Rahim1, Long Chiau Ming2, Yaser Mohammed Ali Al-Worafi3, Md Moklesur Rahman Sarker4
1 Faculty of Pharmacy, Universiti Teknologi MARA, Selangor, Malaysia
2 Faculty of Pharmacy, Universiti Teknologi MARA; Vector-borne Diseases Research Group (VERDI), Pharmaceutical and Life Sciences CoRe, Universiti Teknologi MARA, Selangor, Malaysia
3 Department of Pharmacy Practice, College of Pharmacy, Qassim University, Buraidah, Kingdom of Saudi Arabia
4 Faculty of Pharmacy, Lincoln University College, No. 2, Jalan Stadium SS 7/15, Kelana Jaya, 47301 Petaling Jaya, Selangor, Malaysia
|Date of Web Publication||26-May-2016|
Dr. Long Chiau Ming
Level 11, FF1 Building, Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, Selangor
Source of Support: None, Conflict of Interest: None
Glutathione is a potent antioxidant as well as has important role for DNA synthesis and repair, protein synthesis, amino acid transport, and enzyme activation. Besides this, Glutathione products are now mainly selling as whitening agent which are mainly marketing through social media (Facebook) and different websites. Information is not available whether glutathione product are following the regulatory guidelines of National Pharmaceutical Control Bureau of Malaysia (NPCB) for selling, advertisement and promotion. This review was carried out by extracting information about glutathione from scientific database using PubMed, Cochrane Library and Embase. Analysis of the available information, case example of glutathione products showed that a brand of glutathione (Glutacaps HQ) did not show the product's registration number from NPCB, and also did not show the name, address, contact number of the advertiser, and even not found the name of the manufacture. Without providing the above mentioned information, the product is selling and promoting through social media (fb) which is not allowed by the NPCB guidelines part 4.14. So far, only two clinical trials were conducted on glutathione supplementation for 4 weeks duration. There was no serious or systematic adverse effects reported in clinical trials. As the two clinic trials resulted contradictory outcomes, further studies needed for conformation of the clinic benefits of glutathione. Otherwise, random use of glutathione may be risk for the health of the people. Besides, the marketer mainly promoting glutathione as the skin whitening beauty product instead of using as health supplement, it may cause additional and serious risk to the users as the manufacturer not providing sufficient information about the product, its registration number, manufacturing company, etc.
Keywords: Antioxidant, efficacy, glutathione, health supplement, safety, regulation of healthcare products
|How to cite this article:|
Abd Rahim NH, Ming LC, Al-Worafi YM, Sarker MM. A regulatory review for products containing glutathione. Arch Pharma Pract 2016;7, Suppl S1:57-60
|How to cite this URL:|
Abd Rahim NH, Ming LC, Al-Worafi YM, Sarker MM. A regulatory review for products containing glutathione. Arch Pharma Pract [serial online] 2016 [cited 2019 Jun 20];7, Suppl S1:57-60. Available from: http://www.archivepp.com/text.asp?2016/7/5/57/183029
| Introduction|| |
Glutathione (GSH) is the richest endogenous antioxidant produced by the cell in the body and functioned as the critical oxidative stress and immune response. GSH has multiple functions such as  participating directly in the neutralization of free radicals and reactive oxygen compounds, as well as maintaining exogenous antioxidants such as Vitamins C and E in their active forms, used in metabolic and biochemical reactions such as DNA synthesis and repair, protein synthesis, prostaglandin synthesis, amino acid transport, and enzyme activation for the purpose in the immune system, the nervous system, the gastrointestinal system, and the lungs, and also  vital function in iron metabolism, for example, the yeast cells depleted of or containing toxic levels of GSH show an intense iron starvation-like-response and impairment of the activity of extramitochondrial ISC enzymes.
Oral GSH is currently become widely used due to its antiradical activities; however, less pharmacological trial was found in electronic databases. In systemic circulation, GSH is degraded rapidly by gamma-glutamyl transpeptidase yielding glutamate, cysteine, and glycine. In certain condition, cysteine can be oxidized immediately to cystine (Cys2). It known that extracellular methionine was as strong an antioxidant as cysteine against intracellular reactive oxygen species (ROS). Pharmacokinetic study of injection GSH done by Hong et al. showed that GSH has a very short half-life, which is <10 min, it is difficult to maintain it at a therapeutic concentration, glutamate and cysteine reached their peak concentrations at 10 min, and methionine at 20 min. However, Cys2 increased gradually, peaked at 30 min, and then slowly decreased. The 10- and 20-min concentrations of glutamate, cysteine, and methionine were significantly higher than their baseline values, but no significant change was observed in Cys2. Using metabolite kinetics while assuming that cysteine is a metabolite of GSH and that area under the curve (Cys)single i.v. is 4108.4 µM/min after administering GSH at 50 mg/kg of body weight, the expected cysteine concentration is over 20 µM when this dose is given every 205.4 min. In the same way, when it comes to methionine, the concentration is over 50 µM when the same dose is given every 427.4 min.
| Case Example of Product Containing Glutathione|| |
Glutacaps Plus ® is widely marketed through social media. Searching through Google search engine under search term “Glutacaps” founded 311,000 results, whereas using term “Glutacaps Malaysia” founded 206,000 results. Glutacaps Plus ® was registered under National Pharmaceutical Control Bureau (NPCB) for products other than cosmetics with MAL 15065008NC and using Facebook page (FB) of Glutacaps HQ, the way it is marketed in Malaysia toward Medicine Advertisement Board (MAB) is been assessed.
Effective on September 1, 2015, guideline on advertising of medicines and medicinal products to general publics is intended to complement the provisions of the medicines (advertisement and sale) act 1956 and the MAB Regulation 1976. This guideline to be implemented for products registered with drug control authority and to put responsibility of the advertiser to ensure that advertising medicines and medicinal products does not in any way put patient and consumer safety at risk.
In general, the Glutacaps Plus ® advertisement provides information that is reliable, accurate, informative, balanced, up to date, and good taste. Since Glutacaps Plus ® is a medicinal product containing GSH, hyaluronic acid, and Vitamin C, their advertisement in FB seemed using correct and verifiable information, thus it is not induced to unjustifiable medical use or to give rise to undue risk. However, under the part 4.14 of this guideline, Glutacaps HQ up to this date did not show Kementerian Kesihatan Lembaga Iklan Ubat number, and not even stated the name, address, and contact number of advertiser on every advertisement post. Other than that under part of 5.3, advertisement may include testimonials, but the individual who give the testimony must be genuinely exist and responsible as well as accountable to the advertisement and its testimonial must refer to indications approved. Glutacaps Plus ® FB showed many testimonials being used but they not state for every advertisement “The effect of the product may vary among individuals” and not supported with consent letter containing information such a name of testimony, IC number, signature, and his/her contact number.
In terms of therapeutic claims, Glutacaps Plus ® FB only promoting the use of their products for moisturizing the skin, control acnes, and brings fairer and glowing skin. There is no therapeutic claim of treatment or prevention of disease which prohibited under part 4.4 and above and not diagnosing disease being made from their advertisement in social media. Further assessment on this product, they are should include for each advertisement approved registration number by NPCB anyway in the advertisement in a clear manner and a statement: “This is a supplement product advertisement.”
| Methodology|| |
An electronic search of PubMed, Cochrane Library, and EMBASE to reviews of effects for studies and trials using the following research criteria were carried out Table 1.
Literatures were systemically reviewed, and three most relevant studies are reported in the evidence tables attached.
| Safety and Efficacy of Product|| |
It was reported that there were three mechanisms GSH inhibit melanogenesis in in vitro. One mechanism is the inhibition of tyrosinase activity; this is a well-known function of thiol compounds in general including GSH and cysteine. Tyrosinase is rate-limiting enzyme controlling the production of melanin and catalyze the conversion of L-tyrosine supplied from the blood to 3,4-dihydroxyphenylalanine, then to dopaquinone. Kojic acid, arbutin, and hydroquinone are commonly used to whiten skin and having inhibitory effects on tyrosinase. The second mechanism of skin whitening effect of GSH is activation of the pheomelanin pathway. Synthesis of pheomelanin starts with the conjugation of L-dopaquinone formed from L-tyrosine and cysteine. This reaction yields the pheomelanin precursor cysteinyldopa. When the cysteinyldopa synthesis is induced, it leads to increase production of pheomelanin, which is yellow–red. The third mechanism was the skin whitening effect of GSH is attributed to its antioxidant activity. GSH has the ability to scavenge ROS generated in epidermal cells following ultraviolet exposure and thus prevent ROS-induced melanogenesis. Other skin whitening agents that have antioxidant activity and melanogenesis inhibitory effects include L-ascorbic acid and its derivatives.
Importantly, it is known that the melanogenetic pathway is shifted from eumelanin toward pheomelanin formation when GSH or cysteine is added to melanocytes or melanoma cell lines. Oral dosing of GSH is not well absorbed from the gastrointestinal tract, and thus, intravenous (IV) administration has been used in many countries, especially in Southeast Asia. In Thailand, IV GSH had been banned by the authority for such modality due to severe adverse reactions including anaphylaxis shock.
To the author's knowledge, there were only two clinical trials done on oral GSH supplementation. The first double-blind, randomized, placebo-controlled, 4 weeks duration of a clinical trial of oral GSH supplementation was performed in 2011 by Allen and Bradley with main objective was to determine the effect of oral GSH on biomarkers of systemic oxidative stress in human volunteers. The impact of this study was more on analysis related to mechanistic efficacy than effectiveness. The second study was randomized, double–blind, two–arm, placebo-controlled, 4 weeks duration of clinical trial by Arjinpathana and Asawanonda in 2012 with the main objectives to determine whether orally administered oral GSH affects the skin melanin index compared to placebo.
Assessment of efficacy for oral GSH results from Allen and Bradley using 39 participants showed there were no differences in oxidative stress biomarkers between treatment groups at baseline. Because GSH status is dynamic, the outcome measures were extended beyond GSH status alone to include 8-hydroxy-2'-deoxyguanosine (8-OHdG) and F2-isoprostanes (F2-isoP), in case a change in oxidation status was exemplified by the evidence of reduced oxidation products rather than a change in GSH or GSH: Oxidized GSH (GSH:GSSG) ratio. Changes in creatinine standardized F2-isoP (ng/mg creatinine) and 8-OHdG (lg/g creatinine) were not significant between groups at week 4. Total reduced, oxidized, and ratio measures of GSH status were also unchanged. However, study from Arjinpathana and Asawanonda using analysis of covariance showed there was statistically significant in greater reduction of melanin indices in the GSH group compared to the controls on all sun-exposed areas.
Assessment of safety, in both studies, there were no serious or systematic adverse effects were reported. There were no isolated or combined alterations in clinical laboratory measures including hematology, hepatic, and renal function tests during GSH supplementation. Side effects were generally mild included flatulence, loose stools, flushing, and weight gain.
| Potential Risk to General Public|| |
Since there are two contradictory results of studies, which the first short-term, oral intake of GSH does not improve GSH status, nor reduce markers of oxidative stress in healthy adults, and thus routine supplementation may not offer health benefits in the absence of disease or oxidative challenge. Another study stated that oral GSH significantly reduced melanin indices and showed lighter skin after the trial. These gap differences lead to further research with longer duration, additional outcome measure such as measuring reduced GSH status, demonstrating levels of oxidative stress in the study candidates before the inclusion and/or the study to be performed in populations with increased oxidative burden such as in type 2 diabetes patients.
| Recommendations and Conclusions|| |
The desire for white and fair skin is a global phenomenon, and it is being highly capitalized by both the cosmetic and dermatologic industries. It is an essential role of the healthcare providers to make the public aware that skin lightening agents may progressively revert back the facultative color to the constitutive level and normally this color change will not go beyond the constitutive level. If such a change is claimed, it should be considered to be dangerous as such alterations can become nonreversible resulting in vitiligo and may also predispose to other complications such as skin cancer as the normal biochemical processes are altered. Till date, systemic skin whitening agents do not have much scientific evidence regarding their use and strict laws should be enforced to ban the use of these agents until well-conducted randomized controlled trials are available ensuring the safety and efficacy of these agents.
Financial support and sponsorship
This work was supported by LESTARI Grant Scheme: 600RMI/DANA 5/3/LESTARI (52/2015). The authors would like to express their gratitude to Ministry of Higher Education and Universiti Teknologi MARA (UiTM), Malaysia for financial support for this research.
Conflicts of interest
There are no conflicts of interest.
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Pharmacokinetics of glutathione and its metabolites in normal subjects. J Korean Med Sci 2005;20:721-6.
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Arjinpathana N, Asawanonda P. Glutathione as an oral whitening agent: A randomized, double-blind, placebo-controlled study. J Dermatolog Treat 2012;23:97-102.
Allen J, Bradley RD. Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers. J Altern Complement Med 2011;17:827-33.
Malathi M, Thappa DM. Systemic skin whitening/lightening agents: What is the evidence? Indian J Dermatol Venereol Leprol 2013;79:842-6.