Section G: Other Ingredients

INTRODUCTION

SOURCE

Coenzyme Q₁₀ (CoQ₁₀) is a fat-soluble compound found in all cells in the lipophilic portion of the cell membrane. It is the only lipid-soluble antioxidant synthesized endogenously and, as such, is not a vitamin.² CoQ₁₀ acts as a cofactor in numerous biological processes and contributes to the electron transfer chain responsible for energy production, playing an essential role for electron transport in the mitochondrial respiratory chain (Table 57-1).³ CoQ₁₀ is thought to contribute 95 percent of the body’s adenosine triphosphate (ATP) or energy needs.⁴ It also plays a critical role in endogenous free radical scavenging.¹ In addition to its natural presence in human cells, CoQ₁₀ can be obtained through the diet, with fish and shellfish known to be good sources. As a supplement, the recommended oral dose is 90 to 150 mg daily, though some doctors recommend 200 to 400 mg daily. CoQ₁₀ has a caffeine-like effect and therefore supplements should be taken in the morning to prevent insomnia.

HISTORY

CoQ₁₀ and related compounds have, as Hoppe et al. suggested, developed with biological evolution through millions of years.⁵ It is now known to be widely distributed among humans and animals.⁶ But CoQ₁₀ was first discovered by Crane et al. in 1957, when they identified and isolated the compound from beef heart mitochondria.⁷ The chemical structure was subsequently determined and Peter Mitchell elucidated the role of CoQ₁₀ in oxidative phosphorylation and the electron transport chain in 1961, work for which he was awarded the Nobel Prize in Chemistry in 1978.⁸ A great deal of the literature since that period, and stemming from seminal work by Folkers and Littarru in 1972 on the role of CoQ₁₀ deficiency in human heart disease, has focused on its oral administration for atherosclerosis, muscle contractility, congestive heart failure, and other cardiovascular issues.^2,9,10 A year earlier, Littarru, Folkers, and colleagues reported on CoQ₁₀ deficiency in the gingival tissue of adults with periodontal disease.¹¹ In recent years, the potential application of CoQ₁₀ in the treatment of various health conditions, including neurodegenerative disorders such as Parkinson’s disease and Huntington’s disease, migraine headaches, memory loss, inflammation, and skin aging has garnered considerable research attention.^9,12

CHEMISTRY

CoQ₁₀ is a 1,4-benzoquinone compound. It is also known as ubidecarenone as well as ubiquinone, because it is known to be ubiquitous in all biological systems.^12,13 The “Q” in CoQ₁₀ refers to its inclusion in the quinone family; the “10” identifies the number of isoprenoid units on its side chain, a number that renders the compound highly lipophilic.¹⁴ Its chemical structure consists of a p-benzoquinone ring with a polyisoprenoid side chain.¹⁴ The biosynthesis of CoQ₁₀, which primarily involves 4-hydroxybenzoate and the polyprenyl chain,⁶ is a complex process that depends on an abundance of essential amino acids, such as tyrosine, and numerous vitamins and trace elements. Several studies on the use of CoQ₁₀ in cardiology appear in the literature,¹⁵ and CoQ₁₀ has also been found to exhibit antioxidant properties, with the reduced form of CoQ₁₀ (ubiquinol, Q₁₀H₂) known to be particularly effective as an antioxidant in biological membranes.³ In its oxidized state, as ubiquinone, CoQ₁₀ can accept electrons from free radicals but not donate them.⁹ Multiple in vitro and in vivo studies suggest that CoQ₁₀ imparts protective effects on various markers of oxidative DNA damage and genomic stability.³ CoQ₁₀ has also exhibited a direct antiatherogenic effect in a mouse model.²

In addition, CoQ₁₀ has been demonstrated to influence the production of some key cutaneous proteins and to reduce the expression of some matrix metalloproteinases (MMPs) such as collagenase.⁸ Further, it has been shown to regenerate another potent lipophilic antioxidant, α-tocopherol.⁶ The ability to synthesize CoQ₁₀ endogenously declines after the age of 35 to 40, as does the quantity of CoQ₁₀ in human sebum, deficiencies which can be exacerbated by poor eating habits, stress, and infection; therefore, supplementation is thought to contribute to various health metrics to compensate for the reduced CoQ₁₀ levels that emerge with age.^1,16

ORAL USES

Commercial CoQ₁₀ has the reputation of poor intestinal absorption.¹⁷ Bhagavan and Chopra showed that total plasma CoQ₁₀ and net increase over baseline CoQ₁₀ concentrations gradually rise with increasing doses of orally ingested CoQ₁₀, with the absorption efficiency declining with increasing dose.¹² Extended supplementation of CoQ₁₀ in humans has been shown by Ashida et al. to diminish periocular wrinkle formation. Daily oral supplementation with CoQ₁₀ (0, 1, 100 mg/kg p.o.) for two weeks in adult hairless mice has also been associated with significantly higher levels of CoQ₁₀ in the epidermis, but not in the dermis. The researchers speculated that this might be a precondition for wrinkle reduction and other benefits related to the potent antioxidant and energizing effects of CoQ₁₀ in skin.¹⁸ Notably, CoQ₁₀ is known to be present in humans at 10-fold higher levels in the epidermis than the dermis.¹⁹

In 2010, López et al. studied the in vitro effects of CoQ₁₀, CoQ₂, the synthetic CoQ₁₀ analog idebenone (see Chapter 61, Idebenone), and vitamin C, finding that primary CoQ₁₀ deficiencies can be treated sufficiently with CoQ₁₀ supplementation but not with short-tail analogs (e.g., idebenone and CoQ₂).²⁰ Oral supplementation with CoQ₁₀ has gained in popularity in recent years and such dietary supplements are readily available.¹²

TOPICAL USES

In an early study of the topical application of CoQ₁₀, Giovannini et al. suspended CoQ₁₀ in olive oil and administered it to rats at two different concentrations. Subsequent CoQ₁₀ levels were directly proportional to the concentrations and contact times. They concluded that the topical use of CoQ₁₀ might warrant consideration for use in the dermatologic realm.²¹

In 1999, Hoppe et al. showed that CoQ₁₀ penetrated into the viable layers of the epidermis, and lowered oxidation levels as measured by weak photon emission. They also measured decreases in wrinkle depth after CoQ₁₀ application. Further, the researchers observed that the antioxidant inhibited the expression of collagenase in human dermal fibroblasts after ultraviolet (UV) A exposure and prevented oxidative DNA damage as well as UVA-mediated oxidative stress in keratinocytes. The investigators considered their findings good evidence that CoQ₁₀ displays the capacity to prevent several sequelae of photoaging.⁵

In 2003, Passi et al. set out to ascertain the combined effect of topical and oral lipophilic antioxidants on the antioxidant content of sebum and the stratum corneum (SC). For two months, 50 female volunteers, aged 21 to 40, were treated daily on the face and back with a base cream containing CoQ₁₀, vitamin E, and squalene. To half of the volunteers, an oral preparation including the same ingredients was administered. While the daily topical application resulted in a significant boost in the levels of the lipophilic antioxidants and squalene in the sebum without affecting SC or plasma concentrations, the concomitant oral administration in the one group led to significantly higher lipophilic antioxidant measurements in the SC and plasma but no such increase in sebum levels. The investigators concluded that topically applying the antioxidants raised their levels in sebum and concomitant oral administration increased CoQ₁₀ and vitamin E levels in the SC as well.^16,22

In 2010, Liu and Artmann conducted a double-blind, parallel-design, controlled, single-dose (120 mg) bioavailability study in 20 healthy male and female volunteers to compare a novel colloidal-Q₁₀ delivery system based on new and patented technology with three commercially available CoQ₁₀ products. The colloidal-Q₁₀ formulation was associated with the highest plasma concentrations throughout the 24-hour period along with the greatest relative bioavailability, with statistically significant differences seen in both metrics. The researchers concluded that their novel CoQ₁₀ delivery system enhanced enteral absorption and bioavailability.¹⁷

Also that year, Lee and Tsai demonstrated the efficacy of a liposomal formulation of soybean phosphatidylcholine and α-tocopherol to encapsulate CoQ₁₀ for topical delivery. They found that it augmented CoQ₁₀ accumulation in rat skin over twofold in comparison with an unencapsulated suspension. In addition, lengthening the treatment time and elevating CoQ₁₀ content in the formulation increased CoQ₁₀ levels in rat skin, with inadequate treatment time limiting accumulation. The investigators concluded that their liposomal CoQ₁₀ formulation shows promise as a topical delivery agent for CoQ₁₀ given sufficient treatment duration.¹⁴ It is important to note that topical products containing CoQ₁₀ as the main ingredient should appear to have a yellow tint.

In 2010, Yue et al. developed a novel CoQ₁₀ topical delivery system using a nano-structured lipid carrier to enhance photoprotection. The in vitro protection of fibroblasts against UVA radiation afforded by a CoQ₁₀-loaded nano-structured lipid carrier (CoQ₁₀-NLC) was greater than that provided by a CoQ₁₀ emulsion. In cells treated with CoQ₁₀-NLC, malondialdehyde concentration was reduced by 61.5 percent as compared to the CoQ₁₀ emulsion cells. The presence of CoQ₁₀-NLC also yielded significant increases in the antioxidant enzymes superoxide dismutase and glutathione peroxidase. CoQ₁₀-NLC also exhibited better penetration into the SC and dermis after topical application in Sprague-Dawley rats as compared to the CoQ₁₀ emulsion.²³

In 2012, Gokce et al. investigated CoQ₁₀-loaded liposomes and solid lipid nanoparticles as delivery systems of the compound for antioxidant purposes into the skin, finding that the liposome system exhibited the capacity to promote cell proliferation and the solid lipid nanoparticle system failed to protect against the accumulation of reactive oxygen species.²⁴

Felippi et al. conducted a pilot study in 2012 on the safety and efficacy of a nanoparticle formulation encapsulating various active ingredients, including CoQ₁₀, retinyl palmitate, tocopheryl acetate, grape seed oil, and linseed oil. The nanoparticles demonstrated no irritating, sensitizing, or comedogenic properties and phototoxicity was not evident after exposure to UVA light. In the efficacy assessment with volunteers, significant decreases in wrinkles were observed as compared to controls after 21 days of treatment. The investigators concluded that the antioxidant-loaded nanoparticle formulation is safe for topical administration and, having displayed in vivo antiaging activity, warrants consideration as a cosmetic agent for such purposes.²⁵

In 2013, Chen et al. formulated a CoQ₁₀-NLC using high-pressure microfluidics and assessed it in vitro for epidermal targeting effects. The CoQ₁₀-NLC displayed fast release through the first three hours and extended release subsequently. The accumulation of CoQ₁₀ in rat epidermis was over 10-fold higher with the CoQ₁₀-NLC as compared to a CoQ₁₀ emulsion in an in vitro skin permeation study. Further, the CoQ₁₀ level in CoQ₁₀-NLC fell 5.59 percent as compared to reductions of 24.61 percent in the CoQ₁₀ emulsion and 49.74 percent in a CoQ₁₀ ethanol solution after 24 hours of UV exposure. The investigators concluded that their CoQ₁₀-NLC formulation demonstrated a significant epidermal targeting effect, establishing itself as a potential carrier for the topical application of CoQ₁₀.²⁶

Recent in vivo studies have shown reductions in the symptoms of photoaging through the use of topically applied CoQ₁₀, though bioavailability of CoQ₁₀ has remained poor.¹⁴ In 1999, Blatt et al. showed through in vivo studies that the long-term application of CoQ₁₀ could reduce crow’s feet.²⁷

CoQ₁₀ in Combination Therapy

In 2009, Kharaeva et al. assessed the clinical effects of supplementation of a combination of CoQ₁₀, vitamin E, and selenium in the treatment of 58 patients with severe erythrodermic and arthropathic psoriasis. Patients were randomized into four groups with two groups receiving the antioxidant combination dissolved in soy lecithin for 30 to 35 days. The placebo groups received soy lecithin. The investigators reported that supplementation yielded significant improvements in clinical conditions, correlating with a quicker normalization of oxidative stress markers as compared to the placebo groups. They concluded that the use of these antioxidants merits consideration for managing severe psoriasis.²⁸

Several of the same investigators conducted two controlled clinical trials in 2012 to compare a nutraceutical approach to standard therapy for two mucocutaneous chronic DNA-virus infections. The nutraceutical, containing CoQ₁₀, vitamin E, selenium, and methionine, or a placebo was administered for 180 days to 68 patients with relapsing human papillomavirus skin warts treated with cryotherapy in the first trial. In the second trial, the combination of acyclovir followed by 90 days of nutraceutical administration was compared to acyclovir alone in 60 patients with recurrent herpes or 29 patients with herpes zoster. The nutraceutical was found to provoke significantly more rapid healing with lower relapse incidence in comparison to control groups. In addition, plasma antioxidant capacity was found to be higher in the nutraceutical group as compared to controls.²⁹

SAFETY ISSUES

Oral CoQ₁₀ supplementation can elicit nervousness or a jittery feeling not unlike one of the side effects of caffeine. CoQ₁₀ should be taken during the day to reduce the risk of causing insomnia. Other reported side effects include appetite loss, diarrhea, and mild nausea.³⁰ Overall, the safety of orally administered CoQ₁₀, even at high doses (up to 900 mg/day), has been established.^17,31 No contact dermatitis or any other side effects have been associated with the topical application of CoQ₁₀, which is photostable and well tolerated.⁵ However, the synthetic analog of CoQ₁₀, known as idebenone, has been reported to cause contact dermatitis (see Chapter 61, Idebenone).

ENVIRONMENTAL IMPACT

There is no environmental impact of commercial CoQ₁₀ production known by the author.

FORMULATION CONSIDERATIONS

Low aqueous solubility and the high molecular weight of this compound limit the topical delivery of CoQ₁₀ to deeper skin layers.^24,32 It is a lipophilic compound and to increase penetration must be formulated in liposomes and other formulations designed to increase penetration. Orally ingested solubilized formulations of CoQ₁₀ (both ubiquinone and ubiquinol, the predominant form – 95 percent – of circulating CoQ₁₀) exhibit superior bioavailability to nonsolubilized powder-based products as indicated by their enhanced plasma CoQ₁₀ responses.¹²

USAGE CONSIDERATIONS

CoQ₁₀ is stable in topical formulations. It does not, to the author’s knowledge, interact with other ingredients in a skin care regimen. Products that contain a significant amount of CoQ₁₀ appear yellow.

SIGNIFICANT BACKGROUND

Reduced levels of CoQ₁₀ in humans have been associated with aging as well as with various pathologies (e.g., cardiac disorders, neurodegenerative diseases, AIDS, and cancer).^6,16

Network Antioxidants

Vitamin C and CoQ₁₀ exhibit the ability to recycle vitamin E, donating electrons to return vitamin E to its antioxidant state. The antioxidants identified as acting cooperatively in this fashion have been called network antioxidants.³³ The five compounds designated as network antioxidants are vitamins C and E, glutathione, lipoic acid, and CoQ₁₀. Network antioxidants are a staple in cosmetic preparations, but it is likely that many antioxidants work synergistically, and that the expression “network antioxidant” is actually applicable to many more antioxidants than the five identified as the “network.” For example, in 2013, Wölfle et al. demonstrated that the addition of low concentrations of antioxidants such as CoQ₁₀ and vitamin E synergistically amplified the potent antioxidant and photoprotective activity of the flavonoid luteolin in solar simulator-irradiated human skin fibroblasts.³⁴ One of the same researchers previously demonstrated that a topically applied cream containing luteolin, CoQ₁₀, and vitamin E, in the same ratio as in the in vitro study (4:4:1, luteolin, vitamin E, CoQ₁₀, respectively), was effective in protecting the skin from chemical-induced irritation.³⁵

Antiaging Activity

An age-related decline of CoQ₁₀ levels has been reported in animals and humans.³⁶ Consequently, the antioxidant activities of CoQ₁₀ have been targeted for potential applications in treating aged skin. Hoppe et al. showed that CoQ₁₀ penetrated into the viable layers of the skin and significantly inhibited collagenase expression in human dermal fibroblasts following UVA exposure.⁵

In 2006, Fuller et al. found that CoQ₁₀ has the capacity to inhibit the inflammatory response in dermal fibroblasts induced by UV radiation (UVR) or interleukin (IL)-1. In addition, they observed that CoQ₁₀ suppressed UVR-induced MMP-1 synthesis. In combination with the colorless carotenoids phytoene and phytofluene, CoQ₁₀ enhanced inflammation suppression. The investigators concluded that combining CoQ₁₀ and carotenoids in a topical skin care formulation may render dual protection against photoaging and inflammation.⁹

In 2008, Prahl et al. took skin biopsies of young and old donors and observed marked age-dependent differences in the mitochondrial function of the sampled keratinocytes. This led them to conclude that aging skin is functionally anaerobic, conducted mainly through a nonmitochondrial pathway. They suggested that the topical application of CoQ₁₀ quickly enhances mitochondrial function in skin in vivo, thus conferring antiaging activity.³⁷ Insofar as CoQ₁₀ preserves mitochondrial functioning, thus contributing to energy level maintenance, it acts to prevent aging skin from employing anaerobic energy production mechanisms.⁸

Inui et al. demonstrated in vitro that UVB-induced IL-6 production of normal human keratinocytes was reduced in the presence of CoQ₁₀. MMP-1 synthesis of cultured fibroblasts was also significantly diminished. In the investigators’ clinical study of 31 female subjects aged 27 to 61 years, 1 percent CoQ₁₀ cream used for five months resulted in wrinkle score decreases as noted by a dermatologist. They concluded that CoQ₁₀ appears to rejuvenate wrinkled skin by virtue of suppressing IL-6 production, which spurs fibroblasts in the dermis to upregulate MMP production thus contributing to dermal fiber degradation.^38,39

In an in vitro study in 2012, Zhang et al. considered the effects of CoQ₁₀ on primary human dermal fibroblasts. They showed that CoQ₁₀ exerted a broad array of effects in embryonic and adult cells, including the spurring of fibroblast proliferation, augmenting type IV collagen expression, and lowering the levels of MMPs induced by UV radiation. CoQ₁₀ also dose-dependently fostered elastin gene expression in cultured fibroblasts and markedly reduced IL-1α synthesis in keratinocytes induced by UVR. In addition, they found that the antioxidant inhibited tyrosinase activity similarly to ascorbic acid, suggesting the potential for imparting depigmenting effects. Overall, they concluded that CoQ₁₀ demonstrated activity against intrinsic aging as well as photoaging.⁴⁰

Coenzyme Q₁₀ and Skin Cancer

Patients with breast, lung, or pancreatic cancer have been found to have abnormally low plasma levels of CoQ₁₀.⁴¹ A study by Rusciani et al. examined the usefulness of CoQ₁₀ plasma levels in predicting the risk of metastasis and the length of the metastasis-free interval in melanoma patients. They found that CoQ₁₀ levels were significantly lower in melanoma patients than in control subjects and in patients who experienced metastases as compared to the metastasis-free subgroup. The investigators concluded that baseline plasma CoQ₁₀ levels can serve as a prognostic factor to estimate the risk for melanoma progression.⁴²

Large quantities of ATP are essential for an immune response initiated by interferon (IFN) to be effective in the adjuvant therapy of melanoma. Accordingly, some have theorized that the failure of some patients to respond to IFN therapy may be the result of an inability to meet the excess demand for ATP engendered by this medication. However, CoQ₁₀ is known to play a significant role in the mitochondrial respiratory cycle and ATP synthesis.^43,44 In 2007, Rusciani et al. conducted a clinical trial in stages I and II melanoma patients investigating a postsurgical adjuvant therapy with recombinant IFN α-2b combined with CoQ₁₀ vs. IFN α-2b alone for the control group. In the three-year trial, reported in 2007, patients were given twice-daily administrations of low-dose recombinant IFN α-2b and CoQ₁₀ (400 mg/day). The control group received only low-dose recombinant IFN α-2b in the same dosage and administration. Treatment efficacy was assessed as incidence of recurrences at five years. The risk of developing metastases was found to be about 10 times lower in the IFN + CoQ₁₀ patients compared with the IFN-alone group.⁴⁵ A 10-year follow-up will be needed to yield more significant results.

Gingivitis and Retinopathy

CoQ₁₀ has garnered attention for an increasingly broad array of health conditions. In 2012, Chatterjee et al. conducted a randomized, controlled split-mouth trial with 30 subjects with plaque-induced gingivitis to identify the effects of a solitary application of CoQ₁₀ after 28 days. Significant reductions in gingivitis, bleeding, and plaque scores were observed in areas where the antioxidant was topically applied.⁴⁶

That same year, Hans et al. performed a split-mouth clinical evaluation of topically applied CoQ₁₀, in the form of Perio-Q gel, in 12 patients with chronic gingivitis and periodontitis. The CoQ₁₀ gel was associated with similar clinical results to sub-gingival mechanical debridement. The researchers concluded that there was insufficient clinical support to indicate the superiority of the gel to basic mechanical approaches, but suggested the potential additive effect of CoQ₁₀ while calling for long-term clinical studies to assess the antioxidant.⁴⁷ Previously, Hanioka et al., in a study with 10 male patients in whom 30 periodontal pockets were selected for examination, observed that the topical application of CoQ₁₀ ameliorated adult periodontitis alone as well as in combination with traditional nonsurgical treatment.⁴⁸

Topical applications of CoQ₁₀ have also been emerging in the ophthalmologic armamentarium. For example, Lulli et al. showed that CoQ₁₀ eye drops protected retinal cells from apoptosis in a mouse model of kainite-induced retinal damage, prompting them to conclude that topical CoQ₁₀ be further considered for apoptosis-driven retinopathy therapies.⁴⁹

In a 2011 investigation of the potential of N-trimethyl chitosan (TMC)-coated liposomes containing CoQ₁₀ as an ophthalmic drug delivery system, Wang et al. found that CoQ₁₀ concentration-dependently raised the viability of human lens epithelial cells and lowered oxidative damage. They concluded that the CoQ₁₀-containing liposomes were effective in protecting human lens epithelial cells against hydrogen peroxide-induced oxidative harm and appear to have potential as a suitable ophthalmic drug delivery agent.⁵⁰

In 2013, Fogagnolo et al. assessed the postoperative effects of topical CoQ₁₀ (and vitamin E D-α-tocopheryl polyethylene glycol 1,000) in 40 consecutive patients who were randomized to receive CoQ₁₀ or saline solution twice daily for nine months after uneventful cataract surgery with a temporal port. They found that the antioxidant contributed to restoring the anatomy of the subbasal nerve plexus of the cornea as well as ocular surface stability.⁵¹

CONCLUSION

CoQ₁₀, like melatonin (see Chapter 62, Melatonin), is intriguing insofar as it is found naturally in humans, plays multiple biological roles, and is associated with age-related decline. Indeed, the increased cellular oxidation seen with age may be due, in part, to a decrease in the endogenous synthesis of such antioxidants. Both antioxidants also appear to engage other antioxidants synergistically and are associated with multiple benefits when supplied exogenously through oral supplementation or topical administration. There is a wealth of research on the role of endogenous CoQ₁₀ in the human body and the broad effects of oral administration of this essential substance. While the body of research on the topical administration of CoQ₁₀ is not scant by any means, there remains the need for more randomized, double-blind, placebo-controlled trials, preferably on a larger scale than has been seen thus far, to clearly delineate its potential in the dermatologic armamentarium. The potential for CoQ₁₀ does appear to be vast, though.

REFERENCES

INTRODUCTION

SOURCE

The coffee plant Coffea arabica, a member of the Rubiaceae family, is cultivated throughout the world and is, of course, a source of the globally popular beverage. Extracts of the coffee plant have been demonstrated to display antioxidant activity (Table 58-1).⁴

While much attention has been focused on coffee beans, particularly once roasted, the fruit of the coffee plant has been long ignored, and usually discarded, because it decays rapidly.¹ The fruit that grows on C. arabica, however, is suffused with polyphenols, especially chlorogenic acid (the primary phenolic substance in coffee), condensed proanthocyanidins, quinic acid, caffeic acid, and ferulic acid (see Chapter 53, Caffeic Acid, and Chapter 54, Ferulic Acid).^1,5,6 It is also believed to exhibit higher antioxidant activity than green tea, white tea, pomegranate, blueberries, strawberries, and raspberries (see Chapter 47, Green Tea). Polyphenols, which are secondary metabolites in plants, play an integral role in a healthy human diet, as these compounds are active constituents in various fruits, vegetables, grains, green and black tea, and coffee beans.^7–11 In addition, copious research during the last several years has shown that polyphenols represent a wealth of potential health benefits, typically related to anti-inflammatory and antioxidant properties. Consequently, manufacturers have targeted the activity of polyphenols for medical and cosmetic applications in several pharmaceutical and cosmeceutical products.

The Coffeeberry fruit, which is harvested subripe from the C. arabica plant, has been traditionally ignored, as mentioned above, but a method to translate its claimed prodigious properties has been developed and given the proprietary name Coffeeberry®. Analogous to the patented trade name for the antioxidant Pycnogenol® (see Chapter 49, Pycnogenol), derived from French maritime pine bark, Coffeeberry is a proprietary blend of antioxidants harvested from a natural botanical source.

HISTORY

C. arabica actually comes from Ethiopia and is thought to have been introduced into Arabia before or early in the 1400s, into Java before 1700, and into the West Indies as well as Central and South America in the 1700s.^12,13

CHEMISTRY

Extracts of the beans of C. arabica have demonstrated antioxidant activity after roasting.⁴ In addition to the beans of the coffee plant, the fruit, especially when harvested in a subripened state, also displays peak antioxidant activity.¹⁴ This is due to its constituent polyphenols, particularly chlorogenic acid, condensed proanthocyanidins, quinic acid, caffeic acid, and ferulic acid. Indeed, polyphenols, which are also found in green, white, and black tea, various fruits, vegetables, as well as grains, are known to confer multiple health benefits, mainly due to their anti-inflammatory and antioxidant properties.^15,16

Chlorogenic acid, an ester formed between caffeic and quinic acids (see Chapter 53, Caffeic Acid), is one of the most broadly consumed polyphenols as it is ubiquitous in food and coffee.¹⁷ Both chlorogenic and caffeic acids have been found to inhibit ultraviolet (UV) B-induced skin tumor promotion in mouse skin.¹⁷

ORAL USES

The coffee plant C. arabica is cultivated throughout the world as the source of the widely popular coffee beverage. Only the seeds of the fruit are used to produce the popular beverage. The Coffeeberry fruit is available as an oral supplement as well as in topical cosmetic formulations.

In 2008, Ostojic et al. examined the changes in total antioxidant capacity and aerobic and anaerobic performance in 20 college athletes (14 males, 6 females) engendered by supplementation with an oral Coffeeberry formulation for four weeks. After the trial, total antioxidant capacity was significantly higher in the group supplementing with Coffeeberry as compared to the placebo group. No adverse effects were observed in either group and there were no other significant differences between the groups. The investigators concluded that Coffeeberry supplementation yielded a slight increase in antioxidant capacity, and minimal effects in terms of recovery after exercise.¹⁸

TOPICAL USES

The C. arabica plant is used in some botanical formulations intended to treat cellulite. The caffeine used in this context as an active ingredient is extracted from the leaves, however, not the berries.¹⁹ Green C. arabica seed oil is also being broadly used as an ingredient in cosmetic formulations.²⁰ Therefore, multiple parts of the plant are now under investigation and in active use in the dermatologic realm. Preliminary data on the use of the proprietary fruit suggest that Coffeeberry extract has the potential to ameliorate overall appearance, hyperpigmentation, as well as fine lines and wrinkles.²¹

In 2008, Draelos conducted a double-blind, randomized clinical trial in 50 subjects over age 30 with mild symptoms of photoaging to assess the cutaneous benefits of Coffeeberry extract. Over the 12-week period, both groups used a Coffeeberry facial cleanser twice daily. Afterwards, one group would apply a Coffeeberry day cream in the morning and a Coffeeberry night cream in the evening to the whole face. The other group applied control creams. Compared to the control group, significant improvements were observed in the Coffeeberry extract group along all parameters considered (i.e., erythema, roughness, scaling, wrinkling, and global assessment). Transepidermal water loss decreased from baseline in the Coffeeberry group and increased in the control group. Draelos concluded that the Coffeeberry extract system of facial cleanser and morning and evening creams was well tolerated and led to significant improvements in diminishing multiple symptoms of photoaged skin.^22,23

In a six-week pilot study conducted by McDaniel and sponsored by Stiefel Laboratories, 30 female patients (31–71 years old) with moderate actinic damage used an antioxidant system composed of 0.1 percent Coffeeberry extract facial cleanser as well as 1 percent Coffeeberry extract night and day creams (the latter of which contained octinate and oxybenzone with an SPF of 15).^14,24 Twenty subjects applied all three products to the whole face and 10 subjects applied each to half the face and vehicle on the other half. Compared to vehicle, split-face patients experienced significant improvements in fine lines and wrinkles, pigmentation, and overall appearance. Patients treated on the whole face displayed improvements in all parameters (including fine lines and wrinkles, roughness and dryness, pigmentation, and overall appearance) compared to baseline, with marked changes in pigmentation as the most salient improvement. McDaniel also reported that skin biopsies revealed that the use of Coffeeberry extract led to an increase in key structural dermal proteins (i.e., collagen types I and IV) as well as a decrease in collagenase and inflammatory mediators.²⁴

In late 2010, Palmer and Kitchin reported on their 12-week, double-blind, randomized, controlled clinical usage study of the efficacy and tolerance of a new C. arabica-containing topical high-antioxidant skin care system (facial wash, day lotion, night cream and eye serum) to ameliorate photoaging in 40 Caucasian females. One group of participants used the test system, including twice-daily facial wash, application of the antioxidant day lotion each morning, and nightly application of the antioxidant night cream and eye serum, with the second group using the control products according to the same protocol. The authors observed statistically significant improvements in the appearance of photodamaged skin in the subjects using the test regimen.²⁵

Coffeeberry extract has also been shown, in preclinical and small clinical trials, to confer protection from oxidative damage, UVB-induced pyrimidine dimer formation and inflammation, and to facilitate accelerated recovery from UVB exposure.²⁶

SAFETY ISSUES

Topical products that contain C. arabica, or Coffeeberry extract in particular, are generally regarded as safe, though extensive data are not available.

Some safety studies have been performed on the oral use of Coffeeberry. In 2010, Heimbach et al. conducted a series of genotoxicity studies, three short-term oral toxicity studies, and a 90-day dietary toxicity study of Coffeeberry products, including a ground whole powder, a water extract, and a water-ethanol extract. None of the products exhibited genotoxic or mutagenic potential in murine peripheral cells. Although palatability issues emerged, rats displayed a tolerance for the whole powder and ethanol extracts, with females showing a higher tolerance for both. Finally, no adverse effects were seen in Sprague-Dawley rats fed the ethanol extract for 90 days at concentrations up to 5 percent.¹

In the few preclinical or small clinical trials thus far performed, no serious adverse events have been reported as treatments have been well tolerated.²⁷

ENVIRONMENTAL IMPACT

A significant environmental impact is exacted by C. arabica cultivation, including deforestation, water pollution and other effects of agrochemical use, soil quality degradation, loss of biodiversity, and changes in forest cover and structure.^28–32 The details and depth of the full range of actual and potential effects of industrial coffee growth as well as sustainable management approaches are beyond the scope of this text.

FORMULATION CONSIDERATIONS

Harvesting C. arabica fruit in a subripened state is essential to both optimize antioxidant potency and attenuate the risk of contamination with mycotoxins, which is typical later in the ripening process. The whole berry fruit is crushed and processed for its antioxidant components.²⁷

USAGE CONSIDERATIONS

Coffeeberry®, a proprietary ingredient for the antioxidant derived from the fruit of C. arabica, is the fundamental component in the RevaléSkin™ line of cosmetic products intended to reverse various signs of photodamage and photoaging and to impart photoprotection.³³ The hydroxycinnamic acid ferulic acid, another potent antioxidant, is also an important active ingredient in these products (see Chapter 54, Ferulic Acid). In the oxygen radical absorbance capacity assay (ORAC), Coffeeberry® exhibited greater antioxidant activity than green tea, pomegranate extract, and vitamins C and E [see Chapter 55, Ascorbic Acid (Vitamin C), and Chapter 56, Tocopherol (Vitamin E)].¹⁴ Of note, the proprietary Coffeeberry® technology associated with the cultivation, harvesting, and processing of the whole coffee fruit eliminates the risk of contamination by bacteria or fungi and the potential for generating mycotoxins.^1–3

SIGNIFICANT BACKGROUND

Antioxidant Activity

Two recent studies point to the antioxidant properties of roasted C. arabica. In one, in which coffee model systems were prepared from combinations of compounds, including chlorogenic acid, sucrose, and cellulose, various tests revealed that antioxidant activity exhibited a positive, nonlinear relationship with the level of chlorogenic acid, a known antioxidant, after roasting.⁴

In the other study, both C. arabica and C. robusta (Coffea canephora) demonstrated potent antiradical activity against the hydroxyl radical in an in vitro assay and ex vivo in IMR32 cells. The investigators concluded that both green and roasted coffee exhibit antiradical activity, with 5-O-caffeoyl-quinic acid, a chlorogenic acid isomer, as the most active constituent, and that the roasting process stimulates high molecular weight components to display antiradical activity in coffee. The authors speculated that these findings could account for the neuroprotective effects associated with coffee consumption in several epidemiologic studies.³⁴ In fact, a number of such studies have provided evidence linking regular coffee and caffeine consumption with a lower incidence or reduced risk of developing Parkinson’s disease.^35,36

Coffea Arabica in Skin Care Research

In 2009, green coffee oil was shown through in vitro studies and in ex vivo human skin models to dose-dependently promote the production of the key dermal constituents collagen, elastin, and glycosaminoglycans, as well as stimulate a greater release of the growth factors transforming growth factor-β1 and granulocyte -macrophage colony-stimulating factor. In addition, green coffee oil spurred the expression of aquaporin-3 (AQP-3) mRNA, up to 6.5-fold higher than levels seen in control cultures. The investigators concluded that green coffee oil has potential to contribute to the formation of new connective tissue and improving cutaneous function by mitigating wrinkles and preventing xerosis by raising levels of AQP-3 (see Chapter 29, Aquaporin). Consequently, they suggested that including green coffee oil in cosmetic formulations merits consideration.²⁰

In early 2011, Chiang et al. reported on their investigation of the antiphotoaging effects of C. arabica leaf extract, its hydrolysates, chlorogenic acid, and caffeic acid. The various polyphenol-containing test compounds were subjected to matrix metalloproteinase (MMP) and elastase inhibition tests. They found that C. arabica leaf extracts stimulated type I procollagen expression, suppressed MMP-1, MMP-3, and MMP-9 expression, and hindered the phosphorylation of JNK, ERK and p38. They concluded that the extracts of C. arabica leaves can prevent photodamage by inhibiting MMP expression and the MAP kinase pathway.³⁷

CONCLUSION

Given the widespread cultivation of the Coffea arabica plant, and the growing scientific interest in exploring the ramifications of its use, it would certainly be cost-effective if companies that harvest the plant also made use of its fruit in some capacity. Accordingly, the manufacturers of Coffeeberry® and their researchers deserve credit for resourcefulness and innovative thinking at the very least. In addition, preliminary evidence suggests that Coffeeberry warrants consideration for its strong antioxidant potential. However, claims that Coffeeberry improves wrinkles are likely due to a moisturizing effect as it is well established that antioxidants can prevent wrinkles from developing but do not eliminate wrinkles that are already present. The effects seen on improved hyperpigmentation are not unexpected as antioxidants play a role in the pigmentation process. In the author’s opinion, the “superior antioxidant protection” that any product claims cannot be proven, because there is no consensus on the ideal test to evaluate antioxidant activity. Much more research, preferably in the form of randomized, double-blind, placebo-controlled clinical trials, is necessary to determine the true potential impact of Coffeeberry in the dermatologic arsenal.

REFERENCES

INTRODUCTION

SOURCE

Ginger, the tuberous root or rhizome of Zingiber officinalis, is one of the most widely used species of the tropical and subtropical Zingiberaceae family, particularly as a condiment and spice for many foods and beverages.¹ Indeed, the use of ginger rhizomes, commonly referred to as ginger, in culinary spices and as medicine to treat various conditions has a long-standing and widespread tradition throughout Asia (Table 59-1). The designation ginger is thought to be derived from the Sanskrit word singabera, meaning “horn-shaped,” which alludes to the knobby protuberances of ginger’s rhizomes. It is now cultivated in China, India, Southeast Asia, Mexico, Africa, Fiji, and Australia.² Traditional uses of the herb, to treat nausea, indigestion, joint inflammation, fever and infection, continue today, but the list of indications is expanding as research reveals a wider variety of potential applications.

In fact, ginger is known as one of the most effective herbal remedies for nausea and has a longstanding reputation as a gastroprotective, carminative agent. Its antiemetic properties are attributed to an effect on gastric activity rather than a central nervous system mechanism. Ginger is also touted for its antioxidant, antiviral, antifungal, and antibacterial activity.^3,4 It is thought to be effective against the growth of both Gram-positive and Gram-negative microbes.

Ginger has also been cited as an effective element in treating stomach ulcers, arthritis, rheumatism, and migraines.⁵ Its purported ability to improve circulation and to act as an antioxidant has led to research into its viability as an ingredient in skin care products aimed at enhancing facial complexion. Evidence is gathering, also, of the chemopreventive, antineoplastic activity of ginger.⁶

HISTORY

Native to much of Asia, ginger, dubbed Zingiber officinale in 1807 by English botanist William Roscoe, appears in records of its use in ancient Sanskrit and Chinese writings as well as Greek, Roman, and Arabic medical texts.² Ginger has been used as a traditional herb for over 2,500 years and long considered a universal remedy.^1,7 Generally, it has been employed in traditional Chinese medicine (TCM), Ayurveda, and Tibb-Unani herbal medicine to treat various illnesses involving inflammation and oxidative stress.⁸ In these ancient medical systems as well as Sri Lankan, Arabic, and African traditional medicine, ginger has been used to treat a wide range of ailments, including common colds, fever, sore throats, vomiting, motion sickness, indigestion, constipation, arthritis, rheumatism, sprains, muscular aches, cramps, hypertension, dementia, helminthiasis, and infectious diseases, and continues to be used for such indications as well as asthma, allergy, headaches, diabetes, gingivitis, and stroke in TCM and other Eastern medical practices.^5,6,9–12

In a 2010 study to ascertain the ethnopharmacological application of medicinal plants used to treat skin diseases and in folk cosmetics in northwestern Pakistan, Abbasi et al. identified Zingiber officinale as one of 15 mostly wild and rare plant species used for various skin and hair conditions.¹³

CHEMISTRY

Ginger is widely used as an herbal medicine, particularly due to the presence of homologous phenolic ketones, of which [6]-gingerol (1-[4′-hydroxy-3′-methoxyphenyl]-5-hydroxy-3-decanone) is the primary and most abundant.^14,15 The chemistry of ginger is complicated, though. In fact, the chief components found in ginger oil vary according to the region in which it was grown. An oleoresin, known as “ginger oil,” and terpenes are the major active components of ginger; however, pungent phenolic substances, such as [6]-gingerol and [6]-paradol, are considered the source of the discrete antioxidative and anti-inflammatory action of ginger.^16,17 In addition, ginger has been found to exert anticancer activity, which is also ascribed to [6]-gingerol and [6]-paradol, as well as shogaols (the main dehydration products of gingerols) and zingerone.^1,16,18

Several animal studies have demonstrated the antioxidant capacity of ginger. More than a decade ago, ginger was found to inhibit lipid peroxidation in rat liver microsomes.¹⁹ Researchers also showed that ginger effectively scavenges superoxide anions.²⁰ A study on SENCAR mice demonstrated the antioxidant, anti-inflammatory and anticarcinogenic properties of ginger extracts. Ginger oil placed directly on the skin of mice prevented the development or growth of skin cancer after the mice were exposed to chemicals that promote cancer.²¹ The anti-inflammatory effect is thought to be due to inhibition of cyclooxygenase (COX) and 5-lipoxygenase.²² Further, ginger has been shown to inhibit fibroblast-derived elastase, suggesting a significant role in the prevention of wrinkle formation.²³

ORAL USES

Ginger is commonly used as a condiment for foods and in beverages, particularly tea, throughout the world; it is one of the most frequently and heavily consumed of all the spices.¹⁷ The distinctive, spicy taste of fresh ginger is attributed to the lipid-soluble [6]-gingerol, one of its main phenolic constituents; the pungency of dry ginger is linked to the shogaols.^11,24 In addition to its wide use in foods and beverages, ginger is available as a dietary supplement.

TOPICAL USES

Knee Osteoarthritis

Ginger is one among several adjuvant or secondary options in the treatment of knee osteoarthritis, which affects more than one-third of individuals over the age of 65.²⁵ In a 2011 double-blind, randomized controlled trial with 92 patients, an herbal ointment containing ginger, cinnamon, mastic, and sesame oil was clinically effective and comparable to a salicylate ointment in reducing pain, morning stiffness, and motion limitations.²⁶ Previously, among 247 patients who could be evaluated from an original 261 in a randomized, double-blind, placebo-controlled, multicenter, parallel-group, six-week study, 63 percent of responders in the ginger extract group experienced diminished knee pain as compared to 50 percent in the control group.²⁷ However, a systematic review of the literature to assess the safety and effectiveness of ginger to treat osteoarthritis in adults yielded weak evidence of its effectiveness as a lone therapy.²⁸

Hair Care

Although ginger is used in East Asia in various products touted to stem hair loss and promote growth, Miao et al. pointed out that supportive evidence is lacking. In 2013, they investigated the effects of [6]-gingerol on hair shaft growth and human dermal papilla cells in vitro and in vivo. The researchers found that the ginger constituent inhibited hair growth as well as the proliferation of dermal papilla cells in culture as well as in mice. They concluded that contrary to popular usage in East Asia, [6]-gingerol appears better suited for hair removal than stimulating hair growth.²⁹

SAFETY ISSUES

Ginger is listed by the Food and Drug Administration as generally recognized as safe (GRAS).³⁰ It can be irritating to the skin and should not be used in sensitive skin types, particularly S₂ rosacea types. Contact dermatitis to ginger has been reported.³¹

ENVIRONMENTAL IMPACT

Z. officinale is abundant in tropical regions throughout the world and its harvesting is not known to damage the local environment as it is easily cultivated.³² In fact, ethanol extracts of ginger have shown sufficient antifungal activity to suggest potential for use in agriculture as one of several natural alternatives to conventional synthetic pesticides, which would protect the environment and human health.³³ Nevertheless, in an industry in which there is much money to be made by growers from a cash crop such as ginger, environmental concerns are often supplanted by bottom-line financial interests.

FORMULATION CONSIDERATIONS

The constituents of ginger vary by region and whether the rhizomes are fresh or dry.¹¹ The CO₂ extracts of ginger have the most abundant polyphenolic content and most closely resemble the composition of the Z. officinale rhizome.³²

USAGE CONSIDERATIONS

Ginger is one of the several commonly used herbs, including feverfew, garlic, ginkgo, and ginseng, which may contribute to bleeding during surgical procedures.³⁴

SIGNIFICANT BACKGROUND

Ginger is one of the most widely used herbs on the planet as a flavoring agent in food and for numerous medical indications. It exerts potent antioxidant activity, attenuating or preventing the formation of reactive oxygen species (ROS) and is known to impart anti-inflammatory, antiapoptotic, antitumorigenic, antihyperglycemic, antilipidemic, antiemetic, and immunomodulatory activity.¹¹

Antioxidant and Anti-inflammatory Activity

The phenol [6]-gingerol displayed strong antioxidant activity in 1994 as ascertained by Aeschbach et al., who showed that the compound inhibited phospholipid peroxidation brought on by the FeCl₃-ascorbate system.^17,35

In a 2010 study by Dugasani et al. of the in vitro activities of [6]-gingerol, [8]-gingerol, [10]-gingerol, and [6]-shogaol in scavenging 1,1-diphenyl-2-picyrlhydrazyl (DPPH), superoxide, and hydroxyl radicals, suppression of N-formyl-methionyl-leucyl-phenylalanine (f-MLP)-induced ROS synthesis in human polymorphonuclear neutrophils (PMN), and the hindering of lipopolysaccharide-induced nitrite and prostaglandin E₂ production in RAW 264.7 cells, [6]-shogaol displayed the strongest antioxidant and anti-inflammatory characteristics, with [10]-gingerol exhibiting the greatest potency among the gingerols. The researchers concluded that their findings buttress the use of dry ginger in traditional medical systems.⁸

Also that year, Ghasemzadeh et al. investigated the antioxidant activities of methanol extracts from the leaves, stems, and rhizomes of two Z. officinale varieties. Using various assays, they determined that Halia Bara possessed higher phenolic and flavonoid concentrations and exhibited higher antioxidant activity than Halia Bentong. Their findings supported the potential medical applications of Z. officinale (Halia Bara) leaves and young rhizomes.³²

Previously, Minghetti et al. investigated the ex vivo skin permeation and in vivo topical anti-inflammatory activity of a commercial ginger dry extract and a gingerols-enriched dry extract in mice. Both extracts dose-dependently reduced ear edema induced by Croton oil, though the enriched extract was slightly less potent. Medicated plasters, with 1 mg/cm² of either extract, displayed anti-inflammatory properties and the enriched extract permeated through mouse skin (22.1 μg/cm²) as well as human epidermis (6.9 μg/cm²). The investigators concluded that the anti-inflammatory effects of the extracts noted in mice could also be delivered in human skin.¹⁸

In addition, crude extracts of Z. officinale have been shown to diminish rat paw and skin edema provoked by carrageenan, 48/80 compound, and serotonin.³⁶ The substantial antioxidant potency and anti-inflammatory properties ascribed to ginger are thought to play important roles in exerting photoprotective and chemopreventive activity.

Photoprotection

In 2006, Tsukahara et al. studied the role of elastase in UV-induced wrinkle formation by evaluating the effects of ginger extract. They found that topically applying the extract to rat hind limb skin or hairless mouse dorsal skin strongly suppressed wrinkle development engendered by chronic ultraviolet B (UVB) exposure at a suberythemal dose. The concomitant reduction in skin elasticity that accompanies such exposure was also significantly prevented, as the elasticity of rat hind limb skin was maintained. The authors concluded that herbal extracts with the demonstrated capacity to hinder fibroblast-derived elastase, which is key in UVB-induced wrinkle formation, represent potentially effective antiwrinkling agents.²³

In vitro and in vivo experiments were conducted by Kim et al. in 2007 to characterize the antioxidant, anti-inflammatory, and antiapoptotic activities of the ginger extract [6]-gingerol. Pretreatment with the phenolic lowered, in vitro, UVB-induced intracellular ROS levels, as well as the activation of caspase-3, caspase-8, and caspase-9, Fas expression, and the expression and transactivation of COX-2. In vivo, the topical application of [6]-gingerol to hairless mice before UVB exposure led to the suppression of COX-2 mRNA induction and nuclear factor-κB (NF-κB) translocation. The researchers concluded that [6]-gingerol shows potential as a photoprotective agent against cutaneous disorders caused by UVB exposure.¹⁵ In a separate study, by Pan et al., [6]-shogaol was shown to downregulate inflammatory inducible nitric oxide synthase (iNOS) and COX-2 gene expression in murine macrophages by suppressing the activation of NF-κB.³⁷

The next year, Imokawa reported that a one-year clinical study on human facial skin revealed that a water-soluble ginger extract blocked the UV-induced reduction in skin elasticity, by inhibiting fibroblast-derived elastase, and prevented or diminished wrinkle formation in periorbital skin without altering stratum corneum water content.³⁸

In 2010, Guahk et al. reported that Z. officinale exerts protection of the human keratinocyte cell line HaCaT in vitro and C57BL/6 mice in vivo from inflammation induced by UVB exposure and, therefore, warrants consideration as a photoprotective anti-inflammatory agent.³⁹

In a 2013 study of the protection conferred against UVB-induced DNA damage and cytotoxicity by 15 Thai herb species, Thongrakard et al. found that the greatest UV absorption was associated with the dichloromethane extract of ginger and ethanol extract of turmeric (see Chapter 69, Turmeric). Both extracts promoted the production of the antioxidant protein thioredoxin 1 and the investigators concluded that the herbs exhibit potential to protect human keratinocytes from UV-induced harm thus warranting use in photoprotective cosmetic agents.⁴⁰

Anticarcinogenic Activity

The anticarcinogenic activity of ginger has emerged as the most compelling area of investigation. The pungent phenolic substance [6]-paradol (1-[4′-hydroxy-3′-methoxyphenyl]-3-decanone) has been identified as the component most responsible for inhibiting tumor activity in skin cancer of mice. Other structurally-related derivatives, in addition to [6]-paradol, have been shown to induce apoptosis through a mechanism dependent on caspase-3.^17,41 Both [6]-paradol and the structurally-related [6]-gingerol, acting through different mechanisms, have been shown to inhibit epidermal growth factor (EGF)-induced cell transformation.⁴²

In one of the earlier investigations into the effects of ginger extract on skin tumorigenesis in mice, Katiyar et al. topically applied an ethanol extract of ginger to the skin of SENCAR mice, which significantly and dose-dependently suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced epidermal ornithine decarboxylase (ODC), COX, and lipoxygenase activities as well as ODC mRNA expression. Ginger extract pretreatment also led to substantial suppression of TPA-generated epidermal edema and hyperplasia. Ginger-treated mice also displayed significantly lower tumor incidence than controls after 7,12-dimethylbenz[a]anthracene (DMBA) tumor initiation and TPA tumor promotion. These findings, the investigators concluded, represented the first clear evidence that ginger extract protects against skin tumor promotion.²¹

In a two-stage mouse model, Park et al. showed in 1998 that the topical application of [6]-gingerol onto the shaved backs of female ICR mice before topical doses of the tumor promoter TPA significantly suppressed skin papillomagenesis induced by DMBA. TPA-induced epidermal ODC activity and inflammation were also inhibited by the ginger constituent.¹⁷ Many of the same investigators reported on similar findings the following year, also including [6]-paradol along with [6]-gingerol as exhibiting potential chemopreventive properties. In this study, both ginger substances were topically applied to female ICR mice in the two-stage carcinogenesis model using TPA and DMBA and were found to suppress TPA-stimulated inflammation, tumor necrosis factor (TNF)-α synthesis, as well as epidermal ODC activity. In a separate investigation by the same team, both compounds also inhibited superoxide production spurred by TPA in differentiated HL-60 cells.⁴¹

In 2001, Bode et al. offered the first evidence that [6]-gingerol and [6]-paradol hinder EGF-induced cell transformation, thus blocking a critical pathway in tumor formation.⁴² Two years later, Bode et al. reported a chemopreventive effect after administering 500 mg of [6]-gingerol or a placebo to athymic nude mice three times weekly for two weeks before injecting them with human colon cancer cells. Administering the ginger extract or placebo was resumed then, with the investigators finding that it took longer for tumors to emerge and grow in the gingerol-treated animals.⁴³

In 2004, Kim et al. demonstrated that the topical application of [6]-gingerol blocks phorbol 12-myristate 13-acetate (also known as 12-O-tetradecanoylphorbol-13-acetate)-induced COX-2 expression, which is targeted by several anti-inflammatory and chemopreventive agents. In addition, [6]-gingerol inhibited NF-κB DNA binding activity in mouse skin as well as the phosphorylation of p38 mitogen-activated protein (MAP) kinase, which the authors cited as a possible explanation for the impact of [6]-gingerol on NF-κB and its inhibition of COX-2 expression.²⁴ In 2005, many of the same investigators showed that [6]-gingerol suppressed TPA-induced COX-2 expression in TPA-treated mouse skin in vivo by hindering the p38 MAP kinase-NF-κB signaling pathway.⁷

In 2009, Nigam et al. found that [6]-gingerol evinced significant cytotoxicity in human epidermoid carcinoma A431 cells, engendering ROS increases that provoked reductions in mitochondrial membrane potential and apoptosis. Treatment with [6]-gingerol also yielded an upregulation of cytochrome-c and apoptotic protease-activating factor (Apaf)-1, spurring the caspase cascade, which plays an essential role in apoptosis. The investigators concluded that [6]-gingerol warrants attention as a potentially effective agent in treating skin cancer.¹⁴ In a study the following year, Nigam et al. topically treated mice with [6]-gingerol before inducing skin tumorigenesis through 32 weeks of exposure to benzo[a]pyrene (B[a]P). Pretreatment with the ginger component yielded delays in the onset of tumorigenesis, decreased cumulative tumors, and lower tumor volume. B[a]P-suppressed p53 levels were augmented by [6]-gingerol, which also aided in the release of cytochrome-c, activation of caspases, and the increase in Apaf-1, thus inducing apoptosis. These results further support the investigators’ claims regarding the chemopreventive activity of [6]-gingerol.⁴⁴

Other components of ginger have also been investigated. In 2004, Murakami et al. showed that zerumbone, a sesquiterpene present in the tropical ginger species Zingiber zerumbet, inhibits skin tumor initiation with DMBA and promotion by TPA in ICR mice by inducing antioxidative and phase II drug metabolizing enzymes and interrupting proinflammatory signaling pathways.⁴⁵ In 2011, Shin et al. investigated the effects on mice of topically applied zerumbone, previously found to block chemically-induced papilloma formation in mouse skin. They found that the ginger component upregulated the expression of the protein heme oxygenase-1 (HO-1) through activation of NF-E2-related factor 2 (Nrf2) signaling, which the researchers suggested provided an explanation for the inhibitory effect on skin carcinogenesis exhibited by zerumbone in mice.⁴⁶

In addition, the tropical ginger-derived compound 1’-acetoxychavicol acetate has exhibited the capacity to inhibit skin tumorigenesis in K5.Stat3C mice.⁴⁷

The anticarcinogenic effects of ginger have also been seen in Chinese herbal medicine. The methanolic extract of Alpinia oxyphylla, a member of the Zingiberaceae family, has been found to suppress mouse skin tumor promotion and noted for inducing apoptosis in cultured human promyelocytic leukemia cells.⁴⁸ It is speculated that the antitumor activity of the phenolic diarylheptanoids derived from A. oxyphylla are linked to its anti-inflammatory characteristics.⁴⁸

Wound Healing

In 2009, Bhagavathula et al. topically treated hairless rats for a 21-day period with a combination of 10 percent curcumin and 3 percent ginger extract or with each agent alone. For another 15 days, investigators treated the animals with the corticosteroid Temovate. Superficial abrasions were then induced in treated skin, with healing occurring sooner in skin pretreated with either curcumin or ginger extract alone or in combination as compared to skin treated only with the corticosteroid and vehicle alone. The investigators analyzed skin samples taken at wound closure, finding an increase in collagen production and decrease in matrix metalloproteinase-9 in the skin treated with the herbal ingredients compared to the skin treated with corticosteroid and vehicle. The investigators concluded that a combination of curcumin and ginger extract may have an adjuvant role to play in wound healing.³⁰

In 2012, Chen et al. demonstrated that 10-shogaol, an active ingredient in ginger, exhibited potent radical scavenging activity when tested with the DPPH radical. It was also shown to foster human normal epidermal keratinocyte and dermal fibroblast production as well as the synthesis of multiple growth factors and the migration of keratinocytes and fibroblasts in an in vitro wound-healing assay.⁹

Skin Lightening

Ginger may have yet another indication. Huang et al. showed in 2011 that [6]-gingerol dose-dependently inhibited murine tyrosinase activity and lowered melanin as well as ROS levels. They concluded that [6]-gingerol is an effective suppressor of melanogenesis of B₁₆-F₁₀ melanoma cells and merits attention as a skin-lightening agent.⁴⁹

CONCLUSION

The long history of traditional use and well-established safety profile of ginger make the herb a strong candidate for extensive research regarding its inclusion in drugs and cosmeceuticals. New data on the anticarcinogenic potential of ginger appears especially promising, but the overall antitoxic properties of the perennial herb may very well position ginger to be a key new ingredient in a wider array of skin care products. As is often the case, more randomized, placebo-controlled studies are needed to substantiate the dermatologic uses of popular botanical ingredients such as ginger. Nevertheless, its broad biologic activity has been clearly demonstrated and the antioxidant, anti-inflammatory, and chemopreventive properties manifested by ginger extracts indicate potential for topical dermatologic uses.

REFERENCES

INTRODUCTION

SOURCE

Honeybees, Apis mellifera, play an important but often underappreciated role in our lives (Figure 60-1). Human beings rely on bees for pollinating approximately one-third of our crops, including numerous fruits, vegetables, nuts, and seeds.^6,7 Of course, they also play a pivotal role in the propagation of other plants, flower nectar, and flower pollen. A. mellifera, the European honeybee, is the primary pollinator in Europe and North America but other species, including A. cerana, A. dorsata, A. floria, A. andreniformis, A. koschevnikov, and A. laborisa produce honey.⁸ Further, the honeybee is the only insect that produces food consumed by human beings.³

Honey is a sweet food product produced by honeybees from flower nectar. It contains over 180 substances and is supersaturated in sugar, though it also contains phenolic acids, flavonoids, ascorbic acid, α-tocopherol, carotenoids, the enzymes glucose oxidase and catalase, organic and amino acids, and proteins.⁹ In Ayurvedic medicine, honey has been used to treat diabetes since ancient times.⁸ It has also been used for millennia to treat infected wounds.¹⁰ For dermatologic purposes, honey has and continues to be used in Ayurvedic medicine to treat acne, and is also used in cosmetic formulations such as facial washes, skin moisturizers, and hair conditioners.⁸

Propolis is a yellowish-green to dark brown resinous material that originates in the buds and barks of various plant sources, mostly poplar trees,^1,11,12 and is gathered by honeybees and used in the construction and maintenance of their hives.^13,14 The sources of propolis can vary widely by region and even season, however. In all cases, propolis, used to seal holes and trap predators, stabilizes bee hives and honeycombs and protects bees against cold weather and potential intruders.¹¹ Also known as bee glue, this extract from bee hives has been used for hundreds of years in naturopathic medicine and is known to display biologic and pharmacologic properties. In traditional medicine, it has been used for its purported antioxidant, anticancer, anti-inflammatory, and immunomodulatory effects.¹⁵ Currently, some radiation therapists use propolis to treat actinic stomatitis and mucositis,¹¹ but this bee product is used more often for wound care and minor cutaneous indications as well as a dietary supplement. It is believed to contain as many as 300 constituents, including resin, wax, essential oils, pollen, and organic substances such as phenolic acids and their esters, particularly caffeic acid phenethyl ester (CAPE), flavonoids, terpenes, β-steroids, aromatic aldehydes and alcohols, sesquiterpenes, and stilbene terpenes.^1,9

Royal jelly, a yellowish, viscous secretion from the hypopharyngeal and mandibular glands of worker bees that nourishes bee larvae of all kinds (i.e., drones, workers, queens) after which it becomes the exclusive nourishment for queens throughout their development, has been used by humans for centuries for its health-promoting characteristics.^16–18 Antitumor, antihypercholesterolemic, antibacterial, anti-inflammatory, antioxidant, antiangiogenetic, collagen production-promoting, estrogenic, hypotensive, immunomodulatory, vasodilative, and wound-healing activity have been linked to royal jelly.^9,18–22

HISTORY

Honey, propolis, and royal jelly have all been used for medicinal purposes since ancient times, with honey, the earliest bee product discovered, particularly known for its use in wound healing.^{3,9,11,12,14,23,24} In fact, the topical application of honey for various conditions has been a common traditional medical practice for at least 2,700 years, which many researchers have retrospectively attributed to its antibacterial properties.^3,25 Of course, the antiseptic and antimicrobial properties of honey are recent discoveries,³ with the antibacterial properties of honey reported in 1892 (as cited by Dustmann in 1919).²⁶

In folk remedies, honey has served as a potent anti-inflammatory and antibacterial agent and its use dates back to ancient Egypt [it was even found in the tomb of King Tutankhamun (better known as King Tut)], Greece, and Rome, with the bee products mentioned in writings in Egypt, India, and China dating back to 5500 BCE.^{3,11,12,27,28} Honey has been used in Ayurvedic medicine for at least 4,000 years.³ The use of honey to treat wounds was practiced in China during the Xin dynasty (circa 2000 BCE), and ancient physicians (the Greeks Hippocrates and Dioscorides, Romans Celsus and Galen, and Arabs El Mad Joussy and El Basry) are said to have cited the healing qualities of honey.³ Abu Ali bin Sina (Latinized as Avicenna), a leading Persian doctor and scholar circa 11th century CE, wrote of using cooked honey and myrrh to decrease exudates from wounds contributing to partial tissue loss.^1,29 More recent uses of honey in medicine hewed to wound treatment, including gunshot wounds in the 17th and 18th centuries (it was an official drug in London pharmacopoeias in the 17th century)^5,30 and through World War I usage by the Russians and Germans.^29,31,32 Not until the discovery of antibiotics in the 1940s did the traditional medical use of honey begin to wane.^29,33

The word “propolis” is derived from the Greek words pro (before) and polis (city), which reflects the ancient observation that bees built walls of the substance near the entrance of their hives.^{5,12,14,34,35} It was considered the third natural product of bees (in addition to honey and wax). Ancient Egyptians, making use of the antiputrefactive activity of bee glue, used propolis to embalm their dead.^34,35 The Greek philosopher Aristotle wrote about the basic characteristics of propolis in his work Historia Animalium over 2,000 years ago, with recordings of its use dating back to at least 300 BCE; its use in medical applications was covered by Alexander of Tralles in the 6th century CE.^11,14,34

Propolis has been used for centuries in folk medicine in Europe, the Americas, China, and Japan.¹ In traditional medicine, propolis was most successful in treating a wide range of wounds because of its antiedematous and anti-infectious properties. Propolis was also used in the ancient world for muscle, tendon, and joint pain. In addition, bee glue was used to treat cutaneous conditions such as lichens and condylomata.¹¹ In more recent times, propolis was used to treat wounds during the Anglo-Boer war between 1899 and 1902 as well as World War II, and was an accepted medical ingredient in the former Soviet Union as recently as 1969.¹ Other indications have included burns, sore throat, and stomach ulcers.³⁶ In fact, propolis has continued to be a popular therapeutic choice in the Balkan countries of Southeast Europe for these indications and it is marketed in some European countries for the treatment of prostate hyperplasia.³⁷

Modern studies of the medicinal benefits of propolis are traced to Stan Scheller in 1960s Poland, where the study of its biological characteristics by way of a novel approach to delivering hydrophobic ethanol extracts of propolis into aqueous solutions led to the identification of antioxidant, antibacterial, immunostimulating, and radioprotective qualities.³⁸

The “queen substance” 9-oxo-2-decenoic acid (9-ODA), a queen honeybee pheromone, was isolated from queen honeybee mandibular glands by Butler et al. in 1961.^39,40 Johnston et al. found in 1965 that this minor component of royal jelly rapidly metabolizes into 9-hydroxy-2-decenoic acid (9-HDA), a precursor to royal jelly that stabilizes swarm activity.^39,41,42 Royal jelly is now used in cosmetics, dietary supplements, and beverages. Particularly in Asia, it is deployed as a health tonic.^17,43 Royal jelly has also exhibited effectiveness in alleviating chilliness in young women.⁴⁴.

CHEMISTRY

The myriad biological functions associated with honey (e.g., antibacterial, antioxidant, antitumor, anti-inflammatory, antibrowning, and antiviral), propolis (e.g., antitumor, antioxidant, antimicrobial, anti-inflammatory, and immunomodulatory), and royal jelly (e.g., antibacterial, anti-inflammatory, vasodilative, hypotensive, disinfectant, antioxidant, antihypercholesterolemic, and antitumor) are chiefly ascribed to the plethora of phenolic compounds, such as flavonoids, found in these bee products (Table 60-1).⁹ The flavonoid chrysin is present in honey and propolis and is thought to play a key role in conferring anti-inflammatory activity.⁹

Honey itself contains carbohydrates, proteins, 18 free amino acids (of which proline is the most abundant), vitamins (trace amounts of B₂, B₄, B₅, B₆, B₁₁, and C), minerals (e.g., calcium, chromium, iron, magnesium, manganese, phosphorus, potassium, selenium, and zinc), antioxidants (primarily flavonoids, including pinocembrin, which is found only in honey and propolis), enzymes (e.g., invertase, amylase, glucose oxidase, catalase, and acid phosphorylase), as well as acetic, butanoic, citric, formic, gluconic, lactic, malic, pyroglutamic, and succinic acids.^8,45,46 Medical-grade honeys such as manuka honey (a monofloral honey derived from Leptospermum scoparium, a member of the Myrtaceae family, native to New Zealand) and Medihoney® (a standardized mix of Australian and New Zealand honeys mainly originating from Leptospermum species) are rich in flavonoids.^45,47–49 Honey exhibits a pH ranging between 3.2 and 4.5, an acidity level that hinders the growth of many microorganisms.^29,50–52

Propolis is a complex mixture of partially digested resins from trees and bees wax, containing approximately anywhere from 50 to 300 constituents including balsams, resins, waxes, essential oils, pollen, cinnamyl alcohol, flavonoids, minerals (e.g., calcium, copper, iodine, iron, magnesium, manganese, potassium, sodium, and zinc), as well as vitamins A, B (B₁, B₂, B₆), C, and E.^1,53 Interestingly, Tsai et al. have shown that while propolis acts as an antioxidant, it can also induce oxidative DNA damage by producing hydrogen peroxide (H₂O₂). But they note that propolis-treated cells display a lower level of DNA damage when challenged with another oxidative compound (e.g., amoxicillin). They concluded that this adaptive response may play a role in the beneficial results associated with propolis.⁴ Overall, propolis is thought to confer significant antioxidant activity. Phenolic compounds (particularly vanillic, coumaric, rosmarinic, chlorogenic, caffeic, and ferulic acids) and flavonoids such as quercetin are thought to account for these propolis properties, which has been found, according to in vitro and in vivo studies, to protect skin against ultraviolet (UV)-induced damage.^1,35,54–58

Royal jelly, which bees produce from pollen, contains water, proteins (82–90 percent of which are known as the major royal jelly proteins, with five primary members), lipids, sugars, carbohydrates, free amino acids, vitamins, and minerals.^8,9,19 Its primary unsaturated fatty acid is 10-hydroxy-2-decenoic acid (10-HDA), which is uniquely found in royal jelly.⁵⁹ The benefits to human health associated with royal jelly can be partly attributed to the activity of constituent lipids, primarily aliphatic free fatty acids and few esters, which render the royal jelly emulsion highly acidic and therefore able to impart antimicrobial properties.⁸ These royal jelly components are considered to function in ways that protect against skin aging, modulate the immune system, potentially thwart cancer development, induce neurogenesis, and alleviate symptoms of menopause.¹⁶

ORAL USES

Honey is the oldest sweetener and one of the oldest foods consumed by humans, having been in popular usage in the diet throughout the world for thousands of years. It never spoils and was even found in edible condition in King Tut’s tomb.⁴⁵ The preservative qualities of honey have been attributed to its antioxidant properties.⁵⁸ Darker honeys (such as buckwheat) are associated with greater antioxidant activity.⁵⁸

Propolis is extensively used in food and beverage products to boost human health.^1,60 In 1995, the National Food Institute of Argentina recognized propolis as a dietary supplement.¹ It is typically available in capsule form.

In 1990, Fujii et al. found that orally administered royal jelly exhibited anti-inflammatory activity and wound-healing capacity in streptozotocin-diabetic rats,⁶¹ a result supported by more recent findings.⁶² For instance, in 2003, Taniguchi et al. found that the oral administration of royal jelly hinders the development of atopic dermatitis-like skin lesions in mice.⁶³

TOPICAL USES

In over-the-counter cosmetic formulations, honey is used primarily as a moisturizing agent and in hair conditioning products because it has strong humectant properties. It is also used in home remedies for burns, wounds, eczema, and dermatitis, particularly in Asia.⁸

Propolis has been shown to have several potential topical dental applications worthy of investigation. In a study of the histological effects of propolis topically applied to dental sockets and skin wounds in rats, a 10 percent hydroalcoholic solution of propolis or a 10 percent hydroalcoholic solution alone were compared. Examination of cutaneous wound healing and the socket wound after tooth extraction revealed that topical application of the propolis hydroalcoholic solution accelerated epithelial repair but had no effect on socket wound healing.⁶⁴ Propolis has also been found to be effective in treating aphthous ulceration.^65–67

There are several commercially available products such as lotions, creams, shampoos, lipsticks, toothpastes, and mouthwashes, as well as cough syrups, lozenges, and vitamins that contain propolis as an active ingredient.

Wound Healing

In 2010, Majtan et al. showed that incubation with honey activated human keratinocytes to increase production of mediators including cytokines [tumor necrosis factor-α, interleukin (IL)-1β, and transforming growth factor (TGF)-β1] and matrix metalloproteinase (MMP)-9. In addition, they demonstrated that this increased amount of epidermal MMP-9 facilitated the degradation of collagen type IV in the basement membrane, buttressing the notion that honey has the capacity to accelerate wound healing.²⁴

A 2013 systematic literature review of honey in contemporary wound care included 55 studies revealing that honey does appear to stimulate healing of burns, ulcers, and other wounds. The authors were hesitant to draw many broad conclusions due to methodological concerns, but found that honey displays antibacterial activity in burn treatment and also exerts deodorizing, debridement, anti-inflammatory, and analgesic activity.²⁹ However, a search of the Cochrane Wounds Group Specialized Register, the Cochrane Central Register, Ovid Medline, Ovid Embase, and EBSCO CINAHL completed earlier that year of 25 randomized and quasi-randomized trials assessing honey in the treatment of acute or chronic wounds found that honey might delay healing in partial- and full-thickness burns compared to early excision and grafting, and it does not significantly enhance healing of chronic venous leg ulcers.⁶⁸ The authors suggested that while honey may, indeed, prove to be more effective than some conventional dressings, there is insufficient evidence to support this claim.

Propolis has also been found to exert a wound-healing effect. In 2002, Pachalski et al. assessed the use of propolis in treating the skin of the stumps of 156 patients rehabilitating after lower limb amputation (55 upper leg and 101 lower leg). Patients were treated twice daily with 4 percent propolis ointment for seven days. Treatment was extended to 14 days in cases of unsatisfactory improvement within one week. Patients with upper leg amputations experienced slightly better results, though both groups exhibited the best outcomes with Staphylococcus infections. The investigators noted that topically applied propolis improves circulation, stimulates intracellular metabolism, and alters skin reactivity. They also concluded that propolis ointment is indicated for skin disorders on stumps and local trophic conditions.⁶⁹

Like its associated bee products, royal jelly has reportedly contributed to wound healing. In 2008, Abdelatif et al. conducted a pilot study to ascertain the safety and effectiveness of a new ointment combining royal jelly and panthenol (Pedyphar) in 60 patients with limb-threatening diabetic foot infections. By the end of week 9 and through six months of follow-up, 96 percent of the patients with full-thickness skin ulcers (Wagner grades 1 and 2) or deep tissue infection and suspected osteomyelitis (grade 3) responded well, with all grade 1 and 2 ulcers healing and 92 percent of grade 3 ulcers healing. All patients with gangrenous lesions (grades 4 and 5) healed after surgical excision, debridement, and conservative treatment with the royal jelly/panthenol formulation [see Chapter 27, Vitamin B₅ (Pantothenic Acid/Dexpanthenol)]. The investigators suggested that more double-blind, randomized controlled studies are required to confirm their promising findings that the royal jelly/panthenol combination is safe and effective.⁷⁰

Suemaru et al. compared the effects of topically applied honey, propolis, and royal jelly on 5-fluorouracil (5-FU)-induced experimental oral mucositis in hamsters. The size of the lesions was not diminished by the use of honey (1, 10, and 100 percent) or propolis (0.3, 1, and 3 percent) in comparison to the Vaseline-treated control group. Royal jelly ointments (3, 10, and 30 percent) dose-dependently led to significant improvements and healing, suggesting its possible use in treating chemotherapy-induced moral mucositis in humans.⁷¹ More recently, several of the same investigators furthered their study of royal jelly and its effects on 5-FU-induced oral mucositis in hamsters. Chitosan-sodium alginate film containing royal jelly was used to achieve healing. These films (10 and 30 percent) significantly ameliorated the damage caused by 5-FU, decreasing myeloperoxidase activity and proinflammatory cytokine production. In addition to such anti-inflammatory effects, the investigators noted that royal jelly displayed antioxidant activity. They attributed the healing effect from severe oral mucositis to the anti-inflammatory and antioxidant properties of royal jelly.⁷²

In 2010, Kim et al. treated freshly scratched normal human dermal fibroblasts with different concentrations of royal jelly (0.1, 1, or 5 mg/mL) for up to 48 hours. They found that fibroblast migration peaked at 24 hours after wounding and that royal jelly significantly and dose-dependently accelerated the migration at the eight-hour mark. In addition, various lipids in fibroblasts involved in the wound-healing process were influenced by royal jelly treatment, with the cholesterol level lowered and sphinganines increased.⁶²

The following year, Siavash et al. conducted a small study of eight patients to assess the efficacy of topically applied royal jelly in the treatment of diabetic foot ulcers. Of the eight ulcers treated, seven healed, with a mean healing duration of 41 days. The eighth ulcer improved, with significant reductions in size. The investigators concluded that a royal jelly dressing appears to be an effective alternative treatment option for diabetic foot ulcers.⁷³ However, in 2013, Siavash et al. assessed the efficacy of topical royal jelly on diabetic foot ulcers in a double-blind placebo-controlled clinical trial of 25 patients (6 females, 19 males). The 60 ulcers considered in the final analysis were treated with either 5 percent sterile topical royal jelly or placebo. They found no significant differences in the regimens.²¹

COLLAGEN PRODUCTION

Koya-Miyata et al. have demonstrated that royal jelly fosters collagen production by skin fibroblasts in the presence of ascorbic acid-2-O-α-glucoside (AA-2G) and that its primary fatty acid constituent 10-HDA promotes the synthesis of collagen by AA-2G-treated fibroblasts by initiating the production of TGF-β1 production.²⁰

Seborrheic Dermatitis/Dandruff

In 2001, Al-Waili completed a study in 30 patients (20 males, 10 females aged 15 to 60 years) with chronic seborrheic dermatitis of the scalp, face, and chest to evaluate the potential of topically applied crude honey (90 percent honey diluted in warm water). Treatment over a four-week period consisted of gentle rubbing of the ointment for two to three minutes onto lesions every other day, leaving honey on for three hours before gentle warm water rinsing. A six-month prophylactic phase split the group evenly into a once-weekly treatment group and a control group. Honey application yielded further marked improvements, with itching and scaling resolved within the first week. Within two weeks, skin lesions healed completely. Patients also reported subjective improvement in hair loss. Whereas no patients treated with honey experienced relapse, 12 of the 15 patients in the control group experienced relapse within two to four months of initial treatment cessation. The author concluded that weekly use of crude honey delivers significant improvement in seborrheic dermatitis and related hair loss.⁷⁴

Subsequently, Al-Waili et al. conducted a review of the antimicrobial activity of honey, finding topical effectiveness in the treatment of adult and neonatal postoperative infection, boils, burns, infected and nonhealing wounds and ulcers, necrotizing fasciitis, pilonidal sinus, diabetic foot ulcers, as well as venous ulcers.⁷⁶ Internally, honey lowers prostaglandin levels while raising nitric oxide levels, and displays anti-inflammatory and prebiotic activity.⁷⁵

SAFETY ISSUES

Allergic reactions to honey, propolis, and royal jelly have been reported.^76,77 Propolis is relatively innocuous, though.³⁴ A no-effect level (NOEL) of 1,400 mg/kg body weight/day was found in a 90-mouse study on propolis.¹⁴ Some cases of allergic contact dermatitis as well as allergic contact cheilitis to propolis in humans have been reported.^53,78–81

Royal jelly has been known to provoke an anaphylactic response in some people.^17,82 Asthmatic and anaphylactic reactions to the ingestion of royal jelly have been found to be true IgE-mediated hypersensitivity reactions.⁸³ Contact dermatitis has also been reported in reaction to topical royal jelly.⁸⁴ Indeed, although royal jelly has been linked to broad health benefits, such as promoting growth in children, improving general health, and enhancing longevity, adverse reactions ranging from contact dermatitis, acute asthma, anaphylaxis and even death have been linked to its use.⁸⁵

A 1997 cross-sectional survey of 1,472 hospital employees in Hong Kong conducted by Leung et al. revealed that 461 subjects (31.3 percent) had taken royal jelly in the past. Adverse reactions to royal jelly, including urticaria, eczema, rhinitis, and acute asthma, were reported by nine subjects. Skin tests were conducted on 176 questionnaire respondents (13 of whom had a positive skin test to pure royal jelly) and 300 consecutive asthma clinic patients (23 of whom had positive skin tests). Thirty-five of the 36 participants with positive royal jelly skin tests were atopic to other common allergens.⁸⁶ In a retrospective evaluation of common environmental allergens in adult asthmatic patients completed later that year in Hong Kong, many of the same investigators found that royal jelly was the fifth most common allergen associated with positive skin tests (after Dermatophagoides pteronyssinus, D. farinae, cockroaches, and cat dander).⁸⁷

In a 2008 study aimed at characterizing the major allergens of royal jelly, Rosmilah et al. identified major royal jelly protein 1 and major royal jelly protein 2 as the main allergens in royal jelly that affected the 53 human subjects with royal jelly allergy who were evaluated.⁸⁵

In 2013, Moriyama et al. assessed the hypoallergenicity of alkaline protease-treated royal jelly in vitro and in vivo. They demonstrated that the immunoglobulin E-binding capacity of the treated royal jelly was substantially diminished via in vitro assays of the blood from patients sensitive to royal jelly. In 75 percent of royal jelly-sensitive patients given a skin-prick test, royal jelly did not elicit an allergic reaction.¹⁷

ENVIRONMENTAL IMPACT

As stated above, human beings depend on bees to pollinate approximately one-third of our crops, including a large proportion of the produce that we consume. Among global agricultural crops, the European honeybee is the most economically valuable pollinator.⁸⁸ A. mellifera also plays a significant role in maintaining biodiversity via pollinating several species of plants that need an obligatory pollinator to be fertilized.⁸⁸ Notably, the antibacterial activities of bee products, especially honey and propolis, place bees at an even more potentially crucial position related to human health given the alarming global increase in antibiotic resistance among several bacterial strains. Indeed, Dr. Margaret Chan, director-general of the World Health Organization, has warned of the dangers of increasingly pervasive antibiotic resistance, referring to this insidious threat as the possible “end of modern medicine as we know it.”⁸⁹

Given that honey, in particular, has been exploited since ancient times for its antibacterial properties in treating infected wounds and is currently known to exhibit broad-spectrum effectiveness against antibiotic-resistant strains, this iconic bee product would appear to merit careful consideration and study, as would propolis, along with a concerted effort to stem the overuse, abuse, and misuse of antibiotics. However, the effects of “colony collapse disorder” – the decimation of bee populations – certainly loom as a substantial threat to further exploring a natural alternative to antibiotic resistance within our midst. The etiology of this bee colony disaster has recently become less mysterious, as the use of neonicotinoid pesticides in industrial agriculture appears to account for much of the devastating impact on honeybees, though calls for more larger studies persist.^90,91 The European Commission has banned the use of three neonicotinoids based on such concerns.⁹² Colony collapse disorder is a global phenomenon,⁹³ and poses significant worldwide risk to the produce on which human beings significantly rely. Regardless of the cause or causes, whether it is pesticide use or the parasitic Varroa mite,⁹⁴ colony collapse disorder presents a significant existential impact on honeybees and, possibly, numerous other species including humans.

The greater environmental impact related to bee products, then, is not in the harvesting and processing of these products themselves but, rather, from the marked strains that human industry places on the very existence of the honeybee. We quite possibly continue the use of neonicotinoid pesticides, now believed to have a pernicious effect on bees,⁹⁵ and overuse of antibiotics for livestock⁹⁶ at our own peril.

FORMULATION CONSIDERATIONS

Geographical location, pollen source, climate, environmental conditions, season during collection, genetic factors, and the processing methods it undergoes influence honey composition and quality.^9,33 Because honey is readily contaminated through processing, medical grade honey is sterilized through γ-radiation, which destroys various microorganisms without compromising the compound’s antibacterial activity.^{29,46,97–100}

Like honey, the collection location, time, and plant source affect propolis quality, chemical composition, and biologic activity, thus there is great variability in these products.^1,35,101,102 However, because of the unique ecosystems in which different honeybees live and the variety of plant sources from which bees collect ingredients, propolis does not have a specific chemical connotation or formula.³⁵ Given the potential for its use as a topical agent because of its antioxidant capacity, Marquele-Oliveira et al. found in 2007 that propolis formulations prepared with Polawax exhibited functional and physical stability in percutaneous studies in pig ear skin and hairless mouse skin as well as an in vivo study that indicated the viability of the formulation in protecting human skin from UVB photodamage.¹⁰³

Dosage and safety are among the greatest challenges of using bee products for medical purposes.²³ Honey and royal jelly processed into formulations for wound care first pass through fine filters that remove the majority of pollen and other impurities. Some viable spores, such as clostridia, may be included in honey.²³ Bacterial sensitivity to bee products is influenced by the botanical origin of the product and there is significant variability in bacterial sensitivity to bee products.²³

USAGE CONSIDERATIONS

Honey that is not medical grade is liable to contain viable bacterial spores (including clostridia), and may also exhibit less predictable antibacterial properties.¹⁰ Several countries have approved of the use of medical-grade honey (e.g., manuka, Medihoney) and numerous brands of sterile, irradiated, antibacterial topical honey preparations are available.^{10,33,104,105}

Royal jelly is used in cosmetics, dietary supplements, and beverages. Particularly in Asia, it is deployed as a health tonic.⁴³

SIGNIFICANT BACKGROUND

Manuka honey and Medihoney are the primary forms of honey used in clinical practice. Propolis is one of the most copious sources of polyphenols, particularly flavonoids and phenolic acids, some of the most potent antioxidants yet discovered.^106,107

Antioxidant Activity

In 2005, a study by Marquele et al. of Brazilian propolis extracts alone and in topical pharmaceutical formulations revealed that the antioxidant activity of the extracts was maintained in the topical products. The bee glue was particularly active against the superoxide radical.¹⁰⁸

A 2006 study using New Zealand white rabbits revealed that topical propolis exhibited antioxidant, anti-inflammatory, and antibacterial activity against Staphylococcus aureus keratitis.¹⁰⁹

In 2009, Nakajima et al. compared the antioxidant effects of various bee products, specifically Brazilian green propolis, water-soluble royal jelly, and a bee pollen ethanol extract against H₂O₂, superoxide anion, and hydroxyl radicals. They found water extracts of propolis to have the greatest potency, followed by ethanol extracts of propolis, and pollen. Royal jelly had no effects. Of the primary constituents of propolis, caffeic acid displayed the greatest antioxidant activity, followed by artepillin C, and drupanin.¹¹⁰ Also that year, Izuta et al. found that Brazilian green propolis and Chinese red propolis and their components (CAPE and caffeoylquinic acid derivatives) acted as potent scavengers of the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical.¹¹¹

Recent chemical analyses of Algerian propolis indicated a high content of polyphenols and diterpenes from samples in various north Algerian regions. Using the DPPH assay, Piccinelli et al. found that the polyphenol-rich samples of propolis exhibited potent antioxidant activity.¹¹²

In addition, propolis has been shown to lower oxidative stress, altering catalase, malondialdehyde, and nitric oxide levels, in N_ω-nitro-L-arginine methyl ester (1-NAME)-induced hypertension in rats, suggesting a modulatory impact on the antioxidant system.¹¹³

A 2010 study by Cole et al. showed that Sydney propolis significantly and dose-dependently protected mouse skin against edema, immunosuppression, and lipid peroxidation. The investigators concluded that Sydney propolis has the potential to protect human skin against UV-induced skin cancer and other photodamage.¹¹⁴

In 2011, Fonseca et al. showed that green and brown propolis extracts, with varying composition and properties, both effectively prevented UV-induced glutathione depletion in vivo. Oral administration of extracts in hairless mice yielded a higher recovery of glutathione, after reductions caused by UV exposure, in the green propolis group (30 percent vs. 22.8 percent). Topical propolis pretreatment before UV exposure netted a 14 percent recovery in both groups. The investigators concluded that both green and brown propolis extracts are promising agents for combating oxidative stress in skin.⁵⁵

In 2013, Bolfa et al. studied the wide-ranging effects of a Romanian propolis topically applied in two concentrations (3 mg and 1.5 mg polyphenols/cm²) before or after UVB exposure in a Swiss mouse model. Both concentrations significantly decreased malondialdehyde formation and IL-6 levels while restoring the activity of glutathione peroxidase. Epidermal hyperplasia and dermal inflammation were diminished with the smaller concentration, with only dermal inflammation reduced by pretreatment with the larger concentration. Romanian propolis also decreased sunburn cell formation and exhibited an antigenotoxic effect by significantly attenuating cyclobutane pyrimidine dimer formation. In light of the antioxidant, anti-inflammatory, antiapoptotic, and antigenotoxic properties manifested in their study, the investigators concluded that Romanian propolis provides significant photoprotection in the mouse model and warrants consideration as a chemopreventive agent for mitigating several UVB-induced cutaneous signaling pathways.¹⁰⁸ Also that year, Moniruzzaman et al. found that two Malaysian honeys, longan and sourwood, are good sources of antioxidants as compared to other rubber tree and manuka honeys.¹¹⁵

Antimicrobial and Anti-inflammatory Activity

Potent antibacterial activity is exhibited by honey, propolis, royal jelly, as well as bee venom, with even epidemic strains of methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant Enterococcus (VRE) showing sensitivity.²³ Among the bee products, propolis has shown the greatest antibacterial activity,²³ though clinical trials and laboratory data suggest that honey acts as an effective broad-spectrum antimicrobial agent.^3,76 These wide-ranging functions are thought to be derived from its acidity; bacteriostatic, bactericidal, and antioxidant constituents (i.e., H₂O₂, antioxidants, lysozyme, polyphenols, phenolic acids, flavonoids, methylglyoxal, and bee peptides); osmotic effect; high sugar concentration; induction of cytokine release; as well as immunomodulatory and anti-inflammatory activity.^3,76

In a 2008 evaluation of medical grade honey (Revamil), Kwakman et al. found that within 24 hours 10 to 40 percent (vol/vol) honey eradicated antibiotic-susceptible and -resistant isolates of Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecium, Escherichia coli, Pseudomonas aeruginosa, Enterobacter cloacae, and Klebsiella oxytoca. They also noted a 100-fold decline in forearm skin colonization in healthy volunteers after two days of honey application, with the number of positive skin cultures falling by 76 percent. The investigators concluded that the topical antimicrobial honey agent Revamil displays significant potential to prevent or treat infections, including those engendered by multidrug-resistant bacteria.²⁵ It is worth noting that honey is known to suppress 150 bacteria species, including clinical strains of MRSA and VRE, with no reports of microbial resistance.¹⁰ In fact, honey has been shown to be clinically effective in treating various kinds of wound infections, reducing skin colonization of several bacteria (including MRSA),²⁵ and accelerating wound healing, without provoking adverse effects.¹⁰ A 2009 report by Blair et al. supports the notion that medical-grade honey has the potential to lessen the strain caused by the emergence of antibiotic-resistant bacteria.¹¹⁶

In 2000, Vynograd et al. evaluated propolis for efficacy in the treatment of recurrent genital herpes simplex virus type 2. Ninety adults, all with local symptoms, participated in a randomized, single-blind, masked investigator, controlled study at seven medical centers in which Canadian propolis ointment containing natural flavonoids was compared with ointments of acyclovir and placebo, with 30 people randomized to each group. Study ointments were applied four times daily. Participants were examined on the 3rd, 7th, and 10th days of treatment for clinical symptoms, including the number and size of herpetic lesions, with lesions classified into four stages: vesicular, ulcerated, crusted, and healed. On Day 3, 15 members of the propolis group had crusted lesions as opposed to eight in the acyclovir group and none on placebo. Local symptoms were noted in three propolis group members, eight acyclovir individuals, and nine on placebo. On Day 7, healing was observed in 10 propolis patients, four acyclovir patients, and three in the placebo group. Investigators reported that 24 propolis patients and 14 acyclovir patients had healed by Day 10. Overall, the propolis ointment was considered more effective in healing lesions and reducing local symptoms.¹¹⁷ In an earlier study of 65 patients, a topical ointment containing propolis, Nivcrisol-D, showed a significant therapeutic effect against recurrent herpes and zona zoster, with patients using the study drug healing from outbreaks in an average of four days while patients using placebo took an average of eight days to heal from outbreaks.¹¹⁸

In 2002, Gregory et al. assessed the purported antimicrobial, anti-inflammatory, and scar-healing capacity of a high-grade Brazilian propolis cream. Patients presenting with bilateral superficial second-degree burns over less than 20 percent of their body surface, with wounds of similar depth and quality, were admitted into the study within 48 hours of their injuries and then treated with propolis cream on one wound and silver sulfadiazene applied to a similar one on the other side. Wounds were debrided and dressings changed on the following morning. Patients returned to the clinic at three-day intervals to have their wounds checked and dressings changed, with reapplication of the ointment taking place only at these visits. In addition, investigators cultured the wounds for microbial growth and took photographs to record inflammation and scar formation. No significant differences were noted in microbial colonization, but wounds treated with the propolis cream showed less inflammation and quicker scar formation as compared to the silver sulfadiazene-treated burns. While noting the beneficial effects of propolis on burns, the researchers speculated that more frequent changing of wound dressings would have evinced antimicrobial results also.¹¹⁹

Omani propolis has been found to differ from many known propolis types, as it is derived from the resin of Azadiracta indica (neem tree), Acacia spp. (most probably A. nilotica) and Mangifera indica. However, like many other forms of propolis, the Omani variety contains biologically active phenolic compounds (e.g., prenylflavanones, cardols, and anacardic acids) and has exhibited antimicrobial activity.³⁶

Activity Against Pruritus and Xerosis

In 2011, Duplan et al. assessed the activity of a synthetic counterpart to 10-HDA in several experiments (in vitro, ex vivo, and in vivo) aimed at characterizing its potential use in treating UV-induced xerosis. Hydroxydecine® induced involucrin, transglutaminase-1, and filaggrin protein production in normal human keratinoctyes and yielded increases in these compounds in topical treatment of skin equivalents. In healthy volunteers with UV-induced xerosis, Hydroxydecine cream use led to an increase of 28.8 percent in the hydration index after seven days and 60.4 percent after 21 days of treatment. In the ex vivo findings in a model of inflammation and barrier impairment involving human skin explants maintained alive, the formulation restored skin barrier function and lessened inflammation. The investigators concluded that the synthetic version of 10-HDA also displayed efficacy in activating keratinocyte differentiation in vitro as well as in vivo in hydrating dry human skin.⁶⁰

In 2013, Yamaura et al. examined an experimental allergic contact dermatitis model in hairless mice to ascertain the antipruritic activity of topical royal jelly on chronic pruritus. They found that five weeks of treatment with topical royal jelly (0.01 or 1 percent) and 0.01 percent β-methasone significantly alleviated chronic pruritus induced by five weeks of repeated application of 2,4,6-trinitro-1-chlorobenzene. The level of nerve growth factor mRNA in back skin was elevated in mice with contact dermatitis, lower in those treated with β-methasone, and unchanged in mice treated with royal jelly. The investigators acknowledged the likely different mechanisms of action between royal jelly and β-methasone in suggesting that royal jelly may be a useful ingredient in cosmetics for easing chronic pruritus.⁴³

Anticarcinogenic Activity

Various components of propolis have also been isolated and found to possess anticarcinogenic properties. Flavonoid aglycones are some of the significant constituents of propolis that are believed to contribute to antitumorigenic activity.¹³ A study with a fractionated methanol extract of a Brazilian propolis resulted in the isolation of a tumoricidal substance characterized as a new clerodane diterpenoid, which reduced the growth and number of skin tumors induced by 7,12-dimethylbenz(a)anthracene (DMBA) application on mouse back skin by inhibition of DNA synthesis.¹³

In a study to determine whether CAPE, a propolis constituent, inhibits the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced processes associated with carcinogenesis, low doses of CAPE were topically applied to SENCAR mice. CAPE was found to strongly inhibit several TPA-mediated oxidative processes considered sine qua non for tumor promotion, including: polymorphonuclear leukocyte infiltration into mouse skin and ears; H₂O₂ production; and formation of oxidized bases in epidermal DNA. In addition, researchers noted inhibition of edema and ornithine decarboxylase induction in CD-1 and SENCAR mice after CAPE application, as well as the inhibition of TPA-induced H₂O₂ production in bovine lenses. Researchers concluded that CAPE appears to have potent chemopreventive capacity, particularly in treating disorders associated with strong inflammatory and/or oxidative stress processes, such as cancer and cataracts.²⁷

In a different study on skin tumors, CD-1 mice were initiated with DMBA and then treated twice weekly with topically applied TPA, resulting in 18.8 skin papillomas per mouse. Subsequent topical application of CAPE to the backs of the mice together with TPA twice a week for 20 weeks inhibited the number of skin papillomas and reduced tumor size in a dose-dependent manner. The same combination also decreased the level of 5-hydroxymethyl-2′-deoxyuridine (HMdU) in epidermal DNA produced through the previous initiation with DMBA. In addition, in vitro CAPE introduction to cultured HeLa cells inhibited DNA, RNA, and protein synthesis. All of these inhibitory effects conferred by CAPE were deemed by investigators to be potent.¹²⁰

In a 2004 study on polyphenolic compounds and antitumorigenic properties, a water-soluble derivative of propolis, caffeic acid, CAPE, and quercetin administered to mice resulted in a reduction in the number of lung tumor nodules. Researchers related the antitumor properties of the tested substances to their immunomodulatory capacity, cytotoxicity to tumor cells, and ability to induce apoptosis and necrosis, suggesting that propolis, caffeic acid, CAPE, and quercetin show promising potential for combating tumor growth.¹²¹

In 2011, Watanabe et al. found that propolis appears, in vitro and in vivo, to act against various tumor cells, suggesting its possible role in future anticancer drugs.¹⁵

Photoprotection

In 2011, Park et al. measured the 10-HDA content of royal jelly and investigated its effects on UVB-induced skin photoaging in normal human dermal fibroblasts. The tested royal jelly (0.211 percent 10-HDA) led to increased synthesis of procollagen type I and TGF-β1, without altering MMP-1 levels. The researchers concluded that due to its potential to spur collagen production, royal jelly could be used to protect the skin against UVB-induced photoaging.¹²² Park et al. followed this work up the following year, finding that the synthesis of type I collagen in the dorsal skin of ovariectomized Sprague-Dawley rats was augmented by the dietary supplementation of 1 percent royal jelly extract. Although MMP-1 levels were again unchanged, the investigators suggest that royal jelly may provide an antiaging benefit by virtue of enhanced collagen production alone.¹⁹

In 2013, Zheng et al. studied the protective effects of the royal jelly fatty acid component 10-HDA against UVA-induced damage in human dermal fibroblasts and its inhibitory effects on UVA-induced MMP expression. They found that 10-HDA significantly protected the fibroblasts from UVA-induced cytotoxicity, reactive oxygen species, and cellular senescence. In addition, 10-HDA hindered the UVA-generated expression of MMP-1 as well as MMP-3, and stimulated the production of collagen. Activation of the c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways was also diminished due to 10-HDA treatment. The investigators concluded that this royal jelly fatty acid exhibits potential for use in the prevention and treatment of cutaneous photoaging.²²

In 2013, Angelo et al. demonstrated that the addition of propolis protected L. angustifolia (lavender) essential oil from UV-induced degradation and preserved its antioxidant capacity in cell oxidative damage assessments on B₁₆–F₁₀ melanoma cells as well as in vitro antioxidant assays. The investigators concluded that propolis may act as an efficient UV-protective and antiradical adjuvant to sunscreens, cosmetics, and other products that contain plant extracts (see Chapter 73, Lavandula).¹²³

Skin Whitening

Skin-lightening indications may also be a viable use for royal jelly. Han et al. found that royal jelly dose-dependently suppressed melanin biosynthesis in the B₁₆-F₁ mouse melanocyte cell line by lowering tyrosinase activity. Further, royal jelly decreased mRNA levels of tyrosinase. The researchers concluded that royal jelly merits consideration for inclusion as a therapeutic agent in new skin-whitening products.¹⁸

CONCLUSION

Honey, propolis, and royal jelly, all bee products with a long history of traditional medicinal use, have been found to exhibit sufficient biologic activity to warrant consideration in modern medicine. The antibacterial activity of these products is legendary, and the wide array of additional biologic activities, particularly their antioxidant capacity, suggest broad potential for these agents, meriting greater attention and study for dermatologic application. Indeed, more research, in the form of randomized, controlled trials, is needed prior to incorporating bee products into the armamentarium as first-line therapies, but the potential seems vast.

REFERENCES

INTRODUCTION

SOURCE

Idebenone, also known as 2,3-dimethoxy-5-methyl-6-(10′-hydroxydecyl)-1,4-benzoquinone, CV-2619, or QSA-10, is a synthetic analog of, and similar in structure to, the potent antioxidant ubiquinone, or coenzyme Q₁₀ (CoQ₁₀) (see Chapter 57, Coenzyme Q₁₀). CoQ₁₀ is an integral cell membrane nutrient and contributor to the adenosine triphosphate (ATP)-producing mitochondrial electron transport chain, activity in which idebenone has also been shown to engage.¹ Idebenone has a significantly lower molecular weight and shorter carbon side chain as compared to CoQ₁₀ and, therefore, greater solubility or ability to penetrate the skin than its natural counterpart (Table 61-1).^2–4

HISTORY

Idebenone was first synthesized in 1984, and introduced as an active agent to treat age-related brain impairment in 1986.^5,6 In nearly three decades of extensive research, the preponderance of data that have emerged pertain primarily to the relative success of this benzoquinone compound in comparison to other drugs for treating patients with Alzheimer's disease; its use in organ transplant solutions; and its success in ameliorating various symptoms of Friedreich's ataxia. More recently, idebenone has been included in cosmeceutical products, such as Prevage™, as an antiaging agent.⁶

CHEMISTRY

As a potent free radical scavenger believed to be much stronger and efficient than other well-known antioxidants (e.g., vitamins C and E, CoQ₁₀, kinetin, and α-lipoic acid), idebenone also functions as an electron carrier and is not characterized by occasional activity as a strong pro-oxidant as is the case with CoQ₁₀ under hypoxic conditions. In fact, under such conditions, idebenone is known to preserve ATP formation, protecting against free radical formation and cell damage.^1,7 In addition, idebenone is considered to have potential as a therapy to enhance energy and cognition, to protect organs against excitatory amino acid neurotoxicity, and to retard aging. As a CoQ₁₀ analog, it is thought that idebenone works at least as well as its natural counterpart within the electron transport chain to maintain a high energy level. Idebenone was shown in a rat liver microsomal model to be more effective than CoQ₁₀, though, in protecting against lipid peroxidation.⁸

ORAL USES

Oral administration of idebenone has been demonstrated to improve mitochondrial oxidative metabolism in the brain, suggesting a therapeutic potential in the treatment of myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).^9,10 The protection imparted by idebenone to the brain's myelin sheath and energy-producing mitochondria may also position this antioxidant to play a therapeutic role in multiple sclerosis. Idebenone has been used orally in the treatment of several conditions, including Alzheimer's disease, liver disease, cerebrovascular disease, and Friedreich's ataxia.^1,11 Cutaneous benefits of idebenone are gleaned through topical administration.

TOPICAL USES

Idebenone has been used outside the United States for years as an antiaging agent and for improving cognition in patients with Alzheimer's disease and other neurologic disorders. As a topical agent, idebenone is believed to possess a much greater skin penetration potential and higher oxidative stress protection capacity than CoQ₁₀.¹² Idebenone has also reportedly displayed higher antioxidant activity than vitamins C and E, CoQ₁₀, kinetin, and α-lipoic acid [see Chapter 55, Ascorbic Acid (Vitamin C), and Chapter 56, Tocopherol (Vitamin E)].¹² Idebenone is thought by some, though, to be ineffective in conferring photoprotection to skin when compared to a topical antioxidant combination of vitamins C and E with ferulic acid (see Chapter 54, Ferulic Acid).¹³ There are also reports that suggest greater antioxidant activity has been exhibited by resveratrol as well as L-ergothioneine (see Chapter 50, Resveratrol).^14,15

In 2005, McDaniel et al. conducted a nonvehicle-controlled clinical trial to assess the topical safety and efficacy of 0.5 and 1 percent idebenone commercial formulations in 41 female subjects (from ages 30 to 65 years) with moderate photodamaged skin. Subjects were randomized to use a blind labeled (either 0.5 or 1 percent idebenone in otherwise identical lotion bases) skincare preparation twice daily for six weeks. Significant declines in skin roughness/dryness (by 26 percent) as well as fine lines and wrinkles (by 29 percent) were associated with the use of 1.0 percent idebenone, as were a 37 percent increase in skin hydration, and a 33 percent improvement in global skin assessment. Similar improvements were seen with the use of 0.5 percent idebenone. In addition, immunofluorescence staining indicated reductions in interleukin (IL)-1β, IL-6, and matrix metalloproteinase (MMP)-1 as well as an increase in collagen type I corresponding to both concentrations of idebenone.⁷ As Bruce noted, though, the actual implications of the reported enhancements might have been better illustrated with the addition of a placebo arm in this study.¹⁶ Nevertheless, the stated purpose of the study by McDaniel and colleagues was to ascertain baseline and after effects of the two concentrations of idebenone and not to evaluate the benefits of the antioxidant per se.

Idebenone has also been used along with hyaluronic acid as one of two formulations successfully incorporated into a new minimally invasive mesotherapy technique shown in a study with 50 subjects (ranging in age from 30 to 65 years) who demonstrated significant clinical improvement in terms of the brightness, texture, and firmness of their facial skin. Biopsies at baseline and after three months showed increases in collagen type I as well as decreases in MMP-1, IL-6, and IL-1β.¹⁷

SAFETY ISSUES

Idebenone is found in various over-the-counter topical antiaging products in concentrations ranging from 0.5 to 1 percent.¹¹ It is generally considered safe but there have been a few isolated reports of allergic contact dermatitis associated with idebenone-based Prevage since 2008. Specific symptoms have included erythema, scaling, severe edema, and vesicular dermatitis of the face, ears, and neck.^2,11,18,19 Some suggest that allergies to idebenone may be undetected or more widespread because this substance is not routinely included in standard patch testing.¹⁹ This ingredient is not recommended for sensitive skin types.

ENVIRONMENTAL IMPACT

There is no environmental impact of commercial CoQ₁₀ production known by the author.

FORMULATION CONSIDERATIONS

Although idebenone is considered more capable of permeating the skin barrier than CoQ₁₀, it is known to be irritating in free form.²⁰ In addition, it has been known to degrade and lose antioxidant potency when exposed for a protracted period in conditions with a relative humidity of 75 percent and a temperature of 40°C (104°F).^20,21 Several delivery methods have been investigated to account for such deficiencies and to facilitate its penetration and bioavailability.

In 2010, researchers developed nanoparticles based on chitosan and N-carboxymethylchitosan crosslinked with tripolyphosphate by co-drying with idebenone in different polymer-to-drug ratios with 20 percent (wt/wt) colloidal silicon dioxide and tripolyphosphate. The nanoparticles evinced a tenfold increase of drug stability as compared to the free drug and preserved the in vitro antioxidant activity of idebenone; the nanoparticle formulation resulted in less mucous membrane irritation as compared to the free form of idebenone. The investigators concluded that chitosan and N-carboxymethylchitosan nanoparticles warrant consideration as carriers for the topical and nasal use of hydrophobic and irritation-producing drugs such as idebenone.²⁰

In 2012, Li and Ge investigated the percutaneous permeation of idebenone in ex vivo guinea pig skin after the application of various formulations, including nanostructured lipid carriers, nanoemulsions, and oil solutions. They found that nanostructured lipid carriers exhibited greater chemical stability and more effectively enhanced skin permeation as compared to the other vehicles (delivering nearly threefold the amount of idebenone to the epidermis and dermis) and thus have potential in topical skin care formulations.²² Also that year, Montenegro et al. observed, after an in vitro evaluation, that loading idebenone in solid lipid nanoparticles appears to be an effective mode of drug delivery to the outer skin layers.²¹

In a review published in 2012 that covered the previous two decades, Carbone et al. found a wide range of delivery systems for idebenone, including cyclodextrin inclusion complexes, liposomes, microemulsions, prodrugs, and polymeric and lipid nanoparticles. While direct comparison was difficult, they maintained that these various carriers have successfully increased solubility and facilitated stability and bioavailability. They noted, also, that the controlled release and targeting of idebenone remains a goal in product development.²³

In a particularly interesting meta-analysis regarding the prediction of responses to the use of antiaging cosmeceuticals, Sachs et al. enrolled 100 subjects with 16 to 20 participants applying one cosmeceutical (L-ascorbic acid, pentapeptide, α-lipoic acid, yeast extract, or 1 percent idebenone) to their photodamaged forearms for several weeks. Results varied widely, independent of age or gender, with some experiencing no improvement and others achieving sevenfold increases in collagenesis. Statistical analysis revealed that age, gender, and cosmeceutical type exerted no influence, with preexisting hypocollagenesis as the only factor affecting outcome (volunteers with hypocollagenesis responded 6.4 times more often than those with normal collagenesis). The authors suggested that this parameter might guide the future development of antiaging skin care product formulations.²⁴

USAGE CONSIDERATIONS

In 2009, Wempe et al. investigated the inherent in vitro permeability, metabolism, and cytotoxicity of idebenone and compared it to the idebenone ester idebenone linoleate using pig ear skin and melanoma mouse cells. The researchers observed that idebenone permeated across the porcine tissue, but found no evidence that idebenone linoleate had after four hours. In the porcine tissue as well as mouse melanocytes, idebenone was metabolized to idebenone acid, with minimal idebenone linoleate metabolism noted. Further, no toxicity was associated with idebenone linoleate whereas idebenone exhibited delayed toxicity in melanocytes. The investigators concluded that the metabolic activation of idebenone likely accounts for the skin irritation associated with in vivo use of idebenone, which appears to have an inferior safety profile compared to its ester idebenone linoleate.⁶

SIGNIFICANT BACKGROUND

In studies on rats that paved the way to hypotheses regarding applications to neurologic, cardiologic, and antiaging indications, researchers ascertained that idebenone inhibited lipid peroxidation, protecting cell membranes and mitochondria from oxidative damage and, especially, brain mitochondria from swelling.^1,25,26 In addition, idebenone has been shown to improve cardiac function in patients with Friedreich's ataxia, and has been demonstrated to be effective in treating mitochondrial cardiomyopathy.²⁷

Antioxidant Activity

The ability of idebenone to act as a potent free radical scavenger was demonstrated by Mordente et al. over 15 years ago. In particular, they showed that it could scavenge the organic radicals 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) and diphenylpicrylhydrazyl, the radicals peroxyl and tyrosyl, as well as peroxynitrite. They also found that idebenone suppresses microsomal lipid peroxidation engendered by adenosine diphosphate (ADP)-iron complexes or organic hydroperoxides, thus preventing cytochrome P450 elimination. In addition, the investigators observed in comparative experiments that idebenone manifested antioxidant efficiency ranging from 50 to just short of 100 percent of vitamin E or its water-soluble analog trolox.²⁸

In 2005, McDaniel et al. conducted in vitro and in vivo studies to compare the oxidative stress protective properties of several frequently used antioxidants, including vitamins C and E, kinetin, α-lipoic acid, CoQ₁₀, and idebenone. After establishing a standardized method to summarize all results, including the human sunburn cell assay as well as experiments comparing antioxidant performance by photochemiluminescence, inhibition of ultraviolet B irradiation of human keratinocytes, and measurement of primary and secondary oxidation products, the researchers compiled overall oxidative protection scores of 95, 80, 68, 55, 52, and 41 for idebenone, vitamin E, kinetin, CoQ₁₀, vitamin C, and α-lipoic acid, respectively, as idebenone acted as a potent antioxidant most consistently across various experiments.²⁹ Further, they concluded that idebenone exhibits great potential for inclusion in topical skin protection products.

Neuroprotective Activity

In vitro and in vivo studies suggest that idebenone may reduce nerve cell damage induced by ischemia, repair neurotransmitter defects and/or cerebral metabolism, and enhance memory and learning.¹ Patients with mild dementia have been shown in clinical trials to be more likely to respond than those with greater functional decline.³⁰ In a multicenter, randomized, double-blind, placebo-controlled, parallel trial with Alzheimer's patients, idebenone was shown to be effective in enhancing memory, attention, and orientation as well as slowing disease progression.³¹

In a different study, repeated oral administration of idebenone, which stimulates nerve growth factor (NGF) synthesis, partially restored the age-related reduction of NGF in the frontal and parietal cortices. This is noteworthy because NGF is instrumental in maintaining cholinergic neurons the degeneration of which is linked to the cognitive impairment displayed by Alzheimer's patients. Authors of this study determined then that oral administration of idebenone has potential as a therapeutic agent in preventing cholinergic dysfunction.³² A prospective, randomized, double-blind, placebo-controlled multicenter study of two doses of idebenone in the treatment of patients with Alzheimer's disease further established the efficacy and safety of the drug for this indication.³³

In a subsequent two-year prospective, randomized, double-blind multicenter study of the safety and efficacy of idebenone in the treatment of Alzheimer's patients, the synthetic CoQ₁₀ analog exerted beneficial therapeutic effects on the course of the disease by slowing down its progression. Also, the antioxidant was found to be safe and tolerable.³⁴

CONCLUSION

The synthetic coenzyme Q₁₀ analog idebenone has been investigated for nearly 30 years, yielding an extensive body of research. Its antioxidant and other health benefits are well established, as is its use for various indications outside the United States. Recent research appears to validate the use of idebenone as a topical antiaging agent and its use in Prevage, introduced in 2005, represents the first skin product to contain a clinically tested and proven topical antioxidant. Responses to its use have been mostly favorable, with a few reports of allergic contact dermatitis. Nevertheless, it would be helpful to see studies comparing the results of idebenone-containing topical products and the antiaging retinoid products known to be effective for symptoms of cutaneous aging.

REFERENCES

INTRODUCTION

SOURCE

Melatonin (N-acetyl-5-methoxytryptamine), a tryptophan derivative, is a hormone produced naturally by the pineal gland in humans, and stimulated by β-adrenergic receptors. In addition, it is synthesized in mammals by the eyes, ovaries, bone marrow, gastrointestinal tract, lymphocytes, and skin, where it is also metabolized.^3–6 Additionally, melatonin has been recorded at significant levels in bile fluid, cerebrospinal fluid, and gastral mucosa.⁷ Also found in most animal and plant species as well as fungi and even unicellular organisms, it follows a circadian light-dependent rhythm of secretion, and is derived from tryptophan, which is present in all organisms.^8,9 That is, melatonin is secreted during the dark phase of the light/dark cycle, and also regulates seasonal biorhythms (and is often accordingly referred to as the “hormone of darkness” and the body’s chronological pacemaker).^5,9 In fact, melatonin is best known for regulating and facilitating sleep, with its “chronobiotic” characteristics justifying its use to treat sleep disorders including jet lag, shift-work sleep disruption, and insomnia in elderly and depressive patients.⁵

HISTORY

Although melatonin is a phylogenetically ancient methoxyindole, it was initially isolated from bovine pineal glands in 1958.^5,7–12 Subsequently, researchers learned that melatonin was produced nocturnally and secreted by the pineal gland and other organs in mammals including humans.⁸ Melatonin and its relations to skin function have been studied since its skin-lightening effects on frogs were observed in the late 1950s.^10,13,14 The status of melatonin as a potent free radical scavenger was uncovered in 1993.^8,15,16 That same year, the first evidence emerged of the production of melatonin in the skin.^17–19 Significantly, a melatoninergic antioxidative system that regulates cutaneous homeostasis and exhibits the potential to prevent ultraviolet (UV)-induced skin aging and skin cancer has been recently discovered.^7,8,20,21

CHEMISTRY

Melatonin is a methoxyindole produced primarily by the pineal gland. In the skin, the essential amino acid tryptophan is the precursor; it is converted by tryptophan hydroxylase to 5-OH-Trp and then to serotonin. The acetylation of serotonin leads to the formation of N-acetylserotonin, which is transformed after the hydroxyindole-O-methyltransferase into melatonin.⁹

ORAL USES

Several plants are good sources of dietary melatonin, as it appears ubiquitously in nature and is found in almost 60 herbs used in traditional Chinese medicine.⁵ Melatonin is also used as an oral supplement, primarily to restore regular sleep patterns. Prescriptions are required in some countries for melatonin supplements.

In 2008, Otálora et al., noting that melanoma is known to respond to melatonin in vitro, examined the effects of exogenous melatonin on hindering tumor growth and correcting impaired circadian rhythmicity. They found that melatonin administration (2 mg/kg/ BW/day) restored rhythmicity and improved survival in light-dark (12:12 cycle) conditions, but not under continuous light and circadian disruption, suggesting the need to restrict melatonin administration to the subjective night to hamper melanoma progression.²²

TOPICAL USES

In recent years, melatonin has been gaining increased attention in antiaging medicine and dermatology because it has been found to exert potent antioxidant activity (Table 62-1), particularly against hydroxyl radicals,^5,23 and melatonin levels are known to decrease with age. In addition to its antioxidative and regulatory roles, including in seasonal reproduction control, melatonin is known to play a role in wound healing, to modulate the immune system, and to inhibit inflammation.^9,24 In addition, there is mounting evidence to suggest its viability as an agent to prevent cutaneous aging.⁸ Topical application is preferable to oral administration for deriving cutaneous benefits because orally ingested melatonin is metabolized in the liver, yielding low levels in the blood and available to the skin.^8,25 Further, due to its potent lipophilicity, topical melatonin can penetrate the stratum corneum (SC) and form a reservoir, from where it is continuously released to the rest of the skin and dermal vasculature, potentially complementing and augmenting the activity of endogenous melatonin.^3,8,26

Indeed, it is an important hormone in the dermatologic realm insofar as it is known to inhibit UV-induced erythema; implicated in skin functions such as hair growth, fur pigmentation/molting in various species, and melanoma control; and thought to have potential in treating various human dermatoses (e.g., atopic eczema, psoriasis, and malignant melanoma) as well as conditions such as androgenetic alopecia.^6,9,23 Of note, among the numerous plant species from which cutaneous applications are derived, feverfew is known to contain an appreciable level of melatonin (see Chapter 66, Feverfew).²⁸

Androgenetic Alopecia

In 2004, Fisher et al. also investigated whether topically applied melatonin affects the anagen and telogen hair growth phases in women with androgenetic alopecia or diffuse hair loss. In their double-blind, randomized, placebo-controlled pilot study with 40 women, they instructed participants to apply 0.1 percent melatonin or a placebo preparation to the scalp once daily for six months. In the 12 women with androgenetic hair loss, melatonin contributed to a significantly greater anagen hair rate in occipital hair as compared to placebo. In the 28 participants with diffuse alopecia, melatonin application led to significant growth in frontal hair. Anagen hair growth in the occipital regions was increased in both groups, with insignificant differences. The investigators noted that while melatonin levels rose with treatment, the physiological night peak of serum melatonin was not exceeded. They concluded that their pilot study was the first to their knowledge to demonstrate in vivo that topically applied melatonin has the potential to impact hair growth in humans.²⁹

In 2012, Fischer et al. reported on one pharmacodynamic study and four clinical pre–post studies of topically applied melatonin as a treatment for androgenetic alopecia. All five studies demonstrated positive results, with significant reductions in hair loss seen in multiple tests all of which were associated with good safety and tolerability. In the largest of the studies, a three-month, multicenter (200 centers) study with over 1,800 participants, the percentage of patients with a two- to threefold positive hair-pull test declined from 61.6 percent to 7.8 percent and those with a negative hair-pull test rose from 12.2 percent to 61.5 percent. Seborrheic dermatitis of the scalp was also found to have markedly diminished in these patients. The researchers concluded that the topical application of a cosmetic melatonin solution is a viable therapeutic option for patients with androgenetic alopecia.³⁰

Antioxidant and Anticancer Activity

Melatonin receptors are expressed in several skin cell types, notably normal and malignant keratinocytes, melanocytes, and fibroblasts.^8,14

Endogenous melatonin influences skin functions and structures through cell-surface- and putative-nuclear receptor-mediated expressions in skin cells and the broad expression and pleiotropic activity of the cutaneous melatoninergic system yields a high level of cell-specific selectivity, several investigators have found.^3,7

The dynamic antioxidant activity of melatonin is thought to result from its capacity to scavenge free radicals, reduce free radical generation, and upregulate antioxidant enzymes.³¹ Further, melatonin has been shown to counteract the effects of UV-induced solar damage, specifically thwarting mitochondrial and DNA harm.⁸

The decrease in endogenous melatonin synthesis with age is thought to significantly contribute to the gradual decline of the immune system and thus increased susceptibility to neoplastic disease development.⁴

In 2005, Slominski et al. identified the cutaneous expression of the mechanism of action in the transformation of L-tryptophan to serotonin and melatonin through detection of the corresponding genes and proteins with demonstrated enzymatic activities for tryptophan hydroxylase, serotonin N-acetyl-transferase, and hydroxyindole-O-methyltransferase in extracts from skin and skin cells. The investigators concluded that locally synthesized or topically administered melatonin has the potential to attenuate environmental or endogenous stresses and contribute to homeostasis as well as play a role in treating cutaneous disorders and acting as a photoprotectant.¹⁴

Melatonin has been demonstrated to augment T-helper cell response against malignancy by releasing interleukin (IL)-2, IL-10 and interferon (IFN)-γ. In addition, melatonin has been found to be effective in hindering neoplastic growth in melanoma, as well as breast, prostate, ovarian, and colorectal cancer.⁴ Indeed, multiple studies have shown that melatonin possesses oncostatic activity.⁵

In 2013, Fischer et al. reported that melatonin dose- and time-dependently protected against UV-induced 8-hydroxy-2′-deoxyguanosine (8-OHdG) formation and antioxidant enzyme depletion (i.e., catalase, glutathione peroxidase, and superoxide dismutase) using ex vivo human full-thickness skin. They concluded that melatonin acted as a strong antioxidant and protector of DNA against oxidative skin damage.³² Previously, Fischer et al. had shown that melatonin more strongly scavenged UV-induced reactive oxygen species in leukocytes than either vitamin C or the vitamin E analog trolox [see Chapter 55, Ascorbic Acid (Vitamin C), and Chapter 56, Tocopherol (Vitamin E)].^9,33

Also in 2013, Sierra et al. investigated the in vivo and in vitro protective effects of a new melatonin-containing emulsion combined with UV filters against skin irradiation, finding good physical stability and melatonin permeation in an emulsion with a mixture of three UV filters. The formulation displayed significant radical-scavenging activity and a photoprotective assay revealed that skin treated with melatonin/UV filter formulation was statistically equivalent to nonirradiated control skin. The investigators concluded that melatonin acted in this formulation as a strong antioxidant and also activated endogenous enzymatic protection against oxidative stress.³⁴

In Vitro Studies

In 2001, Ryoo et al. set out to elucidate the antioxidant role of melatonin in reaction to UVB exposure in cultured skin fibroblasts. Pretreatment with melatonin was found to mitigate cell membrane lipid peroxidation, yielding an increase in the absolute number of surviving cells and reducing malondialdehyde levels. Melatonin pretreatment also prevented the pre-G₁ arrest leading to apoptosis. The researchers concluded that melatonin was shown to be an effective inhibitor of membrane peroxidation. This is thought to be the first report on the protection of dermal fibroblasts from UVB by melatonin.³⁵

Melatonin was one of the several substances found to act as a viable antioxidant agent by Trommer and Neubert in 2005. They screened 47 substances (drugs, plant extracts, plant ingredients, and polysaccharides) for new antioxidative compounds for topical administration using skin lipid in vitro models.³⁶

In 2006, Fischer et al. examined the in vitro protective effects of melatonin against UV-induced cell damage in human keratinocytes. They found that pre-incubation is necessary for melatonin to display protective activity, which includes apoptosis inhibition.³⁷

In a 2009 issue of In Vivo, Izykowska et al. reported on the effects of melatonin on melanoma cells in culture medium and after its addition to culture medium for 30 minutes prior to UVA or UVB exposure, finding that melatonin clearly protected cells from UVA and UVB activity in vitro.³⁸ In the same issue of In Vivo, noting previous studies showing a protective effect on cells exerted by melatonin mainly in relation to UVB, Izykowska et al. also reported on the effects of melatonin on keratinocytes and fibroblasts added to culture medium 30 minutes before exposure to UVA and UVB, again finding that melatonin affords protection to skin cells from the activity of UVA as well as UVB in vitro.³⁹

In 2013, Rezzani et al. assessed the effects of pretreating murine fibroblast cells with melatonin before exposure to UVA radiation. They found that melatonin increased heme-degrading enzyme expression and inhibited UVA-induced photodamage, suggesting potential applications for limiting skin aging.³¹

Animal Studies

In 2006, Sener et al. studied the effects of melatonin in treating pressure ulcers in rats. Animals were treated twice daily during reperfusion periods with a locally applied ointment or given intraperitoneal administration of the antioxidant. Topical melatonin treatment was associated with suppressed malondialdehyde levels and attenuated decreases in glutathione in the skin induced by the pressure ulcers. Melatonin treatment also prevented significant increases in alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatinine, lactate dehydrogenase, and collagen levels. In addition, the researchers noted degenerative changes in the dermis and epidermis of the rats, with marked decreases in tissue injury in the animals that received topical melatonin. They concluded that melatonin, delivered topically or systemically, warrants consideration as a pressure ulcer treatment.⁴⁰

Two years later, Pugazhenthi et al. used a full-thickness incisional rat model to evaluate the dermal wound and scar healing effects of melatonin (1.2 mg/kg intradermal). The investigators observed that melatonin significantly ameliorated scar quality. Treatment with melatonin also markedly reduced inducible nitric oxide synthase (iNOS) activity in the acute inflammatory phase but substantially elevated iNOS in the resolving phase. Further, melatonin raised cyclooxygenase-2, which has known anti-inflammatory properties, following wound induction and facilitated angiogenesis. Arginase activity, instrumental in collagen production by synthesizing the building block proline, was increased by melatonin treatment, which also upregulated the protein profiles of heme oxygenase-1 and heme oxygenase-2 isoforms, which are essential in wound repair. The investigators suggested that their findings represented the first report showing that melatonin can significantly enhance wound healing and scar formation.²

In a 2009 study using NC/Nga mice, researchers investigated whether melatonin inhibits the development of 2,4-dinitrofluorobenzene (DNFB)-induced atopic dermatitis-like skin lesions. Topically administered melatonin hindered ear thickness increases and skin lesions engendered by DNFB treatment. Melatonin was also found to significantly inhibit IL-4 and IFN-γ secretion by activated CD4⁺ T cells from the draining lymph nodes of DNFB-treated mice, and diminish serum total IgE levels. The investigators concluded that topically administered melatonin, by lowering total IgE in serum, and IL-4 and IFN-γ synthesis by activated CD4⁺ T cells, inhibits atopic dermatitis-like skin lesion development provoked by DNFB treatment in NC/Nga mice.²⁴

In a 2010 study comparing systemic and topical administration of melatonin in a chronic wound model in rats whose release of basal melatonin was hindered due to pinealectomy, Ozler et al. found that hydroxyproline levels were significantly lower in rats that underwent pinealectomy and wound formation compared to the controls (with wound formation only), with increased wound surface areas. Also compared to the control group, these animals exhibited increased malondialdehyde levels and decreases in superoxide dismutase and glutathione peroxidase compared to control animals. However, superoxide dismutase and glutathione peroxidase enzymes increased in the groups treated with melatonin and malondialdehyde decreased. The researchers concluded that melatonin exerts a positive effect on wound healing, as the absence of melatonin prolonged the healing process. Topical and systemic administration methods were equally effective.⁴¹

Recent studies have also shown that melatonin and the antidiabetes drug metformin have the capacity to suppress skin carcinogenesis as well as lipid peroxidation induced by benz(a)-pyrene in female SHR mice.^42,43

Human Studies

In 1996, in one of the earliest studies of the effects of topically applied melatonin on UV-induced erythema, Bangha et al. conducted a double-blind, randomized study with 20 healthy volunteers. Each subject was exposed to UVB (0.099 J/cm²) on the lower back and then treated with various concentrations of melatonin. The investigators observed a dose–response relationship between melatonin concentration and the degree of erythema, with significantly less redness found in the areas treated with 0.5 percent melatonin as compared to melatonin 0.05 percent or just the vehicle gel.⁴⁴

The next year, Bangha et al. performed another double-blind, randomized study in 20 volunteers to examine the antierythema effects of topical melatonin and the role of the application time in exerting the effect. Investigators treated small areas of the lower back with 0.6 mg/cm² melatonin 15 minutes before or 1, 30, or 240 minutes after simulated UVA and UVB irradiation at twice the individual minimal erythema dose. They found that posttreatment with melatonin exerted no protective effect but pretreatment 15 minutes prior to irradiation yielded significant protective effects against erythema.⁴⁵ In a subsequent similar double-blind, randomized clinical trial with 20 healthy volunteers, this time led by Fischer, the visual score indicated that melatonin application 15 minutes before irradiation significantly hindered erythema as compared to vehicle control. Postirradiation treatment with melatonin did not yield UV inhibition.⁴⁶

In a small study of the penetration kinetics of topical melatonin in six healthy volunteers between the ages of 26 and 34 years old, Bangha et al. found that melatonin has the potential to accumulate in the SC with extended release into the blood system through cutaneous delivery.⁴⁷

In 1998, Dreher et al. conducted a randomized, double-blind study in 12 healthy adults (6 women and 6 men, all Caucasian, ranging in age from 29 to 49 years old) of the short-term photoprotective effects of topically applied melatonin as well as vitamins C and E, alone or in combination. All formulations were applied 30 minutes after UV exposure. A dose-dependent photoprotective effect was associated with melatonin, with modest effects seen with the vitamins alone. Photoprotective activity was clearly enhanced when using melatonin in combination with vitamins C and E. This is thought to be the first in vivo demonstration of a protective effect imparted by topical melatonin in combination with other antioxidants.⁴⁸ The following year, Dreher et al. performed a similar experiment to assess the short-term photoprotective effects of the same compounds. This randomized, double-blind, placebo-controlled human study entailed the topical use of each antioxidant alone or in combination after UV exposure in a single application (immediately or 30 minutes after UV exposure) or in multiple applications 30 minutes, one hour, and two hours after UV exposure (totaling three applications). Interestingly, no photoprotective effects were observed regardless of the number of applications of antioxidants. The investigators concluded that given the speed of damage to skin from UV radiation, antioxidants likely must be delivered at the appropriate site in sufficient concentrations at the outset of and during active oxidative insult.⁴⁹

Similarly, in 2006, Howes et al. studied the effects of topical melatonin applied after solar-simulated UV exposure in 16 healthy Mantoux-positive volunteers and found that melatonin conferred no protection against sunburn or immune suppression.⁵⁰

However, four years prior, Morganti et al. conducted an eight-week randomized, double-blind, placebo-controlled study on 30 xerotic female volunteers (between 48 and 59 years old) to determine the effects of topical and systemic antioxidant-enriched formulation administration on the skin. Subjects applied twice daily a nanocolloidal gel and/or took two capsules per day of an oral diet supplement. The antioxidant-enriched formulations included vitamins C and E, α-lipoic acid, emblica, and melatonin (see Chapter 38, Emblica Extract). Investigators found that oxidative stress and lipid peroxidation declined 30 to 40 percent in the blood serum of all participants who used the topical or systemic antioxidant formulation. Those treated with the antioxidants also experienced declines in free radicals recovered in blood serum and on skin and decreases in reactive oxygen species engendered by UVB irradiation of leukocytes (in vitro). The researchers concluded that the tested compounds indeed delivered topical and systemic photoprotection and represent promising ingredients for combating oxidative stress and photoaging.⁵¹

In 2004, Fischer et al. conducted a clinical study in 15 healthy volunteers to consider the skin penetration activity of melatonin 0.01 percent in a cream and 0.01 and 0.03 percent in a solution. In a 24-hour time window, investigators took blood samples for melatonin measurement prior to application at 9 am as well as 1, 4, 8, and 24 hours after application. Preapplication serum melatonin levels ranged from 0.6 to 15.9 pg/mL. The mean serum value 24 hours later after application of the 0.01 percent melatonin cream was 9.0 pg/mL. For the 0.01 percent solution group, the mean melatonin level was 12.7 pg/mL 24 hours after application. Melatonin levels also markedly increased just 1 and 8 hours later in the 0.03 percent solution group, with cumulative melatonin noted as 7.1 pg/mL in the 0.01 percent cream subjects, 8.6 pg/mL in the 0.01 percent solution participants, and 15.7 pg/mL in the 0.03 percent group. The investigators concluded that markedly lipophilic melatonin penetrates the skin with serum blood levels increasing in a dose- and galenic-dependent manner without causing increases above the physiological range.²⁶

In 2008, a single-blind, randomized study with 145 patients was conducted to ascertain the effectiveness of a formulation containing 2.5 mg melatonin and 100 mg SB-73 (a mixture of magnesium, phosphate, and fatty acids extracted from Aspergillus species, which exhibit activity against the herpes virus) and to compare it to treatment with Acyclovir. Seventy subjects were treated with the melatonin/SB-73 preparation and 75 received 200 mg of Acyclovir (group B). A statistically significant difference between the groups was noted by the authors. After seven days of treatment, 67 participants in the melatonin/SB-73 group (95.7 percent) reported complete symptom resolution; 64 participants (85.3 percent) of the Acyclovir reported such a result.⁵²

In 2012, Morganti et al. conducted a randomized, placebo-controlled, 12-week multicenter study with 70 healthy participants to again examine melatonin in combination. In this case, they considered the combined activity of melatonin, vitamin E, and β-glucan complexed with chitin nanocrystals administered topically and orally. All skin parameters reviewed were significantly better after treatment with the melatonin, vitamin E, β-glucan combination as compared to placebo, with greater improvements observed when these ingredients were complexed with chitin nanocrystals. Specifically, the treatment yielded decreased wrinkling and enhanced skin appearance.⁵³

SAFETY ISSUES

Exogenous melatonin is reported to be safe for short-term (<3 months) use for sleep-related disorders.^54,55 A fixed drug eruption has been reported with the use of oral melatonin.⁵⁶

ENVIRONMENTAL IMPACT

Given the widespread availability of plants containing melatonin, no discrete environmental toll is exacted in the preparation of oral or topical melatonin products.

FORMULATION CONSIDERATIONS

The author has no insight on the challenges of formulating melatonin.

USAGE CONSIDERATIONS

The author has noticed that patients with melasma seem to worsen after taking melatonin supplements. For this reason, it is advised that individuals with pigmented skin (designated as “P” types in the Baumann Skin Type System) not use melatonin-containing preparations. This is due to activation of melanin production by melatonin.

SIGNIFICANT BACKGROUND

Melatonin should be used with care in postmenopausal women not on hormone replacement therapy. Menopause and aging are believed to impair the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. The administration of melatonin increases cortisol levels in postmenopausal women, leading to increased serum glucose levels,⁵⁷ and glycation. Administration of estrogen improves the regulation of the HPA axis and blocks the increase of cortisol levels with melatonin administration.⁵⁸

Kim et al. have shown that melatonin and its metabolite methoxykynuramine appear to stimulate differentiation in human epidermis, suggesting their important role in building the skin barrier.⁵⁹ Further, melatonin receptors are expressed in several skin cell types, notably normal and malignant keratinocytes, melanocytes, and fibroblasts.^8,14

CONCLUSION

There is ample research on the biological functions of melatonin. There is also an interesting, emerging body of evidence on the dermatologic effectiveness of the topical application of this hormone. In fact, there seems to be a wide variety of potential cutaneous uses for melatonin. However, most of the clinical studies have been extremely small, including a couple of investigations that indicated no photoprotective effect associated with melatonin. The effects of melatonin on melanogenesis (skin pigmentation), the skin barrier, and cortisol levels all play a significant but poorly understood role. Clearly, much more research, preferably in the form of randomized, double-blind studies is necessary before adequate recommendations to patients about melatonin use for skin health can be issued.

REFERENCES