Section H: Anti-Inflammatory Agents

INTRODUCTION

In the 1st century CE, Cornelius Celsus described the signs of acute inflammation as: calor (heat), dolor (pain), rubor (redness) and tumor (swelling).¹ This accurate depiction of the sequence of events that occurs in inflammation is characteristic of all types of inflammation regardless of the provocative stimuli, which can include injury, friction, emotion, exposure to irritants or allergens, or infectious agents.² The initial insult to the skin causes vasodilation that is seen as redness. The endothelial lining of the blood vessels becomes more permeable and leads to extravasation. In other words, substances leak out of the vessel causing increased fluid in the tissues, which results in swelling. Inflammatory mediators such as cytokines and interleukins are released and activate multiple pathways that can lead to pain, redness, and swelling as well as serve to beckon immune cells to the area.

The process of inflammation is orchestrated by a large array of inflammatory mediators including histamines, cytokines, eicosanoids (e.g., prostaglandins, thromboxanes, and leukotrienes), complement cascade components, kinins, fibrinopeptide enzymes, and free radicals. For a more extensive review, see Cosmetic Dermatology: Principles and Practice, 2nd edition, Chapter 35 (McGraw-Hill, 2009).

Although the many causes of inflammation are very complicated and beyond the scope of this book, arachidonic acid (AA) and its pathways are important to understand when considering the anti-inflammatory claims of skin care products. AA production is a major cause of inflammation because AA is broken down into inflammation-causing substances such as prostaglandins and leukotrienes. Production of AA is blocked by corticosteroids, which is one of the ways that topical steroids decrease inflammation (they also cause vasoconstriction). Two important pathways involved in the breakdown of AA are worth noting (Figure 64-1).

1. Cyclooxygenase pathway: Results in the production of prostaglandins. This is the pathway in which salicylates (aspirin) and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen work.

2. Lipoxygenase pathway: Results in the production of the inflammatory mediator group leukotrienes.

Several categories of anti-inflammatory ingredients are considered in this section: salicylates, prostaglandin antagonists, leukotriene antagonists, polyphenols, and vasoconstrictors. Examples of salicylates include salicylic acid and Aloe vera.

Prostaglandin antagonists include feverfew, licorice extract, and oatmeal, while turmeric and chamomile are leukotriene antagonists. Coumarin and its derivatives, found in tamanu oil, for example, suppress prostaglandin biosynthesis through inhibition of the lipoxygenase and cycloxygenase systems.³ Horse chestnut is a vasoconstrictor, as are corticosteroids such as hydrocortisone. Polyphenols are also discussed in the Antioxidants section introduction as well as several chapters in that section. Anti-inflammatory polyphenols considered here include calendula, edelweiss, and lavandula. Polyphenols decrease inflammation by neutralizing free radicals.

Inflammation is typically the common denominator for individuals with sensitive skin. The etiology varies depending on the condition. For example, in acne, the cause of inflammation is thought to result from byproducts generated by bacteria as they digest fatty acids. In rosacea, part of the observed inflammation is due to vasodilation of unknown etiology. Those with allergic skin reactions develop inflammation when the immune system cells in the skin are exposed to an allergen.

INFLAMMATION AND AGING

Inflammation is believed to play a role in aging because its activation can lead to the breakdown of skin collagen and elastin and other important cutaneous components in addition to increased glycation, lipofuscin, and free radical production. This is discussed in Chapter 81, Overview of Aging.

Botanical, natural, and organic products often exhibit potent anti-inflammatory activity. The most commonly seen ingredients in anti-inflammatory skin care include feverfew, green tea, cucumber, chamomile, and licorice extract. It is anticipated that many new ingredients will enter the market as our understanding of the causes of rosacea and other inflammatory skin conditions increases.

REFERENCES

INTRODUCTION

SOURCE

A cactus-like perennial succulent and member of the Xanthorrhoeaceae family and the subfamily Liliaceae (lily) native to North Africa and the Arabian peninsula, Aloe vera (also known as Aloe barbadensis) is the most potent of the several aloe species and one of the most widely used herbal products throughout the world (Table 65-1).¹² The plant is now widely distributed throughout Africa, Asia, southern Europe, the Americas, and other areas with tropical climates.¹³ Aloe (from the Arabic alloeh for a “shining bitter substance”) vera (Latin for “truth”) thrives in warm, dry climates, but can survive high temperatures and even humid conditions as long as its roots are not submerged in water.^11,14 Various cultures have used aloe to treat burns (including sunburns), wounds, abrasions, insect bites, cuts, blisters, and frostbite. A. vera has been used for several decades, both topically and systemically, to enhance wound repair based more on traditional and anecdotal evidence than rigorously established scientific study.¹⁵ Its effectiveness in healing wounds and treating infections has been established in laboratory animals, though.⁹

Reputed to have potent anti-inflammatory and antimicrobial effects, the fresh or dehydrated whole aloe leaf is used for treatment of radiation injuries, ulcers, burns, eczema, and psoriasis.¹³ Other anecdotal cutaneous indications may include seborrhea, acne, androgenetic alopecia, and herpes zoster (shingles). Aloe is believed to balance the pH of the skin and is used in hundreds of medicines and over-the-counter (OTC) products such as shampoos, soaps, shaving creams, deodorants, tissue paper products, sunscreens, moisturizers, and other skin creams to soothe, heal, and protect the skin. It is also believed to exhibit antioxidant properties.¹⁶

In fact, the medical establishment recognizes the use of A. vera in treating radiation and stasis ulcers and has acknowledged the antibacterial and antifungal effects of A. vera components.¹⁷ Aloe is also indicated for the treatment of frostbite.¹ The vasoconstrictive effects of thromboxane have been shown to be improved with the application of A. vera cream such as Dermaide.^18,19 Further, A. vera is recognized as one of the many herbal products to contain pharmacologically active ingredients with the potential to enhance wound healing.²⁰ Such ingredients include salicylates and a carboxypeptidase that inactivates bradykinin in vitro.¹⁷ A. vera is considered the most commercially important of the more than 500 species in the genus Aloe.^3,11,21

The manufacturing of A. vera extracts represents one of the largest global botanical industries, and aloe is one of the few herbal agents used broadly in Western cultures.²²

HISTORY

In traditional folk medicine, topical A. vera is used to treat inflammation, cicatrization, and dyspigmentation. Its constituent aloesin has been demonstrated to inhibit tyrosinase activity from human, murine, and mushroom sources.²³ The traditional use of A. vera gel dates back nearly 2,500 years to ancient Egypt (where it was known as the “the plant of immortality”)^11,24, Greece, India, China (where it was dubbed an “elixir of youth”)¹¹, Japan, and Mexico.^11,14,25 It is believed to have been included in the skin care regimens of Egyptian queens Nefertiti and Cleopatra, as well as for embalming and as an offering at funerals for pharoahs.^14,24 Egyptians, Assyrians, and others in the Mediterranean region are said to have used the gel as well as the latex (found inside the leaves).²⁴ Aloe was also reportedly used to treat battlefield wounds in ancient times under Alexander the Great and more than 1,500 years later under Christopher Columbus.¹⁴ The first documentation of healing properties associated with A. vera is attributed to Mesopotamian clay tablets circa 2100 BCE, with medicinal properties characterized with greater detail in Egyptian writings circa 1550 BCE.²²

Through human trade and migration, this dynamic plant became known and widely used to cure burns and wounds throughout ancient civilizations in Persia, Egypt and elsewhere in Africa, Greece, Rome, India, and China and appears in the folklore of Japan, the Philippines, and Hawaii. The Spanish used it and brought it to South America and to such Caribbean locales as Aruba, Curaçao, and Barbados (from which the alternate INCI name Aloe barbadensis nomenclature is derived).²⁶

Aloe is believed to have been first cited in English in John Goodyew’s 1655 translation of De Materia Medica by the Greek physician Dioscorides, who used the plant to treat sores and wounds in the first century CE.^14,22,24 It was used as a laxative in the United States (US) beginning in the early 1800s, and listed in the US pharmacopoeia in 1820 as a purgative and skin protectant.^14,22 Modern clinical use of A. vera began in the 1930s, when it was shown to be effective in treating chronic and severe radiation dermatitis.^14,25 Aloe products have maintained their popularity through the course of time.²⁷ In 1983, the US Food and Drug Administration (FDA) approved topical aloe to treat inflammation.¹⁰ It continues to be used today primarily for anti-inflammatory applications, but several other uses are under investigation. A. vera is also approved as a food flavoring and oral cathartic (Aloe latex).¹⁰ In traditional Chinese medicine, A. vera is used for fungal conditions; in Ayurvedic medicine, it is used to treat cutaneous and other conditions.²²

CHEMISTRY

Rich in glucomannans and other polysaccharides, the gel and sap from the inner core of the full leaf confer healing qualities and pose no risk. Aloe is known to lessen the itching and inflammation associated with minor wounds. The gel is also thought to be effective in eliminating the yeasts, fungi, and bacteria that infiltrate and inhabit wounds and, is believed by some to accelerate collagen production. Research in recent years has determined that aloe contains three agents with significant antitumor potential: emodin, mannose, and lectin. While the use of A. vera has not achieved unqualified acceptance from the medical establishment, components of the plant are under serious scientific investigation.

There is a large body of anecdotal evidence attesting to the efficacy of aloe for the treatment of myriad diseases; unfortunately, exaggerated claims are not uncommon and therefore caution is warranted in the interpretation of some of the available information.²⁸ Explanations of aloe gel efficacy are still varied because it has, in fact, several active constituents operating through different mechanisms.²⁹ Indeed, aloe has been compared to honey as an exceedingly convoluted amalgam of natural components (see Chapter 60, Honey/Propolis/Royal Jelly).³⁰ Its action as a moisturizer is a popular use that may account for many of its effects.³¹ Furthermore, aloe is reputed to exhibit potent anti-inflammatory effects, and the substances that have been proposed as its active anti-inflammatory constituents include salicylates (providing “aspirin-like effects”); magnesium lactate, which is believed to inhibit the production of histamine; bradykinin and thromboxane inhibitors, which provide pain reduction; and polysaccharides, particularly acemannan, which has reported immunomodulatory properties.^16,32,33 Another substance isolated from aloe, C-glucosyl chromone, has exhibited topical anti-inflammatory activity equivalent to that of hydrocortisone (200 μg/mouse ear).³⁴ A glycoprotein fraction of A. vera is thought to account, through cell proliferation and migration, for the wound healing effect associated with extracts of the plant.³⁵

ORAL USES

Aloe is used as a functional food and an ingredient in other food products as well as health-boosting beverages.^3,11 Traditionally, for health purposes, aloe has been used orally as a purgative and antihelminthic agent.¹⁰ In addition, it has been used systemically for ulcers and diverticulitis.³⁶ The oral administration of A. vera has recently been found to be effective in ameliorating the effects of acute radiation-delayed wound healing in rats by increasing transforming growth factor (TGF)-β1 and basic fibroblast growth factor.³⁷ Overall, however, oral use of aloe is thought to exacerbate some chronic conditions and to be susceptible to multiple drug interactions.³⁶Therefore, despite some evidence of systemic efficacy, oral use of aloe is not recommended.³⁶

Acemannan, a polysaccharide extracted from A. vera, has been shown to be an effective and safe alternative for treating oral aphthous ulcers for patients who prefer to avoid steroid therapy, though it is less effective than 0.1 percent triamcinolone acetonide.³⁸

In 2009, Cho et al. investigated the cutaneous antiaging effects of dietary A. vera gel in 30 healthy females over 45 years old who received either a low-dose (1,200 mg/d) or high-dose (3,600 mg/d) supplement for 90 days, with baseline status serving as control. The researchers noted significant improvement in facial wrinkles in both groups, and facial elasticity was enhanced in the group using the low-dose supplement. Based on skin samples taken before and after supplementation, matrix metalloproteinase (MMP)-1 mRNA levels were found to be significantly diminished in the high-dose group. In both groups, type I procollagen immunostaining was significantly elevated. The investigators concluded that although no dose-response relationship was found, oral administration of aloe gel appeared to significantly improve signs of photoaged human skin, with increases noted in collagen synthesis and decreases in collagen-degrading MMP-1 gene expression.³⁹

A. vera is also a featured ingredient in a multi-phytonutrient liquid dietary supplement that contains a proprietary blend of fruits, vegetables, and catechin complex from green tea (VIBE Cardiac & Life) found in vitro to have exerted antimutagenic, and DNA-protective effects on human epidermal cells exposed to ultraviolet (UV)-induced DNA damage.

There are indications that the oral use of gel may lower blood glucose levels in type 2 diabetes mellitus, alleviate mild-to-moderate ulcerative colitis, and even stabilize metastatic cancer. Much more research is necessary to corroborate such findings, according to Foster et al.²²

TOPICAL USES

In 2008, Reuter et al. conducted a randomized, double-blind, placebo-controlled, Phase III study in 40 volunteers to evaluate the anti-inflammatory activity of a highly concentrated A. vera gel (97.5 percent). After test sites on the back were exposed to 1.5-fold minimal erythema dose (MED) of UVB, these areas were treated for the next two days with A. vera gel, positive controls (0.25 percent prednicarbate, 1 percent hydrocortisone in placebo gel, and 1 percent hydrocortisone cream), or a placebo gel. After 48 hours, the A. vera gel was found to have significantly lowered UV-induced erythema more effectively than 1 percent hydrocortisone in placebo gel, but less efficiently than 1 percent hydrocortisone cream. Nevertheless, the researchers suggested the potential use of highly concentrated A. vera gel for topically treating inflammatory skin conditions.⁴⁰

Oyelami et al. reported in 2009, based initially on an open, non-comparative study, that the crude gel of A. vera was used successfully in Nigeria to treat five patients with scabies. Subsequently, the investigators compared the efficacy of the botanical agent (16 subjects) with that achieved with benzyl benzoate lotion (14 subjects) in 30 patients. After two courses of treatment, three of the patients using benzyl benzoate lotion and two of those using A. vera still complained of pruritus. Lesions were found to have essentially disappeared in all patients, with no detectable side effects. The researchers concluded that A. vera gel is as effective as benzyl benzoate for treating scabies.⁴¹

Earlier that year, Feily and Namazi performed a literature search for in vitro, in vivo, and clinical trial data on dermatologic uses of A. vera, finding 40 pertinent studies. Oral administration in mice was seen as effective in wound healing, reducing the number and size of papillomas, and lowering the incidence of tumors and leishmaniasis. The researchers found that while topically applied aloe offered no photoprotective or radioprotective activity, it was noted for efficacy in treating aphthous stomatitis, burns and other wounds, frostbite, genital herpes, human papilloma virus, inflammation, lichen planus, psoriasis, seborrheic dermatitis, and xerosis. They added that data support the use of aloe as a biological vehicle, an antimicrobial and antifungal agent, and a potential option for photodynamic therapy for some forms of cancer. Finally, the authors cautioned that while encouraging results have been obtained for A. vera for a broad range of dermatologic applications, the clinical data establishing effectiveness of oral and topical A. vera remain insufficient.¹³

Psoriasis

Aloe is rarely, if ever, mentioned among the wide array of products comprising the dermatologic armamentarium for psoriasis. There is some evidence suggesting its usefulness, however. Syed et al. performed a double-blind, placebo-controlled examination of A. vera extract 0.5 percent in a hydrophilic cream for the treatment of psoriasis vulgaris.⁴² Psoriatic plaques cleared in only two of 30 subjects on placebo while the aloe group showed clearance in 25 of 30 patients, and significant improvement in desquamation, erythema, and Psoriasis Area Severity Index (PASI) score.^42,43 Inflammation remains a major indication for aloe products. Research has established the anti-inflammatory effects of A. vera gel extracts, which may also impart inhibitory activity, via cyclooxygenase, on the arachidonic acid pathway.⁴⁴ Immunomodulatory properties of the gel polysaccharides, particularly the acetylated mannans (now a proprietary compound under several patents), have been reported.²⁹

In 2005, Paulsen et al. led a randomized, double-blind, placebo-controlled, right/left comparison study in 41 patients with stable plaque psoriasis to determine the efficacy of a commercial A. vera gel. Results were modest, with the gel not shown to be superior to placebo. However, the researchers suggested that the high response rate to placebo might have left the aloe gel looking less effective than it actually was.⁴⁵

A 2010 randomized, comparative, double-blind, eight-week study of 80 patients conducted by Choonhakarn et al. suggested that A. vera may be more effective than 0.1 percent triamcinolone acetonide in the treatment of mild-to-moderate plaque psoriasis. The mean PASI score decreased from 11.6 to 3.9 over eight weeks in the A. vera group and from 10.9 to 4.3 in the triamcinolone acetonide group. The researchers noted, though, that both treatments displayed similar efficacy in improving quality of life for psoriasis patients.⁴⁶

In 2012, Dhanabal used a mouse tail model to assess the antipsoriatic activity of A. vera, showing that an ethanolic extract of the gel generated a significant differentiation in the epidermis as well as a significant increase in relative epidermal thickness compared to negative control and the lack of change in the standard positive control (tazarotene). The investigators concluded that A. vera exerted an overall antipsoriatic activity of 81.95 percent in the mouse tail model, as compared to 87.94 percent for tazarotene.⁴⁷

Wound Healing

A. vera has been used for several decades, both topically and systemically, to enhance wound repair based more on traditional and anecdotal evidence than rigorously established scientific study.¹⁵

A few recent studies buttress the long-standing anecdotal evidence in support of aloe in the treatment of wounds. An investigation using rats showed that full-thickness wounds treated with A. vera displayed elevated biosynthesis of collagen and its degradation, suggesting that aloe affected the wound-healing process by enhancing collagen turnover in the wounded tissue.⁴⁸ In another study using rats, A. vera exhibited both anti-inflammatory and wound-healing activity when applied to second-degree burns.⁴⁹ Similar effects have been seen in studies with humans. Researchers observed that the partial thickness burn wounds of 27 patients treated with A. vera gel evinced early epithelialization and faster healing time than the area treated with Vaseline gauze. Some patients reported mild discomfort.⁵⁰

After an exhaustive literature search in 1999 of controlled clinical trials on aloe, Vogler and Ernst sounded skeptical notes, however. They concluded that the topical application of A. vera may be effective for genital herpes and psoriasis, but its effectiveness in promoting wound healing was, as yet, unproven, and its use does not prevent radiation-induced injuries.⁵¹

Ten years later, topically applied A. vera gel was shown in a study in 63 male rats to reduce wound diameter significantly when administered twice daily as compared to once-daily treatment or control groups.⁵²

A 2012 report by Inpanya et al. demonstrated that a blended fibroin/aloe gel film could accelerate wound healing in streptozotocin-induced diabetic rats, with wounds treated with the blended film enhancing the attachment and proliferation of skin fibroblasts compared to aloe-free fibroin film and yielding smaller wounds after day 7 compared to untreated diabetic wounds. The investigators concluded that their fibroin/aloe gel film may have potential for treating diabetic non-healing skin ulcers in humans.⁵³

Also that year, in a randomized, controlled, comparative study by Tarameshloo et al., topically applied A. vera gel more rapidly accelerated the healing process than silver sulfadiazine 1 percent, thyroid hormone, or vehicle in skin wounds surgically induced in Wistar rats (see Chapter 80, Silver).⁵⁴ Hosseinimehr et al. previously found that aloe cream was significantly more effective than silver sulfadiazine in augmenting reepithelialization in burn wounds in rats.⁵⁵

Human trials have been lacking, however. Indeed, Dat el. conducted a 2012 search of several databases (the Cochrane Wounds Group Specialized Register, the Cochrane Central Register of Controlled Trials, Ovid MEDLINE, Ovid AMED, and EBSCO CINAHL) for all randomized controlled trials assessing the effectiveness of A. vera, aloe-derived products, and dressings combining A. vera and other components in treating acute or chronic wounds. Seven trials, with a total of 347 subjects treated, met inclusion criteria, but were deemed to be of such poor quality that trial results should be viewed cautiously. The authors cited the paucity of high quality clinical trials on the use of A. vera topical products or dressings for treating acute and chronic wounds as a justification for withholding support for such treatments.²

Lichen Planus

In 2010, Cheng et al. conducted a comprehensive database search [the Cochrane Skin Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE (from 2005), EMBASE (from 2007), and LILACS (from 1982)] to evaluate the results of treatment for erosive lichen planus involving the anogenital, oral, and/or esophageal regions. They identified 15 randomized controlled trials (473 total subjects) pertaining to oral lichen planus only. Notably, in a study with 45 patients, A. vera gel was found to be six times more likely than placebo to yield at least a 50 percent decline in pain symptoms.⁵⁶

A. vera juice and gel were shown to be effective in a case study of a 38-year-old man who was successfully treated for lichen planus of the skin and oral mucosa with a two-month course of the botanical agent.⁵⁷

Atopic Dermatitis and Xerosis

In 2006, Dal’Belo et al. assessed the effects of cosmetic preparations containing various concentrations of freeze-dried A. vera extract on the skin hydration of the volar forearm of 20 female volunteers. Stratum corneum (SC) water content and transepidermal water loss (TEWL) were evaluated after a single application as well as after one and two weeks of daily use of stable formulations containing 5 percent (w/w) of a trilaureth-4 phosphate-based blend with 0.10, 0.25, or 0.50 percent (w/w) of freeze-dried A. vera extract. SC water content increased after one application of the formulations supplemented with 0.25 and 0.50 percent (w/w) A. vera extract. After two weeks, SC water content was higher as a result of using any of the formulations. When compared with vehicle, TEWL was unaltered by any of the products. The investigators concluded that freeze-dried A. vera extract is effective at enhancing skin hydration and would be useful in cosmetic moisturizers.⁵⁸

In 2010, Kim et al. demonstrated in a study of the effects of Scutellariae radix and A. vera gel, alone or in combination, on NC/Nga mice that both plants modulate immunological responses in atopic dermatitis primarily by suppressing interleukin (IL)-5 and IL-10 levels.⁵⁹

A. vera was cited as one of nine botanical extracts by Casetti et al. in a 2011 PubMed database search for botanical extracts noted for enhancing the skin barrier and/or facilitating keratinocyte differentiation in vivo after topical application. The researchers suggested that while further investigation is necessary, A. vera and the other herbs appear to have potential as dermocosmetic agents for treating dry skin.^60,61

Aloe-coated Examination Gloves

A. vera-infused gloves were first shown to be effective in a 2003 open, contralateral comparison study by West and Zhu. This investigation involved 30 adult females with bilateral dry skin due to occupational exposure on a factory assembly line who were directed to use the dry-coated A. vera glove on one hand for eight hours/day and no glove on the other hand for 30 days. The investigators reported that the gradual delivery of aloe to the skin yielded uniformly enhanced skin integrity, diminished fine wrinkling, and reduced erythema.⁶² In a letter responding to West and Zhu’s study, Mitchell emphasized that their study involved factory not health care workers, who must be vigilant about hand hygiene. Further, she noted that hands not decontaminated after patient contact risk serving as disease vectors, but speculated that decontaminating hands after using A. vera gloves would also negate any benefits of the herbal agent. Finally, she wondered whether the soothing feeling conferred to hands by the A. vera-infused gloves might discourage some users from decontaminating their hands after use.⁶³

In a 2007 quasi-experimental pilot study of 272 health care workers as controls and 203 health care workers as test subjects, investigators working in three US hospitals and one Canadian hospital found that the use of A. vera-impregnated medical exam gloves improved perceived skin condition and attitudes about hand hygiene.⁶⁴ Although such gloves are available on the market in the UK, a report by Ford and Phillips earlier in 2007 suggested that it has not been established that the coating contains active aloe, whether the physical or chemical properties of the gloves are altered by aloe, and what, if any, long-term effects there are for users of the gloves. They did acknowledge that no adverse reactions had been published.⁶⁵

Healing from Radiotherapy

In 2005, Richardson et al. systematically reviewed biomedical and alternative medicine databases for randomized controlled trials on the effectiveness of A. vera gel for treating radiation-induced skin reactions. In the five published trials as well as two unpublished randomized controlled trials that they identified, they found no evidence that topically applied A. vera is effective in preventing or attenuating radiation-induced cutaneous reactions in cancer patients.⁶⁶ Nevertheless, Wang et al. demonstrated during the previous year that aloe polysaccharides exerted radioprotective effects in vitro and in vivo in mice through suppressing apoptosis.⁶⁷

In a literature review published after the database investigation by Richardson and colleagues, Maddocks-Jennings et al. found data to suggest that A. vera gel is as effective as mild steroid creams (e.g., 1 percent hydrocortisone) in mitigating reactions to radiotherapy, with the added benefit of not provoking adverse side effects.⁶⁸

In a 2009 study with Swiss albino mice, Goyal and Gehlot showed that A. vera leaf extract displays radioprotective effects against the biochemical alterations engendered by whole-body γ-irradiation.⁶⁹

Combination Therapies: In Use or Under Investigation

A. vera extract is considered a key ingredient in a formulation also containing wheat germ oil and turmeric extract found to be an effective moisturizer in a small study with human volunteers (see Chapter 69, Turmeric).⁷⁰

In 2008, Gupta et al. found that a poly-herbal topical formulation combining the aqueous lyophilized leaf extracts of Hippophae rhamnoides and A. vera and the ethanol rhizome extract of Curcuma longa (in an optimized ratio of 1:7:1) accelerated wound healing in normal and diabetic rats (see Chapter 69, Turmeric).⁷¹

Mendonça et al. performed a study with Wistar rats in 2009 that compared the wound-healing effects of topically applied A. vera gel alone or not with microcurrent application. The group treated only with aloe gel experienced accelerated wound healing compared to the control group. Animals treated only with microcurrent and those treated with aloe and microcurrent exhibited earlier proliferative phase activity compared to the control and aloe-only groups. The investigators concluded that A. vera gel and microcurrent acted synergistically in treating open wounds and has potential as a therapeutic option.⁷²

A. vera extract is also an active ingredient in a cream containing Dead Sea minerals that was shown in 2009 to display antioxidant, anti-inflammatory, and photoprotective activity against UVB irradiation when topically applied to human skin organ cultures.⁷³

Aloe is included in a 4 percent hydroquinone/10 percent L-ascorbic acid treatment system shown in 2011 to be effective in attenuating the early signs of photodamage in the normal to oily skin of 30 female subjects enrolled in a study by Bruce and Watson [see Chapter 36, Hydroquinone, and Chapter 55, Ascorbic Acid (Vitamin C)].⁷⁴

In a 2012 randomized, double-blind, clinical trial with 67 patients, an A. vera/olive oil cream was demonstrated to be as effective as β-methasone 0.1 percent in treating sulfur mustard-induced chronic skin lesions, characterized by pruritus, xerosis, a burning sensation, and scaling.⁷⁵

Aloe is also included in Menpentol Leche, an emulsion based on hyperoxygenated fatty acids, A. vera, and Mimosa tenuiflora that was found in a nonrandomized open clinical evaluation to be beneficial in alleviating the cutaneous symptoms prior to the appearance of ulcers in patients susceptible to vascular ulcers and diabetic foot ulcers.⁷⁶

SAFETY ISSUES

The Cosmetic Ingredient Review Expert Panel has found that anthraquinone levels have been well characterized and understood in A. vera products and should not exceed 50 parts per million (ppm) in cosmetic products.⁹ Further, the panel reports that the phototoxicity associated with some anthraquinone constituents of A. vera has been undermined by multiple clinical studies using amounts of the ingredient typical of commercial preparations that have revealed no phototoxicity, suggesting that the concentrations of anthraquinones are too low in A. vera preparations to cause phototoxicity.⁹ Anthraquinones are found in the sap of aloe, but not the leaf gel, which is the source of most aloe ingredients used in commercial preparations.³⁰

The yellow juice from the outer margins of the leaf is the traditional source for a laxative and while used by many, the FDA issued a statement in 2001 identifying the stimulant laxative aloe ingredients (aloe extract and aloe flower extract) in OTC drug products as misbranded and not generally safe and effective.⁷⁷

Although the use of topical A. vera products is recognized as safe, with reports of truly adverse reactions extremely rare, dermatologic side effects, including acute eczema, contact urticaria, and dermatitis have been documented.^9,25,78 Mild discomfort has been linked to aloe use in some patients. Specifically, products containing A. vera (as well as vitamin E) as the major active ingredient are contraindicated in the immediate weeks after surgery for patients undergoing dermabrasion or chemical peels.⁷⁹ Application of aloe gel is not contraindicated in women who are pregnant or lactating, but no standards regarding a maximum treatment period have been established.

A. vera is considered a sensitizing ingredient in emollients, and may exacerbate xerosis, particularly in the elderly.⁸⁰

In 2007, Xia reported on findings that suggest humans exposed to formulations that contain A. vera whole leaf extract may experience amplified sensitivity to UV light, likely due to the anthraquinones present in the leaf extract, which have been demonstrated to produce reactive oxygen species due to UVA exposure.⁸¹

ENVIRONMENTAL IMPACT

There are no significant challenges or effects on the environment imposed by A. vera plant cultivation known by the author, though it is one of the largest botanical industries in the world.²² As a succulent, it actually acts against desertification.

FORMULATION CONSIDERATIONS

Cole and Heard showed in 2007 that A. vera juice displayed skin permeation-enhancing activity.⁸²

In a 2007 study of vehicles for topically applied A. vera as well as Arnica montana, Bergamante et al. found that a gel formulation, containing Sepigel 305, had the capacity to decrease the release and permeation of aloin, a key constituent of A. vera extract known to exhibit antibacterial activity. Limiting aloin to surface activity was considered important because human skin fibroblasts can metabolize absorbed aloin and render the skin more sensitive to UV light.⁸³

Two years later, Takahashi et al. showed that liposome encapsulation of A. vera leaf gel extracts significantly enhanced bioavailability and spurred proliferation and synthesis of type I collagen in normal human neonatal skin fibroblasts.⁸⁴

Based on in vitro findings in 2012, Popadic et al. suggested caution regarding the use and proper labeling of aloe emodin in topical products given the capacity of this hydroxyanthraquinone constituent of A. vera to suppress the proliferation of adult human keratinocytes.⁸⁵ Topically applied aloe emodin has also been demonstrated to intensify cutaneous sensitivity to the effects of UV exposure.^86,87 In addition, aloe emodin has been shown to induce apoptosis in nonmelanoma skin cancer cells, with such effects accelerated by the incorporation of aloe emodin in a liposomal formulation, which enhances transdermal delivery.⁸⁸

In 2013, Vandana et al. formulated A. vera gel into a base to prepare nimesulide emulgel with a higher drug-load capacity than commercial nimesulide gel (86.4 vs. 70.5 percent) and characterized by significant anti-inflammatory potential.⁸⁹

USAGE CONSIDERATIONS

Known traditionally for its soothing and multifaceted capacity to treat a wide variety of skin lesions, A. vera use as an active ingredient has exploded in the lucrative field of cosmetics and cosmeceuticals. Aloe and α-hydroxy acids are the natural products and extracts used most often in skin care formulations (see Chapter 82, Hydroxy Acids). Hundreds of such products have flooded the market since the mid-1990s. Aloe is even included in a new protective garment. Quantum Labs received FDA approval in April 2002 for its SoftSkin A. vera gel-coated glove with vitamin E. The broad array of processed and commercially available aloe products are known to contain several ingredients, but little is known regarding the stability of the active ingredients. Some such products have so little aloe or active ingredients that the agent is rendered diluted or unstable to the point of providing no therapeutic effects. Products that list “aloe vera extract” tend to be more dilute, while those listing “aloe gel” are more likely effective, but the lack of meaningful regulation of these products makes proper selection a significant challenge for consumers. Indeed, aloe is known to be ineffective in concentrations below 50 percent; for optimal benefits, 100 percent is recommended.⁶

SIGNIFICANT BACKGROUND

A. vera is widely used in various products, including cosmetics, pharmaceuticals, food supplements, and beverages. An increasing array of biological activity has been associated with this plant long associated with the healing of minor wounds.

Antioxidant and Anti-inflammatory Activity

Aloe constituents such as salicylic acid, magnesium lactate, and several polysaccharides are instrumental in reducing levels of thromboxane A₂, thromboxane B₂, and prostaglandin E₂, thus rendering anti-inflammatory effects (see Chapter 78, Salicylic Acid).²⁴

In a wide-ranging 2003 study of the anti-inflammatory and antioxidant properties of various aloe isolates, including cinnamoyl, p-coumaroyl, feruloyl, caffeoyl aloesin, and related compounds, Yagi et al. found that the involvement of the caffeoyl, feruloyl, and coumaroyl groups bound to aloesin was well established, and the contact hypersensitivity response suggested that aloesin prevented UVB-induced immune suppression. In addition, they noted that aloesin inhibited the tyrosine hydroxylase and DOPA oxidase activities of tyrosinase in normal human melanocyte cell lysates. The investigators concluded that the potent antioxidant and anti-inflammatory effects imparted by aloesin derivatives helped to explain, in part, the anti-inflammatory and wound-healing properties of A. vera.^90,91 Further, in 2013, López et al. observed in vitro antioxidant activities displayed by methanol extracts of A. vera leaf skin and flowers, using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) and ferric antioxidant reducing power (FRAP) assays. The leaf skin fraction was more active, also exhibiting activity against tested microbial strains.⁹²

Anticancer Activity

Aloe emodin has emerged as the focus of much of the research into the capacity of A. vera for cancer inhibition. A hydroxyanthra-quinone naturally present in A. vera leaves, aloe emodin has been noted for its strong inhibition of Merkel cell carcinoma (MCC) proliferation, but has been found to be nontoxic to normal cells.^1,93 The antineuroectodermal tumor activity of aloe emodin has been noted in vitro and in vivo and may represent a significant new direction for antitumor drugs, according to some researchers.⁹⁴

Key factors in the anticarcinogenic potential of aloe are its active constituents found to have immunomodulating activity. The small molecular weight compounds prevent UVB-induced immune suppression in the skin by repairing UVB-induced damages on epidermal Langerhans cells (LC).^95,96 These substances may also play a role in natural cancer therapy. Investigators have identified some therapeutic benefits, such as disease stabilization and survival, from natural cancer therapy with melatonin plus A. vera extracts for patients with advanced solid tumors and for whom no other standard therapies are judged appropriate.⁹⁷ Also, a combination of vitamin C and A. vera gel extract supplementation was found to be effective in reducing the severity of chemical hepatocarcinogenesis in a study using Sprague-Dawley rats.⁹⁸

In 2007, Chaudhary et al. used a two-stage skin carcinogenesis model in mice to ascertain the chemopreventive potential of A. vera. Tumorigenesis was induced in Swiss albino mice with a single topical application of 7,12-dimethylbenz(a)anthracene (DMBA) and promoted with croton oil for 16 weeks. A. vera leaf extract was orally administered (1,000 mg/kg body weight/d) and/or aloe gel topically applied (1 mL/9 cm²/mice/d). Combined aloe treatment was found to reduce the number and size of papillomas, with a significantly lower tumor incidence seen in animals treated with aloe compared with 100 percent tumor incidence in the DMBA-treated control group. In addition, significantly fewer papillomas were seen in aloe-treated mice as compared to controls during a 16-week observation period; a significantly longer average latency period and reduced tumor burden and tumor yield were associated with the aloe-treated animals.⁹⁹

In a 2010 one-year study of the potential of A. vera in skin care formulations enhancing UV-induced skin cancer, the National Toxicology Program evaluated topical creams containing aloe plant extracts (aloe gel, whole leaf, decolorized whole leaf) or aloe emodin on SKH-1 hairless mice exposed to simulated solar light. A weak enhancing effect exerted by aloe gel or aloe emodin was identified in female but no male mice based on histologic analysis. There was also a weak enhancing effect rendered by whole or decolorized whole leaf in male and female SKH-1 mice as indicated by histologically-ascertained squamous cell neoplasms. No effect from the creams was seen during the in-life phase.¹⁰⁰

Also that year, Saini et al. investigated the antitumor activity of aloe in a two-stage skin carcinogenesis model in Swiss albino mice, using DMBA to induce and croton oil to promote tumors. The mice were randomly divided into four groups, with the first group exposed only to DMBA and croton oil and serving as controls; the second group received topical A. vera gel; the third group was treated with oral A. vera extract; and the fourth group received both topical A. vera gel and oral A. vera extract. Tumor incidence was 100 percent in the first group, and dipped to 50, 60, and 40 percent, in the second, third, and fourth groups, respectively. The number of papillomas, tumor yield, and tumor burden in the treatment groups were also significantly diminished compared to controls, while the average latency period increased significantly as compared to controls. The investigators concluded that A. vera exerts a protective effect against DMBA-croton oil-induced skin papillomagenesis in mice due to its high concentration of beneficial constituents, including vitamins A, C, and E, glutathione peroxidase, superoxide dismutase isozymes, selenium, zinc, and polysaccharides.⁸

Antimicrobial Activity

Antibacterial, antifungal, and antiviral activities have been associated with A. vera.^1,17 A 2007 study by Habeeb et al. explored reports of antimicrobial effects associated with the plant.^17,101 Using a simple in vitro assay, they determined the effect of the inner gel of aloe on bacterial-induced proinflammatory cytokine production (namely, TNF-α and IL-1β) from human leukocytes stimulated with Shigella flexneri. Results demonstrated the suppression of both bacterial-induced cytokines with the use of aloe inner gel.¹⁰¹ Further studies are still needed for a deeper and more precise understanding of aloe constituents and their varied biological activities.

A 2009 in vitro comparison of a copper biocide/A. vera-based hand rub (Xgel) revealed that the agent was less cytotoxic to human skin cells than seven commercially available products and more effective than Purell against all tested bacteria (i.e., methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumanii, and Clostridium difficile).¹⁰²

Photoprotection

In a recent in vitro study, Hwang et al. demonstrated that immature aloe shoot extracts (one-month old) were more effective than adult aloe extracts in protecting normal human dermal fibroblasts from UVB-induced damage, better inhibiting MMP-1, MMP-3, and IL-6 levels. The younger shoots also contributed to increasing type I procollagen and TGF-β1 levels.¹⁰³

CONCLUSION

For decades, the use of A. vera has been promoted for a seemingly limitless variety of conditions. It remains one of the most popular botanical products in mainstream usage, if not the most popular, in the US. Often patients know more than doctors about the purported benefits. Topical products that contain A. vera appear to be safe, but there is a scarcity of clinical evidence establishing efficacy. Aloe appears to have great potential for a wide range of medical applications. Its use in a plethora of OTC topical products, though, is likely yet another attempt by manufacturers to capitalize on deeply entrenched cultural knowledge and more casual popular awareness regarding the benefits of the aloe plant. The risks of using such products are low, but much more clinical evidence is necessary from randomized, double-blind, case-controlled studies to quantify any benefits of aloe as a primary active ingredient. Such work is clearly warranted by current findings, especially when noting the cogent evidence on natural or less dilute forms of the plant. While clinical effectiveness has not yet been sufficiently defined, promising outcomes have been seen.

REFERENCES

INTRODUCTION

SOURCE

Tanacetum parthenium, an aromatic perennial herb native to the Balkan peninsula and better known as feverfew, belongs to the Asteraceae or Compositae family and has long been used in traditional medicine (Table 66-1).⁶ The plant (also known by previous botanical names, including Chrysanthemum parthenium, Pyrethrum parthenium, Matricaria pyrethrum, and Matricaria parthenium)^1,4,7 is now broadly dispersed throughout the world, primarily the northern hemisphere, and is particularly prolific in Iran and Turkey.^2,3,8 The expression “feverfew” is believed to be a corruption of the word “febrifuge,” derived from the Latin febris (fever) and fugure (to drive away) to describe the antipyretic actions of the plant.^1,2 Feverfew has long been cultivated for ornamental and medicinal purposes.⁹ The term “parthenium” is derived from the ancient Greek name for the plant bestowed, according to legend, because the plant was used to save the life of a worker who had fallen from the Parthenon during its 5th century BCE construction.^6,10 Modern evidence of the anti-inflammatory properties of feverfew has been accruing over the last several decades and is now considered well established.¹¹

HISTORY

For over 2,000 years, folk medicine has incorporated feverfew for internal use to regulate menstruation, assist in labor during childbirth, and treat fevers, headaches, and infertility; externally, it has been used as an analgesic.^4,6 The first century CE Greek physician Dioscorides recommended feverfew for all inflammatory conditions.^6,10 Known as aqhovan in Iran, the roots and rhizomes of feverfew have been used in Iranian traditional medicine to treat gastrointestinal disorders.² Early European herbalists also used feverfew.⁹ The Kallaway people of the Andes mountains of South America have used feverfew to treat colic, stomach and kidney pain, as well as morning sickness.⁴ Native Mexican peoples have, for centuries, used feverfew to treat fever, arthritis, and migraines.^12,13 The broad range of traditional medical uses of feverfew also includes therapeutic applications for allergies, arthritis, asthma, coughs and colds, constipation, depression, dermatitis, earache, edema, infant colic, inflammatory conditions, insect bites, kidney stones, labor, potential miscarriage, nausea and vomiting, psoriasis, skin wounds, spasms, tinnitus, toothache, vertigo, and worms.^4,5,9,14 Nonmedical applications have included cosmetics, balsams, dyes, preservatives, and insecticides.³ Feverfew gained more modern, nontraditional adherents in the late 1970s and 1980s, with several reports suggesting its effectiveness as an oral agent in preventing migraine headaches.^4,15,16

CHEMISTRY

Feverfew, vitamin E, coenzyme Q₁₀, and turmeric are among the antioxidants found in the lipophilic portion of the cell membrane [see Chapter 56, Tocopherol (Vitamin E), Chapter 57, Coenzyme Q₁₀, and Chapter 69, Turmeric]. Other fat-soluble antioxidants include carotenoids (e.g., lycopene) and idebenone, the synthetic analog of coenzyme Q₁₀ (see Chapter 61, Idebenone).

T. parthenium is known to suppress the release of proinflammatory mediators from macrophages and lymphocytes.¹⁷ In a Medline literature review of herbal agents that many people take but that might warrant discontinuing before dermatologic surgery, authors cited feverfew for its known success as a treatment for migraines,¹⁵ and arthritis as well as its anti-inflammatory activity in blocking phospholipase breakdown of arachidonic acid into prostaglandins and leukotrienes.^18,19 They noted that platelet aggregation is also induced by the feverfew extract parthenolide and a byproduct of the arachidonic acid cascade, thromboxane A₂.^18,20,21

Many of the anti-inflammatory, antioxidant, and antiproliferative characteristics of feverfew are ascribed to its primary constituent parthenolide, a hydroalcoholic extract of the aerial parts of the plant known to inhibit nuclear factor-κB (NF-κB), which contributes to anti-inflammatory activity, and to exhibit exceptional anticancer and antiproliferative properties.^11,12,14,22 In fact, the sesquiterpene lactone parthenolide (within the subclass germacranolides)²³ is the first small molecule discovered to act selectively against cancer stem cells.⁵ Notably, parthenolide, which is not present in all varieties of feverfew, is thought to account for the antimigraine activity of the herb.⁶ In 2011, Majdi et al. discovered that glandular trichomes of T. parthenium are the secretory tissues where the production and accumulation of parthenolide occur.²⁴ Parthenolide can be very irritating when applied topically; therefore, manufacturers have marketed topical preparations with the parthenolide component removed from the molecule. Feverfew imparts numerous benefits that are not derived from parthenolide. The strong antioxidant melatonin is also found in feverfew.^7,25 In addition, the lipophilic flavonoid tanetin, present in feverfew leaves, flowers, and seeds, has been found to inhibit prostaglandin production.^4,26,27

Investigations of parthenolide do represent a significant portion of research into feverfew, though. In 2008, Parada-Turska et al. conducted an in vitro study of the effects of parthenolide on the proliferation of the rabbit synoviocytes cell line HIG-82, rheumatoid arthritis fibroblast-like synoviocytes, and human skin fibroblasts. They found that parthenolide suppressed the proliferation of HIG-82 as well as the rheumatoid arthritis fibroblast-like synoviocytes, with human skin fibroblasts inhibited but less effectively. The researchers concluded that their findings highlighted the antiproliferative potential of parthenolide, particularly in relation to rheumatoid arthritis.²⁸

ORAL USES

Oral uses of feverfew have included infusions to treat arthritis, fever, migraine headaches, and stomach aches.²⁹ The fresh leaves can be chewed fresh, freeze-dried- or dried, and supplements containing the dried leaves are available in capsule, tablet, or liquid extract form in Europe and the United States.^4,10

In 1999, Jain and Kulkarni demonstrated that orally administered feverfew extract dose-dependently exerted significant antinociceptive and anti-inflammatory activity against acetic acid-induced writhing in mice and carageenan-induced paw edema in rats.⁹

An orally bioavailable analog of parthenolide, dimethylaminoparthenolide (DMAPT), has been developed as a result of structure–activity relationship studies of the feverfew constituent, and may have implications pertaining to the antiproliferative properties of the compound, particularly for patients with leukemia.⁵

Headache Treatment

Cady et al. conducted a one-month, multicenter, double-blind, placebo-controlled pilot study with 60 subjects in 2011, finding that a sublingual feverfew and ginger preparation (LipiGesic™ M) was safe and effective as a first-line therapy for patients who typically experience a mild headache before the onset of a moderate-to-severe migraine (see Chapter 59, Ginger).³⁰ De Weerdt et al. performed a randomized, double-blind, placebo-controlled crossover trial in 1996 based on the encouraging results of two studies in the 1980s, but their results indicated that feverfew did not exert a significant prophylactic effect against migraines.³¹

In 2012, a randomized study of 69 female volunteers was conducted by Ferro et al. to examine the efficacy and tolerability of acupuncture, T. parthenium, or a combination for the treatment of chronic migraines. Twenty-two patients received acupuncture in 20 sessions over 10 weeks; 23 patients received 150 mg/day of feverfew; and 23 patients received combination therapy. Using the Short-Form 36 quality of life assessment score, Migraine Disability Assessment, and a visual analog scale, the investigators determined that acupuncture along with T. parthenium was substantially more effective than either therapy alone, with statistically significant differences in yielding a greater analgesic effect and improved quality of life.³²

However, Loder et al. reviewed the American Headache Society and the American Academy of Neurology 2012 updated treatment guideline recommendations along with a systematic Medline search, including recent guidelines for migraine prevention from the Canadian Headache Society and the European Federation of Neurological Societies, and found significant differences of opinion regarding the use of feverfew for migraines.³³ Goodyear-Smith contends that, at present, there is insufficient data from five randomized, double-blind trials on migraine headaches and one on rheumatoid arthritis to support the use of feverfew to prevent migraines or treat rheumatoid arthritis.³⁴ Triptans remain the “gold standard” for first-line migraine therapy, according to Cady et al.³⁰

TOPICAL USES

Topically applied feverfew is thought to improve the appearance of the skin.³⁵ It is included in moisturizing agents to impart a calming, soothing effect. A parthenolide-free formulation has recently been studied for treatment of acne and rosacea, with some indications of efficacy.^36,37 In fact, parthenolide-free Feverfew PFE™ is a nonsteroidal anti-inflammatory topical product found to suppress multiple pathways related to skin irritation.³⁸

SAFETY ISSUES

The Compositae family (ragweed is an example) is known to cause contact dermatitis in susceptible individuals, and Compositae allergy is among the top ten contact sensitivities in Europe. Sesquiterpene lactones are considered to be the primary sensitizing constituents in these plants.³⁹ Nevertheless, feverfew is considered safe, with reactions typically mild to moderate and manifested by those with Compositae allergy. Indeed, feverfew has long been acknowledged as a key sensitizer in European Compositae-allergic patients due to parthenolide, which is known as a potent skin sensitizer.^16,40 In 2007, there was a report of two patients experiencing contact dermatitis from using a topical moisturizer containing feverfew.⁴¹ Such reactions prompted the development of parthenolide-depleted formulations even though adverse reactions to feverfew are considered to be minimal and rare.

Sensitivity to parthenolide-depleted agents remains possible, nevertheless. In a small study with seven patients conducted in 2010, Paulsen et al. used patch tests to examine the tolerance of individuals with known contact allergy to topical parthenolide-depleted feverfew formulations. Subjects were patch tested with two parthenolide-depleted creams. The researchers noted that four patients tested positive to one of the agents and reactivity was linked to simultaneous positive response to parthenolide. Two years later, Paulsen and colleagues analyzed the cream, finding no parthenolide, which they ascribed to degradation of the compound.⁴⁰

When feverfew is ingested orally for migraines, oral ulcers have been reported.³⁴ Use of feverfew may increase the risk of bleeding during surgical procedures.⁴² Similarly, feverfew may elevate such risk for patients using warfarin or aspirin.³⁴ Feverfew is contraindicated in pregnant women as it acts as an emmenagogue.

ENVIRONMENTAL IMPACT

Feverfew is one of several wild medicinal plants in the Concord area of New England that have undergone accelerated flowering times due to climate change.⁴³

Fonseca et al. have shown that changing environmental conditions immediately before harvest affects secondary metabolites in feverfew, with parthenolide yields higher with light and reduced water and phenolic yields higher with water and little light. They suggest that the controlled environment of a greenhouse might be the ideal setting for harnessing the optimal phytochemicals from T. parthenium.^27,44

Parthenolide content in feverfew plants is recognized as high in France and Germany, but the plants in Serbia, the US, and Mexico almost completely lack parthenolide.⁴⁵ Beyond regional and geographical differences, the parthenolide content of feverfew can also be influenced by processing and extraction methods (including drying temperature and extraction solvent used).^45–47

FORMULATION CONSIDERATIONS

Researchers have developed a form of feverfew with the parthenolide portion removed, rendering it safer as a topical ingredient.

In vitro and in vivo antioxidant efficacy of a parthenolide-depleted feverfew extract (PD-Feverfew) was reported by Martin et al. in 2008. The extract restored cigarette smoke-mediated depletion of cellular thiols, diminished the formation of ultraviolet (UV)-induced hydrogen peroxide, and hindered proinflammatory cytokine release in vitro, manifesting greater radical scavenging-potency than vitamin C. In addition, the topical formulation reduced UV-induced epidermal hyperplasia, DNA damage, and apoptosis in vivo. Phototoxicity and photoallergy tests for the formulation were consistently negative, and clinical tolerance testing in over 1,200 individuals showed that formulations containing PD-Feverfew did not elicit allergic reactions. The researchers also reported that a clinical study (randomized, placebo-controlled, double-blinded with 12 females and males, Fitzpatrick types II and III) revealed that treatment significantly mitigated UVB-induced erythema as compared to placebo 24 hours after exposure. They concluded that their parthenolide-depleted feverfew formulation protects the skin from exogenous oxidizing factors.⁴⁸

In 2009, some of the same investigators assessed the anti-inflammatory capacity of the parthenolide-depleted feverfew extract that they developed. In vitro, the extract hindered the activity of several proinflammatory enzymes (i.e., 5-lipoxygenase, phosphodiesterase-3, and phosphodiesterase-4) as well as the release of proinflammatory mediators. In vivo, the extract thwarted oxazolone-induced dermatitis and was more effective than regular feverfew in treating 12-O-tetradecanoylphorbol-13-acetate-induced dermatitis. In a clinical assessment, the investigators found that their extract diminished erythema in a methyl nicotinate-induced vasodilation model. They concluded that PD-Feverfew exhibits strong anti-inflammatory activity but without the accompanying sensitizing activity characteristic of whole feverfew.¹⁶

In a three-week screening study in 2007, Jin et al. found that parthenolide is comparatively stable when the environmental pH is in the range of 5 to 7, and is unstable when the pH is less than 3 or above 7. They also found that it is compatible with frequently used excipients under stressed conditions. Further, they noted that parthenolide degradation in feverfew solution seems to be a typical first-order reaction but its degradation in the solid state fits no obvious reaction model. The degradation rate was found to be highly influenced by moisture content and temperature, with an increase from 18 percent to 32 percent degradation of parthenolide after six months of storage under 40°C at a relative humidity of 75 percent.⁴⁵

The following year, the same researchers evaluated the flowability, hygroscopicity, compressibility, and compactibility of multiple commercial feverfew extracts, and ascertained the parthenolide content of the formulations. They found poor to very poor flowability, and highly variable hygroscopicity and compactibility among the products, with no tested products actually containing the parthenolide quantity as claimed by the labels. Parthenolide content varied even in different batches from the same manufacturers. The investigators suggested that proper quality controls are necessary for manufacturers, who should also be cognizant of inconsistent physicochemical characteristics in the feverfew provided by myriad suppliers.⁴⁹

USAGE CONSIDERATIONS

Stability studies of feverfew products have not yet appeared in the literature.⁴⁵ It is unknown how feverfew is affected by interaction with other ingredients. Feverfew should not be used in patients with a known ragweed allergy.

SIGNIFICANT BACKGROUND

Feverfew is known to provide a broad range of biologic activity with or without its primary constituent parthenolide. The anti-inflammatory activity of feverfew is thought by some to be more potent than that of Aloe vera, Camellia sinensis, licorice extract, and other Asteraceae family members such as chamomile and echinacea (see Chapter 47, Green Tea, Chapter 65, Aloe Vera, Chapter 67, Licorice Extract, and Chapter 70, Chamomile).^50,51

In 2013, Rodriguez et al. assessed the influence of a purified parthenolide-depleted feverfew extract on the nuclear factor erythroid 2-related factor-2 (Nrf2)/antioxidant response element (ARE) pathway and DNA repair in primary human keratinocytes or KB cells (subline of the keratin-forming tumor cell line HeLa). The investigators observed that the feverfew extract induced Nrf2 nuclear translocation and dose-dependently augmented ARE activity. Activation of this pathway is known to restore cutaneous oxidative homeostasis. The findings of this experiment led the authors to conclude that the parthenolide-depleted feverfew extract promoted skin cell DNA repair through a phosphoinositide (PI)3-kinase-dependent Nrf2/ARE pathway and may contribute to protection against environmental insult.⁵²

Antibacterial Activity

Polatoglu et al. examined the water-distilled essential oils of T. parthenium from two different regions in Turkey in 2010. Camphor was a key ingredient in samples collected from the Davutpasa-Istanbul area as well as the remote eastern part (Savşat-Ardahan region) of the country. Camphene and trans-chrysanthenyl acetate were also found in the Istanbul samples; camphene was identified in the eastern sample. The oil of the Istanbul sample evinced mild antibacterial activity against Bacillus subtilis and methicillin-resistant Staphylococcus aureus. Similarly, the eastern sample demonstrated mild activity against S. aureus. Both oils demonstrated toxicity against Vibrio fischeri.⁸

In 2011, Mohsenzadeh et al. examined the components of the hydrodistilled essential oils of preflowering, flowering, and postflowering T. parthenium from western Iran, identifying camphor and bornyl acetate as prevalent among 29 components. They also found that the essential oils displayed appreciable activity against four Gram-positive and four Gram-negative bacteria without significant toxicity, with the antibacterial properties strongest during the flowering stage. They concluded that their findings suggest the viability of T. parthenium essential oil as a natural health product.³

Parthenolide, Skin Cancer, and Photoaging

Parthenolide has been consistently shown to exhibit in vitro antitumor activity.⁵³ In 2004, Won et al. conducted in vitro and in vivo investigations of the cancer chemopreventive potential of parthenolide using a UVB-induced skin cancer model, revealing that SKH-1 hairless mice given parthenolide exhibited later onset of papilloma, significantly fewer papillomas/mouse, and smaller lesions in comparison to mice exposed only to UVB but not fed the primary component of feverfew. The in vitro phase of the study, using cultured JB6 murine epidermal cells, showed that noncytotoxic concentrations of parthenolide pretreatment significantly suppressed UVB-induced activator protein-1 DNA binding and transcriptional activity as well as c-Jun-N-terminal kinase (JNK) and p38 kinase signaling activation, all of which might be crucial in the anticancer mechanism of action of parthenolide, according to the authors.¹¹ Three of the same investigators have also noted that parthenolide sensitizes UVB-induced apoptosis through pathways that depend on protein kinase C.⁵⁴ Further, parthenolide has been found to reduce the number of viable adherent cells in melanoma cultures.⁵⁵

The primary constituent of feverfew has become known as an NF-κB inhibitor. In a 2005 study, parthenolide effectively blocked the gene expression mediated by NF-κB and the synthesis of basic fibroblast growth factor (bFGF) and matrix metalloproteinase-1 as well as the UVB-induced proliferation of keratinocytes and melanocytes in mouse skin, leading the authors to conclude that NF-κB inhibitors, especially parthenolide, may have a role in preventing photoaging.⁵⁶ This conclusion has since been reinforced.⁵⁷

In 2010, Tanaka et al. found that the NF-κB inhibitors par-thenolide and magnolol can effectively block NF-κB-mediated gene expression as well as UVB-induced proliferation of keratinocytes and melanocytes in murine skin, suggesting that both compounds may play a role in preventing photoaging.⁵⁷

Also that year, Lesiak et al. studied the anticancer effects of parthenolide in melanoma cells in vitro, in melanoma cell lines and melanocytes, as well as melanoma cells obtained from a surgical excision, finding that the herbal compound decreased the number of viable adherent cells in melanoma cultures. The researchers also noted that preincubation of parthenolide with the thiol nucleophile N-acetyl-cysteine shielded melanoma cells from parthenolide-induced cell death, implying, as they interpreted, that the mechanism attributable to parthenolide activity is the reaction with intracellular thiols. They concluded that the apparent anticancer activity of parthenolide warrants further evaluation for melanoma therapy.⁵⁵ Parthenolide has demonstrated potential activity in vitro against several other cancer types, including acute myelogenous leukemia, breast cancer, cholangiocarcinoma, and pancreatic adenocarcinoma, as well as in vivo in an adjuvant breast cancer metastasis model.^53,58–60

Mathema et al. reported in 2012 that parthenolide exhibits potent NF-κB and signal transduction and activation of transcription (STAT)-mediated transcriptional inhibition of proapoptotic genes. They also suggested that the unique capacity of parthenolide to spare normal cells while provoking sensitization to extrinsic and intrinsic apoptosis signaling in cancer cells renders the compound primed for use in treating cancer and disorders involving inflammation.²² Koprowska and Czyz have added that parthenolide also protects normal cells from UVB and oxidative stress and appears to have the potential to target some cancer stem cells. In addition, they asserted that the low toxicity and diverse biological activity of parthenolide position the sesquiterpene lactone as a promising agent with potentially vast pharmacologic applications.²⁹

Other Potential Applications of Parthenolide

In addition to its potential activity against skin cancer and photoaging, the feverfew constituent parthenolide confers other benefits pertinent to dermatology. In 2005, investigators identified potent intracellular antioxidant activity displayed by parthenolide in hippocampal HT22 cells, properties that are mediated by an increase of glutathione but not found to mediate the sesquiterpene lactone’s antiproliferative activities or its inhibition of NF-κB.¹² Parthenolide has also shown marked leishmanicidal activities suitable enough, according to researchers, to be considered for inclusion in the development of new drugs to treat this disease.¹⁴ While several in vitro studies have indicated that parthenolide delivers anti-inflammatory effects, a recent in vivo study with mice demonstrated that the sesquiterpene lactone component of feverfew modestly suppressed only one gene, interleukin-6 after lipopolysaccharide-induced increases.⁶¹ The authors concluded that more study of the effects of parthenolide and other herbal constituents on inflammatory gene expression using animal models is needed to assess the efficacy of various supplements.⁶¹

Parthenolide was found, in 2006, to display significant activity in suppressing hepatitis C virus (HCV), which is often a precursor to cirrhosis and hepatocellular carcinoma.⁶² In addition, parthenolide has also been found to enhance in hepatoma cells the apoptosis induced by fenretinide (N-4-hydroxyphenyl retinamide, 4HPR), a synthetic anticancer retinoid and established apoptosis-inducing agent. In a study focusing on the relationship of these two compounds, parthenolide was found to up- or downregulate 35 apoptosis-related genes and its role as an adjuvant anticancer agent against hepatoma was elucidated.⁶³

It is worth noting that while parthenolide has been cited as the main active ingredient in feverfew, a double-blind study revealed that it could not be the only active ingredient, and that melatonin is an antioxidant component of the plant, though its role in feverfew potency is not clearly understood.^7,31

CONCLUSION

Feverfew is best known as an effective herbal alternative for treating migraine headaches. New evidence is emerging that numerous other health benefits might be derived from this plant, and particularly its chief component parthenolide. The findings regarding anticarcinogenic and anti-inflammatory capacity are promising and may soon have dermatologic implications. Cancer clinical trials using parthenolide are ongoing.

Feverfew contains parthenolide and melatonin, both of which exhibit antioxidant activity. T. parthenium formulations must be developed to account for the allergenic potential of parthenolide while still harnessing its strong ameliorative properties. Notably, recent success has been observed with parthenolide-depleted feverfew. It remains unclear what role melatonin plays in such formulations. The ability to take a naturally occurring ingredient and improve it by removing an undesirable part of the chemical structure appears to be an integral part of the future of “natural” skin care. While more research is needed, particularly randomized, controlled trials, cutaneous applications of feverfew are likely to proliferate.

REFERENCES

INTRODUCTION

SOURCE

Licorice (also spelled as “liquorice”) is best known in its popular confectionery form of black or red candy. Although it is not often thought of as a plant, it is derived from the roots and rhizomes of multiple Glycyrrhiza species and has been used in systemic and topical herbal medications for approximately 4,000 years (Table 67-1). In fact, licorice is one of the oldest and most popular herbs used in traditional Chinese medicine (TCM), second only to ginseng.^8–10 Members of the Fabaceae or Leguminosae family (better known as the legume, pea, or bean family), Glycyrrhiza glabra (also known as Liquiritiae officinalis) and G. inflata are the species that have displayed the most therapeutic actions among the 18 known Glycyrrhiza species, with G. glabra the most used since antiquity. G. inflata is actually the Chinese licorice root, while G. glabra grows around the Mediterranean Sea, the Middle East, and central and southern Russia.¹¹ The Roman physician of Greek extraction Pedanius Dioscorides, who practiced in the 1st century CE, is credited with bestowing the botanical name of the plant based on the Greek glukos (sweet) and riza (root).^7,12,13 The Latin name “Liquiritiae” is a corruption of the Greek “Glycyrrhiza.”¹²

G. glabra is a perennial herb that originated on the land surrounding the Mediterranean Sea as well as central and southern Russia and the Middle East.¹¹ Licorice is now cultivated throughout much of Asia, Europe, and the Middle East, though, and is also used globally as a pharmacologic agent,¹⁴ particularly as an effective anti-inflammatory product.¹⁵ In addition to anti-inflammatory potency, licorice root is believed to possess antiviral, antiulcer, and anticarcinogenic properties.¹⁰ In China, licorice root has served as a folk elixir and antidote, and long been used as a demulcent (an agent that provides a soothing film over a mucous membrane).¹¹ One of its active components, glycyrrhetinic acid, has traditionally been used in Asian and European herbal medicine to treat skin and pulmonary diseases, hepatitis, and peptic ulcers.^2,16,17 A panel from the University of Würzburg, the World Wildlife Fund, and TRAFFIC chose licorice (G. glabra) as “medicinal plant of the year” for 2012 in recognition of its important roles in human health.¹⁸

HISTORY

Licorice has been used for medicinal and dietary purposes for thousands of years, with such use dating back to ancient Egypt, Greece, and Rome in the West and to the times of the Han Dynasty (300–200 BCE) in ancient China.³ Asthma, dry cough, and lung disorders were described by the Roman naturalist Theophrastus (circa 372–287 BCE) as indications for licorice root.^12,19 Gastric ulcer and various forms of inflammation have also been targets of licorice root in traditional medicine.⁶

The radices of G. uralensis and herbal preparations containing Glycyrrhiza spp. have been used for thousands of years as an herbal medicine for the treatment of viral-induced cough, viral hepatitis, and viral skin diseases like ulcers in China.²⁰ At least six Glycyrrhiza species, mainly G. uralensis and G. inflata, are used in Chinese licorice gan-cao, or “sweet herb” (and known as kanzo in Japan).^19,21 G. inflata has a wide range of pharmaceutical and dietary applications and is related to G. glabra.²²

In contemporary times, licorice remains one of the most frequently used herbs in TCM.^3,7 Licorice was introduced into Japan from China in the 8th century,³ and is also an important herb in Kampo (the Japanese adaptation of TCM) and Ayurvedic medicine.^23,24 During the past 75 years, a glycyrrhizin formulation called Stronger Neo-Minophagen C™ (SNMC) has been used in the clinical setting in Japan as an antiallergic and antihepatitis treatment.³ In 1946, the Dutch physician Revers recommended licorice extracts to treat gastric ulcer, but side effects led to its swift removal from the market.³ In the United Kingdom, a licorice preparation was used to treat peptic ulcers.³ The modern scientific investigation into the pharmacologic properties of licorice species began in earnest in the 1950s and quickly revealed a broad range of biologic activity.²⁴ The long history of traditional uses of licorice root and its extensive study over the last several decades make licorice one of the most widely researched plants for medicinal purposes.

CHEMISTRY

More than 400 compounds have been isolated from Glycyrrhiza species.²⁵ Of the six major Glycyrrhiza species, G. glabra, G. uralensis, and G. inflata produce glycyrrhizin as a major saponin; G. echinata, G. macedonica, and G. pallidiflora produce macedonoside C as a major saponin. G. uralensis and G. inflata are closely related,²⁶ but G. inflata is more often used medically and in the diet. G. glabra, G. inflata, and G. uralensis are the three species of licorice most often used medically, and are the focus of this discussion.

Glycyrrhiza Glabra

Extracts from this more Western species of licorice, sometimes referred to as European licorice, are increasingly found in anti-inflammatory products.^5,14 Glycyrrhizin, the primary water-soluble constituent of licorice, has been shown to confer numerous pharmacological benefits, though various derivatives also possess such properties.¹¹ A sweet-tasting triterpene saponin exhibiting poor blood solubility as compared with other saponins, glycyrrhizin is typically present in the root in 5 to 10 percent concentrations,^14,27 and is the source of the plant’s sweetness.²⁸ In addition to the triterpenoid glycyrrhizin, and its aglycone form glycyrrhizic acid, licorice root contains polysaccharides and various polyphenols, such as the isoflavone formononetin, to which antioxidant characteristics have been ascribed.¹⁰

Glabridin, which is the main component in the hydrophobic fraction of licorice extract, was also found to exhibit inhibitory effects on melanogenesis and inflammation when evaluated using cultured murine melanoma cells and guinea pig skin.²⁹ A prenylated isoflavonoid of G. glabra roots, glabridin was first described in 1976 and has since been characterized as exhibiting broad biologic activity, including antioxidant, anti-inflammatory, antiatherogenic, energy metabolism regulating, estrogenic, neuroprotective, antiosteoporotic, and skin whitening. Its anti-inflammatory, antiatherogenic, estrogenic, and energy-regulating capacities are currently thought to be most prominent.⁵

Glycyrrhiza Inflata

The primary active ingredient isolated and extracted from Chinese licorice roots is licochalcone A, also known as 3-a, a-dimethylallyl-4,4ʹ-dihydroxy-6-methoxychalcone, an oxygenated or reversely-constructed chalcone or “retrochalcone.”^22,30,31 Licochalcone A has been shown to exhibit antiparasitic and antibacterial properties as well as antitumorigenic activity.^31–33 This extract has also demonstrated anti-inflammatory activity against arachidonic acid- and 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced mouse ear edema and been reported to manifest in vivo antitumor properties in mouse skin papilloma initiated by 7,12-dimethylbenz(a)anthracene (DMBA) and promoted by TPA.³¹ Chalcones exhibit activity against oxidative stress. A study assessing their radical-scavenging activity revealed that licochalcones B and D potently delay superoxide anion production.³⁴

Noting that the herbal formulation PC-SPES, which contains licorice root, has been shown to possess potent estrogenic activity in vitro, in animals, and in patients with prostate cancer, researchers investigated whether the flavonoid licochalcone A shared these characteristics. Through a range of assays, they determined that licochalcone A is a phytoestrogen, demonstrates antitumor activity, enhancing the effects of paclitaxel and vinblastine, and can affect the apoptotic protein bcl-2 in human cell lines derived from several cancers.³³

In 2010, Cho et al. studied the capacity of the recently isolated licochalcone E to influence the synthesis of interleukin (IL)-12p40, a subunit of IL-12 and IL-23, and found that the G. inflata extract inhibited IL-12p40 expression and attenuated symptoms induced by oxazolone in a chronic allergic contact dermatitis model. They concluded that licochalcone E displays potential for use in treating cutaneous inflammation.³⁵

Glycyrrhiza Uralensis

Li et al. used a calcineurin inhibitory test in 2010 to identify glycyrol, a benzofuran coumarin isolate, as an effective immunosuppressant in G. uralensis. Various assays revealed that glycyrol exerted immunosuppressive activity by blocking calcineurin activity, thus inhibiting the synthesis of IL-2 and regulating T lymphocytes. The investigators concluded that glycyrol shows promise as an immunomodulatory agent.³⁶ Previously, glycyrol had been shown to exert in vitro anti-inflammatory effects.³⁷

ORAL USES

Licorice is used broadly as a natural sweetening agent in food as well as tobacco products.^7,25 Notably, glycyrrhizin is 50-fold sweeter than sugar.¹⁹ Indeed, in the United States, it is used more often as a flavoring and sweetening agent in food products than for salutary purposes,¹⁰ though licorice candy is typically flavored with anise oil, not licorice. Glycyrrhizin can be found in the confection, though, in concentrations ranging from 1 to 25 percent, with a minimum of 4 percent found in good quality licorice.¹⁹ Licorice is also widely available in supplement form.²⁴

Various herbal product companies provide licorice oral supplements as well as some topical preparations that contain licorice extract amid a cocktail of other botanical ingredients. Licorice extract is widely used as an anti-inflammatory in Europe and has been reported to be effective as an antiviral medication for chronic hepatitis.²⁷ The use of oral licorice is approved by the German Commission E for bronchitis and chronic gastritis.

G. glabra has also been shown to effectively protect against or treat oral mucositis engendered by radiation and chemotherapy for head and neck malignancies.³⁸

TOPICAL USES

Modern research has shown that licorice extracts are comparably effective to corticosteroids in treating dermatitis, eczema, and psoriasis.³⁹ Licorice extracts are also among the compounds known to be effective in topical creams intended to repair the skin barrier.⁴⁰

G. glabra has been used for a wide range of medical indications. Among the cutaneous indications, the extract has been used to treat dermatitis, eczema, pruritus, cysts,⁴¹ and skin irritation.⁴² In the modern pharmacopoeia, licorice is incorporated into cosmetics for acne patients as well as the treatment of sunburn.⁴²

Anti-inflammatory Uses

The topical anti-inflammatory properties and antiulcer capacity of licorice root have been attributed mainly to glycyrrhetic acid, the biologically active metabolite of glycyrrhizic acid,^27,43,44 which has been used successfully to treat inflammation without secondary infection.⁴⁵ It has been reported to have anti-inflammatory activity in subacute and chronic dermatoses, and therefore has been used to treat eczema, pruritus, contact dermatitis, seborrheic dermatitis, and psoriasis.⁴¹ In a series of animal studies in 1988, glyderinine, a derivative of glycyrrhizic acid isolated from G. glabra, was shown by Azimov et al. to exhibit anti-inflammatory effects as well as analgesic and antipyretic properties. The researchers concluded that glyderinine is an appropriate ointment for treating skin diseases.⁴⁶

Studies have shown that glycyrrhetic acid is able to exert a cortisone-like effect, thus inhibiting proinflammatory prostaglandins and leukotrienes.⁴⁷ Licorice (glycyrrhetic acid) has not been demonstrated to be superior to topical corticosteroids in treating acute inflammation, such as atopic dermatitis.⁴¹ The combination of corticosteroids with glycyrrhetic acid has been proven to be effective, however. One study displayed effective potentiation of hydrocortisone activity in skin by the addition of 2 percent glycyrrhetic acid.⁴⁸

A 2002 study assessing the effects of five different chalcones, including licochalcone A, revealed that four of the five tested chalcones, including licochalcone A, inhibited the production of proinflammatory cytokines from monocytes and T cells. The investigators concluded that licochalcone A and some of its synthetic analogs may have immunomodulatory effects, potentially rendering them suitable agents for the treatment of infectious and other inflammatory diseases.³²

Furuhashi et al., in 2005, studied the in vitro anti-inflammatory effects of licochalcone A on the formation of chemical mediators [e.g., prostaglandin E₂ (PGE₂) and cytokines) by IL-1β in human skin fibroblasts and compared it to the effects of other compounds. The steroid dexamethasone was found to inhibit PGE₂, prostaglandin F(2α) [PGF(2α)], IL-6, and IL-8 production, and potently blocked cyclooxygenase (COX)-2 mRNA and protein expression, whereas licochalcone A, in response to IL-1β, hindered PGF(2α) generation and PGE₂ synthesis, but had no effect on increased levels of COX-2 mRNA and protein in cells or IL-6, and IL-8 production. The investigators concluded that the licorice isolate engenders anti-inflammatory activity by suppressing COX-2-dependent PGE₂ synthesis with a response to IL-1β that is markedly divergent from that of dexamethasone.⁴⁹

In 2008, Kwon et al. reported on the dynamic anti-inflammatory properties of licochalcone A as demonstrated in vitro and in animal models. The G. inflata extract inhibited the generation of nitric oxide (NO), PGE₂, inflammatory cytokines such as IL-1 and IL-6, as well as the expression of inducible NO synthase (iNOS) and COX-2 induced by lipopolysaccharide (LPS) in RAW264.7 cells in vitro. In addition, the investigators speculated that licochalcone A may have suppressed inflammatory cytokine and NO synthesis in the process of protecting BALB/c mice from LPS-induced endotoxin shock in an animal model. They concluded that licochalcone A might be considered for use in treating various inflammatory conditions.⁵⁰

Studies by Furusawa et al. in 2009 revealed that the anti-inflammatory activity of G. inflata could be attributed to potent suppression of nuclear factor (NF)-κB exerted by licochalcones A, B, and D.⁶

Funakoshi-Tago et al. have shown in mice that licochalcone A potently suppresses tumor necrosis factor-α-induced NF-κB activation and that the fixed structure of licochalcone A is pivotal in imparting its anti-inflammatory properties. They also noted, in 2010, that licochalcone A demonstrates great promise in vivo as an anti-inflammatory agent.⁵¹

In 2013, Lee et al. demonstrated that topically applied licochalcone E displayed strong anti-inflammatory properties in a TPA-induced mouse ear edema model and similar effects when the G. inflata extract was administered in vitro in an LPS-stimulated RAW 264.7 murine macrophage model. They found that licochalcone E inhibited AKT and p38 mitogen activated protein kinase (MAPK), thus suppressing NF-κB and activator protein (AP)-1 transcriptional activity, which in turn facilitates the decline of proinflammatory cytokines.⁵²

Also that year, Fu et al. isolated six flavonoids from G. inflata and G. uralensis, with all six compounds [5-(1,1-dimethylallyl)-3, 4,4ʹ-trihydroxy-2-methoxychalcone, licochalcones A and B, echinatin, glycycoumarin, and glyurallin B] found to possess varying degrees of antioxidant and anti-inflammatory characteristics.²⁵

Acne

In a 2003 study of antiacne activity displayed by Asian herbal extracts, Name et al. found that G. glabra showed significant antibacterial activity against Propionibacterium acnes without inducing noteworthy resistance. The investigators suggested that a formulation combining three herbal extracts, including G. glabra, Angelica dahurica, and Coptis chinensis, may be suitable for preventing and treating acne.⁵³

Ten years later, Angelova-Fischer et al. conducted a nine-week, randomized, double-blind, vehicle-controlled study with 60 volunteers with mild-to-moderately severe acne to evaluate and provide proof-of-concept for a formulation containing licochalcone A, L-carnitine and 1,2-decanediol. After one week for standardization of the cleansing procedure, the participants (40 females and 20 males between the ages of 14 and 40 years old) were randomized to apply either the test formulation or vehicle to the face twice daily for eight weeks. At the end of the study, the mean total lesion count and papular lesions were decreased in the active formulation group compared to baseline. Significant reductions in pustules, sebum levels, and P. acnes were recorded in the active formulation subjects along with improvements in Dermatology Life Quality Index (DLQI), whereas no significant improvements were observed in the vehicle group. Evidence of acne improvement associated with the licochalcone A-containing formulation was noted in both physician and patient assessments.⁵⁴

Atopic Dermatitis

G. glabra is one among various plant constituents demonstrated to be effective in treating atopic dermatitis.^55,56 In a 2003 double-blind study over two weeks, investigators evaluated the effect of 1 and 2 percent topical licorice extract preparations on atopic dermatitis in two 30-patient groups. Results indicated that the 2 percent licorice topical gel was more effective in reducing erythema, edema, and pruritus. Significantly, the authors also concluded that licorice extract was effective in treating atopic dermatitis.⁴¹

In 2011, Udompataikul and Srisatwaja conducted a six-week, randomized, controlled, investigator-blinded comparative pilot study of the effects of moisturizers containing licochalcone A or hydrocortisone on children with atopic dermatitis (mean age, 5.8 years). Twenty-six patients completed the protocol, which included twice-daily application of licochalcone A on one side of the body and hydrocortisone on the other side. The response rate to both treatments was found to be 73.33 percent, with no significant differences in scoring atopic dermatitis (SCORAD) score reductions from treatment. Edema and erythema resolved more rapidly with hydrocortisone, but the relapse rate associated with hydrocortisone was higher; in both cases, the differences were not significant. The investigators concluded that licochalcone A lotion, which was found to be equally effective as hydrocortisone lotion, is an option to treat mild-to-moderate childhood atopic dermatitis in the maintenance as well as acute phases.⁵⁷

In 2013, Wananukul et al. led a four-week, prospective, multicenter, randomized, double-blind, split-side study in 55 children (three months to 14 years of age) with mild-to-moderate atopic dermatitis to compare the efficacy of a licochalcone A-containing moisturizer and 1 percent hydrocortisone. Simultaneous treatment with either the licochalcone A preparation or 1 percent hydrocortisone on opposite sides of the lesion were administered twice daily. The SCORAD declined significantly for both treatments from baseline, with no statistically significant differences between the treatments. Transepidermal water loss was found to be significantly decreased from baseline on the side that received licochalcone A treatment. The investigators also reported that continuing treatment with licochalcone A for four weeks maintained clinical and skin barrier benefits.⁵⁸

Hyperpigmentation

Licorice extracts are included among the array of topical tyrosinase inhibitors used to lighten hyperpigmented areas of the skin.^59–61 Glabridin, found in concentrations between 10 and 40 percent in commercial depigmenting agents, is thought to be the chief ingredient in licorice to provide skin-lightening activity.⁶¹ Draelos has noted that the status of licorice extracts as the safest of options among skin-lightening agents while eliciting the fewest side effects accounts for its popularity for this purpose.^62,63

In a study of 20 women between the ages of 18 and 40 with a clinical diagnosis of bilateral and symmetrical idiopathic epidermal melasma, liquiritin cream was applied on one side of the face and a vehicle cream on the other twice daily for four weeks. Liquiritin is a flavonoid component of licorice that, along with other ingredients, contributes to the natural yellow pigment. Individuals with dermal melasma, melasma with pregnancy, and those receiving hormone replacement therapy were excluded from the study. Topical sunscreen use was encouraged during the treatment period while sun exposure was discouraged. Sixteen patients (80 percent) were characterized as exhibiting excellent responses from liquiritin, with no discernible differences between the normal skin and previously pigmented areas. Two patients (10 percent) showed a good response on the liquiritin side, and two patients (10 percent) had fair responses from liquiritin, with moderate pigmentation, while moderate improvement was seen in only 20 percent on the vehicle side.⁶⁴

Nerya et al. found in 2003 that in addition to glabridin, glabrene, and isoliquiritigenin (2ʹ,4ʹ,4-trihydroxychalcone), constituents of licorice root extract contributed significantly and dose-dependently in the observed potent tyrosinase-inhibiting activity displayed by the plant.⁶⁵

In a 2010 single-blind, 60-day study with 56 women between 18 to 60 years old, Costa et al. found that a formulation combining belides, emblica, and licorice was as effective as hydroquinone 2 percent in ameliorating the effects of melasma (see Chapter 38, Emblica Extract). There were no statistically significant differences between the groups and the herbal combination was associated with fewer adverse effects.⁶⁶

In 2008, Adhikari et al. screened 52 crude drugs traditionally used in Nepal to treat hyperpigmentation for inhibitory activity against mushroom tyrosinase, finding that methanolic extracts of G. glabra manifested the greatest inhibitory activity, with kojic acid used as a positive control.⁶⁷ Licorice extract is frequently combined with other skin-lightening ingredients (see Chapter 32, Overview of the Pigmentation Process). Vitamin C is often combined with licorice extracts or soy when deployed for skin-lightening purposes [see Chapter 40, Vitamin C (Ascorbic Acid), and Chapter 45, Soy].⁶⁸

Psoriasis

Cassano et al. conducted a pilot, randomized, open-label, parallel-group trial in 40 patients in 2010 to assess the effects of an emollient cream containing milk proteins and G. glabra extracts in the treatment of palmar and/or plantar psoriasis treated with topical corticotherapy. Twenty patients were treated only with mometasone furoate ointment for four weeks and 20 patients received the same corticosteroid in combination with the licorice-containing emollient, which was applied twice daily during the four-week study period. Statistically significant decreases in the severity of all clinical signs of psoriasis were seen in all patients, all of whom completed the study. In the group treated with the test emollient, significantly greater reductions in desquamation, affected surface area, and subjective symptoms were reported as compared with the corticosteroid-only treatment group. The investigators concluded that their findings support the adjuvant use of this new emollient combining G. glabra extracts and milk proteins for psoriasis management.⁶⁹

The topical application of Tuhuai, a Chinese herbal medicine that includes licorice, has also been found by Man et al. to exhibit antiproliferative and anti-inflammatory activity in murine models of inflammatory dermatoses. The investigators suggest the herbal formulation may offer an effective, relatively safe, and inexpensive option to treat inflammatory disorders such as psoriasis.⁷⁰

Sensitive Skin/Rosacea

In 2006, Weber et al. assessed the cutaneous compatibility and efficacy of a skin care regimen containing licochalcone A in 62 patients with mild-to-moderate rosacea over eight weeks. The regimen was well tolerated and effective in reducing erythema, as indicated by clinical evaluations, subject response, and photographic review. Responses to quality-of-life questionnaires revealed subjective improvements, and average erythema scores at four and eight weeks indicated significant improvements. The investigators concluded that licochalcone A use is suitable for patients with sensitive facial skin, as characterized by rosacea, and that the tested licochalcone A-containing regimen was compatible with daily metronidazole application.⁷¹

That same year, Kolbe et al. showed in prospective, randomized, vehicle-controlled clinical trials that licochalcone A displays significant anti-irritative efficacy in cosmetic formulations and is thus well suited for sensitive or irritated skin. They also showed in vitro that licochalcone A-rich extracts of G. inflata as well as synthetic licochalcone A potently inhibit proinflammatory responses.⁷² Licorice extract is a popular ingredient in over-the-counter skin care products designed to treat rosacea, although few studies supporting its use in rosacea are published.

SAFETY ISSUES

Most, if not all, pharmacopoeias around the world recognize and include licorice extract.¹² The United States Food and Drug Administration (FDA) bestowed generally recognized as safe (GRAS) status upon licorice in 1983.²⁸ The dietary ingredient licorice flavonoid oil, in which glabridin is a primary bioactive flavonoid, has been found to be safe when used once daily up to 1,200 mg/day.⁷³

The rare side effects from the oral administration of licorice are dose-dependent and occur more frequently in women and with the use of oral contraceptives.⁷⁴ At doses of less than 10 mg of glycycrrhizin daily, side effects are thought to be nominal.⁷⁵ Chronic use of high doses of glycyrrhizin or glycyrrhetinic acid can result in adverse effects such as edema, hypertension, and hypokalemia. Chemical modifications to licorice formulations have been made to enhance therapeutic benefits while reducing the risk of side effects.³ Oral licorice is contraindicated in pregnancy according to the German Commission E, though doses up to 3 g daily are thought to be safe; hypertension, cardiac or renal histories, various liver conditions, hypokalemia, and edema are also contraindications.^24,27,75

The Cosmetic Ingredient Review (CIR) Expert Panel suggested that acute, short-term, subchronic, or chronic toxicity is minimal and deemed the use of all licorice constituents safe for skin care in the current usage and concentration practices.¹⁷

ENVIRONMENTAL IMPACT

The CIR Expert Panel noted that the chemicals isolated from the licorice plant may have pesticide and toxic metal residues, and advised that polychlorobiphenyl (PCB)/pesticide contamination should be no higher than 40 parts per million. They further cautioned that toxic metal levels should be limited to 3 mg/kg of arsenic, 1 mg/kg of lead, and 0.002 percent heavy metals.¹⁷

In 2003, Yamamoto et al. acknowledged that cultivation of G. uralensis had emerged to compensate for the waning supply of wild Glycyrrhiza plants in China incurred by collection restrictions spurred by over-collection of wild plants.^21,76 Six years later, Gao et al. reported on the ramifications of using G. uralensis seeds flown on a recoverable satellite for 18 days. After their return to earth, the seeds were planted and grown to maturity. Analysis of the content of the roots of the seeds flown in space revealed glycyrrhizic acid as 2.19 times higher than a control group and liquiritin content as 1.18 times that of the control. The investigators suggested that extraterrestrial breeding warrants attention as an approach to future breeding of what is considered an endangered medicinal plant.⁷⁶

FORMULATION CONSIDERATIONS

The licorice derivatives glycyrrhizin and glycyrrhetinic acid occasionally cause edema, hypertension, and hypokalemia when used orally in patients treated over a long period and with higher doses. Topical use has not been associated with these side effects. Chemical modifications to the myriad compounds have enhanced the anti-inflammatory activities of the various forms of licorice extract,³ and several products have been formulated with the intent to increase penetration of the active compounds.

Hao et al. demonstrated in 2010 that glycyrrhetinic acid, a metabolite of glycyrrhizic acid, could better penetrate the skin when combined with organic bases (triethanolamine or triethylamine) in nonaqueous solvent comprising isopropyl myristate and alcohols (ethanol, butanol, octanol, and dodecanol). Specifically, they found that an ion pair between glycyrrhizic acid and an organic base enhanced the solubility of the extract in the stratum corneum as well as its partition into the viable skin, thus fostering the penetration of the licorice component into the skin.⁷⁷

Marianecci et al. found in 2012 that using niosomes composed of surfactants (Tween 85 and Span 20) loaded with ammonium glycyrrhizinate is potentially effective for treating various inflammatory disorders, as the delivery system was shown to exhibit good skin tolerability and no toxicity while enhancing the drug anti-inflammatory activity in mice. Skin erythema chemically induced in a human model was also found to be improved by the ammonium glycyrrhizinate-infused vesicles.³⁹

Early in 2014, Mostafa et al. reported on the formulation of a stable, cost-effective, easy-to-use transdermal microemulsion system (ME3) for G. glabra delivery that delivers 13-fold higher ex vivo antioxidant capacity than the licorice extract solution itself.⁷⁸

USAGE CONSIDERATIONS

No topical products with licorice extract as the primary active ingredient are FDA approved for the treatment of melasma, rosacea, acne, or other inflammatory skin disorders.²⁷ Glycyrrhetinic acid is used in many cosmeceuticals at concentrations of up to 2 percent and glycyrrhizic acid, up to 0.1 percent.¹⁷ Studies have not been performed to investigate how other agents affect efficacy and penetration when used in combination with various forms of licorice extract.

SIGNIFICANT BACKGROUND

In some of the earlier research on licorice extract, the use of topical ointments containing active isomers of glycyrrhetic acid reportedly showed anti-inflammatory activity in subacute and chronic dermatoses, such as contact dermatitis, seborrheic dermatitis, and psoriasis. Topical corticosteroids were more effective than the glycyrrhetic acid formulation in treating acute atopic dermatitis.⁷⁹ But glycyrrhetic acid has been characterized as exerting a cortisone-like effect, rendering it viable as an anti-inflammatory agent, and has inhibited proinflammatory prostaglandins and leukotrienes.^47,80 Combining glycyrrhetic acid with corticosteroids has also been shown to be effective. Results from topical corticosteroid application were significantly improved with the addition of 2 percent glycyrrhetic acid in one study.⁴⁸

Antioxidant Activity

Assays of physical stability and antioxidant activity of topical preparations containing various plant extracts performed by Di Mambro and Fonseca in 2005 revealed that G. glabra and Ginkgo biloba are suitable for incorporation into topical formulations intended to protect skin from the deleterious effects of free radical and reactive oxygen species.⁸¹

In 2011, Veratti et al. investigated the potential protective properties of glycyrrhizin, 18β-glycyrrhetinic acid, and glabridin against UVB-induced damage in human keratinocyte cultures. They found that 18β-glycyrrhetinic acid and glabridin exhibit strong antioxidant activity by blocking oxidative DNA fragmentation as well as the induction of apoptosis in human keratinocytes.⁸²

Also during that year, Li et al. employed novel techniques to screen and characterize 35 radical scavengers in G. inflata, G. glabra, G. pallidflora, and G. uralensis, with 21 identified as flavonoids.⁹

The phenolic compounds licochalcone A-D and echinatin, retrochalcones isolated from G. inflata roots, have exhibited activity against an array of oxidative stresses. A study assessing their inhibitory capacity on lipid peroxidation and radical scavenging activity, specifically, revealed that licochalcones B and D potently hindered superoxide anion production in the xanthine/xanthine oxidase system, protected red cells from oxidative hemolysis, and displayed potent scavenging activity.³⁴ These retrochalcones have also demonstrated antimicrobial activity. Specifically, licochalcones A and C have been shown to exert potent activity against some Gram-positive bacteria and hamper oxygen consumption in vulnerable bacterial cells.⁸³

Antibacterial Activity

In a study evaluating the in vitro activities of licochalcone A against some food contaminant microorganisms, the licorice derivative exhibited activity against all Gram-positive bacteria tested, particularly all Bacillus spp. tested, but was ineffective against tested Gram-negative bacteria and eukaryotes at 50 μg/mL. This study demonstrated the potential viability of licochalcone A as an integral constituent in antibacterial products designed to preserve food high in salts and proteases.²²

Flavonoid extracts of several species of licorice plant have been shown to exhibit antiulcer activity for peptic ulcers. Inhibitory activity against Helicobacter pylori growth has also been observed in vitro among glabridin and glabrene (components of G. glabra), licochalcone A (G. inflata), as well as licoricidin and licoisoflavone B (G. uralensis). Among these licorice constituents, anti-H. pylori activity was also identified against a clarithromycin- and amoxicillin-resistant strain.²³

In 2013, Long et al. showed that high concentrations of 18β-glycyrrhetinic acid, a constituent of the root of several Glycyrrhiza species, were bactericidal to methicillin-resistant Staphylococcus aureus (MRSA). In addition, both in vitro and in vivo, the licorice component, at sublethal doses, decreased virulent gene expression in S. aureus.⁸⁴

Chemopreventive/Photoprotective Activity

Oral feeding of licorice extract to Sencar mice was shown in 1991 to protect against skin tumorigenesis caused by DMBA initiation and TPA promotion. Tumors developed in much less time in mice not fed the licorice preparation; treated mice also had significantly fewer tumors during and at the end of the study. Researchers concluded that the considerable antitumorigenic activity of licorice extract might ultimately be proved useful in protecting against some forms of human cancer.¹¹ Since the time that this study was published, the polyphenols in licorice have been shown to induce apoptosis in cancer cells, as licorice constituents have exhibited significant antimutagenic, anticarcinogenic, and tumor-suppressive capacity in animal models.¹⁰ In fact, the National Cancer Institute has formally recognized the chemopreventive worth of licorice root and its primary constituent glycyrrhizin.^82,85

In 2005, Rossi et al. assessed the effect of glycyrrhizin and its aglycone metabolite 18β-glycyrrhetinic acid on UVB-irradiated human melanoma cells, finding that glycyrrhizin has the potential to confer photoprotection, though it is ineffective on metastatic cells.⁸⁶

Also that year, Agarwal et al. reported that 18β-glycyrrhetinic acid inhibits TPA-mediated oxidative stress and tumor promotion in murine skin, attenuating the activity of ornithine decarboxylase, incorporation of [3H]-thymidine in DNA, and induction of oxidative stress. The licorice component also suppressed DMBA/TPA-induced skin tumor formation in mice. The researchers concluded that the antioxidant glycyrrhetinic acid may be a viable chemopreventive agent.⁸⁷

In 2007, Rahman et al. investigated the chemopreventive effects of glycyrrhizin on TPA-induced cutaneous oxidative stress and tumor protection in Swiss albino mice. Pretreatment of animals with the licorice compound prior to TPA yielded significant reductions in cutaneous microsomal lipid peroxidation and restoration of cutaneous glutathione and its dependent enzymes. The investigators suggested that glycyrrhizin provided substantial protection to mice from pernicious TPA-induced effects.⁸⁸

Cherng et al. showed in 2011 that oral administration of glycyrrhizic acid to SKH-1 hairless mice prior to UVB exposure (180 mJ/cm² per exposure) mitigates UVB-induced tumorigenesis through downregulation of cell proliferation controls (i.e., thymine dimer-positive cells, proliferative cell nuclear antigen expression, apoptosis, and transcription factor NF-κB) and inflammatory responses (i.e., COX-2, PGE₂, and NO) and upregulation of p53 and p21/Cip1 to preclude damage while mediating repair to DNA.¹

Afnan et al. conducted an in vitro study in 2012 of the effects of glycyrrhizic acid against UVB-induced photoaging in human dermal fibroblasts, finding that treatment with the licorice extract diminished reactive oxygen species, NF-κB, cytochrome c, and caspase 3 levels and hindered hyaluronidase. The investigators speculated, though, that the botanical ingredient significantly suppressed photoaging primarily through inhibiting matrix metalloproteinase-1 activation and altering NF-κB signaling. They concluded that glycyrrhizic acid appears to have potential as a key ingredient in natural and safe products intended to protect against UVB-induced damage.⁴

Dry, Itchy Scalp

A G. inflata extract containing licochalcone A was included in a formulation with urea, lactate, and polidocanol that was tested by Schweiger et al. in 2013 in 30 volunteers with dry and itchy scalp conditions. Participants applied the leave-on tonic three times each week for four weeks on one side of the scalp. Investigators found that scalp moisture was significantly enhanced after treatment with the tonic, while pruritus was significantly diminished. A substantial decrease in key proinflammatory markers was also confirmed through scalp wash-up analyses. The investigators concluded that the formulation containing anti-inflammatory licochalcone A, urea, lactate, and polidocanol displayed great efficacy in normalizing scalp lipid disturbances and, more importantly, relieving scalp dryness, itching, and microinflammation.⁸⁹

Infantile Seborrheic Dermatitis

In 2012, Wananukul et al. conducted a two-week, prospective, randomized, double-blind, split-side comparison study of a 0.025 percent licochalcone-containing moisturizer and 1 percent hydrocortisone in 75 infants (72 of whom completed the study) with infantile seborrheic dermatitis. Patients were treated twice daily on opposite sides of the lesion. A significantly higher clearance rate (42 percent vs. 32 percent) was recorded in the licochalcone group at days 3 to 4, with the products appearing equally effective at days 6 to 7 and 14.⁹⁰

Other Biologic Activity

Shin et al. conducted in vitro and in vivo investigations of the antiallergic effects of G. glabra and its constituents in 2007, reporting that glycyrrhizin, 18β-glycyrrhetinic acid, and liquiritigenin are primarily responsible for imparting antiallergic activity that can alleviate the symptoms of immunoglobulin E-mediated allergic conditions such as dermatitis and asthma.⁹¹

Pellati et al. showed in vitro in 2009 that 18β-glycyrrhetinic acid substantially stemmed, in a pH-dependent manner, the growth of clinical isolates of Candida albicans strains from patients with recurrent vulvovaginal candidiasis. The researchers suggested that the constituent of Glycyrrhiza species has potential as a topical therapeutic option for patients with the condition.⁹²

Peng et al. showed in 2011 that glycyrrhetinic acid extracted from G. uralensis induced the dose-dependent expression of Toll-like receptor 4 in Ana-1 murine macrophages and activated its downstream signaling pathway, which is involved in the regulation of the innate immune reaction to encroaching pathogens.¹⁶

Kato et al. studied the extracts of 25 plants used in Kampo medicine in 2012 to identify anti-UV and anti-HIV activity. Of the plants tested, licorice displayed the second highest anti-UV activity (gardenia fruit was first) and was one of only six plants to display some anti-HIV activity.⁹³

In 2013, Wang et al. extracted the radices of G. uralensis with hot water and reported antiviral activity against enterovirus 71 and coxackievirus A16, validating the use of the botanical extract against the etiological sources of hand, foot, and mouth disease, with glycyrrhizic acid identified as the primary antiviral component of G. uralensis.²⁰

CONCLUSION

Licorice root has been used in traditional medicine in the East and West for well over two millennia. In addition, it has been evaluated in a vast range of modern scientific studies, and licorice extracts have been included in the cosmeceutical as well as medical realm. The reputed anti-inflammatory and depigmenting properties of licorice root are particularly intriguing. The great challenge in producing cosmeceutical products – harnessing the identified strengths of a given ingredient and bottling it, delivering health benefits in a topical formulation – applies here as in most cases discussed in this text. The wealth of evidence points to the benefits of several species of licorice plant, indicating that such benefits have been reaped in oral and topical preparations of the extract. Given the relative wealth of history and research supporting its use, licorice root is likely to be incorporated into an increasing number of products. Several medical applications have been derived from various species of licorice, particularly G. glabra, G. inflata, and G. uralensis. Overall, there appears to be ample reason for optimism regarding the role of licorice extracts in dermatology.

REFERENCES

INTRODUCTION

SOURCE

Avena sativa (also known as oatstraw or wild oats, and Jai or Javi on the Indian sub-continent)⁵ has a long history of traditional folk use, particularly as a poultice or soak, to alleviate pruritus and irritation related to dry skin conditions (Table 68-1).^6,7 As a cultivated plant, this annual cereal grain and member of the Poaceae (also known as Gramineae or true grasses) family, is grown for its seeds for multiple uses. In recent decades, colloidal oatmeal (CO), dehulled oats ground into a fine powder, has been used, typically in a bath, for purposes similar to the traditional ones, namely lessening the irritation and mild pruritus characteristic of eczema, insect bites, rashes, poison ivy, and other contact allergens.⁸ CO has also been used for decades as an adjunct in the treatment of atopic dermatitis.⁹ Generally, better benefits are seen with the use of oat fractions than whole oat-meal.¹⁰

Evidence suggests that CO, the modern version of the traditional elixir, is effective in protecting and repairing skin and hair damaged from environmental insults such as ultraviolet (UV) radiation, smoke, bacteria, and free radicals as well as alleviating cutaneous inflammation and discomfort.¹⁰ In addition, CO appears to have the capacity to repair damage from other chemicals such as α-hydroxy acids, surfactants, and bleaches.¹¹

A. sativa is also believed to promote the release of luteinizing hormone, which is integral in the production and release of sex hormones such as testosterone. This might account for its traditional use as an aphrodisiac and the origin of the expression “sowing wild oats.”

HISTORY

The skin care application of A. sativa dates back earlier than 2000 BCE to its native Mediterranean region, particularly Egypt and the Arabian Peninsula, and oatstraw was widely cultivated in Europe by 2000 BCE.⁶ Early references to the medical application of oats were made by Hippocrates (circa 460–370 BCE) and, later, by Dioscorides, Galen, and Pliny the Elder in the 1st century CE.^12–14 The use of oats as a food source has been traced to the 1st century CE.¹⁰ As teas, food, and in baths, oats were used for centuries to treat anxiety, insomnia, and various cutaneous conditions, including burns and eczema.¹⁵ Consumption of whole grain oats is now associated with a lower risk for coronary heart disease.^5,16

In the 19th and early 20th centuries, oatmeal baths were frequently used for the treatment of pruritic inflammatory skin conditions, such as eczema and burns. A ready-to-use CO preparation, created by finely grinding and then boiling the oat to extract the colloidal substance, became available in 1945.^2,14 In the late 1950s, Dick and Sompayrac reported separately that CO baths were demonstrably effective in the management of pediatric atopic dermatitis.^17,18 As a component of the modern dermatologic armamentarium, CO has replaced rolled oats and plain oatmeal, and has been used for decades to ameliorate inflammatory and pruritic conditions. CO is composed of dehulled oats ground to a fine powder that retains the moisturizing effects of the whole oat grain and disperses more easily in bath water. It can also be added to creams and lotions for use in topical products.

CHEMISTRY

CO consists primarily of polysaccharides (60–85 percent), proteins and enzymes, such as superoxide dismutase (10–20 percent), lipids (3–11 percent), β-glucan (5 percent), fiber (5 percent), and avenanthramides (0.03 percent).^2,13 The remaining constituents include saponins, vitamins, flavonoids, and inhibitors of prostaglandin synthesis. Oat lipids contribute to the viscosity of CO and help decrease transepidermal water loss, a key factor in skin dryness.^19,20 Phenols in oatmeal contribute to the antioxidant and anti-inflammatory activity of the extract, and some oat phenols exhibit potent UV-absorbing properties.¹⁴ Constituent saponins are responsible for most of the cleansing activity of oat.¹⁴ In addition, oatmeal proteins exhibit emulsification, hydration, and antioxidant activity along with low foaming potential. CO proteins and polysaccharides bind to skin and provide a protective barrier to external insults. The proteins further act as a buffer against strong acids and bases.²¹ The protective and water-retaining properties of CO are thought to result from its high concentration of starches (polysaccharides), particularly β-glucan.¹⁴ Oat β-glucan is believed to be immunomodulatory.CO lotion application is also known to affect arachidonic acid, cytosolic phospholipase A₂, and tumor necrosis factor (TNF)-α pathways in exerting potent anti-inflammatory activity.²² The biologic activity of oat compounds appears to be quite dynamic. The activity of whole oat flour is characterized as antioxidant, prostaglandin synthesis-inhibiting, cleansing, and protective in nature.

Avenanthramides

The therapeutic and cosmetic uses of oatmeal have been enhanced by the isolation and identification of specific oat components. Oatmeal has been found to contain 20 unique polypenolic alkaloids, avenanthramides, which act as phytoalexins, exhibiting antimicrobial properties that serve to protect the plant.¹³ Found exclusively in oats, avenanthramides, which are substituted N-cinnamoylanthranilic acids with hydroxycinnamic acid and anthranilic acid moieties, have exhibited potent antioxidant activity in vitro and in vivo as well as anti-inflammatory, antiproliferative, and antipruritic activity.^4,16 This is not surprising insofar as phenolics, as a group, display a broad range of biologic activities including prevention of inflammation and oxidation.²³ In fact, phenolics are the strongest antioxidants found in nature,²⁴ although within this class of compounds, individual substances exert varying levels of antioxidant activity. Oat phenolic compounds including avenanthramides have been identified as potent antioxidants that scavenge reactive oxygen and nitrogen species.²³ Of the oat phenolics, avenanthramides are thought to manifest 10 to 30 times the antioxidant activity of other oat phenolics such as caffeic acid or vanillin.²⁵ Furthermore, they have been reported to inhibit prostaglandin biosynthesis nearly as well as the synthetic anti-inflammatory agent indomethacin.²⁶ Indeed, avenanthramides are now being credited with imparting many of the beneficial effects of CO.²⁷

A 2007 study by Wallo et al. provided more evidence that avenanthramides evince potent anti-inflammatory activity. The investigators incubated keratinocytes with an inducer of proinflammatory interleukin (IL)-8 in the presence of vehicle or avenanthramides. The phenolic compounds diminished the release of the proinflammatory cytokine IL-8 by 10 to 25 percent.²⁸ Avenanthramides in topical formulations have also been shown in multiple preclinical and preliminary clinical studies to suppress the activity of nuclear factor-κB (NF-κB) and the release of proinflammatory cytokines and histamine, thus blocking the activation of inflammatory pathways in the skin.^20,27 In addition, avenanthramides have been demonstrated to mitigate skin irritation and erythema induced by exposure to UVB irradiation.²⁰

After previously showing that avenanthramides significantly inhibited IL-1β-stimulated secretion of proinflammatory cytokines, such as IL-6, IL-8, and monocyte chemotactic protein (MCP)-1, by human aortic endothelial cells, Guo et al. showed in 2008 that oat polyphenols reduce the expression of endothelial proinflammatory cytokines, in part, via blocking NF-κB activation by suppressing the phosphorylation of the inhibitor of nuclear factor κB (IκB) complex (IKK) and IκB, and hindering proteasome activity.³

In 2008, Sur et al. found that avenanthramides, typically present in oats at approximately 300 parts per million (ppm), suppressed the degradation of IκB-α in keratinocytes in concentrations as low as 1 part per billion. In this in vitro study, they also found that avenanthramide-treated cells significantly inhibited TNF-α-induced NF-κB luciferase activity as well as IL-8 release. In murine models, the investigators showed that topically applied avenanthramides (in concentrations of 1–3 ppm) attenuated inflammation and diminished scratching. They concluded that avenanthramides are strong anti-inflammatory compounds that account for the anti-irritant activity manifested by oats.¹³

A year later, Lee-Manion et al. used assays to assess the antioxidant and antigenotoxic activity of synthetic avenan-thramides, hydroxycinnamic acids, Tranilast, and ascorbic acid. They observed that N-(3′,4′-dihydroxy-(E)-cinnamoyl)-5-hydroxyanthranilic acid, an avenanthramide compound found in copious amounts in oats, displayed the highest activity, indicating that avenanthramides possess antioxidant and antigenotoxic characteristics similar to those of ascorbic acid with the potential to deliver beneficial physiological effects.⁴

ORAL USES

A. sativa and oat products have been consumed since the 1st century CE.¹⁰ Oatmeal is known for its calming effects when taken internally, and remains a staple typically among breakfast options particularly among health-conscious consumers.

TOPICAL USES

The combination of components and properties of CO renders it suitable for various uses in the care of inflammatory skin conditions, such as cleaning, moisturizing, protecting (i.e., barrier preservation), and relieving pruritus in inflamed skin. In fact, oatmeal is one of the few natural products recognized by the United States Food and Drug Administration (FDA) as an effective skin protectant.²⁹ As a consequence, CO is one of the few botanicals subject to FDA regulation.²⁹ The range of dermatologic applications for CO is extensive and includes adjunctive therapy in inflammatory and pruritic skin conditions such as atopic dermatitis; allergic and irritant contact dermatitis including contact to poison ivy, oak, and sumac; chicken pox; cercarial dermatitis; diaper dermatitis; epidermolysis bullosa; ichthyosis; insect bites; pediatric and senile dermatoses; prickly heat; pruritic conditions; psoriasis; rashes; sunburn; urticaria; and xerosis.^{15,17,21,30,31} CO also prevents and repairs damage caused by environmental insults such as UV radiation, smoke, bacteria, and free radicals.¹⁰ In addition, oatmeal baths are included in the accepted treatment arsenal for erythroderma, also known as exfoliative dermatitis, which affects the majority of the cutaneous surface.³² Oatmeal extracts also confer modulating effects in the sodium lauryl sulfate skin irritancy model.

In a small study with 20 patients in 2007, the application of topical CO lotion (derived from A. rhealba®, which is a white oat cultivar of A. sativa) was shown to be effective in treating acneiform eruptions associated with the use of small-molecule tyrosine-kinase inhibitors in treating epidermal growth factor (EGFR)-positive cancers, thus facilitating continued neoplastic therapy.²²

Further, Wu contends that CO is well suited as a treatment option for rosacea due to its barrier and skin-protective, antipruritic, anti-inflammatory, and antioxidant properties.³³

Atopic Dermatitis

Several studies have shown that the daily use of CO-containing moisturizers and/or cleansers has significantly improved the symptoms of patients, from infants to those in their 60s, with mild-to-moderate atopic dermatitis and proven to be safe and well tolerated.³⁴

In 2007, Grimalt et al. conducted a six-week randomized controlled study in 173 infants treated for inflammatory lesions with moderate- or high-potency topical corticosteroids to assess the effects of an oat extract-containing emollient on the amount of steroid needed for treatment. While the 7.5 percent lower use of moderate-strength corticosteroids in the emollient group compared to the control group was not significant, the oatmeal emollient treatment significantly decreased the use of high-potency topical corticosteroid use in infants with atopic dermatitis by 42 percent compared to controls.³⁵

Also that year, Boussault et al. reported findings from a study of 302 prospectively recruited children with atopic dermatitis who were referred for allergy testing between June 2001 and December 2004. Various sensitivity tests revealed that oat sensitization in atopic children under the age of two who were seen for allergy testing was higher than the investigators expected. They speculated that repeated applications of oat-containing cosmetics on an already susceptible epidermal barrier may account for this phenomenon, concluding that such oat products should be avoided in infants with atopic dermatitis.³⁶

SAFETY ISSUES

In 1997, the FDA, based on evidence that consumption of oatmeal or oat bran decreased low-density lipoproteins and total plasma cholesterol (largely attributed to its constituent β-glucan), approved the heart-health benefit claim on labels of food containing oat-soluble fiber.^5,16 Oatmeal is also one of the few natural products or ingredients acknowledged by the FDA as an effective skin protectant. Indeed, CO has been found to be safe, cosmetically stable, and nonirritating. With the issuance of its Over-The-Counter Final Monograph for Skin Protectant Drug Products issued in June 2003, the FDA began regulating CO as a skin protectant and its preparation is standardized in the United States Pharmacopeia.^14,37 It is also approved for use in Germany for inflammatory skin conditions.⁶

While rare, cases of allergic contact dermatitis and urticaria have been reported in reaction to the use of CO preparations.³⁸ No adverse drug interactions have been reported in association with CO.³⁹ Overall, oatmeal has an excellent safety profile in the treatment of dermatologic disorders.

In 2012, Criquet et al. performed a series of studies to examine the safety and efficacy of personal care products (i.e., creams, cleansers, and lotions) containing CO. They found a very low potential in these agents for engendering irritation and allergenic sensitization. Of 2,291 participants, one subject developed a persistent but dubious (because it was confirmed with the product but not with A. sativa) mild edema during the challenge phase in a test of 12 personal care products containing CO. In the induction phase of insult patch testing, 1 percent of subjects experienced similarly low-level reactions. The investigators also reported that skin moisturization was sustained in subjects with dry skin, extending to two weeks beyond discontinuation of the product. They noted that no allergies were documented in the 80 subjects observed following patch testing after in-use application or by consumers of 445,820 products sold during a three-year period. Criquet and colleagues concluded that personal care products containing CO are safe and effective.⁴⁰

ENVIRONMENTAL IMPACT

The environmental impact from the cultivation and commercial use of A. sativa is not well documented to the author’s knowledge.

FORMULATION CONSIDERATIONS

Most oatmeal products come in the form of colloidal baths, but shampoos, soaps, body washes, shaving gels, and moisturizing lotions and creams are also prepared with oatmeal.¹⁴

USAGE CONSIDERATIONS

As part of a daily skin care regimen, CO is appropriate for cleansing (especially dry, sensitive, or atopic skin), moisturizing, and providing protection to the skin.

SIGNIFICANT BACKGROUND

In a literature review of in vitro, in vivo, and clinical studies of oatmeal preparations in 2012, Pazyar et al. found that oatmeal exhibits antioxidant and anti-inflammatory activity in its effective medical use for conditions including acneiform eruptions, atopic dermatitis, pruritus, and viral infections as well as in cosmetic formulations in providing photoprotection to the skin.² Cerio et al. have noted that CO has also demonstrated effectiveness in treating psoriasis and drug-induced rashes.^2,27

Human Studies

In a 1997 double-blind, randomized patch study of two concentrations of colloidal oat and rice grains (0.007 and 0.7 percent), the products were applied topically to the backs of 65 Italian children between 6 months and 2 years old (of whom 43 were atopic and 22 were normal). Both topical colloidal grains showed efficacy as adjuncts in the treatment of mild atopic dermatitis, with no evidence of inducing sensitization.⁹

In a 2001 10-month assessor-blind clinical study to identify an adequate treatment to alleviate pruritus experienced by 35 acute burn patients, the comparative effectiveness of two shower and bath oils, one containing liquid paraffin with 5 percent CO and the other containing liquid paraffin, was evaluated. Analysis of patient assessments of pain (recorded twice daily) and the daily number of their antihistamine requests showed that the CO group reported significantly less pruritus and requested significantly less antihistamine.⁴¹

In an influential study on 12 healthy individuals, researchers evaluated the anti-inflammatory activity of two topically applied oatmeal extracts, A. sativa and A. rhealba®, using the sodium lauryl sulfate irritation model, finding that both extracts displayed preventive effects on skin irritation.⁴²

Further, Boisnic et al. developed a clinical model of cutaneous inflammation involving the effects of an oatmeal extract oligomer on skin tissue fragments exposed to vasoactive intestinal peptide, a proinflammatory neuromediator. The application of the peptide augmented inflammation, which was significantly reduced by treatment with the oatmeal extract.⁴³

Antioxidant Activity

In 2013, Feng et al. investigated the protective effect of oat bran extract by enzymatic hydrolysates on hydrogen peroxide (H₂O₂)-induced human dermal fibroblast injury. They found, using a 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging assay that peptide-rich oat bran extracts concentration-dependently exhibited direct antioxidant activity. Further, they showed that incubating human dermal fibroblasts with oat bran extracts for 24 hours prior to exposure led to the significant suppression of H₂O₂-induced damage, but simultaneously applying oat peptides with H₂O₂ did not yield a similar result. However, the oat pretreatment also markedly reversed the H₂O₂-induced reduction of superoxide dismutase as well as malondialdehyde inhibition. The investigators concluded that oat peptides have potent antioxidant properties and that oat peptide-rich extract warrants further study and consideration as an antioxidant functional food with the capacity to prevent or mitigate cutaneous aging when incorporated into skin care products.⁴⁴

CONCLUSION

Oatmeal has a surprisingly long tradition in skin care and rare recognition by the FDA as a skin protectant. Over the last several decades, the amassed research and clinical evidence appear to bear out the anti-inflammatory and other protective activities ascribed to oats in folk medicine.

REFERENCES

INTRODUCTION

SOURCE

Native to the Indian subcontinent and Southeast Asia, turmeric (Curcuma longa), a member of the Zingiberaceae (ginger) family, is best known as a spice and coloring agent used primarily in Asian cuisine, particularly curry, and in prepared mustard, margarine, as well as carbonated and other beverages.¹⁰ Turmeric is one of the best researched spices for pharmacologic application.¹¹ It is used as a preservative, aromatic, cosmetic ingredient, and in some traditional Indian communities as a topical burn treatment.¹² In fact, turmeric has long been used as an anti-inflammatory agent in various traditional medical systems (Table 69-1). Specifically, turmeric has been deployed in Ayurvedic medicine to treat sprains and edema due to injury.^11,13–15 It has also been used topically, orally, and by inhalation for anti-inflammatory action.¹⁶ The rhizome of the curcuma plant is the portion used for medicinal purposes.¹⁴

In Samoa, the powdered rhizome of C. longa is sprinkled on newborn infants to mend the belly button after severing the umbilical cord; to prevent diaper rash; to maintain skin softness and resilience; and to treat, as a paste or poultice, skin ulcers and eruptions.¹⁴ The wide array of modern dermatologic uses of turmeric and its principal active ingredient curcumin also includes prevention or treatment of psoriasis, acne, wounds, burns, eczema, photodamage, and photoaging.¹⁷ The turmeric rhizome is used topically in Thailand to treat wounds, insect bites, ringworm, and bleeding.^11,18 It is also a popular medicinal plant in Nepal, and one of the top two medicinal plants for use in skin ailments and cosmetics in the northeastern Indian state of Assam.^19,20 Notably, curcumin is incorporated into cosmetics, particularly for those used in Hindu rituals and ceremonies.^10,21

HISTORY

The turmeric rhizome has been used for medicinal purposes for thousands of years, with documented uses dating to 600 BCE in Assyria, where it was used in herbal therapy, and to ancient Rome, where the Greece-born physician Dioscorides (circa 40–90 CE) was said to have cited it.²² Turmeric is believed to have been used for therapeutic purposes in Ayurvedic medicine as early as 1900 BCE and its use in traditional Chinese medicine dates back to ancient times.² The traditional uses in these medical systems, as well as Unani medicine, included treatment for inflammation, skin wounds, acne, skin rashes, warts, and liver disorders.^23,24 Turmeric was introduced into Europe during the 14th century.²⁵

In 1815, Vogel and Pelletier were the first in modern history to report extracting a “yellow coloring-agent” from C. longa, which they named “curcumin.”^10,26,27 In 1842, Vogel became the first to isolate curcumin, but he did not document its formula.^3,26 Although several scientists, including Daube and Ivanov, reported on possible structures in the ensuing decades, Lampe and Milobedzka, in 1910, became the first to identify the structure of curcumin (C₂₁H₂₀O₆) as diferuloylmethane.^3,26,28 Three years later, they became the first to synthesize the compound.²⁶ The first article to address the medical use of curcumin, specifically considering the effects on patients with biliary diseases, was published in The Lancet in 1937.^10,27 In a Nature article in 1949, Schraufstatter and Bernt identified antibacterial activity against Mycobacterium tuberculosis, Salmonella paratyphi, Staphylococcus aureus, and Tricophyton gypseum displayed by curcumin.^26,29 Over the ensuing 20 years, only five papers were published, but during the 1970s, antidiabetic, antioxidant, and anti-inflammatory properties of the polyphenolic compound were observed, and anticancer activity was displayed by curcumin and documented based on in vitro and in vivo models in the 1980s by Kuttan and colleagues.^26,30 In 1995, Singh and Aggarwal were the first to report that curcumin evinced anti-inflammatory activity by inhibiting nuclear factor (NF)-κB.^26,31 Over 6,400 research articles had been published on curcumin and included in the National Institutes of Health PubMed database as of early 2014, dating back to Schraufstatter and Bernt’s 1949 article, with more than 6,000 published since 1980.

CHEMISTRY

Turmeric tubers contain curcuminoids: the most abundant (~77 percent) curcumin I [diferuloylmethane or bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione], curcumin II, or demethoxycurcumin (6–17 percent), curcumin III, or bisde-methoxycurcumin (0.3–3 percent), and curcumin IV, or cyclocurcumin (typically less abundant than curcumin III).^5,6,32 The key biologically active constituent of turmeric, curcumin I, or simply curcumin, is a small-molecular-weight naturally-occurring polyphenol found in the root of C. longa that confers a distinctive flavor and yellow color to food.^14,33–36 Curcumin is the lipid-soluble component of turmeric; turmerin is its water-soluble component.^8,37 Curcumin displays more acute anti-inflammatory effects when compared to the volatile oil fraction of turmeric.³⁸ Indeed, it has displayed great potency against acute inflammation,¹³ and is associated with few adverse effects.³⁹ It is an exceedingly pleiotropic molecule with multiple disease targets related to the skin.⁴⁰

Evidence compiled over the last several decades reveals that curcumin exhibits a broad array of biologic activities, such as anti-inflammatory, anticarcinogenic, antioxidant, antimicrobial, and wound healing.^15,41–44 These effects are mediated through the regulation of numerous signaling pathways, transcription factors, growth factors, inflammatory cytokines, protein kinases, adhesion molecules, apoptotic genes, angiogenesis regulators, and enzymes, such as cyclooxy-genase (COX) and glutathione S-transferases.^45–47 But inhibition of NF-κB is thought to be the linchpin of the anti-inflammatory and antioxidant activity of the curcuminoid.²⁴ Curcumin is also known, at various levels, to suppress other signaling pathways such as transforming growth factor (TGF)-β and the mitogen-activated protein kinase pathway, in particular.^24,47 Further, it affects angiogenesis and cell–cell adhesion, and exerts immunomodulatory activity.⁴⁷ This broad range of biologic activity forms the basis for additional study of the potential applications of curcumin to prevent or treat photoaging and photocarcinogenesis.⁴⁸

The anticarcinogenic characteristics of curcumin are particularly well documented as are its demonstrated antioxidant and lipid peroxidation properties.^{8,21,44,49–52} Antibacterial, antiparasitic, and anti-HIV activities have also reportedly been manifested by turmeric or curcumin.⁵³ In 1987, an ethanol extract of turmeric and an ointment with curcumin as its active ingredient demonstrated efficacy in relieving patients of pruritus associated with external cancerous lesions.⁵⁴ In addition, curcumin reportedly has greater anti-inflammatory capacity than ibuprofen.^13,55 More importantly, it has been shown to protect against ultraviolet (UV)-induced photodamage by inhibiting inflammation and attenuating oxidative stress.⁴⁸ Curcumin is also a selective inhibitor of phosphorylase kinase, which fosters photocarcinogenesis in photodamaged skin by activating NF-κB signaling pathways and suppressing apoptosis of photodamaged cells.^56,57

ORAL USES

Turmeric is consumed regularly in the diet, particularly in the Indian subcontinent. It is approved in Germany for the treatment of dyspepsia.¹¹ The systemic and topical use of turmeric for medicinal purposes is also officially sanctioned in Thai-land.^11,18

Curcumin is available in oral supplement form throughout the world.¹⁰ When used orally, curcumin inhibits leukotriene formation as well as platelet aggregation and stabilizes neutrophilic lysosomal membranes, thus inhibiting inflammation at the cellular level.⁵⁸ Notably, it produces varying dose-dependent effects: at low dose curcumin can be a prostaglandin inhibitor, while at higher levels it stimulates the adrenal glands to secrete cortisone.⁵⁹ Overall, though, it is known to exhibit poor systemic bioavailability after oral administration, except in the gastrointestinal tract, where biologically active levels have been recorded in animal and human studies.^60,61 Low curcumin bioavailability to organs such as the skin partially accounts for the impetus for investigations into transdermal and other modes of delivery (see the Formulation Considerations section below).

In 2013, Ryan et al. conducted a randomized, double-blind, placebo-controlled clinical trial to evaluate the effects of oral curcumin on radiation dermatitis in 30 adult female breast cancer patients. They found that 6 g of daily intake of curcumin during radiotherapy mitigated radiation dermatitis.⁶¹

TOPICAL USES

A limited number of cosmetic products contain curcumin at the present time as its distinct and pungent aroma and color render it especially challenging to formulate into a cosmetically elegant product. More clinical trials are required to assess the influence of topical curcumin on human skin. Bioavailability in topical products has also been problematic. A recent examination of the inhibitory activity of encapsulated curcumin on UV-induced photoaging in mice represents the first clinical support for the topical delivery of curcumin to minimize the effects of photoaging.⁶²

In 2013, Heng showed that the topical application of curcumin gel in the clinical setting yielded rapid healing of burns, nominal or no scarring, and also ameliorated various signs of photodamage, such as hyperpigmentation, solar elastosis, advanced solar lentigines, actinic poikiloderma, and actinic keratoses.⁵⁷ Curcumin is also thought to have a therapeutic role in eczema and scleroderma.⁶³

SAFETY ISSUES

No adverse effects, drug interactions, or general contraindications have been reported in association with the oral use of turmeric.¹¹ Allergic reactions are thought to be rare. It has also been found to be safe in human trials.¹⁶ The United States Food and Drug Administration, the Natural Health Products Directorate of Canada, and the Expert Joint Committee of the Food and Agriculture Organization/World Health Organization on food additives have deemed turmeric and curcumin food products safe for consumption.^10,64 Even at high doses, curcumin is characterized by a favorable safety profile for oral and cutaneous use.⁶⁵ The German Commission E does claim that the use of turmeric is contraindicated in patients whose biliary tract is obstructed.²² Oral curcumin has been shown in animal models to inhibit the activity of some chemotherapy drugs and enhance the activity of others.³ The National Cancer Institute in the United States has listed curcumin as one among approximately 35 plant-based foods [including genistein from soybeans, epigallocatechin gallate (ECGC) from green tea, resveratrol from grapes, and gingerol from ginger] to have cancer-preventive characteristics (see Chapter 45, Soy, Chapter 47, Green Tea, Chapter 50, Resveratrol, and Chapter 59, Ginger).⁶⁴

ENVIRONMENTAL IMPACT

As a perennial spice plant, C. longa is cultivated extensively throughout India and Southeast Asia.³ In fact, much of the world’s turmeric is grown by India, which consumes approximately 90 to 95 percent of what is produced, with the remainder exported.¹⁰ For investigations into its potential medical applications or incorporation into topical formulations, it is likely that a significant majority of the turmeric, and curcumin in particular, can be attributed to synthesis in the laboratory. Therefore, the environmental impact of turmeric in skin care products is likely not substantial.

FORMULATION CONSIDERATIONS

Topical curcumin is inexpensive, nontoxic, and safe.^12,28,66 However, given the undesirability of the yellow pigment and the strong smell being transferred to the skin via topical application, turmeric and curcumin have posed formulation challenges, though some authors believe new technologies may soon remedy this problem.¹³ In fact, there are cosmetics containing curcumin available throughout the world, particularly India and Japan.⁶⁷ In addition, extensive research into more cosmetically elegant and biologically active delivery systems to achieve skin permeability is well underway. These options also address the instability of curcumin when exposed to light or heat, and loss of activity in storage.⁶⁸

The myriad technologies, which merit continuing attention, include various forms of nanoencapsulation: β-cyclodextrin-curcumin nanoparticle complex in a hydrophilic matrix gel to foster skin permeability and enhanced bioavailability⁶⁰; curcumin-loaded monoolein aqueous dispersions (for extended curcumin activity) and lecithin organogels for conditions requiring rapid curcumin activity, as percutaneous delivery systems^69,70; curcumin-loaded micelles and thermosensitive hydrogels⁷¹; curcumin/xanthan:galactomannan hydrogels⁷²; curcumin-loaded oleic acid-based polymeric bandages⁷³; curcumin-loaded proniosomal gel bases⁷⁴; C. longa-loaded vesicular systems (niosomes, liposomes, ethosomes, and transferomes) incorporated in cream formulations or carbopol gel or other curcuminoid niosomes^75–78; turmeric oil in chitosan-alginate nanocapsules⁷⁹; and curcumin in eucalyptol microemulsions.⁸⁰

In 2012, Basnet et al. also showed that liposomal delivery of curcumin appears to have potential as an appropriate formulation for treating vaginal inflammation.⁸¹ During the same year, Liu et al. found that curcumin-loaded myristic acid microemulsions were capable of inhibiting the growth of Staphylococcus epidermidis on neonate pig skin. They suggested that this combination of curcumin and myristic acid in a microemulsion carrier has potential as an option for treating conditions associated with S. epidermidis as well as acne.⁸²

USAGE CONSIDERATIONS

Curcumin, in the form of a mouthwash used twice daily, was found in a small 2013 study of seven pediatric and young adult oncology patients to be safe, well tolerated, and effective in lowering pain scale scores associated with oral mucositis.⁸³ Over-the-counter products such as Johnson & Johnson’s Band-Aids™ include turmeric for the Indian market.²⁵

SIGNIFICANT BACKGROUND

In vitro studies have demonstrated that curcumin dose-dependently increases tumor cell apoptosis, slows cell growth, and lowers the number of clonogenic cells.¹² Topical curcumin has also been identified as one of the only safe therapies for radiation exposure and appears to be one of the only chemicals known to protect skin after exposure to radiation or during radiotherapy.¹² Also, curcumin is known, along with other curcuminoids, to inhibit fibrosis and has recently been shown to have potential as a chemopreventive agent to prevent or treat keloids.⁸⁴

Antifungal activity was displayed by curcumin in a 2013 murine model study of oral candidiasis. Dovigo et al. showed that the phenolic substance worked as a photosensitizer in the photoinactivation of Candida albicans. They found that curcumin-mediated photodynamic therapy exerted antifungal effects without damaging the murine host tissue.⁸⁵

In 2012, Takahashi et al. set out to identify plants with bioactive potential for dermatologic purposes by screening methanol extracts of 47 medical and edible plants cultivated in Okinawa, Japan. In testing for proliferative effects on skin fibroblast cells in vitro, the investigators reported that C. longa led to higher fibroblast proliferation than the control and augmented collagen production. They noted that, as compared to the positive control (ascorbic acid), expression of the collagen synthesis marker TGF-β1 was higher after C. longa treatment.⁸⁶ The ability of C. longa to increase fibroblast proliferation and increase collagen production could have implications for the use of curcumin in wound healing and photoprotection.

Curcumin has also been reported to hinder melanogenesis in B16 melanoma cells and been shown in vitro to inhibit melanogenesis in human melanocytes by activating the Akt/glycogen synthase kinase 3 (GSK 3β), extracellular signal-regulated kinase (ERK) or p38 MAPK signaling pathways. While more research is needed according to the authors Tu et al., their findings suggest the potential application of curcumin as a whitening agent for hyperpigmentation.⁸⁷

Curcumin and Wound Healing

Wound closure was shown by Sidhu et al. to occur significantly faster in curcumin-treated normal and genetically diabetic animals as compared to controls. The improvement of neovascularization and reepithelialization, the increase of TGF-β1 and fibronectin expression and synthesis, and the reduction of apoptosis were cited as the mecha-nisms by which curcumin contributed to this enhanced healing effect.^88,89 Collagen deposition and fibroblast and vascular density have also been bolstered by curcumin treatment, enhancing normal as well as impaired wound healing. The observed proangiogenic effect of curcumin in wound healing has been attributed to the induction of TGF-β, which in turn spurs angiogenesis and the accumulation of extracellular matrix.⁹⁰

In a study using Swiss albino mice, researchers assessed the effects on wound contraction of pretreatment with doses of 25, 50, 100, 150, or 200 mg/kg body weight of curcumin before exposure to 6 Gy whole-body γ-radiation. While irradiation resulted in delayed wound healing, curcumin pretreatment was associated with a dose-dependent increase in wound contraction in comparison to control, with optimal contraction noted with the 100 mg/kg dose. The authors concluded that curcumin shows great potential as a therapeutic agent for wound repair, particularly in reducing healing delays caused by radiation and involving combined injuries.³⁶

A 2005 study by Kundu et al. compared the wound-healing capacity of fresh turmeric paste to that of honey and a control in full-thickness circular wounds in 18 rabbits (see Chapter 60, Honey/Propolis/Royal Jelly). The investigators found that compared to the control group, wound healing in animals in the turmeric and honey treatment groups was considerably more rapid, with statistically significant differences in healing time.⁹¹

C. longa was included in another polyherbal formulation that Gupta et al. investigated in 2008 for its effects in treating diabetic wound healing in rats. The preparation combined the aqueous lyophilized leaf extracts of Hippophae rhamnoides and Aloe vera along with the ethanol rhizome extract of C. longa (optimized ratio of 1:7:1) (see Chapter 65, Aloe Vera). The investigators found that the topically applied polyherbal formulation augmented cellular proliferation and collagen production at the wound site in normal rats as compared to positive controls. Wound contraction was accelerated in normal and streptozotocin-induced diabetic rats, and the formulation was found to have fostered angiogenesis.⁹²

In 2009, Bhagavathula et al. examined the effects of a combination of topical curcumin and ginger extracts on wound healing in corticosteroid-impaired hairless rats (see Chapter 59, Ginger). For 21 days, the researchers treated animals with a combination of 10 percent curcumin and 3 percent ginger extract or each herbal agent alone, followed by a 15-day period of topical application of the corticosteroid Temovate. Superficial abrasions were induced in the treated skin after the treatment period. Healing was more rapid in the skin of control animals compared to animals treated only with Temovate, and in all of the groups pretreated with botanicals compared to animals treated with Temovate and vehicle alone. Skin samples obtained at wound closure revealed that collagen synthesis was higher and matrix metalloproteinase (MMP)-9 synthesis lower in rats treated with the herbal combination as opposed to those treated with Temovate and vehicle.⁹³

In 2011, López-Jornet et al. conducted a prospective, randomized study with mice to evaluate the effects of topical curcumin on skin wounds induced by CO₂ laser. Three groups of 30 mice, each given three wounds, were divided into a control group that received no treatment, a vehicle group (which received 5 mg/day per wound of vehicle), and the treatment group that received 5 mg/day per wound of topical curcumin. After seven days, 73.33 percent of the curcumin-treated wounds displayed complete reepithelialization whereas 41.67 percent in the vehicle group and 37.50 percent in the control group showed such improvement. All wounds in the curcumin group were healed after 14 days.⁹⁴

The topical application of curcumin was shown by Kulac et al. to be effective in accelerating wound healing of burns in Wistar albino rats, with enhanced collagen deposition, angiogenesis, granulation tissue formation, and epithelialization.⁹⁵

C. longa is one of four herbs combined in a Thai herbal phytopharmaceutical agent that Chusri et al. found in 2013 to exert strong antibacterial activities in vitro against methicillin-resistant Staphylococcus aureus (MRSA) isolates as well as anti-inflammatory and antioxidant activities and low toxicity on Vero cells. They concluded that given such potent properties, this formulation is suitable for use in treating wounds.⁹⁶

Also that year, Chereddy et al. demonstrated using a mouse excisional wound model that a combination of poly(lacticco-glycolic) acid (PLGA) and curcumin nanoparticles exhibited twofold greater wound-healing activity compared to PLGA or curcumin alone.⁹⁷

Psoriasis

The anti-inflammatory potency of curcumin is considered a potential source for psoriasis therapy. A small study with 12 patients taking curcumin orally showed a low response rate.^98,99 Nevertheless, curcumin has displayed effectiveness in treating psoriasis.^28,66,100

An in vitro study in 2011 by Saelee et al., who had previously shown that three Thai medicinal herbs, including C. longa, had antipsoriatic activity, considered the psoriasis-inhibiting potential of these herbs through the regulation of NF-κB signaling biomarkers. Specifically, they analyzed the influence of C. longa, Alpinia galangal, and Annona squamosa on 10 genes of the NF-κB signaling network in HaCaT cells. The investigators found that all of the herbs tested appear to have the capacity to suppress psoriasis by controlling the expression of NF-κB signaling biomarkers, with C. longa found to significantly reduce CSF-1, interleukin (IL)-8, NF-κB1, NF-κB2, and RelA expression.¹⁰¹

In 2012, Sun et al. found in vitro that curcumin reversed the antiapoptotic action of tumor necrosis factor (TNF)-α, thus allowing for the induction of apoptosis in HaCaT cells treated with TNF-α. Their findings, they suggested, provide encouragement for the use of curcumin in psoriasis treatment.⁵⁶ The following year, Sun et al. used a mouse model to determine that the topical application of curcumin suppressed imiquimod-induced psoriasis-like inflammation. They deduced that the polyphenol was able to alter the IL-23/IL-17A cytokine axis, which serves a crucial function in psoriasis etiology, by suppressing IL-1β/IL-6 and then obliquely downregulating the synthesis of IL-17A/IL-22. These effects, which were similar to those of clobetasol, reinforced the authors’ belief that curcumin will have a role to play in the psoriasis armamentarium.¹⁰²

Antioxidant and Anti-inflammatory Activities of Curcumin

Curcumin is a potent scavenger of various reactive oxygen species (ROS), including superoxide anion radicals, hydroxyl radicals, and nitrogen dioxide radicals at neutral and acidic pH levels.^47,54 It is thought to exhibit 10-fold the potency of vitamin E as an antioxidant [see Chapter 56, Tocopherol (Vitamin E)].²⁸ The turmeric constituent has manifested particularly high reactivity toward peroxyl radicals.¹⁰³ In mouse models, curcumin has been shown to impart antioxidant and anti-inflammatory activity, indicating that curcumin has a beneficial effect against chemo- and photocarcinogenesis. More research is needed to ascertain whether topical applications or oral intake of curcumin can prevent or inhibit skin carcinogenesis in humans.^51,104,105

Several studies have shown that curcumin displays broad inhibitory action against phospholipase, lipoxygenase, COX-2, leukotrienes, thromboxane, prostaglandins, nitric oxide, collagenase, elastase, hyaluronidase, monocyte chemoattractant protein (MCP)-1, interferon-inducible protein, TNF-α, and IL-12.¹⁶

A 2001 study on wound healing revealed that the antioxidant effects of curcumin potently inhibited hydrogen peroxide-induced damage in cultured human keratinocytes and fibroblasts.⁴⁴

The anti-inflammatory potency of curcumin was apparent in the results of a 2012 randomized, double-blind trial among 96 male Iranian veterans with chronic sulphur mustard-induced pruritic skin lesions. Panahi et al. found that curcumin supplementation attenuated inflammation and pruritus in these patients, with significant increases in serum IL-8 and high-sensitivity C-reactive protein, and decreases in calcitonin gene-related peptide; substantial improvements in quality of life were also reported.¹⁰⁶

In 2013, Thongrakard et al. examined the protective effects on human keratinocytes of extracts of 15 Thai herb species against UVB-induced DNA damage and cytotoxicity. Analysis revealed that the highest antioxidant activity was exhibited by the dichloromethane extract of turmeric. Further, the ethanol extract of turmeric and the dichloromethane extract of ginger demonstrated the maximum UV absorptions and stimulated the production of the antioxidant protein thioredoxin 1, as well as the capacity to protect human keratinocytes from the deleterious effects of UV exposure. The investigators concluded that their findings suggest the viability of incorporating turmeric and ginger extracts into anti-UV cosmetic formulations.¹⁰⁷

Curcumin, Skin Cancer, and Photoaging

While the anti-inflammatory activity of turmeric and, more recently, curcumin has been the focus of most of its medical applications through the millennia, the preponderance of modern research on curcumin seems to pertain to its anticarcinogenic capacity. In 1988, Huang et al. evaluated the effects of topically applied curcumin as well as caffeic, chlorogenic, and ferulic acids on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced epidermal ornithine decarboxylase (ODC) activity, epidermal DNA synthesis, and skin tumor promotion in female CD-1 mice. Results showed that ODC activity was inhibited by 42 percent in the case of caffeic acid (91 percent by curcumin, 46 percent by ferulic acid, and 25 percent by chlorogenic acid). Curcumin was more successful than the hydroxycinnamic acids in suppressing TPA-promoted DNA synthesis, and more effectively inhibited the number of TPA-induced tumors per mouse after twice weekly topical application with TPA after previous initiation with 7,12-dimethylbenz[a]anthracene (DMBA) (98 percent inhibition by curcumin, 60 percent by chlorogenic acid, 35 percent by ferulic acid, and 28 percent by caffeic acid).⁵¹

In various animal models, topical application of curcumin has been shown to inhibit initiation and promotion of tumorigenesis. Specifically, curcumin has been shown to block the growth in a broad range of tumors initiated by benzo[a]pyrene (B[a]P) and in TPA-induced or TPA-promoted skin tumors in mice.^34,35 Topical application of curcumin was shown in the early 1990s to exhibit antimutagenic and anticarcinogenic properties, specifically displaying potent inhibitory effects on TPA-induced tumor promotion and DNA synthesis as well as TPA-induced ODC activity and inflammation in mouse skin,^51,104,108 reversing the UVA-enhancing effects of ODC induction.⁶⁷ The phytochemical isolate from turmeric has also exhibited significant inhibitory activity against arachidonic acid-induced inflammation in vivo in mouse skin and edema of mouse ears, and epidermal lipoxygenase and COX in vitro.^34,50,104

In addition, very low doses of topically applied curcumin have been found to mediate TPA-induced oxidation of DNA bases in the epidermis and tumor promotion in the skin.¹⁰⁹ Pretreatment with curcumin has exhibited the same inhibitory effects on TPA-mediated dermatitis.⁶⁷

An evaluation of four nutraceuticals for their comparative effectiveness against DMBA-initiated and croton oil-promoted skin tumors showed that the topical application of turmeric rhizomes one hour before croton oil exposure resulted in decreases in skin tumor incidence and number of skin tumors, and later onset of skin tumors (30 percent skin tumor incidence, 87.2 percent decrease in skin tumors, and a five-week delay in skin tumor formation) compared with the positive control.¹¹⁰ Previously, a dose- and time-dependent anticarcinogenic effect of dietary turmeric had been demonstrated on B[a]P-induced forestomach neoplasia and DMBA-induced skin tumorigenesis in female Swiss mice.¹¹¹

Curcumin and its derivatives have been shown in animal models to inhibit the progression of chemically-induced colon and skin cancers. A study of the capacity of curcumin to inhibit the proliferation of primary endothelial cells in the presence and absence of basic fibroblast growth factor (bFGF), and the proliferation of an immortalized endothelial cell line revealed that curcumin imparts direct antiangiogenic activity in vitro and in vivo, which the researchers believe may account for its cancer-retarding effects in diverse organs.³³

Other promising findings related to skin cancer include the demonstrated potency of curcumin to potently inhibit the glutathione S-transferase activity towards 1-chloro-2, 4-dinitrobenzene in intact human IGR-39 melanoma cells and its capacity to induce apoptosis in human basal cell carcinoma cells in a dose- and time-dependent manner.^112,113 The molecular mechanisms of action underlying its chemopreventive effects remain undetermined,¹¹⁴ but in recent research using female ICR mice, investigators found that the topical application of curcumin was associated with the suppression of COX-2 expression by inhibiting ERK activity and NF-κB activation. The researchers believe this may account for the molecular mechanisms that would explain the antitumorigenic effects of curcumin in mouse skin.¹¹⁴

In numerous tumor model systems, including skin neoplastic models, curcumin has demonstrated the capacity to inhibit carcinogenesis.^50,111,115 Although its mechanism of action has not been clearly elucidated, curcumin is believed to inhibit cancer initiation, promotion, and progression.¹¹⁶ In addition, curcumin is known to suppress UVA-induced metallothionein (MT) expression and ODC activity, and to initiate p53-mediated apoptosis, as well as cell membrane-mediated apoptosis through Fas receptor induction and caspase-8 activation.^113,117 Curcumin is also known to be a selective noncompetitive inhibitor of phosphorylase kinase, which fosters photocarcinogenesis in photodamaged skin by activating NF-κB signaling pathways and suppressing apoptosis of photodamaged cells.^56,57

Recent data suggest a paradoxical aspect to curcumin properties, though. The anticancer activity of the antioxidant has actually promoted the generation of ROS. Chen et al. investigated the antioxidant and anticancer activity of curcumin in human myeloid leukemia (HL-60) cells, finding that the anticancer activity of curcumin was effective in a concentration- and time-dependent manner in lowering the proliferation and viability of leukemia cells, but its effect on ROS depended on concentration. Low concentrations of curcumin reduced ROS generation, but high concentrations yielded the opposite effect. The researchers also found that adding water-soluble antioxidants amplified the antioxidant and anticancer activity of low curcumin concentrations.¹¹⁸

In 2009, Sumiyoshi and Kimura examined the effects of a turmeric extract on a cascade of long-term, low-dose UVB exposure in melanin-possessing hairless mice. The researchers found that the polyphenol administered twice daily prevented chronic UVB exposure from enhancing skin thickness and diminishing skin elasticity. Further, the extract thwarted the development of wrinkles and melanin and inhibited the expression of MMP-2.²³

In a 2010 review article, Heng found that curcumin has shown the capacity to inhibit multiple targets on signaling pathways thus blunting the effects of UV-induced skin aging and carcinogenesis.⁴⁸

Chatterjee and Pandey reported in 2011 that the combination of tamoxifen and curcumin shows potential as chemotherapy. Specifically, they found in vitro that chemoresistant melanoma sensitized by tamoxifen to low-dose curcumin resulted in apoptosis and autophagy of melanoma cells while noncancerous cells were unaffected.¹

Based on experiments in 2011 indicating that curcumin suppressed cutaneous squamous cell carcinoma xenograft growth in SCID mice, Phillips et al., in 2013, performed a randomized experimental study using SKH-1 mice to test the anticancer effects of curcumin.¹¹⁹ For 14 days, animals were pretreated with oral or topical curcumin or oral or topical control. For 24 weeks, mice were exposed to UVB three times weekly or not at all. No significant differences were observed between groups receiving oral or topical curcumin. Control mice exhibited significantly shorter time to tumor onset and significantly greater tumor formation than the curcumin groups. The researchers concluded that curcumin manifests appreciable chemopreventive potential against skin cancer that warrants investigation in human subjects.¹²⁰

In the previous year, some of the same researchers found that a topical curcumin-based cream was equally effective as dietary curcumin in exerting antiproliferative effects in an aggressive skin cancer cell line tested in a mouse skin cancer model. The investigators, noting that their study was the first to compare topical and oral curcumin, concluded that the turmeric constituent merits use as a chemopreventive agent for cutaneous squamous cell carcinoma particularly when condemned skin is an issue.¹²¹

Tsai et al. also demonstrated in 2012 that topical application of curcumin to SKH-1 hairless mice delivered significant protective effects against UVB-induced skin tumor formation. Delays in tumor emergence and growth and limited tumor size resulted from the topical application of curcumin before UVB exposure. A significant decline in UVB-induced thymine dimer-positive cells and apoptotic sunburn cells and an increase in p53 and p21/Cip1-positive epidermal cells, among other changes, were generated when curcumin was applied topically before and immediately after a single dose of UVB radiation (180 mJ/cm²). Curcumin was also found to have significantly suppressed levels of NF-κB, COX-2, prostaglandin E₂, and nitric oxide.¹²²

In 2013, Hwang et al. found in an in vitro investigation using human dermal fibroblast cells that curcumin blocked the UVB-induced expression of MMP-1 and MMP-3 as well as ROS generation, the activation of NF-κB and activator protein-1, and the phosphorylation of p38 and c-Jun N-terminal kinase. The researchers concluded that the potent inhibitory anti-inflammatory activity of curcumin suggests its potential utility in the prevention and treatment of photoaging.¹²³

CONCLUSION

The body of research on turmeric and curcumin is increasingly impressive, revealing great potential especially related to its anticarcinogenic and anti-inflammatory activity. Of course, more clinical research is necessary to determine how these promising findings may be applied effectively in the dermatologic armamentarium. The traditional dietary and medical uses of the C. longa rhizome provide additional evidence that researchers are moving in the right direction here. Indeed, there appears to be sufficient data to suggest that the potential medical applications of turmeric may certainly prompt some people to pay much more attention to their spice racks.

REFERENCES