Scientific Paper

The following information was researched and prepared by Amanda Vickers, Director United States Botanical Safety Laboratory (USBSL) in a paper titled:  “3-Fold Activity Robinson’s Remedies Lip Repair”. USBSL formulates our products.

I. Penetrate

St. John’s Wort (Hypericum perforatum in this case) has two well-known light- mediated anti-viral constituents, hypericin and pseudohypericin. Under ideal conditions (exposure to light), the antiviral effects of hypericin have been well- documented.1,2 It is likely that discrepancies existing in the clinical literature regarding antiviral activity of this ingredient, those which indicate a lack of HSV- inhibition for hypericin, are due to non-ideal conditions in which the hypericin was not photoactivated during treatment protocol.3,4 Robinson’s remedies uses a hydro- ethanolic extract of St. John’s Wort to rapidly penetrate the skin surface in addition to an infused oil of St. John’s Wort, suitable for the care of damaged, sensitive skin.

Lemonbalm (Melissa officinalis L.) is used as an antiviral, specifically for treating cold sores5. Lemonbalm has shown to prevent replication of herpes simplex virus type 2 in HEp-2 cells, as well as inhibit viral infectivity in both herpes simplex virus type 1 and 26. Lemonbalm is able to exert a direct antiviral effect on the herpes virus by affecting attachment and penetration of the virus to the host cells.7,8

The cellular ratio of the amino acids arginine and lysine has been shown in tissue culture studies to determine whether or not a virus is able to direct a host cell to create viral capsids at the expense of host cell histones5. In a lysine-heavy cell, viral replication is suppressed and the viral pathogenicity of the herpes simplex virus is greatly reduced.9 The inclusion of lysine, which is water-soluble, in a topical application, is intended to provide cells at the site of a herpes outbreak with a localized source of extracellular lysine in the event that these cells are lysine-poor.

The use of Glyceryl laurate in Robinson’s Remedies’®  Lip Repair is three-fold. First, it is used as a co-emulsifer that has been shown to be nonirritating and is not a photosensitizer.10 Second, Glyceryl laurate helps penetrate through the skin’s surface. This helps carry active ingredients in the Lip Repair to treat the cold sore at its source. 11 Third, glyceryl laurate is known as monolaurin, a dietary supplement with GRAS (Generally Recognized As Safe) status by the Food and Drug Administration.12 Monolaurin has antibacterial and antivirial effects. Monolaurin has been shown to inactivate the lipid-coated viruses, such as the Herpes simplex virus.13,14

II. Protect

UV radiation damage is one trigger for sores of the lip and mouth region, including cold sore outbreaks and canker sores.15,16 Raspberry and coconut oils are natural plant oils with absorbance spectra in partially overlapping portions of the UV spectrum responsible for most sun-induced skin damage17. Robsinson’s Remedies makes no claims of a specific SPF; however, these oils’ primary role in the current formula is to protect skin from the stress caused by UV exposure–raspberry and coconut oils have nourishing and protective activities that may protect skin from the oxidative damage that normally occurs during UV radiation exposure.

Similarly, olive (Olea Europea) leaf extract also helps protect skin from stress caused by UV exposure. Olive leaf extract is the richest source in olive phenolic compounds such as oleuropein, hydroxytyrosol, and tyrosol. 18 “These phenolic compounds present antimicrobial, anticarcinogenic, anti-inflammatory and antioxidant activities”19.

Behenyl alcohol or Docosanol is a natural fatty alcohol that can be used as an alternative to wax and as an emulsifier. Docosanol has been reported to show substantial inhibitory effects on the replication of herpes simplex virus. 20 It is the active ingredient in the well-known antiviral Abreva ® . Docosanol protects the potential target cells by interfering with early intracellular events preventing viral entry and thus replication of the virus.21

Both tea tree (Melaleuca alternifolia) and peppermint (Mentha x piperita) essential oils are a widely recognized as having broad spectrum antimicrobial activity.22,23

Leucidal Liquid and AMTicide Coconut are included in the Robinson’s Remedies’ Lip Repair as natural preservatives. Leucidal Liquid is based on an antimicrobial peptide originally derived from Leuconostoc kimchii, which restricts microbial growth by acidifying its environment. Leucidal Liquid has also been shown to provide skin moisturization properties.24 AMTicide Coconut is created by fermenting Coconut (Cocos nucifera) fruit with Lactocacillus, which restricts fungal growth by disrupting the cellular structures of fungus. AMTicide Coconut also offers moisturizing and conditioning benefits.25

Butylated hydroxytoluene (BHT): The CRC Handbook (1992) classifies butylated BHT as an antioxidant, which is generally recognized as safe (USDA GRAS-listed) at the following levels:

• Food: <.02% total fat and oil (flavorings and essential oils can contain up to .5%)

• Drugs: <.2%

• Cosmetics: 0.01-0.1%

The FDA’s regulatory listing for injestible BHT lists a “no-effect” level as being equivalent to 50mg/kg of body weight per day. In the present formula, an entire 8- ml tube of lip repair contains approximately 8ug of BHT. With a “no-effect” level for a 70kg adult at 3500mg per day, consumption of an entire tube of Lip Repair would be on the order of 1/(4 X 106) of the “no effect” dose.

The information on the metabolism and toxicology of BHT is extensive. There is ample evidence of efficacy of this compound as an antioxidant. It has been suggested that BHT in fatty tissue may even have some effect similar to that of vitamin E. There are some data to indicate that BHT in diets reduces the incidence of certain tumors and the rate of fetal absorption in the rat. The available evidence does not support the view that BHT interferes in any specific way with cellular metabolism. There is no evidence that demonstrates that BHT causes frank biochemical lesions in the liver; moreover, it is obvious that high doses of BHT are needed to induce biochemical alterations. With 0.1% BHT in the diet in rats there are differing data in the literature concerning the effect of such treatment on liver growth and liver enzymes. At 0.05 % in the diet, no toxic effects are discernible. This “no-effect level” is equivalent to 50 mg per kg per day.26

A 1985 animal study evaluated the effect of topical treatment with BHT (5, 10, or 15%) on the recurrence and severity of lesion outbreaks in guinea pigs inoculated with genital herpes simplex virus, demonstrating a reduction in lesion duration during the first outbreak after inoculation:

“Treatment with placebo, 5%, 10%, or 15% BHT was initiated 48 h after viral inoculation and continued 4 times daily for 15 days. During primary infection no differences in maximum lesion severity or titers of virus in lesions were observed, however, lesion duration was reduced in BHT-treated animals resulting in a significantly smaller lesion score-day area under the reporting curve. In a second experiment using U.S.P. mineral oil as an additional placebo, BHT placebo and 15% BHT in a double blind trial, similar results were obtained.27”

In hairless mice infected with herpes simplex virus type 1, BHT was found to be effective in reducing the clearance time of cutaneous lesions when applied topically to the infected area (information on dosage not available to public at this time).28

III. Soothe

Arnica (Arnica MontanaI L.) flower infused oil makes up 2% of our total formula, or about 8% of our oil phase. In addition, we add a concentrated arnica flower CO2 extract to the arnica infused oil to increase potency. It must be noted that much of the literature finding inconclusive results for arnica in reduction of swelling and healing time is not conducted on a therapeutic dose of the plant constituents as is used in this formula, but on extremely dilute homeopathic preparations. Lip repair uses not homeopathic arnica, but a topical infused oil and CO2 extract. Extracts of arnica that include functional doses of the herb (between 1:10 and 1:100 herb weight to final volume) have been clinically shown to reduce painful swelling after surgeries and to increase healing time29,30. In this formula arnica is used to reduce painful swelling that accompanies early onset cold sores and to restore fluidity to the tissues surrounding a lesion.

Ahiflower ®  (Buglossoides arvensis) seed oil is a safe and sustainable addition of essential Omega 3 fatty acids in Robinson’s Remedies Lip Repair. Omega 3s helps reduce inflammation, as well as moisturize your skin. 31,32

Glycerin is a naturally occurring sugar alcohol, which is one of the most commonly used and safe humectants, cosmetic ingredients that attract water from the air to the skin, causing a moisturizing effect. Glycerin is also more stable than water, and is bacteriostatic. Robinson’s Remedies uses only USP, vegetable-derived glycerin in Lip Repair and all its skin repair products. Glycerin is also approved by the FDA for use as a skin protectant active for use in the case of fever blisters and cold sores.

Glyceryl Stearate Citrate, Polyglyceryl-3 Stearate, Hydrogenated Lecithin and C12- 16 alcohols: These phospholipid emulsifiers create the creamy consistency of Lip Repair, and act as a protective second skin when applied to the lips, entrapping the nutritive and active oils of Lip Repair on the skin’s surface, while allowing the water- soluble lysine and St. John’s Wort extract to penetrate. Lysolecithin and Sclerotium Gum and Xanthan Gum and Pullulan also help to stabilize the emulsion, while providing a smooth, but non greasy feel on application.33 Potassium cetyl phosphate is an emulsifier and stabilizer, which are vital to a formulation to ensure that it maintains its homogenous mixture.

The herb responsible for the sweet flavor of Robinson’s Remedies’ Lip Repair is known as the sweet leaf, Stevia rebaudiana (Bertoni) Bertoni a plant of the Asteraceae family which is used in traditional cultures of Paraguay for sweetening teas such as yerba mate. Now, stevia is widely available under a plethora of brand names, with highly purified Rebaudioside A preparations being granted GRAS status in the US in 2009. Robinson’s Remedies uses a high quality food-grade stevia extract. In addition, stevia has been found to have anti-microbial and anti- inflammatory effects in vitro.34,35

Manuka honey is a monofloral honey, produced from the nectar of the Manuka honey bush, and is referred to as the “gold standard” of honey.36 The honey was added to Robinson’s Remedies’ Lip Repair to help soothe skin by decreasing inflammation and exudation that is common with cold sores. Honey has also been shown to be a safe and effective way to decrease the healing time of herpes simplex lesions. 37

TRADEMARKS

Robinson’s Remedies is a registered trademark of RR Health LLC

Abreva is a registered trademark of GlaxoSmithKline PLC

Ahiflower is a registered trademark of Technology Crops, LLC

Footnotes:

1 Hudson, J. B., I. Lopez-Bazzocchi, and G. H. N. Towers. “Antiviral activities of hypericin.” Antiviral research 15.2 (1991): 101-112.

2 Cohen, P. A., J. B. Hudson, and G. H. N. Towers. “Antiviral activities of anthraquinones, bianthrones and hypericin derivatives from lichens.” Experientia 52.2 (1996): 180-183.

3 Hudson, J. B., I. Lopez-Bazzocchi, and G. H. N. Towers. “Antiviral activities of hypericin.” Antiviral research 15.2 (1991): 101-112.

4 Lopez‐Bazzocchi, I., J. B. Hudson, and G. H. N. Towers. “Antiviral activity of the photoactive plant pigment hypericin.” Photochemistry and photobiology 54.1 (1991): 95-98.

5 Moradkhani, H., Sargsyan, E., Bibak, H., Naseri, B., Sadat-Hosseini, M., Fayazi-Barjin, A., & Meftahizade, H. (2010). Melissa officinalis L., a valuable medicine plant. J. Med. Plants Res, 4, 2753-2759.

6 Allahverdiyev, A., Duran, N., Ozguven, M., & Koltas, S. (2004). Antiviral activity of the volatile oils of Melissa officinalis L. against Herpes simplex virus type-2. Phytomedicine, 11(7-8), 657-661.

  7 Schnitzler, P., Schuhmacher, A., Astani, A., & Reichling, J. (2008). Melissa officinalis oil affects infectivity of enveloped herpesviruses. Phytomedicine, 15(9), 734-740.

8 Astani, A., Heidary Navid, M., & Schnitzler, P. (2014). Attachment and Penetration of Acyclovir‐resistant Herpes Simplex Virus are Inhibited by Melissa officinalis Extract. Phytotherapy research, 28(10), 1547-1552.

9 Griffith, RichardS, et al. “Success of L-lysine therapy in frequently recurrent herpes simplex infection.” Dermatology 175.4 (1987): 183-190.

10 Raposo, S., Salgado, A., Gonçalves, L., Pinto, P. C., Urbano, M., & Ribeiro, H. M. (2013). Safety assessment and biological effects of a new cold processed SilEmulsion for dermatological purpose. BioMed research international, 2013.

11 Final Report of the Amended Safety Assessment of Glyceryl Lau rate, Glyceryl Lau rate SE, Glyceryl Laurate/Oleate, Glyceryl Adipate, Glyceryl Alginate, Glyceryl Arachidate, Glyceryl Arachidonate, Glyceryl Behenate, Glyceryl Caprate, Glyceryl Caprylate, Glyceryl Caprylate/Caprate, Glyceryl Citrate/Lactate/Linoleate/Oleate, Glyceryl Cocoate, Glyceryl Collagenate, Glyceryl Erucate, Glyceryl Hydrogenated Rosinate, Glyceryl Hydrogenated Soyate, Glyceryl Hydroxystearate, Glyceryl Isopalmitate, Glyceryl Isostearate, Glyceryl Isostearate/Myristate, Glyceryl Isostearates, Glyceryl Lanolate, Glyceryl Linoleate, Glyceryl Linolenate, Glyceryl Montanate, Glyceryl Myristate, Glyceryl Isotridecanoate/Stearate/Adipate, Glyceryl Oleate SE, Glyceryl Oleate/Elaidate, Glyceryl Palmitate, Glyceryl Palmitate/Stearate, Glyceryl Palmitoleate, Glyceryl Pentadecanoate, Glyceryl Polyacrylate, Glyceryl Rosinate, Glyceryl Sesquioleate, Glyceryl/Sorbitol Oleate/Hydroxystearate, Glyceryl Stearate/Acetate, Glyceryl Stearate/Maleate, Glyceryl Tallowate, Glyceryl Thiopropionate, and Glyceryl Undecylenate1. (2004). International Journal of Toxicology, 23(2_suppl), 55–94. doi: 10.1080/10915810490499064

12 CHAPTER, I. CFR-Code of Federal Regulations Title 21.

13 Lieberman, S., Enig, M. G., & Preuss, H. G. (2006). A review of monolaurin and lauric acid: natural virucidal and bactericidal agents. Alternative & Complementary Therapies, 12(6), 310-314.

14 HIERHOLZER, J. C., & KABARA, J. J. (1982). IN VITRO EFFECTS OF MONOLAURIN COMPOUNDS ON ENVELOPED RNA AND DNA VIRUSES 1. Journal of Food Safety, 4(1), 1-12.

15 Wheeler Jr, Clayton E. “The herpes simplex problem.” Journal of the American Academy of Dermatology 18.1 (1988): 163-168.

16 Esmann, Jørgen. “The many challenges of facial herpes simplex virus infection.” Journal of antimicrobial Chemotherapy 47.suppl 1 (2001): 17-27.

7 Schnitzler, P., Schuhmacher, A., Astani, A., & Reichling, J. (2008). Melissa officinalis oil affects infectivity of enveloped herpesviruses. Phytomedicine, 15(9), 734-740.

8 Astani, A., Heidary Navid, M., & Schnitzler, P. (2014). Attachment and Penetration of Acyclovir‐resistant Herpes Simplex Virus are Inhibited by Melissa officinalis Extract. Phytotherapy research, 28(10), 1547-1552.

9 Griffith, RichardS, et al. “Success of L-lysine therapy in frequently recurrent herpes simplex infection.” Dermatology 175.4 (1987): 183-190.

10 Raposo, S., Salgado, A., Gonçalves, L., Pinto, P. C., Urbano, M., & Ribeiro, H. M. (2013). Safety assessment and biological effects of a new cold processed SilEmulsion for dermatological purpose. BioMed research international, 2013.

11 Final Report of the Amended Safety Assessment of Glyceryl Lau rate, Glyceryl Lau rate SE, Glyceryl Laurate/Oleate, Glyceryl Adipate, Glyceryl Alginate, Glyceryl Arachidate, Glyceryl Arachidonate, Glyceryl Behenate, Glyceryl Caprate, Glyceryl Caprylate, Glyceryl Caprylate/Caprate, Glyceryl Citrate/Lactate/Linoleate/Oleate, Glyceryl Cocoate, Glyceryl Collagenate, Glyceryl Erucate, Glyceryl Hydrogenated Rosinate, Glyceryl Hydrogenated Soyate, Glyceryl Hydroxystearate, Glyceryl Isopalmitate, Glyceryl Isostearate, Glyceryl Isostearate/Myristate, Glyceryl Isostearates, Glyceryl Lanolate, Glyceryl Linoleate, Glyceryl Linolenate, Glyceryl Montanate, Glyceryl Myristate, Glyceryl Isotridecanoate/Stearate/Adipate, Glyceryl Oleate SE, Glyceryl Oleate/Elaidate, Glyceryl Palmitate, Glyceryl Palmitate/Stearate, Glyceryl Palmitoleate, Glyceryl Pentadecanoate, Glyceryl Polyacrylate, Glyceryl Rosinate, Glyceryl Sesquioleate, Glyceryl/Sorbitol Oleate/Hydroxystearate, Glyceryl Stearate/Acetate, Glyceryl Stearate/Maleate, Glyceryl Tallowate, Glyceryl Thiopropionate, and Glyceryl Undecylenate1. (2004). International Journal of Toxicology, 23(2_suppl), 55–94. doi: 10.1080/10915810490499064

12 CHAPTER, I. CFR-Code of Federal Regulations Title 21.

13 Lieberman, S., Enig, M. G., & Preuss, H. G. (2006). A review of monolaurin and lauric acid: natural virucidal and bactericidal agents. Alternative & Complementary Therapies, 12(6), 310-314.

14 HIERHOLZER, J. C., & KABARA, J. J. (1982). IN VITRO EFFECTS OF MONOLAURIN COMPOUNDS ON ENVELOPED RNA AND DNA VIRUSES 1. Journal of Food Safety, 4(1), 1-12.

15 Wheeler Jr, Clayton E. “The herpes simplex problem.” Journal of the American Academy of Dermatology 18.1 (1988): 163-168.

16 Esmann, Jørgen. “The many challenges of facial herpes simplex virus infection.” Journal of antimicrobial Chemotherapy 47.suppl 1 (2001): 17-27.

17 Oomah, B. Dave, et al. “Characteristics of raspberry (< i> Rubus idaeus</i> L.) seed oil.” Food Chemistry 69.2 (2000): 187-193.

18 De Bock, M., Thorstensen, E. B., Derraik, J. G., Henderson, H. V., Hofman, P. L., & Cutfield, W. S. (2013). Human absorption and metabolism of oleuropein and hydroxytyrosol ingested as olive (Olea europaea L.) leaf extract. Molecular nutrition & food research, 57(11), 2079-2085.

19 Ribeiro, Ana Sofia, et al. “Main benefits and applicability of plant extracts in skin care products.” Cosmetics 2.2 (2015): 48-65.

20 Katz, D. H., Marcelletti, J. F., Khalil, M. H., Pope, L. E., & Katz, L. R. (1991). Antiviral activity of 1-docosanol, an inhibitor of lipid-enveloped viruses including herpes simplex. Proceedings of the National Academy of Sciences, 88(23), 10825-10829.

21 Pope, L. E., Marcelletti, J. F., Katz, L. R., Lin, J. Y., Katz, D. H., Parish, M. L., & Spear, P. G. (1998). The anti-herpes simplex virus activity of n-docosanol includes inhibition of the viral entry process. Antiviral research, 40(1-2), 85-94.

22 Cox, S. D., et al. “The mode of antimicrobial action of the essential oil of Melaleuca alternifolia (tea tree oil).” Journal of applied microbiology 88.1 (2000): 170-175.

23 Hammer, Katherine A., C. F. Carson, and T. V. Riley. “Antimicrobial activity of essential oils and other plant extracts.” Journal of applied microbiology 86.6 (1999): 985-990.

24 Leucidal® Liquid. (n.d.). Retrieved from https://activemicrotechnologies.com/product/leucidal-liquid/

25 AMTicide® Coconut. (n.d.). Retrieved from https://activemicrotechnologies.com/product/ amticide-coconut/

26 Butylated Hydroxytoluene—FDA Proposed Rule, Vol 42, No. 104, Federal Register, page 27606, May 1977

27 Richards, James T., Mary Ellen Katz, and Earl R. Kern. “Topical butylated hydroxytoluene treatment of genital herpes simplex virus infections of guinea pigs.” Antiviral research 5.5 (1985): 281-290.

28 Keith, Alec D., et al. “The antiviral effectiveness of butylated hydroxytoluene on herpes cutaneous infections in hairless mice.” Experimental Biology and Medicine 170.2 (1982): 237-244.

29 Huber, Roman, et al. “Arnica and stinging nettle for treating burns–A self- experiment.” Complementary therapies in medicine 19.5 (2011): 276-280.

30 Kučera, Miroslav, et al. “Arnica/Hydroxyethyl salicylate combination spray for ankle distortion: A four-arm randomised double-blind study.” Pain research and treatment 2011 (2011). 

 31 Cumberford, G., & Hebard, A. (2015). Ahiflower oil: A novel non‐GM plant‐ based omega‐3+ 6 source. Lipid Technology, 27(9), 207-210.

32 Prasad, P., Savyasachi, S., & Reddy, L. P. A. (2019). Physico-chemical Characterization, Profiling of Total Lipids and Triacylglycerol Molecular Species of Omega-3 Fatty Acid Rich B. arvensis Seed Oil from India. Journal of oleo science, 68(3), 209-223.

33 Moldovan, M., Lahmar, A., Bogdan, C., Părăuan, S., TOMUŢĂ, I., & CRIŞAN, M. (2017). Formulation and evaluation of a water-in-oil cream containing herbal active ingredients and ferulic acid. Clujul Medical, 90(2), 212.

34 Jayaraman, Sathishkumar, Muthu Saravanan Manoharan, and Seethalakshmi Illanchezian. “In-vitro antimicrobial and antitumor activities of Stevia rebaudiana (Asteraceae) leaf extracts.” Tropical Journal of Pharmaceutical Research 7.4 (2008): 1143-1149.

35 Boonkaewwan, Chaiwat, Chaivat Toskulkao, and Molvibha Vongsakul. “Anti- inflammatory and immunomodulatory activities of stevioside and its metabolite steviol on THP-1 cells.” Journal of agricultural and food chemistry 54.3 (2006): 785- 789.

36 Ahmed, S., & Othman, N. H. (2013). Review of the medicinal effects of tualang honey and a comparison with manuka honey. The Malaysian journal of medical sciences: MJMS, 20(3), 6.

37 Al-Waili, N. S. (2004). Topical honey application vs. acyclovir for the treatment of recurrent herpes simplex lesions. Medical Science Monitor, 10(8), MT94-MT98.